Sandbox:Dildar

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Dildar Hussain, MBBS [2]

Kawasaki Disease

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [3]; Associate Editor(s)-in-Chief: Cafer Zorkun, M.D., Ph.D. [4] Arzu Kalayci, M.D. [5]

Diagnosis

Diagnostic Criteria

Kawasaki disease is diagnosed clinically (by medical signs and symptoms), and there exists no specific laboratory test that can tell if someone has it. It is normally difficult to establish the diagnosis, especially early in the course of illness, and frequently children are not diagnosed until they have seen their doctor several times, or visited a number of different health care providers. Many other serious illnesses can cause similar symptoms, and must be considered in the differential diagnosis, including scarlet fever, toxic shock syndrome, and juvenile idiopathic arthritis.

Classically, five days of fever plus four of five diagnostic criteria must be met in order to establish the diagnosis.

The criteria are:

(1) Mucositis: erythema of the palatine mucosa, fissure erythematous lips, "strawberry tongue"

(2) Rash: Polymorphus, usually urticarial erythematous rash mainly in external extremities. The rash can spread to trunk

(3) Extremities changes: Edema of hand and feet, erythema of palms & soles, desquamation of fingertips

(4) Bilateral non-exudative conjuctival erythema

(5) Cervical lymphadenopathy for at least 15 milimeters

Many children, especially infants, eventually diagnosed with Kawasaki disease do not exhibit all of the above criteria. In fact, many experts now recommend treating for Kawasaki disease even if only three days of fever have passed and at least three diagnostic criteria are present, especially if other tests reveal abnormalities consistent with Kawasaki disease. In addition, the diagnosis can be made purely by the detection of coronary artery aneurysms in the proper clinical setting.

History and Symptoms

Kawasaki disease often begins with a high and persistent fever that is not very responsive to normal doses of acetaminophen or ibuprofen. The fever may persist steadily for up to two weeks and is normally accompanied by irritability. Affected children develop red eyes, red mucous membranes in the mouth, red cracked lips, a "strawberry tongue", iritis, keratic precipitates (detectable by an ophthalmologist but usually too small to be seen by the unaided eye), and swollen lymph nodes. Skin rashes occur early in the disease, and peeling of the skin in the genital area, hands, and feet (especially around the nails and on the palms and soles) may occur in later phases. Some of these symptoms may come and go during the course of the illness. If left untreated, the symptoms will eventually relent, but coronary artery aneurysms will not improve, resulting in a significant risk of death or disability due to myocardial infarction (heart attack). If treated in a timely fashion, this risk can be mostly avoided and the course of illness cut short.

• High-grade fever (greater than 39 °C or 102 °F; often as high as 40 °C or 104 °F) that normally lasts for more than a week if left untreated.
• Red eyes (conjunctivitis) without pus or drainage, also known as "conjunctival injection"
• Bright red, chapped, or cracked lips
• Red mucous membranes in the mouth
• Strawberry tongue, white coating on the tongue or prominent red bumps (papillae) on the back of the tongue
• Red palms of the hands and the soles of the feet
• Swollen hands and feet
• Rash which may take many forms, but not vesicular (blister-like), on the trunk
• Swollen lymph nodes (frequently only one lymph node is swollen), particularly in the neck area
• Joint pain (arthralgia) and swelling, frequently symmetrical
• Irritability
• Tachycardia (rapid heart beat)
• Peeling (desquamation) palms and soles (later in the illness); peeling may begin around the nails

AHA Scientific Statement on Kawasaki Disease

Recommendations for Cardiovascular Assessment for Diagnosis and Monitoring During the Acute Illness

Class I

"1. Echocardiography should be performed when the diagnosis of KD is considered, but unavailability or technical limitations should not delay treatment.(Level of Evidence: B) "

"2. Coronary arteries should be imaged, and quantitative assessment of luminal dimensions, normalized as Z scores adjusted for body surface, should be performed.(Level of Evidence: B) "

"3. For uncomplicated patients, echocardiog- raphy should be repeated both within 1 to 2 weeks and 4 to 6 weeks after treatment.(Level of Evidence: B) "

"4. For patients with important and evolving coronary artery abnormalities (Z score >2.5) detected during the acute illness, more fre- quent echocardiography (at least twice per week) should be performed until luminal dimensions have stopped progressing to determine the risk for and presence of thrombosis.(Level of Evidence: B) "

Class IIa

"1. To detect coronary artery thrombosis, it may be reasonable to perform echocardiography for patients with expanding large or giant aneurysms twice per week while dimensions are expanding rapidly and at least once weekly in the first 45 days of illness, and then monthly until the third month after illness onset, because the failure to escalate thromboprophylaxis in time with the rapid expansion of aneurysms is a primary cause of morbidity and mortality . (Level of Evidence: C) "

Physical Examination

A physical examination will demonstrate many of the features listed above.

Laboratory Findings

• There are no specific laboratory findings associated with [disease name].

• A [positive/negative] [test name] is diagnostic of [disease name].
• An [elevated/reduced] concentration of [serum/blood/urinary/CSF/other] [lab test] is diagnostic of [disease name].
• Other laboratory findings consistent with the diagnosis of [disease name] include [abnormal test 1], [abnormal test 2], and [abnormal test 3].

Blood tests

• Complete blood count (CBC) may reveal normocytic anemia and eventually thrombocytosis
• Erythrocyte sedimentation rate (ESR) will be elevated
• C-reactive protein (CRP) will be elevated
• Liver function tests may show evidence of hepatic inflammation and low serum albumin

Other Diagnostic Studies

Other tests (may or may not be performed)

• Electrocardiogram may show evidence of ventricular dysfunction or, occasionally, arrhythmia due to myocarditis
• Echocardiogram may show subtle coronary artery changes or, later, true aneurysms.
• Ultrasound or computerized tomography may show hydrops (enlargement) of the gallbladder
• Urinalysis may show white blood cells and protein in the urine (pyuria and proteinuria) without evidence of bacterial growth
• Lumbar puncture may show evidence of aseptic meningitis
• Angiography was historically used to detect coronary artery aneurysms and remains the gold standard for their detection, but is rarely used today unless coronary artery aneurysms have already been detected by echocardiography.

Treatment

Medical Therapy

Intravenous Immunoglobulin (IVIG) and aspirin are indicated in the treatment of Kawasaki Disease. It is imperative that treatment be started as soon as the diagnosis is made to prevent damage to the coronary arteries. Except for Kawasaki disease and a couple of other indications, aspirin is otherwise normally not recommended for children due to its association with Reye's syndrome. Children with Kawasaki disease should be hospitalized.

• 1. Initial treatment

• Preferred regimen: IVIG 2 g/kg single infusion within the first 7-10 days of illness AND Aspirin 80-100 mg/kg/day qid , reduce the aspirin dose after the child has been afebrile for 48 to 72 hours, then begin low-dose aspirin (3 to 5 mg/kg/day) and maintain it until the patient shows no evidence of coronary changes by 6 to 8 weeks after the onset of illness
• Note (1): Other clinicians continue highdose aspirin until day 14 of illness and 48 to 72 hours after fever cessation
• Note (2): For children who develop coronary abnormalities, aspirin may be continued indefinitely

• 2. Treatment of Patients Who Failed to Respond to Initial Therapy (persistent or recrudescent fever ≥ 36 hours after completion of the initial IVIG infusion)

• Preferred regimen: IVIG 2 g/kg q24h for 1-3 days OR Methylprednisolone 30 mg/kg IV for 2-3 hours q24h for 1-3 days

AHA Scientific Statement on Kawasaki Disease

Recommendations for Initial Treatment With Intravenous Immunoglobulin (IVIG) and Asetil Salisilat Acid (ASA)

Class I

"1. Patients with complete KD criteria and those who meet the algorithm criteria for incomplete KD should be treated with high-dose IVIG (2 g/kg given as a single intravenous infusion) within 10 days of illness onset but as soon as possible after diagnosis.(Level of Evidence: A) "

Class IIa

"1. It is reasonable to administer IVIG to children presenting after the 10th day of illness (ie, in whom the diagnosis was missed earlier) if they have either persistent fever without other explanation or coronary artery abnormalities together with ongoing systemic inflammation, as manifested by elevation of ESR or CRP (CRP >3.0 mg/dL). (Level of Evidence: B) "

"2. Administrationofmoderate-(30–50mg·kg−1·d−1) to high-dose (80–100 mg·kg−¹·d−¹) ASA is reasonable until the patient is afebrile, although there is no evidence that it reduces coronary artery aneurysms. (Level of Evidence: C) "

Class III

"1. IVIG generally should not be administered to patients beyond the tenth day of illness in the absence of fever, significant elevation of inflammatory markers, or coronary artery abnormalities . (Level of Evidence: C) "

"2. The ESR is accelerated by IVIG therapy and therefore should not be used to assess response to IVIG therapy. A persistently high ESR alone should not be interpreted as a sign of IVIG resistance. (Level of Evidence: C) "

Recommendations for Adjunctive Therapies for Primary Treatment

Class IIb

"1. Administration of a longer course of corticosteroids (eg, tapering over 2–3 weeks), together with IVIG 2 g/kg and ASA, may be considered for treatment of high-risk patients with acute KD, when such high risk can be identified in patients before initiation of treatment. (Level of Evidence: B) "

Class III

"1. Single-dose pulse methylprednisolone should not be administered with IVIG as routine primary therapy for patients with Kawasaki Disease. (Level of Evidence: B) "

Recommendations for Additional Therapy in the IVIG-Resistant Patient

Class IIa

"1. It is reasonable to administer a second dose of IVIG (2 g/kg) to patients with persistent or recrudescent fever at least 36 hours after the end of the first IVIG infusion. (Level of Evidence: B) "

Class IIb

"1. Administration of high-dose pulse steroids (usually methylprednisolone 20–30 mg/kg intravenously for 3 days, with or without a subsequent course and taper of oral prednisone) may be considered as an alternative to a second infusion of IVIG or for retreatment of patients with KD who have had recurrent or recrudescent fever after additional IVIG. (Level of Evidence: B) "

"2. Administration of a longer (eg, 2–3 weeks) tapering course of prednisolone or prednisone, together with IVIG 2 g/kg and ASA, may be considered in the retreatment of patients with KD who have had recurrent or recrudescent fever after initial IVIG treatment. (Level of Evidence: B) "

"3. Administration of infliximab (5 mg/kg) may be considered as an alternative to a second infusion of IVIG or corticosteroids for IVIG-resistant patients. (Level of Evidence: C) "

"4. Administration of cyclosporine may be considered in patients with refractory KD in whom a second IVIG infusion, infliximab, or a course of steroids has failed. (Level of Evidence: C) "

"5. Administration of immunomodulatory monoclonal antibody therapy (except TNF-α block- ers), cytotoxic agents, or (rarely) plasma exchange may be considered in highly refractory patients who have failed to respond to a second infusion of IVIG, an extended course of steroids, or infliximab. (Level of Evidence: C) "

Recommendations for Treatment of Coronary Artery Thrombosis

Class I

"1. Coronary artery thrombosis with actual or impending occlusion of the arterial lumen should be treated with thrombolytic therapy or, in patients of sufficient size, by mechanical restoration of coronary artery blood flow at cardiac catheterization.(Level of Evidence: C) "

"2. Thrombolytic agents should be administered together with low-dose ASA and low-dose heparin, with careful monitoring for bleeding.(Level of Evidence: C) "

Class IIb

"1. Treatment of coronary artery thrombosis with substantial thrombus burden and high risk of occlusion with a combination of reduced-dose thrombolytic therapy and abciximab may be considered. (Level of Evidence: C) "

Risk-Stratified Recommendations for Long-Term Evaluation and Management

No Involvement (Z Score Always <2)

Class IIa

"1. It is reasonable to use echocardiographic coronary artery luminal dimensions converted to BSA-adjusted Z scores to determine risk stratification. (Level of Evidence: B) ". (Level of Evidence: C) "

Type and frequency of additional cardiology assessment (other cardiology testing)

Class IIa

"1. It is reasonable that no additional cardiology assessment be performed. (Level of Evidence: B) ". (Level of Evidence: C) "

Cardiovascular risk factor assessment and management

Class IIa

"1. It is reasonable to provide general counseling regarding healthy lifestyle and activity promotion at every visit; this may be provided by the primary care provider. (Level of Evidence: B) ". (Level of Evidence: C) "

"2. It is reasonable to assess blood pressure, fast- ing lipid profile, body mass index (and plot), waist circumference, dietary and activity assessment, and smoking at least once and ideally at least 1 year from the episode of acute KD; this may be performed by the primary care provider. (Level of Evidence: B) ". (Level of Evidence: C) "

Medical therapy (β-blockers, angiotensin-converting enzyme inhibitor [ACEI], statin)

Class III

"1. No additional medical therapy should be given. (Level of Evidence: C) "

Thromboprophylaxis

Class IIa

"1. It is reasonable to give low-dose ASA for up to 4 to 6 weeks after the episode of acute KD, which should be discontinued thereafter. (Level of Evidence: C) ". (Level of Evidence: C) "

Physical activity

Class IIa

"1. It is reasonable to provide physical activity counseling at every visit with no restrictions or precautions at any time. (Level of Evidence: B) ". (Level of Evidence: C) "

Reproductive counselling

Class IIa

"1. It is reasonable to provide age-appropriate counseling regarding contraception and pregnancy without modification. (Level of Evidence: B) ". (Level of Evidence: C) "

Dilation Only (Z Score ≥2 but <2.5, or a Decrease in Z Score During Follow-up ≥1)

Class IIa

"1. If luminal dimensions have returned to normal by 4 to 6 weeks after KD onset, it is reasonable to discharge the patient from cardiology care, although ongoing follow-up to 12 months may be considered. (Level of Evidence: B) ". (Level of Evidence: C) "

"2. If dilation remains present at 4 to 6 weeks after KD onset, then it is reasonable to continue follow-up to 12 months. If the luminal dimensions return to normal before then, it is reasonable to discharge the patient from ongoing cardiology care. (Level of Evidence: B) ". (Level of Evidence: C) "

"3. Resolution is expected within 1 year. If dilation persists at 1 year, consider whether this represents a dominant branch. If this is a probable explanation, then it is reasonable to discharge the patient from ongoing cardiology care, although ongoing follow-up every 2 to 5 years may be considered. Patients and families should be advised to remember that having had KD is part of the patient’s permanent medical history. (Level of Evidence: C) ". (Level of Evidence: C) "

Type and frequency of additional cardiology assessment (other cardiology testing)

Class IIa

"1. It is reasonable that no additional cardiology assessment be performed. (Level of Evidence: B) ". (Level of Evidence: C) "

Cardiovascular risk factor assessment and management

Class IIa

"1. It is reasonable to provide general counseling regarding healthy lifestyle and activity promotion at every visit; this may be provided by the primary care provider. (Level of Evidence: C) ". (Level of Evidence: C) "

"2. It is reasonable to assess blood pressure, fasting lipid profile, body mass index (and plot), waist circumference, dietary and activity assessment, and smoking at least once and ideally at least 1 year from the episode of acute KD; this may be performed by the primary care provider. (Level of Evidence: C) ". (Level of Evidence: C) "

Medical therapy (β-blockers, ACEI, statin)

Class III

"1. No additional medical therapy should be given. (Level of Evidence: C) "

Thromboprophylaxis

Class IIa

"1. It is reasonable to give low-dose ASA until 4 to 6 weeks after the acute episode, which should be discontinued thereafter. (Level of Evidence: C) ". (Level of Evidence: C) "

Physical activity

Class IIa

"1. It is reasonable to provide physical activity counseling at every visit with no restrictions or precautions at any time. (Level of Evidence: B) "

Reproductive counseling

Class IIa

"1. It is reasonable to provide age-appropriate counseling regarding contraception and pregnancy without modification. (Level of Evidence: B) "

Regression to Normal Z Score or Dilation Only

Frequency of cardiology assessment (to include history and physical examination, echocardiography, electrocardiography)

Class IIa

"1. It is reasonable to assess every 1 to 3 years. It is reasonable not to perform echocardiogra- phy unless there is evidence for inducible myocardial ischemia or the patient has symptoms suggestive of ischemia or signs suggestive of ventricular dysfunction. (Level of Evidence: B) "

Type and frequency of additional cardiology assessment (other cardiology testing)

Class IIa

"1. It is reasonable to assess for inducible myocardial ischemia (stress echocardiography, stress with MRI, stress NM perfusion imaging, PET) every 3 to 5 years or if the patient has symptoms suggestive of ischemia or signs suggestive of ventricular dysfunction. (Level of Evidence: B) "

Class IIb

"1. Further imaging with angiography (CT, MRI, invasive) may be considered only if there is evidence for inducible myocardial ischemia or ventricular dysfunction. (Level of Evidence: C) "

Cardiovascular risk factor assessment and management

Class IIa

"1. It is reasonable to provide general counseling regarding healthy lifestyle and activity promotion at every visit; this may additionally be provided by the primary care provider.(Level of Evidence: C) "

"2. It is reasonable to assess blood pressure, fasting lipid profile, body mass index (and plot), waist circumference, dietary and activity assessment, and smoking every 2 years; this may be performed by the primary care provider. It is reasonable to obtain a follow- up fasting lipid profile. (Level of Evidence: C) "

Medical therapy (β-blockers, ACEI, statin)

Class IIb

"1. Empirical statin therapy for non–lipid-lowering (pleiotropic) effects may be considered.(Level of Evidence: C) "

Class III

"1. Empirical treatment with β-blockers is not indicated.(Level of Evidence: C) "

Thromboprophylaxis

Class IIb

"1. Ongoing treatment with low-dose ASA may be considered, although it is reasonable to discontinue.(Level of Evidence: C) "

Class IIa

"1. Use of an alternative antiplatelet agent (eg, a thienopyridine such as clopidogrel) instead of ASA is reasonable if the patient is intol- erant or resistant to ASA.(Level of Evidence: C) "

Physical activity

Class IIa

"1. It is reasonable to provide physical activity counseling at every visit with no restrictions or precautions at any time .(Level of Evidence: C) "

Reproductive counselling

Class IIa

"1. It is reasonable to provide age-appropriate counseling regarding contraception and pregnancy without modification.(Level of Evidence: B) "

Medium Aneurysms (Z Score ≥5 to <10, With an Absolute Luminal Dimension <8 mm)

Current or Persistent Medium Aneurysms

Frequency of cardiology assessment (to include history and physical examination, echocardiography, electrocardiography)

Class IIa

"1. It is reasonable to provide physical activity counseling at every visit with no restrictions or precautions at any time .(Level of Evidence: B) "

Type and frequency of additional cardiology assessment (other cardiology testing)

Class IIa

"1. It is reasonable to assess for inducible myo- cardial ischemia (stress echocardiography, stress with MRI, stress NM perfusion imaging, PET) every 1 to 3 years or if the patient has symptoms suggestive of ischemia or signs suggestive of ventricular dysfunction.(Level of Evidence: B) "

Class IIb

"1. Further imaging with angiography (CT, MRI, invasive) may be considered for periodic sur- veillance every 2 to 5 years.(Level of Evidence: C) "

Cardiovascular risk factor assessment and management

Class IIa

"1. It is reasonable to provide general counseling regarding healthy lifestyle and activity promotion at every visit; this may additionally be provided by the primary care provider.(Level of Evidence: C) "

"2. It is reasonable to assess blood pressure, fasting lipid profile, body mass index (and plot), waist circumference, dietary and activity assessment, and smoking at least once and ideally at least 1 year from the episode of acute KD; this may be performed by the primary care provider. It is reasonable to obtain a follow-up fasting lipid profile.(Level of Evidence: C) "

Medical therapy (β-blockers, ACEI, statin)

Class IIb

"1. Empirical statin therapy for non–lipid-lowering (pleiotropic) effects may be considered.(Level of Evidence: C) "

Class III

"1. Empirical treatment with β-blockers is not indicated.(Level of Evidence: C) "

Thromboprophylaxis

Class I

"1. Patients should be treated with low-dose ASA.(Level of Evidence: C) "

Class IIa

"1. Use of an alternative antiplatelet agent (eg, a thienopyridine such as clopidogrel) instead of ASA is reasonable if the patient is intoler- ant or resistant to ASA.(Level of Evidence: C) "

Class IIb

"1. Additional patient and coronary artery characteristics may be considered in decision making regarding intensification of thromboprophylaxis.(Level of Evidence: C) "

"2. Dual-antiplatelet therapy with an additional antiplatelet agent (eg, a thienopyridine such as clopidogrel) may be considered.(Level of Evidence: C) "

Class III

"1. Use of anticoagulation (warfarin, LMWH) is not indicated.(Level of Evidence: C) "

Physical activity

Class I

"1. For patients taking dual-antiplatelet therapy, activities involving a risk of bodily contact, trauma, or injury should be restricted or modified.(Level of Evidence: B) "

Class IIa

"1. It is reasonable to provide physical activity counseling at every visit without restrictions or precautions. Participation in competitive sports or high-intensity activities should be guided by results from testing for inducible myocardial ischemia or exercise-induced arrhythmias.(Level of Evidence: C) "

Reproductive counselling

Class IIa

"1. It is reasonable to discourage use of oral contraceptive drugs that increase thrombosis risk, to recommend that pregnancy be supervised by a multidisciplinary team including a cardiologist, and to alter thromboprophylaxis management during pregnancy and delivery.(Level of Evidence: B) "

Regression to Small Aneurysms

Frequency of cardiology assessment (to include history and physical examination, echocardiography, electrocardiography)

Class IIa

"1. Ongoing follow-up assessment every year is reasonable.(Level of Evidence: B) "

Type and frequency of additional cardiology assessment (other cardiology testing)

Class IIa

"1. It is reasonable to assess for inducible myocardial ischemia (stress echocardiography, stress with MRI, stress NM perfusion imaging, PET) every 2 to 3 years or if the patient has symptoms suggestive of ischemia or signs suggestive of ventricular dysfunction.(Level of Evidence: B) "

Class IIb

"1. Further imaging with angiography (CT, MRI, invasive) may be considered for periodic surveillance every 3 to 5 years.(Level of Evidence: C) "

Cardiovascular risk factor assessment and management

Class IIa

"1. It is reasonable to provide general counseling regarding healthy lifestyle and activity promotion at every visit; this may additionally be provided by the primary care provider.(Level of Evidence: C) "

"2. It is reasonable to assess blood pressure, fasting lipid profile, body mass index (and plot), waist circumference, dietary and activ- ity assessment, and smoking every year; this may be performed by the primary care provider. It is reasonable to obtain a follow- up fasting lipid profile.(Level of Evidence: C) "

Medical therapy (β-blockers, ACEI, statin)

Class IIb

"1. Empirical statin therapy for non–lipid-lowering (pleiotropic) effects may be considered.(Level of Evidence: C) "

Class III

"1. Empirical treatment with β-blockers is not indicated.(Level of Evidence: C) "

Thromboprophylaxis

Class I

"1. Patients should be treated with low-dose ASA.(Level of Evidence: C) "

Class IIa

"1. Use of an alternative antiplatelet agent (eg, a thienopyridine such as clopidogrel) instead of ASA is reasonable if the patient is intolerant or resistant to ASA.(Level of Evidence: C) "

Class IIb

"1. Dual-antiplatelet therapy with an additional antiplatelet agent (eg, a thienopyridine such as clopidogrel) may be considered.(Level of Evidence: C) "

"2. Additional patient and coronary artery characteristics may be considered in decision making regarding intensification or discontinuation of thromboprophylaxis.(Level of Evidence: C) "

Class III

"1. Use of anticoagulation is not indicated.(Level of Evidence: C) "

Physical activity

Class I

"1. For patients taking dual-antiplatelet therapy, activities involving a risk of bodily contact, trauma, or injury should be restricted or modified.(Level of Evidence: B) "

Class IIa

"1. It is reasonable to provide physical activity counseling at every visit without restrictions or precautions. Participation in competitive sports or high-intensity activities should be guided by results from testing for inducible myocardial ischemia or exercise-induced arrhythmias.(Level of Evidence: C) "

Reproductive counselling

Class IIa

"1. It is reasonable to discourage use of oral contraceptive drugs that increase thrombo- sis risk, to recommend that pregnancy be supervised by a multidisciplinary team includ- ing a cardiologist, and to alter thromboprophylaxis management during pregnancy and delivery.(Level of Evidence: B) "

Regression to Normal Z Score or Dilation Only

Frequency of cardiology assessment (to include history and physical examination, echocardiography, electrocardiography)

Class IIb

"1. It is reasonable to discourage use of oral contraceptive drugs that increase thrombo- sis risk, to recommend that pregnancy be supervised by a multidisciplinary team includ- ing a cardiologist, and to alter thromboprophylaxis management during pregnancy and delivery.(Level of Evidence: B) "

Type and frequency of additional cardiology assessment (other cardiology testing)

Class IIa

"1. It is reasonable to assess for inducible myocardial ischemia (stress echocardiography, stress with MRI, stress NM perfusion imaging, PET) every 2 to 4 years or if the patient has symptoms suggestive of ischemia or signs suggestive of ventricular dysfunction.(Level of Evidence: B) "

"2. It is reasonable to perform no further imaging with angiography (CT, MRI, invasive) in the absence of evidence of inducible myocardial ischemia. (Level of Evidence: C) "

Cardiovascular risk factor assessment and management

Class IIa

"1. It is reasonable to provide general counseling regarding healthy lifestyle and activity promotion at every visit; this may additionally be provided by the primary care provider.(Level of Evidence: C) "

"2. It is reasonable to assess blood pressure, fasting lipid profile, body mass index (and plot), waist circumference, dietary and activ- ity assessment, and smoking every 2 years; this may be performed by the primary care provider. It is reasonable to obtain a follow- up fasting lipid profile.(Level of Evidence: C) "

Medical therapy (β-blockers, statin)

Class IIb

"1. Empirical statin therapy for non–lipid-lowering (pleiotropic) effects may be considered.(Level of Evidence: C) "

Class III

"1. Empirical treatment with β-blockers is not indicated.(Level of Evidence: C) "

Thromboprophylaxis

Class IIa

"1. It is reasonable to continue treatment with low-dose ASA.(Level of Evidence: C) "

"2. Use of an alternative antiplatelet agent (eg, a thienopyridine such as clopidogrel) instead of ASA is reasonable if the patient is intolerant or resistant to ASA.(Level of Evidence: C) "

Class IIb

"1. Use of an additional antiplatelet agent (eg, a thienopyridine such as clopidogrel) is not recommended except in the presence of inducible myocardial ischemia.(Level of Evidence: C) "

"2. Additional patient and coronary artery characteristics may be considered in decision making regarding intensification or discontinuation of thromboprophylaxis.(Level of Evidence: C) "

Class III

"1. Use of anticoagulation (warfarin/LMWH) is not indicated.(Level of Evidence: C) "

Physical activity

Class IIa

"1. It is reasonable to provide physical activity counseling at every visit without restrictions or precautions. Participation in competitive sports or high-intensity activities should be guided by results from testing for inducible myocardial ischemia or exercise-induced arrhythmias.(Level of Evidence: C) "

Reproductive counselling

Class IIa

"1. It is reasonable to provide age-appropriate counseling regarding contraception and pregnancy without modification.(Level of Evidence: B) "

Large and Giant Aneurysms (Z Score ≥10 or Absolute Dimension ≥8 mm)

Frequency of cardiology assessment (to include history and physical examination, echocardiography, electrocardiography)

Class IIa

"1. It is reasonable to assess patients at 1, 2, 3, 6, 9, and 12 months after the episode of acute KD in the first year and every 3 to 6 months thereafter.(Level of Evidence: C) "

Type and frequency of additional cardiology assess- ment (other cardiology testing)

Class IIa

"1. It is reasonable to assess for inducible myocardial ischemia (stress echocardiography, stress with MRI, stress NM perfusion imaging, PET) every 6 to 12 months or if the patient has symptoms suggestive of ischemia or signs suggestive of ventricular dysfunction.(Level of Evidence: B) "

Class IIb

"1. Further imaging with angiography (CT, MRI, invasive) may be considered for diagnostic and prognostic purposes during the first year and may be considered for periodic surveillance every 1 to 5 years thereafter.(Level of Evidence: C) "

Cardiovascular risk factor assessment and management

Class IIa

"1. It is reasonable to provide general counseling regarding healthy lifestyle and activity promotion at every visit; this may additionally be provided by the primary care provider.(Level of Evidence: C) "

Class IIa

"1. It is reasonable to assess blood pressure, body mass index (and plot), waist circumference, dietary and activity assessment, and smoking every 6 to 12 months; this may be performed by the primary care provider. It is reasonable to obtain a fasting lipid profile during follow- up.(Level of Evidence: C) "

Medical therapy (β-blockers, ACEI, statin)

Class IIb

"1. Empirical statin therapy for non–lipid-lowering (pleiotropic) effects may be considered.(Level of Evidence: C) "

"2. Empirical treatment with β-blockers may be considered .(Level of Evidence: C) "

Thromboprophylaxis

Class I

"1. Patients should be treated with low-dose ASA.(Level of Evidence: C) "

Class IIa

"1. Use of an alternative antiplatelet agent (eg, a thienopyridine such as clopidogrel) instead of ASA is reasonable if the patient is intolerant or resistant to ASA.(Level of Evidence: C) "

"2. Use of warfarin to achieve a target international normalized ratio of 2 to 3 is reasonable.(Level of Evidence: B) "

"3. Use of LMWH to achieve target anti-factor Xa levels of 0.5 to 1.0 U/mL is reasonable as an alternative to warfarin.(Level of Evidence: C) "

Class IIb

"1. Use of an additional antiplatelet agent (eg, a thienopyridine such as clopidogrel) may be considered together with ASA and warfarin/ LMWH (triple therapy) for thromboprophylaxis in the setting of very extensive or distal coronary artery aneurysms, or if there is a history of coronary artery thrombosis.(Level of Evidence: C) "

"2. Additional patient and coronary artery characteristics (Table 9) may be considered in decision making regarding adjustments to strategy for thromboprophylaxis.(Level of Evidence: C) "

Physical activity

Class I

"1. Activities involving a risk of bodily contact, trauma, or injury should be restricted or modified if the patient is on dual-antiplatelet or anticoagulation therapy.(Level of Evidence: B) "

Class IIa

"1. It is reasonable to provide physical activity counseling at every visit without restrictions or precautions. Participation in competitive sports or high intensity activities should be guided by results from testing for inducible myocardial ischemia or exercise-induced arrhythmias.(Level of Evidence: C) "

Reproductive counselling

Class IIa

"1. It is reasonable to discourage use of oral contraceptive drugs that increase thrombosis risk, to recommend that pregnancy be super- vised by a multidisciplinary team including a cardiologist, and to alter thromboprophylaxis management during pregnancy and delivery.(Level of Evidence: B) "

Regression to Medium Aneurysms

Frequency of cardiology assessment (to include history and physical examination, echocardiography, electrocardiography)

Class IIa

"1. It is reasonable to assess the patient every 6 to 12 months.(Level of Evidence: C) "

Type and frequency of additional cardiology assessment (other cardiology testing)

Class IIa

"1. It is reasonable to assess for inducible myocardial ischemia (stress echocardiography, stress with MRI, stress NM perfusion imaging, PET) every year or if the patient has symptoms suggestive of ischemia or signs suggestive of ventricular dysfunction.(Level of Evidence: B) "

Class IIb

"1. Further imaging with angiography (CT, MRI, invasive) may be considered for periodic surveillance every 2 to 5 years.(Level of Evidence: C) "

Cardiovascular risk factor assessment and management

Class IIa

"1. It is reasonable to provide general counseling regarding healthy lifestyle and activity promotion at every visit; this may additionally be provided by the primary care provider.(Level of Evidence: C) "

"2. It is reasonable to assess blood pressure, body mass index (and plot), waist circumference, dietary and activity assessment, and smoking every year; this may be performed by the primary care provider. It is reason- able to obtain a follow-up fasting lipid profile.(Level of Evidence: C) "

Medical therapy (β-blockers, ACEI, statin)

Class IIb

"1. Empirical statin therapy for non–lipid-lowering (pleiotropic) effects may be considered.(Level of Evidence: C) "

"2. Empirical treatment with β-blockers may be considered.(Level of Evidence: C) "

Thromboprophylaxis

Class I

"1. Patients should be treated with low-dose ASA.(Level of Evidence: C) "

Class IIa

"1. Use of an alternative antiplatelet agent (eg, a thienopyridine such as clopidogrel) instead of ASA is reasonable if the patient is intolerant or resistant to ASA.(Level of Evidence: C) "

"2. Discontinuation of anticoagulation (warfarin/ LMWH) and substitution with an additional antiplatelet agent (eg, a thienopyridine such as clopidogrel) is reasonable.(Level of Evidence: C) "

Class IIb

"1. Additional patient and coronary artery characteristics may be considered in decision making regarding adjustments to strategy for thromboprophylaxis.(Level of Evidence: C) "

Class III

"1. Use of anticoagulation (warfarin, LMWH) is not indicated.(Level of Evidence: C) "

Physical activity

Class I

"1. Activities involving a risk of bodily contact, trauma, or injury should be restricted or modified for patients on dual-antiplatelet or anticoagulation therapy.(Level of Evidence: B) "

Class IIa

"1. It is reasonable to provide physical activity counseling at every visit without restrictions or precautions. Participation in competitive sports or high-intensity activities should be guided by results from testing for inducible myocardial ischemia or exercise-induced arrhythmias.(Level of Evidence: C) "

Reproductive counselling

Class IIa

"1. It is reasonable to discourage use of oral contraceptive drugs that increase thrombosis risk, to recommend that pregnancy be super- vised by a multidisciplinary team including a cardiologist, and to alter thromboprophylaxis management during pregnancy and delivery.(Level of Evidence: B) "

Regression to Small Aneurysms

Frequency of cardiology assessment (to include history and physical examination, echocardiography, electrocardiography)

Class IIa

"1. It is reasonable to assess the patient every 6 to 12 months.(Level of Evidence: C) "

Type and frequency of additional cardiology assessment (other cardiology testing)

Class IIa

"1. It is reasonable to assess for inducible myocardial ischemia (stress echocardiography, stress with MRI, stress NM perfusion imaging, PET) every 1 to 2 years or if the patient has symptoms suggestive of ischemia or signs suggestive of ventricular dysfunction.(Level of Evidence: B) "

Class IIb

"1. Further imaging with angiography (CT, MRI, invasive) may be considered for periodic surveillance every 2 to 5 years.(Level of Evidence: C) "

Cardiovascular risk factor assessment and management

Class IIa

"1. It is reasonable to provide general counseling regarding healthy lifestyle and activity promotion at every visit; this may additionally be provided by the primary care provider.(Level of Evidence: C) "

"2. It is reasonable to assess blood pressure, body mass index (and plot), waist circumference, dietary and activity assessment, and smoking every year; this may be performed by the primary care provider. It is reason- able to obtain a follow-up fasting lipid profile.(Level of Evidence: C) "

Medical therapy (β-blockers, ACEI, statin)

Class IIb

"1. Empirical statin therapy for non–lipid-lowering (pleiotropic) effects may be considered.(Level of Evidence: C) "

"2. Empirical treatment with β-blockers may be considered.(Level of Evidence: C) "

"3. Discontinuation of additional medical therapy may be considered.(Level of Evidence: C) "

Thromboprophylaxis

Class I

"1. Patients should be treated with low-dose ASA.(Level of Evidence: C) "

Class IIa

"1. Use of an alternative antiplatelet agent (eg, a thienopyridine such as clopidogrel) instead of ASA is reasonable if the patient is intolerant or resistant to ASA.(Level of Evidence: C) "

Class IIb

"1. Additional patient and coronary artery char- acteristics may be considered in decision making regarding adjustments to strategy for thromboprophylaxis.(Level of Evidence: C) "

Class III

"1. Anticoagulation or dual-antiplatelet therapy is not indicated.(Level of Evidence: C) "

Physical activity

Class I

"1. For patients on anticoagulation or dual-antiplatelet therapy, activities involving a risk of bodily contact, trauma, or injury should be restricted or modified.(Level of Evidence: B) "

Class IIa

"1. It is reasonable to provide physical activity counseling at every visit without restrictions or precautions. Participation in competitive sports or high-intensity activities should be guided by results from testing for inducible myocardial ischemia or exercise-induced arrhythmias.(Level of Evidence: C) "

Reproductive counselling

Class IIa

"1. It is reasonable to provide age-appropriate counseling regarding contraception. It is reasonable to recommend that pregnancy be supervised by a multidisciplinary team including a cardiologist and to alter thromboprophylaxis management during pregnancy and delivery.(Level of Evidence: B) "

Regression to Normal Z Score or Dilation Only

Frequency of cardiology assessment (to include history and physical examination, echocardiography, electrocardiography)

Class IIa

"1. It is reasonable to assess the patient every 1 to 2 years. Not performing routine 2D echocardiography may be considered unless there is evidence for inducible myocardial ischemia or the patient has symptoms suggestive of ischemia or signs suggestive of ventricular dysfunction.(Level of Evidence: C) "

Type and frequency of additional cardiology assessment (other cardiology testing)

Class IIa

"1. It is reasonable to assess for inducible myocardial ischemia (stress echocardiography, stress with MRI, stress NM perfusion imaging, PET) every 2 to 5 years or if the patient has symptoms suggestive of ischemia or signs suggestive of ventricular dysfunction.(Level of Evidence: B) "

Cardiovascular risk factor assessment and management

Class IIa

"1. It is reasonable to provide general counseling regarding healthy lifestyle and activity promotion at every visit; this may additionally be provided by the primary care provider.(Level of Evidence: C) "

"2. It is reasonable to assess blood pressure, body mass index (and plot), waist circumference, dietary and activity assessment, and smoking every 2 years; this may be performed by the primary care provider. It is reasonable to obtain a follow-up fasting lipid profile as per the Expert Panel guidelines.(Level of Evidence: C) "

Medical therapy (β-blockers, ACEI, statin)

Class IIb

"1. Empirical statin therapy for non–lipid-lowering (pleiotropic) effects may be considered.(Level of Evidence: C) "

Class III

"1. Empirical treatment with β-blockers is not indicated.(Level of Evidence: C) "

Thromboprophylaxis

Class IIa

"1. It is reasonable to continue treatment with low-dose ASA.(Level of Evidence: C) "

"2. Use of an alternative antiplatelet agent (eg, a thienopyridine such as clopidogrel) instead of ASA is reasonable if the patient is intol- erant or resistant to ASA.(Level of Evidence: C) "

Class IIb

"1. Additional patient and coronary artery characteristics may be considered in decision making regarding intensification or discontinuation of thromboprophylaxis.(Level of Evidence: C) "

Class III

"1. Use of anticoagulation (warfarin/LMWH) or dual-antiplatelet therapy is not indicated.(Level of Evidence: C) "

Physical activity

Class I

"1. For patients on anticoagulation or dual-anti- platelet therapy, activities involving a risk of bodily contact, trauma, or injury should be restricted or modified.(Level of Evidence: B) "

Class IIa

"1. It is reasonable to provide physical activity counseling at every visit without restrictions or precautions. Participation in competitive sports or high-intensity activities should be guided by results from testing for inducible myocardial ischemia or exercise-induced arrhythmias.(Level of Evidence: C) "

Reproductive counselling

Class IIa

"1. It is reasonable to provide age-appropriate counseling regarding contraception. It is reasonable to recommend that pregnancy be supervised by a multidisciplinary team including a cardiologist and to alter thrombo- prophylaxis management during pregnancy and delivery.(Level of Evidence: B) "

Recommendations for Testing for Inducible Ischemia

Class IIa

"1. It is reasonable to use stress echocardiography or CMRI, NM MPI, or PET for assessment of inducible myocardial ischemia. Note: The general principle is to minimize risk to the patient, particularly cumulative radiation dose, and this should guide selection of testing modality based on patient and institutional characteristics(Level of Evidence: B) "

Class III

"1. Exercise treadmill electrocardiographic testing alone should not be used for assessment for inducible myocardial ischemia.(Level of Evidence: C) "

Recommendation for Assessment of Patients With Inducible Myocardial Ischemia

Class I

"1. Patients with evidence of inducible myocardial ischemia on testing should undergo invasive coronary angiography.(Level of Evidence: B) "

Recommendations for Indications for Mechanical Revascularization

Class I

"1. Adult patients with remote history of KD presenting with STEMI should be referred emergently for coronary angiography for determination of best means of flow restoration in the culprit artery.(Level of Evidence: C) "

"2. Revascularization should be performed in KD patients with stable angina and high-risk coronary anatomy including left main CAD, multi- vessel coronary disease with reduction in LV function, multivessel coronary disease with diabetes mellitus, or high-risk noninvasive ischemia testing.(Level of Evidence: C) "

"3. Revascularization should be performed for patients with non–ST-segment elevation and coronary anatomy amenable to revascularization on coronary angiography.(Level of Evidence: C) "

Class IIa

"1. Revascularization for patients with stable angina and symptoms refractory to maximal medical therapy is reasonable. (Level of Evidence: C) "

Class IIb

"1. Revascularization for KD patients with silent ischemia and ischemia involving >10% of LV mass may be considered. (Level of Evidence: C) "

Class III

"1. Revascularization should be avoided in KD patients in the acute/subacute phase of the illness with STEMI attributable to acute thrombotic occlusion of an aneurysm.(Level of Evidence: C) "

Recommendations for Modes of Revascularization

Class I

"1. CABG is preferred to PCI in KD patients with left main CAD, multivessel CAD with reduced LV function, multivessel CAD with lesions not amenable to PCI, and multivessel CAD in diabetic patients.(Level of Evidence: B) "

"2. CABG is preferred to PCI in older children and adults with KD and multivessel involvement .(Level of Evidence: C) "

"3. CABG should be performed with bilateral internal thoracic arterial grafts where possible.(Level of Evidence: B) "

"4. PCI is preferred in patients with single-vessel or focal multivessel disease amenable to PCI.(Level of Evidence: C) "

"5. RA and stents should be used in PCI of calcified lesions.(Level of Evidence: C) "

Class IIa

"1. The use of multivessel PCI is reasonable for KD patients with focal lesions amenable to PCI. (Level of Evidence: C) "

"2. The use of DESs during PCI is reasonable for KD patients who do not require long- term anticoagulation. (Level of Evidence: C) "

"3. The use of IVUS is reasonably indicated during PCI in KD patients to ensure adequate stent sizing and deployment. (Level of Evidence: C) "

Class IIb

"1. Multivessel PCI may be considered for patients who are acceptable CABG candidates but prefer to avoid CABG, provided the risks and benefits of both approaches are discussed with and understood by the patient. (Level of Evidence: C) "

"2. The use of DESs during PCI may be considered for KD patients who require anti- coagulation, provided the bleeding risk of the patient is acceptable. (Level of Evidence: C) "

Class III

"1. Stand-alone balloon angioplasty should not be used for PCI in KD patients with coronary obstructions.(Level of Evidence: C) "

Recommendation for Cardiac Transplantation

Class IIa

"1. The use of multivessel PCI is reasonable for KD patients with focal lesions amenable to PCI. (Level of Evidence: C) "

Prevention

AHA Scientific Statement on Kawasaki Disease

Recommendations for Prevention of Thrombosis During the Acute Illness

Class I

"1. Low-dose ASA (3–5 mg·kg−¹·d−¹) should be administered to patients without evidence of coronary artery changes until 4 to 6 weeks after onset of illness.(Level of Evidence: C) "

Class IIa

"1. For patients with rapidly expanding coronary artery aneurysms or a maximum Z score of ≥10, systemic anticoagulation with LMWH or warfarin (international normalized ratio target 2.0–3.0) in addition to low dose ASA is reasonable. (Level of Evidence: B) "

Class IIb

"1. For patients at increased risk of thrombosis, for example, with large or giant aneurysms (≥8 mm or Z score ≥10) and a recent history of coronary artery thrombosis, “triple therapy” with ASA, a second antiplatelet agent, and anticoagulation with warfarin or LMWH may be considered. (Level of Evidence: C) "

Class III

"1. Ibuprofen and other non steroidal anti-inflammatory drugs with known or potential involvement of cyclooxygenase pathway may be harmful in patients taking ASA for its antiplatelet effects. (Level of Evidence: B) "

Recommendations for Risk Stratification of Coronary Artery Abnormalities

Class IIa

"1. It is reasonable to use echocardiographic coronary artery luminal dimensions converted to BSA-adjusted Z scores to determine risk stratification. (Level of Evidence: B) "

"2. It is reasonable to incorporate both maximal and current coronary artery involvement in risk stratification. (Level of Evidence: C) "

"3. It is reasonable to incorporate the presence of additional features other than coronary artery luminal dimensions into decisions regarding risk stratification. (Level of Evidence: C) "

External links

• Kawasaki Disease Foundation
• Kawasaki Disease Forum
• Kawasaki Disease Canada
• Kawasaki Disease Research Program
• Kawasaki Disease information from Seattle Children's Hospital Heart Center
• Template:GPnotebook

Template:WikiDoc Sources

INTRODUCTION — Kawasaki disease (KD, previously called mucocutaneous lymph node syndrome) is one of the most common vasculitides of childhood [1]. KD also occurs rarely in adults. It is typically a self-limited condition, with fever and manifestations of acute inflammation lasting for an average of 12 days without therapy [2]. However, complications such as coronary artery (CA) aneurysms, depressed myocardial contractility and heart failure, myocardial infarction, arrhythmias, and peripheral arterial occlusion may develop and lead to significant morbidity and mortality. (See "Cardiovascular sequelae of Kawasaki disease: Clinical features and evaluation".)

The clinical manifestations and diagnosis of KD are discussed in this review. The epidemiology, etiology, treatment, and complications of KD, including cardiac sequelae, are presented separately. Incomplete (atypical) KD and unique features in infants and adults are also reviewed separately. (See "Kawasaki disease: Epidemiology and etiology" and "Kawasaki disease: Initial treatment and prognosis" and "Cardiovascular sequelae of Kawasaki disease: Clinical features and evaluation" and "Incomplete (atypical) Kawasaki disease" and "Kawasaki disease: Complications".)

CLINICAL MANIFESTATIONS — The clinical features of KD reflect widespread inflammation of primarily medium-sized muscular arteries. Diagnosis is based upon evidence of systemic inflammation (eg, fever) in association with signs of mucocutaneous inflammation. The characteristic bilateral nonexudative conjunctivitis, erythema of the lips and oral mucosa, rash, extremity changes, and cervical lymphadenopathy typically develop after a brief nonspecific prodrome of respiratory or gastrointestinal symptoms [3-8] (see 'Other findings' below). These characteristic clinical signs are the basis for the diagnostic criteria for KD (table 1) [9].

Oral mucous membrane findings are seen in approximately 90 percent of cases of KD, polymorphous rash in 70 to 90 percent, extremity changes in 50 to 85 percent, ocular changes in >75 percent, and cervical lymphadenopathy in 25 to 70 percent [7,10-12].

These findings are often not present at the same time, and there is no typical order of appearance. As an example, some patients have only developed fever and cervical lymphadenopathy by the time of admission (so-called KD with isolated cervical lymphadenopathy, KDiL) [13]. In one case series, these patients tended to be older and to have a more severe course, with increased risk of coronary artery (CA) disease and lack of response to intravenous immune globulin (IVIG). Thus, repeated histories and physical examinations are important both for making a timely diagnosis of KD in children who fail to meet diagnostic criteria, as well as for appropriate consideration of alternative diagnoses. (See 'Diagnosis' below.)

Fever — An elevated body temperature is the most consistent manifestation of KD. Fever is minimally responsive to antipyretic agents, and it typically remains above 38.5ºC (101.3ºF) during most of the illness. On the other hand, fever may be intermittent and may be missed by parents who use tympanic, temporal, axillary, or similar temperature measurement methods that are less reliable than oral or rectal methods. Thus, the diagnosis should be considered in all children with prolonged, unexplained fever ≥5 days but should still be considered in seemingly afebrile children who have other findings consistent with KD. (See "Incomplete (atypical) Kawasaki disease".)

Conjunctivitis — Bilateral nonexudative conjunctivitis is present in more than 90 percent of patients. A predominantly bulbar injection typically begins within days of the onset of fever, and the eyes often have a brilliant erythema, which characteristically spares the limbus (picture 1). Children also are frequently photophobic. In addition, anterior uveitis may develop in up to 70 percent of children with ocular findings [12,14]; therefore, slit-lamp examination may be helpful in ambiguous cases. The presence of uveitis provides further evidence for the diagnosis of KD since it is more commonly seen in KD than in other diseases with similar presentations. (See "Uveitis: Etiology, clinical manifestations, and diagnosis".)

Mucositis — Mucositis often becomes evident as KD progresses. Cracked, red lips (picture 2) and a strawberry tongue (picture 3) are characteristic. The latter is a result of sloughing of filiform papillae and denuding of the inflamed glossal tissue. These manifestations of oral mucositis may occur singly, in a very mild form, or not at all. Discrete oral lesions, such as vesicles or ulcers, and tonsillar exudate are suggestive of a disease process other than KD [6].

Rash — The cutaneous manifestations of KD are polymorphous. The rash usually begins during the first few days of illness, typically as perineal erythema and desquamation, followed by macular, morbilliform, or targetoid skin lesions of the trunk and extremities. Vesicular or bullous lesions generally are not observed, but KD may trigger a psoriasiform eruption in children not previously recognized to have psoriasis [15-18]. Patients may also have redness or crust formation at the site of Bacille Calmette-Guérin (BCG) inoculation. This finding is more useful for increasing the level of suspicion for KD in countries where BCG vaccine is routinely given. (See 'Diagnosis' below.)

Extremity changes — Changes in the extremities are generally the last manifestation to appear. Children develop an indurated edema of the dorsum of their hands and feet (picture 4) and a diffuse erythema of their palms and soles.

The convalescent phase of KD is often characterized by sheet-like desquamation that begins in the periungual region of the hands and feet (picture 5) and by linear nail creases (Beau's lines). The prevalence of periungual desquamation in patients with KD has been reported to vary from 68 to 98 percent [19].

Lymphadenopathy — Cervical lymphadenopathy is the least consistent feature of KD, absent in as many as one-half to three-quarters of children with the disease [11]. When present, lymphadenopathy tends to primarily involve the anterior cervical nodes overlying the sternocleidomastoid muscles [20]. Often, only a single, large node is palpable, although ultrasound imaging of the neck typically reveals numerous discrete nodes arranged like a bunch of grapes [21].

Diffuse lymphadenopathy or other signs of reticuloendothelial involvement (eg, splenomegaly) should prompt a search for alternative diagnoses. (See 'Differential diagnosis' below.)

Cardiovascular findings — Cardiovascular findings are not part of the diagnostic criteria, but they support the diagnosis since most conditions that mimic KD do not involve the heart. Cardiac manifestations during the first week to 10 days of illness may include tachycardia out of proportion to the degree of fever, gallop sounds, and muffled heart tones [2]. With improved echocardiographic techniques and use of Z-scores for determining CA diameter, approximately 30 percent of patients with KD are found to have CA dilatation at diagnosis [22,23]. Frank aneurysms are usually not seen until after day 10 of illness. Severely ill patients, particularly young infants, may develop fusiform aneurysms of the brachial arteries that are easily palpable or visible in the axillae. In addition, young infants may have cold, pale, or cyanotic digits of the hands and feet due to reduced perfusion. Gangrene may, in rare cases, cause loss of fingers or toes during this acute period. The cardiac complications associated with KD are discussed in detail separately. (See "Kawasaki disease: Complications", section on 'Cardiac complications' and "Cardiovascular sequelae of Kawasaki disease: Clinical features and evaluation".)

Arthritis — Arthritis is not included in the diagnostic criteria but has been reported in 7.5 to 25 percent of patients with KD [24,25]. The prevalence of arthritis was 7.5 percent in a retrospective Canadian study of 414 consecutive patients diagnosed with KD [24]. The large joints (ie, knee, ankle, and hip) were primarily involved. Oligoarticular involvement (arthritis of four or fewer joints) occurred in 16 patients and polyarticular involvement (arthritis of five or more joints) in 15 patients. With only very rare exceptions, the arthritis is self-limited and nondeforming. Patients with arthritis were more likely to have increased levels of inflammatory markers (C-reactive protein [CRP] or erythrocyte sedimentation rate [ESR]) and neutrophils. Otherwise, there were no differences in clinical features, response to therapy, or clinical outcomes between patients with or without arthritis.

Other findings — The following nonspecific symptoms commonly occur in children within the first 10 days before diagnosis of KD but are not included in the diagnostic criteria [2,5]:

●Diarrhea, vomiting, or abdominal pain – 61 percent

●Irritability – 50 percent (older children with KD may present more with lethargy than irritability)

●Vomiting alone – 44 percent

●Cough or rhinorrhea – 35 percent

●Decreased intake – 37 percent

●Joint pain – 15 percent

LABORATORY FINDINGS — No laboratory studies are included among the diagnostic criteria for typical KD. However, certain findings may support the diagnosis of KD, particularly in incomplete cases [1] (see 'Diagnosis' below and "Incomplete (atypical) Kawasaki disease", section on 'Laboratory tests'):

●Systemic inflammation is characteristic of KD. Typical manifestations include elevation of acute-phase reactants (eg, C-reactive protein [CRP] or erythrocyte sedimentation rate [ESR]), thrombocytosis that generally develops after the seventh day of illness, leukocytosis, and a left-shift (increased immature neutrophils) in the white blood cell (WBC) count.

CRP elevations resolve well before ESR. However, patients with more severe disease can have persistently high levels of CRP for weeks. Treatment with intravenous immune globulin (IVIG) usually raises the ESR, so this lab marker should not be measured after a child receives IVIG. On the other hand, control of inflammation by IVIG accelerates the decrease in CRP, making this a more useful marker of disease activity in a treated child.

Ferritin is another acute-phase reactant that is elevated in inflammatory conditions such as KD, usually less than five times the upper limit of normal. Much higher values, typically >5000 ng/mL, are seen in macrophage activation syndrome (MAS), a serious but rare complication of KD. Elevations of that magnitude are essentially diagnostic of MAS in the setting of KD. (See "Kawasaki disease: Complications", section on 'Macrophage activation syndrome' and "Clinical features and diagnosis of hemophagocytic lymphohistiocytosis", section on 'Rheumatologic disorders/MAS'.)

Lymphocyte numbers typically drop during the acute phase of KD, then rise dramatically during convalescence. Early in the course of disease, a complete blood count with a lymphocytic rather than neutrophilic preponderance is more suggestive of a viral illness. (See 'Differential diagnosis' below.)

Platelet counts generally rise by the second week of illness and may reach 1,000,000/mm3 (reactive thrombocytosis) in the most severe cases. In some studies, the degree of thrombocytosis correlates with the risk of coronary artery (CA) changes in KD. On the other hand, rare children with KD develop thrombocytopenia due to a consumptive coagulopathy. These patients are at significantly increased risk of morbidity and mortality, particularly the development of CA abnormalities [26]. (See "Kawasaki disease: Complications", section on 'Cardiac complications'.)

Thrombocytopenia, high triglycerides, low sodium, elevated liver function tests, and monocytes/macrophages in cerebral spinal fluid (CSF) can all be signs of subclinical MAS and may warrant further diagnostic testing. (See "Kawasaki disease: Complications", section on 'Macrophage activation syndrome'.)

●Children with KD often present with a normocytic, normochromic anemia. Hemoglobin concentrations more than two standard deviations below the mean for age are noted in one-half of patients within the first two weeks of illness (table 2).

●Urinary microscopy commonly reveals WBCs [27]. Pyuria can be of urethral origin and therefore may be missed on urinalyses obtained by bladder tap or catheterization [28]. The WBCs are not polymorphonuclear leukocytes and therefore are not detected by dipstick tests for leukocyte esterase. Thus, children with suspected KD should have a clean voided or bagged urine specimen collected for microscopic examination in order to detect this characteristic feature.

●In one retrospective series of 259 patients, 45 percent had at least one abnormal liver function test [29]. In a case-control series, approximately 30 percent of 280 patients with KD had mild-to-moderate elevation of transaminases (eg, serum alanine aminotransferase >50 units/L) [6]. The reason for this transaminitis is unclear. In addition, a minority of children develop obstructive jaundice from hydrops of the gallbladder.

●CSF may display a mononuclear pleocytosis without hypoglycorrhachia (decreased CSF glucose) or elevation of CSF protein. In a retrospective review, 46 of 520 children with KD underwent lumbar puncture [30]. In this subset of patients, 39 percent had elevated CSF WBC counts. The median count was 22.5 cells/mm3 with 6 percent neutrophils and 92 percent mononuclear cells, although cell counts as high as 320/mm3 with up to 79 percent neutrophils were reported.

●Similarly, arthrocentesis of involved joints typically demonstrates a pleocytosis, with 125,000 to 300,000 WBCs/mm3, primarily neutrophils [31].

●Children with KD develop significant perturbations in serum lipid profiles, including elevated triglycerides and low-density lipoproteins, and depressed high-density lipoproteins [2,32-34], as is often observed in a variety of infectious and inflammatory conditions. A return to normal generally occurs within weeks or months following IVIG therapy, though abnormalities may persist for years in untreated children [33].

●Hyponatremia (serum sodium <135 mEq/L) may be seen and is associated with an increased risk of CA aneurysms [35].

DIAGNOSIS — Diagnosis of KD according to the criteria established by Tomisaku Kawasaki in 1967 [36] requires the presence of fever lasting ≥5 days, combined with at least four of the five following physical findings, without an alternative explanation (table 1) [1,2,37]:

●Bilateral bulbar conjunctival injection (picture 1)

●Oral mucous membrane changes, including injected or fissured lips (picture 2), injected pharynx, or strawberry tongue (picture 3)

●Peripheral extremity changes, including erythema of palms or soles, edema of hands or feet (acute phase) (picture 4), and periungual desquamation (convalescent phase) (picture 5)

●Polymorphous rash

●Cervical lymphadenopathy (at least one lymph node >1.5 cm in diameter)

Redness or crust formation at the site of Bacille Calmette-Guérin (BCG) inoculation is also suggested as a useful sign in several diagnostic guidelines [2,9]. In one series of 15,524 patients with KD and a history of BCG vaccination, 50 percent had this finding compared with none of the 53 children admitted with respiratory syncytial virus or rotavirus infection who served as the control group [38].

As with all clinical criteria, these are imperfect guidelines with less than 100 percent sensitivity and specificity. In addition, Dr. Kawasaki published his guidelines before cardiac involvement was recognized in this disease, so they were never intended to identify children at risk for developing coronary artery (CA) abnormalities. Thus, it is not surprising that at least 10 percent of children who develop CA aneurysms never meet criteria for KD [39]. Children who do not meet the criteria may have an incomplete form of KD. An algorithmic approach can help identify such cases (algorithm 1) [2]. (See "Incomplete (atypical) Kawasaki disease".)

Rash and conjunctival injection are seen with many illnesses, but other KD features, such as red, cracked lips and redness and swelling of the hands and feet, are unusual in the illnesses in the differential diagnosis and should increase the suspicion for KD. (See 'Differential diagnosis' below.)

Laboratory evaluation — As noted above, Dr. Kawasaki identified the first 50 cases of "mucocutaneous lymph node syndrome" on the basis of clinical findings rather than laboratory or imaging studies [36]. Thus, no laboratory values are included in the classical diagnostic criteria, but they nonetheless may support a diagnosis of KD in ambiguous cases. In fact, some laboratory tests are explicitly included in the algorithm for diagnosis of atypical KD (algorithm 1) [2]. (See "Incomplete (atypical) Kawasaki disease", section on 'Laboratory tests'.)

The following blood tests are typically obtained on children in whom a diagnosis of KD is being considered:

●Complete blood counts with differential white blood cell (WBC) counts

●Liver function tests including aspartate transaminase (AST), alanine transaminase (ALT), and albumin

●C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR)

●Urinalysis

Elevated WBC and platelet counts, transaminases, and acute-phase reactants, as well as anemia and pyuria, are suggestive of KD.

In addition, when specific mimics of KD are strongly suspected, studies that are more specific for these alternative diagnoses may help confirm the diagnosis. These can include rapid viral testing (eg, adenovirus), serologic testing for leptospirosis and other bacterial infections, and blood cultures.

Echocardiography — Echocardiography should be performed in all patients with KD as soon as the diagnosis is suspected in order to establish a baseline for longitudinal follow-up (algorithm 1). Pretreatment CA diameters establish a baseline for assessment of treatment efficacy and longitudinal follow-up. In addition, initial CA diameter is a factor in identifying patients at high risk of developing a coronary aneurysm and therefore warranting augmentation of initial intravenous immune globulin (IVIG) therapy (see "Kawasaki disease: Complications", section on 'Risk factors for coronary artery aneurysms'). Finally, CA diameters are useful for identifying patients who should be treated with IVIG despite failing to meet classical diagnostic criteria for KD. Echocardiography evaluation for KD is discussed in greater detail separately. (See "Cardiovascular sequelae of Kawasaki disease: Clinical features and evaluation", section on 'Initial evaluation' and "Incomplete (atypical) Kawasaki disease", section on 'Echocardiography'.)

DIFFERENTIAL DIAGNOSIS — KD is most commonly confused with infectious exanthems of childhood [2,40,41]. Early in the course, KD is often mistaken for more routine childhood illnesses, such as viral gastroenteritis, viral upper respiratory tract infection, or pneumonia, depending upon the other presenting symptoms, such as vomiting or cough. Concurrent viral infections are common, and, therefore, the presence of respiratory symptoms or positive respiratory viral polymerase chain reaction (PCR) testing does not exclude the diagnosis of KD [42]. Meningitis is sometimes suspected due to irritability.

Infectious diseases and other mimics of KD may have the following clinical features not commonly found in KD [2]:

●Exudative conjunctivitis (eg, adenovirus)

●Exudative pharyngitis (eg, streptococcal pharyngitis)

●Discrete intraoral lesions (eg, Koplik spots in measles)

●Bullous or vesicular rash (eg, Stevens-Johnson syndrome)

●Generalized lymphadenopathy (eg, Epstein-Barr virus [EBV] infection)

The presence of any of these findings and/or the absence of fever should suggest a diagnosis other than KD. Of note, concurrent infections (both viral and bacterial) are common in patients with KD, found in up to 33 percent of children in one study [43]. In this review of 129 consecutive children seen with KD in Toronto, infection at the time of diagnosis did not affect response to therapy or outcome. In any event, diagnosis of an infectious condition does not preclude a concurrent diagnosis of KD.

The differential diagnosis of KD includes (table 3):

●Measles, echovirus, adenovirus [44], and EBV – These viral illnesses may share many of the signs of mucocutaneous inflammation, but they typically have less evidence of systemic inflammation and generally lack the extremity changes seen in KD. (See "Measles: Clinical manifestations, diagnosis, treatment, and prevention" and "Enterovirus and parechovirus infections: Clinical features, laboratory diagnosis, treatment, and prevention" and "Pathogenesis, epidemiology, and clinical manifestations of adenovirus infection" and "Clinical manifestations and treatment of Epstein-Barr virus infection".)

●Toxin-mediated illnesses, especially group A streptococcal infections (eg, scarlet fever and toxic shock syndrome) – These usually lack the ocular and articular involvement typical of KD, though patients with staphylococcal toxic shock syndrome occasionally have conjunctival erythema. Patients with toxic shock often have generalized edema. The edema is rarely confined to the hands and feet. Patients with scarlet fever may have periungual desquamation. (See "Epidemiology, clinical manifestations, and diagnosis of streptococcal toxic shock syndrome" and "Staphylococcal toxic shock syndrome" and "Group A streptococcal (Streptococcus pyogenes) bacteremia in children", section on 'Clinical manifestations'.)

●Rocky Mountain spotted fever and leptospirosis – Headache and gastrointestinal complaints typically are prominent features of these infections. (See "Clinical manifestations and diagnosis of Rocky Mountain spotted fever" and "Epidemiology, microbiology, clinical manifestations, and diagnosis of leptospirosis".)

●Drug reactions such as Stevens-Johnson syndrome or serum sickness – These may mimic KD but with subtle differences in the ocular and mucosal manifestations, and laboratory markers of inflammation are generally normal or only mildly elevated. (See "Stevens-Johnson syndrome and toxic epidermal necrolysis: Pathogenesis, clinical manifestations, and diagnosis".)

●Systemic juvenile idiopathic arthritis – Children with this condition generally lack the conjunctival and oral findings of KD. Lymphadenopathy also is generalized, and it may be accompanied by splenomegaly, unlike in KD. (See "Systemic juvenile idiopathic arthritis: Clinical manifestations and diagnosis".)

Delayed diagnosis — Treatment with intravenous immune globulin (IVIG) within the first 10 days of illness reduces the prevalence of coronary artery (CA) aneurysms fivefold compared with children not treated with IVIG [45,46]. Thus, it is desirable to diagnose KD as soon as possible after the onset of symptoms in order to initiate treatment and reduce the risk of CA lesions [47]. However, timely identification is challenging because the diagnosis is based upon nonspecific clinical signs and there is no definitive diagnostic test. Thus, the clinicians in a medical facility with the most experience taking care of patients with KD should be consulted as early in the course of the evaluation of suspected KD as possible. These clinicians may include pediatric rheumatologists, infectious disease specialists, cardiologists, and/or hospitalists, depending upon the institution.

In a retrospective study of 562 patients diagnosed with KD at eight North American centers, 92 cases (16 percent) were diagnosed after the first 10 days of illness (ie, late diagnosis) [48]. Predictors of a delay in diagnosis of KD included age below six months, clinical presentation of incomplete KD, greater distance from a tertiary center, and variability between clinical centers. In contrast, socioeconomic status was not associated with a delay in diagnosis.

These findings suggest that practice variation in confirming a diagnosis of KD may in part contribute to a delayed diagnosis. The results of this study underscore the need for a high index of suspicion of KD, especially in young infants and patients who present with incomplete KD, in order to identify and treat patients in a timely manner. (See "Incomplete (atypical) Kawasaki disease".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Kawasaki disease".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topic (see "Patient education: Kawasaki disease (The Basics)")

SUMMARY

●Kawasaki disease (KD, also called mucocutaneous lymph node syndrome) is one of the most common vasculitides of childhood. KD occurs only rarely in adults. It is typically a self-limited condition, with fever and manifestations of acute inflammation lasting for an average of 12 days without therapy. (See 'Introduction' above.)

●KD is characterized by systemic inflammation manifested by fever and mucocutaneous involvement, including bilateral nonexudative conjunctivitis, erythema of the lips and oral mucosa, rash, extremity changes, and cervical lymphadenopathy (table 1). These findings are often not present at the same time. Thus, repeated histories and physical examinations are important in making a timely diagnosis of KD in children with fever and signs of mucocutaneous inflammation. (See 'Clinical manifestations' above.)

●No laboratory studies are included among the diagnostic criteria for typical KD. However, the presence of compatible laboratory features strongly supports the diagnosis. (See 'Laboratory findings' above and "Incomplete (atypical) Kawasaki disease", section on 'Laboratory tests'.)

●The diagnosis of KD according to classical criteria requires the presence of fever ≥5 days, combined with at least four of the other five signs of mucocutaneous inflammation, without any other explanation (table 1). Additional clinical and laboratory features are often used to guide diagnosis in children who have fewer than five criteria for KD (incomplete KD). (See 'Diagnosis' above and "Incomplete (atypical) Kawasaki disease".)

●KD is most commonly confused with infectious exanthems of childhood. The presence of clinical features not commonly found in KD, including exudative conjunctivitis, exudative pharyngitis, discrete intraoral lesions, bullous or vesicular rash, splenomegaly, and/or generalized lymphadenopathy, suggest another diagnosis (table 3). Nonetheless, KD is sufficiently pleomorphic that none of these findings can definitively exclude the diagnosis. Children with KD can have concurrent infections, particularly with viruses circulating in the community at the time of their diagnosis. (See 'Differential diagnosis' above.)

Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES Burns JC, Glodé MP. Kawasaki syndrome. Lancet 2004; 364:533. McCrindle BW, Rowley AH, Newburger JW, et al. Diagnosis, Treatment, and Long-Term Management of Kawasaki Disease: A Scientific Statement for Health Professionals From the American Heart Association. Circulation 2017; 135:e927. Morens DM, Anderson LJ, Hurwitz ES. National surveillance of Kawasaki disease. Pediatrics 1980; 65:21. Huang GY, Ma XJ, Huang M, et al. Epidemiologic pictures of Kawasaki disease in Shanghai from 1998 through 2002. J Epidemiol 2006; 16:9. Baker AL, Lu M, Minich LL, et al. Associated symptoms in the ten days before diagnosis of Kawasaki disease. J Pediatr 2009; 154:592. Burns JC, Mason WH, Glode MP, et al. Clinical and epidemiologic characteristics of patients referred for evaluation of possible Kawasaki disease. United States Multicenter Kawasaki Disease Study Group. J Pediatr 1991; 118:680. Ozdemir H, Ciftçi E, Tapisiz A, et al. Clinical and epidemiological characteristics of children with Kawasaki disease in Turkey. J Trop Pediatr 2010; 56:260. Cai Z, Zuo R, Liu Y. Characteristics of Kawasaki disease in older children. Clin Pediatr (Phila) 2011; 50:952. Ayusawa M, Sonobe T, Uemura S, et al. Revision of diagnostic guidelines for Kawasaki disease (the 5th revised edition). Pediatr Int 2005; 47:232. Fukushige J, Takahashi N, Ueda Y, Ueda K. Incidence and clinical features of incomplete Kawasaki disease. Acta Paediatr 1994; 83:1057. Sung RY, Ng YM, Choi KC, et al. Lack of association of cervical lymphadenopathy and coronary artery complications in Kawasaki disease. Pediatr Infect Dis J 2006; 25:521. Germain BF, Moroney JD, Guggino GS, et al. Anterior uveitis in Kawasaki disease. J Pediatr 1980; 97:780. Nomura Y, Arata M, Koriyama C, et al. A severe form of Kawasaki disease presenting with only fever and cervical lymphadenopathy at admission. J Pediatr 2010; 156:786. Smith LB, Newburger JW, Burns JC. Kawasaki syndrome and the eye. Pediatr Infect Dis J 1989; 8:116. Eberhard BA, Sundel RP, Newburger JW, et al. Psoriatic eruption in Kawasaki disease. J Pediatr 2000; 137:578. Kishimoto S, Muneuchi J, Takahashi Y, et al. Psoriasiform skin lesion and supprative acrodermatitis associated with Kawasaki disease followed by the treatment with infliximab: a case report. Acta Paediatr 2010; 99:1102. Ergin S, Karaduman A, Demirkaya E, et al. Plaque psoriasis induced after Kawasaki disease. Turk J Pediatr 2009; 51:375. Liao YC, Lee JY. Psoriasis in a 3-month-old infant with Kawasaki disease. Dermatol Online J 2009; 15:10. Wang S, Best BM, Burns JC. Periungual desquamation in patients with Kawasaki disease. Pediatr Infect Dis J 2009; 28:538. April MM, Burns JC, Newburger JW, Healy GB. Kawasaki disease and cervical adenopathy. Arch Otolaryngol Head Neck Surg 1989; 115:512. Kanegaye JT, Van Cott E, Tremoulet AH, et al. Lymph-node-first presentation of Kawasaki disease compared with bacterial cervical adenitis and typical Kawasaki disease. J Pediatr 2013; 162:1259. Dominguez SR, Anderson MS, El-Adawy M, Glodé MP. Preventing coronary artery abnormalities: a need for earlier diagnosis and treatment of Kawasaki disease. Pediatr Infect Dis J 2012; 31:1217. Printz BF, Sleeper LA, Newburger JW, et al. Noncoronary cardiac abnormalities are associated with coronary artery dilation and with laboratory inflammatory markers in acute Kawasaki disease. J Am Coll Cardiol 2011; 57:86. Gong GW, McCrindle BW, Ching JC, Yeung RS. Arthritis presenting during the acute phase of Kawasaki disease. J Pediatr 2006; 148:800. Melish ME. Kawasaki syndrome: a 1986 perspective. Rheum Dis Clin North Am 1987; 13:7. Nofech-Mozes Y, Garty BZ. Thrombocytopenia in Kawasaki disease: a risk factor for the development of coronary artery aneurysms. Pediatr Hematol Oncol 2003; 20:597. Shike H, Kanegaye JT, Best BM, et al. Pyuria associated with acute Kawasaki disease and fever from other causes. Pediatr Infect Dis J 2009; 28:440. Watanabe T, Abe Y, Sato S, et al. Sterile pyuria in patients with Kawasaki disease originates from both the urethra and the kidney. Pediatr Nephrol 2007; 22:987. Eladawy M, Dominguez SR, Anderson MS, Glodé MP. Abnormal liver panel in acute kawasaki disease. Pediatr Infect Dis J 2011; 30:141. Dengler LD, Capparelli EV, Bastian JF, et al. Cerebrospinal fluid profile in patients with acute Kawasaki disease. Pediatr Infect Dis J 1998; 17:478. Hicks RV, Melish ME. Kawasaki syndrome. Pediatr Clin North Am 1986; 33:1151. Salo E, Pesonen E, Viikari J. Serum cholesterol levels during and after Kawasaki disease. J Pediatr 1991; 119:557. Newburger JW, Burns JC, Beiser AS, Loscalzo J. Altered lipid profile after Kawasaki syndrome. Circulation 1991; 84:625. Cabana VG, Gidding SS, Getz GS, et al. Serum amyloid A and high density lipoprotein participate in the acute phase response of Kawasaki disease. Pediatr Res 1997; 42:651. Nakamura Y, Yashiro M, Uehara R, et al. Use of laboratory data to identify risk factors of giant coronary aneurysms due to Kawasaki disease. Pediatr Int 2004; 46:33. Kawasaki T. [Acute febrile mucocutaneous syndrome with lymphoid involvement with specific desquamation of the fingers and toes in children]. Arerugi 1967; 16:178. Centers for Disease Control. Kawasaki disease — New York. MMWR Morb Mortal Wkly Rep 1980; 29:61. Uehara R, Igarashi H, Yashiro M, et al. Kawasaki disease patients with redness or crust formation at the Bacille Calmette-Guérin inoculation site. Pediatr Infect Dis J 2010; 29:430. Sundel RP. Update on the treatment of Kawasaki disease in childhood. Curr Rheumatol Rep 2002; 4:474. Yanagihara R, Todd JK. Acute febrile mucocutaneous lymph node syndrome. Am J Dis Child 1980; 134:603. Barron KS. Kawasaki disease in children. Curr Opin Rheumatol 1998; 10:29. Turnier JL, Anderson MS, Heizer HR, et al. Concurrent Respiratory Viruses and Kawasaki Disease. Pediatrics 2015; 136:e609. Benseler SM, McCrindle BW, Silverman ED, et al. Infections and Kawasaki disease: implications for coronary artery outcome. Pediatrics 2005; 116:e760. Jaggi P, Kajon AE, Mejias A, et al. Human adenovirus infection in Kawasaki disease: a confounding bystander? Clin Infect Dis 2013; 56:58. Furusho K, Kamiya T, Nakano H, et al. High-dose intravenous gammaglobulin for Kawasaki disease. Lancet 1984; 2:1055. Newburger JW, Takahashi M, Burns JC, et al. The treatment of Kawasaki syndrome with intravenous gamma globulin. N Engl J Med 1986; 315:341. Newburger JW, Takahashi M, Gerber MA, et al. Diagnosis, treatment, and long-term management of Kawasaki disease: a statement for health professionals from the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease, Council on Cardiovascular Disease in the Young, American Heart Association. Pediatrics 2004; 114:1708. Minich LL, Sleeper LA, Atz AM, et al. Delayed diagnosis of Kawasaki disease: what are the risk factors? Pediatrics 2007; 120:e1434.

Obstructive lung disease DD

Obstructive lung disease

Diseases		Clinical manifestations										Diagnosis
		Symptoms					Signs					Lab findings	PFT				Imaging			Gold standard	Other features
		Cough	Dyspnea	Hemoptysis	Fever	Weight loss	Cyanosis	Clubbing	JVD	Peripheral edema	Auscultation		ABGs	FEV1/FVC	TLC	DLCO
																	CXR	CT scan	Other tests
Asthma	Stable Asthma	+	+	−	−	−	−	−	−	−	Wheeze Rhonchi	↑IgE	Normal	↓FEV1 FEV1:FVC =<0.7	↑TLC	Normal/↑DLCO	Pulmonary hyperinflation	Extensive air trapping	Bronchoprovocation testing Peak expiratory flow measurement	Physical Exam Spirometry	Associated with: Allergic rhinitis GERD and obesity can mimic asthma
	Status Asthmaticus	+	+	-	±	-	-	-	+	-	Wheeze Absent or ↓Breath sounds	↑TLC ↑Glucose	↑PCO2 ↓PO2	↓FEV1:FVC < 30% of predictive value	↑TLC	↑DLCO	Pulmonary hyperinflation Atypical presentation	-	Peak expiratory flow<50% of baseline	Clinical diagnosis	Pulses paradoxus
COPD	Chronic bronchitis	+	+	±	+	−	−	−	−	−	Wheeze Rhonchi Egophony Rales ↓Bronchial breath sounds(present in consolidation)	↑Procalcitonin	Normal	↓FEV1	↑TLC	Normal	Thickening of the bronchial walls in the lower lobes	Thickening of the bronchial walls in the lower lobes	Microbiological testing is done in cases of: Influenza Pertusis	Clinical diagnosis Chest radiograph	Secondary to URTI
	Emphysema	+	+	–	+	+	+	+	–	–	Expiratory wheeze Hyperinflation	↓alpha-1 antitrypsin deficency	Respiratory alkalosis Metabolic acidosis	↓FEV1	↑TLC	–	Flattening of the diaphragm Vertical heart	Small subpleural collections of gas Centriacinar emphysema Panacinar emphysema Paraseptal emphysema	Pulse oximetry	Physical Exam Spirometery	Barrel Chest
Bronchiolitis		+	+	−	+	−	−	−	−	–	Wheeze Crackles		Normal	↓	↑TLC	↓DLCO	Bronchovascular markings	Air trapping Bronchial wall thickening	Bronchoscopy Lung biopsy	Thoracoscopic lung biopsy	Can be associated with: Organ transplantation
Bronchiectasis		+	+	+	+	–	+	+	–	–	Rhonchi Wheeze Crackles	↑Neutrophils		↓FEV1:FVC	↑TLC	↓DLCO	Tram track opacities	Signet-ring sign Airway dilation	Flexible bronchoscopy	HRCT	Chronic productive cough
Heart failure		+	+	–	–	–	+	–	+	+	S3 gallop Wheeze Rales	↑Pro-BNP ↑Troponin Anemia Hyponatremia ↑BUN ↑Creatinine	Respiratory alkalosis		Normal TLC	Normal	Bat wing appearance Cardiomegaly Pulmonary congestion Pulmonary interstitial edema Pleural effusion		MRI Cardiac catheterization Exercise testing Ambulatory ECG monitoring
Tuberculosis		+	+	+	+	+	–	–	–	–	Diminished breath sounds Rhonchi Wheeze	↑ESR ↑C-reactive protein Normocytic anemia Hypercalcemia			↑TLC	Normal	Upper lobe infiltrate Upper lobe cavitation Hilar adenopathy Solitary nodules Pleural effusion Mediastinal lymphadenopathy Fibrotic leisons Distortion of the lung parenchyma	Centrilobular 2 to 4 mm nodules Branching linear lesions Patchy small lower lobe infiltrates	Interferon gamma release assay Sputum smear positive for AFB Nucleic acid amplification test	Culture for AFB	Night Sweats Chest pain Fatigue Anorexia
Lymphangioleiomyomatosis		+	+	+(<5%)	-	-	-	+(rare)	-	+	Wheeze Hyperinflation Absent or ↓Breath sounds	↑Vascular endothelial growth factor-D	Respiratory acidosis in severe disease	↓FEV1:FVC	Normal TLC	↓DLCO	Ground glass appearance Interstetial pulmonary edema Septal thickening	Pulmonary cyst Pnuemothorax Pleural masses Pleural thickening Mediastianl lymphadenopathy Pleural effusion	VQ Scan PET Scan Advanced lymphatic imaging	Surgical lung biopsy	Chylothorax(most common lymphatic manifestation) Chyloperitonium Renalangiomyolipoma
Cystic fibrosis		+	+	+	+	-	+	+	-	-	Crackles	Sweat Chloride test: >60 mEq/L	↑PCO2 ↓PO2	↓FEV1:FVC	↑TLC	↓ In severe lung impairment	Hyperinflation Peribronchial thickening Bilateral infiltrates		↑Nasal potential difference measurement test	HRCT	Meconium ileus Volvulus Malabsorption

SCLC

SCLC accounts for approximately 15% of bronchogenic carcinomas.

At the time of diagnosis, approximately 30% of patients with SCLC will have tumors confined to the hemithorax of origin, the mediastinum, or the supraclavicular lymph nodes. These patients are designated as having limited-stage disease (LD).[1] Patients with tumors that have spread beyond the supraclavicular areas are said to have extensive-stage disease (ED).

SCLC is more responsive to chemotherapy and radiation therapy than other cell types of lung cancer; however, a cure is difficult to achieve because SCLC has a greater tendency to be widely disseminated by the time of diagnosis.

Incidence and Mortality The overall incidence and mortality rates of SCLC in the United States have decreased during the past few decades.[2]

Estimated new cases and deaths from lung cancer (SCLC and non-small cell lung cancer [NSCLC] combined) in the United States in 2018:[3]

New cases: 234,030. Deaths: 154,050. Risk Factors Increasing age is the most important risk factor for most cancers. Other risk factors for lung cancer include:

Current or history of tobacco use: cigarettes, pipes, and cigars.[4] Exposure to cancer-causing substances in secondhand smoke.[5,6] Occupational exposure to asbestos, arsenic, chromium, beryllium, nickel, and other agents.[7] Radiation exposure from any of the following: Radiation therapy to the breast or chest.[8] Radon exposure in the home or workplace.[9] Medical imaging tests, such as computed tomography (CT) scans.[10] Atomic bomb radiation.[11] Living in an area with air pollution.[12-14] Family history of lung cancer.[15] Human immunodeficiency virus infection.[16] Beta carotene supplements in heavy smokers.[17,18] Clinical Features Lung cancer may present with symptoms or be found incidentally on chest imaging. Symptoms and signs may result from the location of the primary local invasion or compression of adjacent thoracic structures, distant metastases, or paraneoplastic phenomena. The most common symptoms at presentation are worsening cough, shortness of breath, and dyspnea. Other presenting symptoms include the following:

Chest pain. Hoarseness. Malaise. Anorexia. Weight loss. Hemoptysis. Symptoms may result from local invasion or compression of adjacent thoracic structures, such as compression involving the esophagus causing dysphagia, compression involving the laryngeal nerves causing hoarseness, or compression involving the superior vena cava causing facial edema and distension of the superficial veins of the head and neck. Symptoms from distant metastases may also be present and include neurological defect or personality change from brain metastases or pain from bone metastases.

Infrequently, patients with SCLC may present with symptoms and signs of one of the following paraneoplastic syndromes:

Inappropriate antidiuretic hormone secretion. Cushing syndrome from secretion of adrenocorticotropic hormone. Paraneoplastic cerebellar degeneration. Lambert-Eaton myasthenic syndrome.[2] Physical examination may identify enlarged supraclavicular lymphadenopathy, pleural effusion or lobar collapse, unresolved pneumonia, or signs of associated disease such as chronic obstructive pulmonary disease.

Diagnosis Treatment options for patients are determined by histology, stage, and general health and comorbidities of the patient. Investigations of patients with suspected SCLC focus on confirming the diagnosis and determining the extent of the disease.

The procedures used to determine the presence of cancer include the following:

History. Physical examination. Routine laboratory evaluations. Chest x-ray. Chest CT scan with infusion of contrast material. Biopsy. Before a patient begins lung cancer treatment, an experienced lung cancer pathologist must review the pathologic material. This is critical because SCLC, which responds well to chemotherapy and is generally not treated surgically, can be confused on microscopic examination with NSCLC.[19] Immunohistochemistry and electron microscopy are invaluable techniques for diagnosis and subclassification, but most lung tumors can be classified by light microscopic criteria.

(Refer to the Staging Evaluation section in the Stage Information for SCLC section of this summary for more information about tests and procedures used for staging.)

Prognosis and Survival Regardless of stage, the current prognosis for patients with SCLC is unsatisfactory despite improvements in diagnosis and therapy made during the past 25 years. Without treatment, SCLC has the most aggressive clinical course of any type of pulmonary tumor, with median survival from diagnosis of only 2 to 4 months. About 10% of the total population of SCLC patients remains free of disease during the 2 years from the start of therapy, which is the time period during which most relapses occur. Even these patients, however, are at risk of dying from lung cancer (both small and non-small cell types).[20] The overall survival at 5 years is 5% to 10%.[1,20-22]

An important prognostic factor for SCLC is the extent of disease. Patients with LD have a better prognosis than patients with ED. For patients with LD, median survival of 16 to 24 months and 5-year survivals of 14% with current forms of treatment have been reported.[1,21,23,24] Patients diagnosed with LD who smoke should be encouraged to stop smoking before undergoing combined-modality therapy because continued smoking may compromise survival.[25]

Improved long-term survival in patients with LD has been shown with combined-modality therapy.[24,26][Level of evidence: 1iiA] Although long-term survivors have been reported among patients who received either surgery or chemotherapy alone, chemotherapy combined with thoracic radiation therapy (TRT) is considered the standard of care.[27] Adding TRT increases absolute survival by approximately 5% over chemotherapy alone.[26,28] The optimal timing of TRT relative to chemotherapy has been evaluated in multiple trials and meta-analyses with the weight of evidence suggesting a small benefit to early TRT.[1,29,30][Level of evidence: 1iiA]

In patients with ED, median survival of 6 to 12 months is reported with currently available therapy, but long-term disease-free survival is rare.

Prophylactic cranial radiation prevents central nervous system recurrence and can improve survival in patients with good performance status who have had a complete response or a very good partial response to chemoradiation in LD or chemotherapy in ED.[31,32][Level of evidence: 1iiA]

Thoracic radiation may also improve long-term outcomes for these patients.[33]

All patients with this type of cancer may appropriately be considered for inclusion in clinical trials at the time of diagnosis. Information about ongoing clinical trials is available from the NCI website.

References Murray N, Coy P, Pater JL, et al.: Importance of timing for thoracic irradiation in the combined modality treatment of limited-stage small-cell lung cancer. The National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 11 (2): 336-44, 1993. [PUBMED Abstract] Govindan R, Page N, Morgensztern D, et al.: Changing epidemiology of small-cell lung cancer in the United States over the last 30 years: analysis of the surveillance, epidemiologic, and end results database. J Clin Oncol 24 (28): 4539-44, 2006. [PUBMED Abstract] American Cancer Society: Cancer Facts and Figures 2018. Atlanta, Ga: American Cancer Society, 2018. Available onlineExit Disclaimer. Last accessed January 5, 2018. Alberg AJ, Ford JG, Samet JM, et al.: Epidemiology of lung cancer: ACCP evidence-based clinical practice guidelines (2nd edition). Chest 132 (3 Suppl): 29S-55S, 2007. 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[PUBMED Abstract] Berrington de González A, Kim KP, Berg CD: Low-dose lung computed tomography screening before age 55: estimates of the mortality reduction required to outweigh the radiation-induced cancer risk. J Med Screen 15 (3): 153-8, 2008. [PUBMED Abstract] Shimizu Y, Kato H, Schull WJ: Studies of the mortality of A-bomb survivors. 9. Mortality, 1950-1985: Part 2. Cancer mortality based on the recently revised doses (DS86). Radiat Res 121 (2): 120-41, 1990. [PUBMED Abstract] Katanoda K, Sobue T, Satoh H, et al.: An association between long-term exposure to ambient air pollution and mortality from lung cancer and respiratory diseases in Japan. J Epidemiol 21 (2): 132-43, 2011. [PUBMED Abstract] Cao J, Yang C, Li J, et al.: Association between long-term exposure to outdoor air pollution and mortality in China: a cohort study. J Hazard Mater 186 (2-3): 1594-600, 2011. [PUBMED Abstract] Hales S, Blakely T, Woodward A: Air pollution and mortality in New Zealand: cohort study. J Epidemiol Community Health 66 (5): 468-73, 2012. [PUBMED Abstract] Lissowska J, Foretova L, Dabek J, et al.: Family history and lung cancer risk: international multicentre case-control study in Eastern and Central Europe and meta-analyses. Cancer Causes Control 21 (7): 1091-104, 2010. [PUBMED Abstract] Shiels MS, Cole SR, Kirk GD, et al.: A meta-analysis of the incidence of non-AIDS cancers in HIV-infected individuals. J Acquir Immune Defic Syndr 52 (5): 611-22, 2009. [PUBMED Abstract] The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. The Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group. N Engl J Med 330 (15): 1029-35, 1994. [PUBMED Abstract] Omenn GS, Goodman GE, Thornquist MD, et al.: Effects of a combination of beta carotene and vitamin A on lung cancer and cardiovascular disease. N Engl J Med 334 (18): 1150-5, 1996. [PUBMED Abstract] Travis WD, Colby TV, Corrin B, et al.: Histological typing of lung and pleural tumours. 3rd ed. Berlin: Springer-Verlag, 1999. Johnson BE, Grayson J, Makuch RW, et al.: Ten-year survival of patients with small-cell lung cancer treated with combination chemotherapy with or without irradiation. J Clin Oncol 8 (3): 396-401, 1990. [PUBMED Abstract] Fry WA, Menck HR, Winchester DP: The National Cancer Data Base report on lung cancer. Cancer 77 (9): 1947-55, 1996. [PUBMED Abstract] Lassen U, Osterlind K, Hansen M, et al.: Long-term survival in small-cell lung cancer: posttreatment characteristics in patients surviving 5 to 18+ years--an analysis of 1,714 consecutive patients. J Clin Oncol 13 (5): 1215-20, 1995. [PUBMED Abstract] Turrisi AT 3rd, Kim K, Blum R, et al.: Twice-daily compared with once-daily thoracic radiotherapy in limited small-cell lung cancer treated concurrently with cisplatin and etoposide. N Engl J Med 340 (4): 265-71, 1999. [PUBMED Abstract] Jänne PA, Freidlin B, Saxman S, et al.: Twenty-five years of clinical research for patients with limited-stage small cell lung carcinoma in North America. Cancer 95 (7): 1528-38, 2002. [PUBMED Abstract] Videtic GM, Stitt LW, Dar AR, et al.: Continued cigarette smoking by patients receiving concurrent chemoradiotherapy for limited-stage small-cell lung cancer is associated with decreased survival. J Clin Oncol 21 (8): 1544-9, 2003. [PUBMED Abstract] Pignon JP, Arriagada R, Ihde DC, et al.: A meta-analysis of thoracic radiotherapy for small-cell lung cancer. N Engl J Med 327 (23): 1618-24, 1992. [PUBMED Abstract] Chandra V, Allen MS, Nichols FC 3rd, et al.: The role of pulmonary resection in small cell lung cancer. Mayo Clin Proc 81 (5): 619-24, 2006. [PUBMED Abstract] Warde P, Payne D: Does thoracic irradiation improve survival and local control in limited-stage small-cell carcinoma of the lung? A meta-analysis. J Clin Oncol 10 (6): 890-5, 1992. [PUBMED Abstract] Perry MC, Eaton WL, Propert KJ, et al.: Chemotherapy with or without radiation therapy in limited small-cell carcinoma of the lung. N Engl J Med 316 (15): 912-8, 1987. [PUBMED Abstract] Takada M, Fukuoka M, Kawahara M, et al.: Phase III study of concurrent versus sequential thoracic radiotherapy in combination with cisplatin and etoposide for limited-stage small-cell lung cancer: results of the Japan Clinical Oncology Group Study 9104. J Clin Oncol 20 (14): 3054-60, 2002. [PUBMED Abstract] Aupérin A, Arriagada R, Pignon JP, et al.: Prophylactic cranial irradiation for patients with small-cell lung cancer in complete remission. Prophylactic Cranial Irradiation Overview Collaborative Group. N Engl J Med 341 (7): 476-84, 1999. [PUBMED Abstract] Slotman B, Faivre-Finn C, Kramer G, et al.: Prophylactic cranial irradiation in extensive small-cell lung cancer. N Engl J Med 357 (7): 664-72, 2007. [PUBMED Abstract] Slotman BJ, van Tinteren H, Praag JO, et al.: Use of thoracic radiotherapy for extensive stage small-cell lung cancer: a phase 3 randomised controlled trial. Lancet 385 (9962): 36-42, 2015. [PUBMED Abstract]

Treatment options

Chemotherapy and radiation therapy have been shown to improve survival for patients with small cell lung cancer (SCLC).

Chemotherapy Chemotherapy improves the survival of patients with limited-stage disease (LD) or extensive-stage disease (ED), but it is curative in only a minority of patients.[1,2] Because patients with SCLC tend to develop distant metastases, localized forms of treatment, such as surgical resection or radiation therapy, rarely produce long-term survival.[3] With incorporation of current chemotherapy regimens into the treatment program, however, survival is prolonged, with at least a fourfold to fivefold improvement in median survival compared with patients who are given no therapy.

The combination of platinum and etoposide is the most widely used standard chemotherapeutic regimen.[4-6][Level of evidence: 1iiA] No consistent survival benefit has resulted from platinum versus nonplatinum combinations, increased dose intensity or dose density, altered mode of administration (e.g., alternating or sequential administration) of various chemotherapeutic agents, or maintenance chemotherapy.[7-12][Level of evidence: 1iiA]

Radiation Therapy SCLC is highly radiosensitive and thoracic radiation therapy improves survival of patients with LD and ED tumors.[13-16][Level of evidence: 1iiA] Prophylactic cranial ir (PCI) prevents central nervous system recurrence and may improve the long-term survival of patients with good performance status who have responded to chemoradiation therapy [17-19][Level of evidence: 1iiA] and offers palliation of symptomatic metastatic disease.

Treatment for patients with LD, ED, or recurrent SCLC is summarized in Table 1.

Table 1. Standard Treatment Options for Patients With SCLC Stage Standard Treatment Options ED = extensive-stage disease; LD = limited stage disease (LD) Chemotherapy and radiation therapy Combination chemotherapy alone Surgery followed by chemotherapy or chemoradiation therapy Prophylactic cranial irradiation (ED) Combination chemotherapy Radiation therapy Prophylactic cranial irradiation Recurrent disease Chemotherapy Palliative therapy Despite treatment advances, most patients with SCLC die of their tumor even with the best available therapy. Most of the improvements in the survival of patients with SCLC are attributable to clinical trials that have attempted to improve on the best available and most accepted therapy. Patient entry into such studies is highly desirable.

Information about ongoing clinical trials is available from the NCI website.

References Comis RL, Friedland DM, Good BC: Small-cell lung cancer: a perspective on the past and a preview of the future. Oncology (Huntingt) 12 (1 Suppl 2): 44-50, 1998. [PUBMED Abstract] Agra Y, Pelayo M, Sacristan M, et al.: Chemotherapy versus best supportive care for extensive small cell lung cancer. Cochrane Database Syst Rev (4): CD001990, 2003. [PUBMED Abstract] Prasad US, Naylor AR, Walker WS, et al.: Long term survival after pulmonary resection for small cell carcinoma of the lung. Thorax 44 (10): 784-7, 1989. [PUBMED Abstract] Johnson BE, Grayson J, Makuch RW, et al.: Ten-year survival of patients with small-cell lung cancer treated with combination chemotherapy with or without irradiation. J Clin Oncol 8 (3): 396-401, 1990. [PUBMED Abstract] Lassen U, Osterlind K, Hansen M, et al.: Long-term survival in small-cell lung cancer: posttreatment characteristics in patients surviving 5 to 18+ years--an analysis of 1,714 consecutive patients. J Clin Oncol 13 (5): 1215-20, 1995. [PUBMED Abstract] Fry WA, Menck HR, Winchester DP: The National Cancer Data Base report on lung cancer. Cancer 77 (9): 1947-55, 1996. [PUBMED Abstract] Ihde DC, Mulshine JL, Kramer BS, et al.: Prospective randomized comparison of high-dose and standard-dose etoposide and cisplatin chemotherapy in patients with extensive-stage small-cell lung cancer. J Clin Oncol 12 (10): 2022-34, 1994. [PUBMED Abstract] Arriagada R, Le Chevalier T, Pignon JP, et al.: Initial chemotherapeutic doses and survival in patients with limited small-cell lung cancer. N Engl J Med 329 (25): 1848-52, 1993. [PUBMED Abstract] Klasa RJ, Murray N, Coldman AJ: Dose-intensity meta-analysis of chemotherapy regimens in small-cell carcinoma of the lung. J Clin Oncol 9 (3): 499-508, 1991. [PUBMED Abstract] Elias AD, Ayash L, Frei E 3rd, et al.: Intensive combined modality therapy for limited-stage small-cell lung cancer. J Natl Cancer Inst 85 (7): 559-66, 1993. [PUBMED Abstract] Murray N, Livingston RB, Shepherd FA, et al.: Randomized study of CODE versus alternating CAV/EP for extensive-stage small-cell lung cancer: an Intergroup Study of the National Cancer Institute of Canada Clinical Trials Group and the Southwest Oncology Group. J Clin Oncol 17 (8): 2300-8, 1999. [PUBMED Abstract] Amarasena IU, Walters JA, Wood-Baker R, et al.: Platinum versus non-platinum chemotherapy regimens for small cell lung cancer. Cochrane Database Syst Rev (4): CD006849, 2008. [PUBMED Abstract] Pignon JP, Arriagada R, Ihde DC, et al.: A meta-analysis of thoracic radiotherapy for small-cell lung cancer. N Engl J Med 327 (23): 1618-24, 1992. [PUBMED Abstract] Warde P, Payne D: Does thoracic irradiation improve survival and local control in limited-stage small-cell carcinoma of the lung? A meta-analysis. J Clin Oncol 10 (6): 890-5, 1992. [PUBMED Abstract] Murray N, Coy P, Pater JL, et al.: Importance of timing for thoracic irradiation in the combined modality treatment of limited-stage small-cell lung cancer. The National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 11 (2): 336-44, 1993. [PUBMED Abstract] Slotman BJ, van Tinteren H, Praag JO, et al.: Use of thoracic radiotherapy for extensive stage small-cell lung cancer: a phase 3 randomised controlled trial. Lancet 385 (9962): 36-42, 2015. [PUBMED Abstract] Turrisi AT 3rd, Glover DJ: Thoracic radiotherapy variables: influence on local control in small cell lung cancer limited disease. Int J Radiat Oncol Biol Phys 19 (6): 1473-9, 1990. [PUBMED Abstract] Aupérin A, Arriagada R, Pignon JP, et al.: Prophylactic cranial irradiation for patients with small-cell lung cancer in complete remission. Prophylactic Cranial Irradiation Overview Collaborative Group. N Engl J Med 341 (7): 476-84, 1999. [PUBMED Abstract] Slotman B, Faivre-Finn C, Kramer G, et al.: Prophylactic cranial irradiation in extensive small-cell lung cancer. N Engl J Med 357 (7): 664-72, 2007. [PUBMED Abstract]

Limited-Stage SCLC Treatment

Standard Treatment Options for Patients With Limited-Stage SCLC Chemotherapy and radiation therapy Combination chemotherapy alone Surgery followed by chemotherapy or chemoradiation therapy PCI Neurologic sequelae Treatment options for older patients Treatment Options Under Clinical Evaluation Current Clinical Trials Standard Treatment Options for Patients With Limited-Stage SCLC Standard treatment options for patients with limited-stage small-cell lung cancer (SCLC) include the following:

Chemotherapy and radiation therapy. Combination chemotherapy alone. Surgery followed by chemotherapy or chemoradiation therapy. Prophylactic cranial irradiation (PCI). Chemotherapy and radiation therapy Combined-modality treatment with etoposide and cisplatin with thoracic radiation therapy (TRT) is the most widely used treatment for patients with limited-stage disease (LD) SCLC.

Evidence (combined modality treatment):

Survival. The following results have been reported in clinical trials: Mature results of prospective randomized trials suggest that combined-modality therapy produces a modest but significant improvement in survival of 5% at 3 years compared with chemotherapy alone.[1-3][Level of evidence: 1iiA] Clinical trials have consistently achieved median survivals of 18 to 24 months and 40% to 50% 2-year survival rates with less than a 3% treatment-related mortality.[3-7][Level of evidence: 1iiA] No consistent survival benefit has resulted from the following:[8-16] Increased dose intensity. Increased dose density. Administration of additional drugs or other (non–etoposide-containing) platinum-based combination regimens. Altered modes of administration of various chemotherapeutic agents. Maintenance chemotherapy. Length of treatment. The optimal duration of chemotherapy for patients with LD SCLC is not clearly defined, but no improvement exists in survival after the duration of drug administration exceeds 3 to 6 months. The preponderance of evidence available from randomized trials indicates that maintenance chemotherapy does not prolong survival for patients with LD SCLC.[8-15][Level of evidence: 1iiA] Dose and timing. The optimal dose and timing of TRT remain controversial. Multiple clinical trials and meta-analyses addressing the timing of TRT have been published, with the weight of evidence suggesting a small benefit to early TRT (i.e., TRT administered during the first or second cycle of chemotherapy administration).[3-6,8,9,15,17-20][Level of evidence: 1iiA] The amount of time from start to completion of TRT in LD SCLC may also effect overall survival (OS). In an analysis of four trials, the completion of therapy in less than 30 days was associated with an improved 5-year survival rate (relative risk, 0.62; 95% confidence interval, 0.49–0.80; P = .0003).[20][Level of evidence: 1iiA] Both once-daily and twice-daily chest radiation schedules have been used in regimens with etoposide and cisplatin. One randomized study showed a modest survival advantage in favor of twice-daily radiation therapy given for 3 weeks compared with once-daily radiation therapy to 45 Gy given for 5 weeks (26% vs. 16% at 5 years; P = .04).[17][Level of evidence: 1iiA] Esophagitis was increased with twice-daily treatment. Twice-daily radiation therapy has not been broadly adopted. Once-daily fractions to higher doses of greater than 60 Gy are feasible and commonly used; their clinical benefits are yet to be defined in phase III trials.[21-25][Level of evidence: 3iiiA] Combination chemotherapy alone Patients with a contraindication to radiation therapy could be treated with chemotherapy alone. Patients presenting with superior vena cava syndrome are treated immediately with combination chemotherapy, radiation therapy, or both, depending on the severity of presentation.[26,27] (Refer to the PDQ summary on Cardiopulmonary Syndromes for more information.)

Surgery followed by chemotherapy or chemoradiation therapy The role of surgery in the management of patients with SCLC is unproven. Small case series and population studies have reported favorable outcomes for the minority of LD patients with very limited disease, with small tumors pathologically confined to the lung of origin or the lung and ipsilateral hilar lymph nodes from surgical resection with adjuvant chemotherapy.[28-32][Level of evidence: 3iiiDii] Patients who have undergone surgery and then been diagnosed with SCLC generally receive adjuvant chemotherapy with or without radiation therapy. In patients who receive chemotherapy with radiation therapy, there is no improvement in survival with the addition of surgery.[32][Level of evidence: 3iiiDii] Given the absence of data from randomized trials, the role of surgery in the management of individual patients with SCLC must be considered, both in terms of potential benefit and risk from the surgical procedure.

Evidence (role of surgery):

A randomized study evaluating the role of surgery in addition to chemoradiation therapy enrolled 328 patients with LD SCLC and found no OS benefit with the addition of pulmonary resection.[33][Level of evidence: 1iiA] PCI Patients who have achieved a complete remission can be considered for administration of PCI. Patients whose cancer can be controlled outside the brain have a 60% actuarial risk of developing central nervous system (CNS) metastases within 2 to 3 years after starting treatment.[32,34,35] Most of these patients relapse only in their brain, and nearly all of those who relapse in their CNS die of their cranial metastases. The risk of developing CNS metastases can be reduced by more than 50% with the administration of PCI.[34]

Evidence (role of PCI):

A meta-analysis of seven randomized trials evaluating the value of PCI in patients in complete remission reported improvement in brain recurrence, disease-free survival, and OS with the addition of PCI. The 3-year OS was improved from 15% to 21% with PCI.[34][Level of evidence: 1iiA] A randomized study (RTOG-0212) of 720 patients with LD SCLC in complete remission after chemoradiation therapy demonstrated that standard-dose PCI (25 Gy in 10 fractions) was as effective as and less toxic than higher doses of brain radiation.[36] Randomized trials such as EORTC-22003-08004 (NCT00005062) showed that doses higher than 25 Gy in 10 daily fractions do not improve long-term survival.[36-38] Neurologic sequelae Retrospective studies have shown that long-term survivors of SCLC (>2 years from the start of treatment) have a high incidence of CNS impairment.[32,35,39-41] Prospective studies have shown that patients treated with PCI do not have significantly worse neuropsychological function than patients not treated.[41] Most patients with SCLC have neuropsychological abnormalities present before the start of PCI and have no detectable decline in their neurological status for as long as 2 years after the start of their PCI.[41] Patients treated for SCLC continue to have declining neuropsychologic function after 2 years from the start of treatment.[39-41] Additional neuropsychologic testing of patients beyond 2 years from the start of treatment will be needed before concluding that PCI does not contribute to the decline in intellectual function.

Treatment options for older patients The optimal therapeutic approach in older patients remains unclear. A population analysis showed that increasing age was associated with a decreased performance status and increased comorbidity.[42] Older patients were less likely to be treated with combined chemoradiation therapy, more intensive chemotherapy, and PCI. Older patients were also less likely to respond to therapy and had poorer survival outcomes. Whether this was a result of age and its associated comorbidities or suboptimal treatment delivery remains uncertain.

No specific phase III trial in older patients with LD SCLC has been reported; however, three secondary analyses of two cooperative group trials have been published evaluating outcomes in patients aged 70 years or older.[43-45] The survival outcomes for the older patients were identical to their younger counterparts in both trials. The older patients experienced more toxic effects, particularly hematologic, compared with younger patients. There was a significant increase in treatment-related mortality in the EST-3588 trial that compared etoposide and cisplatin with either once-daily or twice-daily radiation therapy (1% for patients aged <70 years vs. 10% for patients aged ≥70 years; P = .01).[44] Because the older patients enrolled in these phase III trials may not be representative of LD SCLC patients in the general population, caution must be exercised in extrapolating these results to the general population of older patients.

Treatment Options Under Clinical Evaluation Treatment options under clinical evaluation for patients with LD SCLC include the following:

New drug regimens. Surgical resection of the primary tumor. New radiation therapy schedules and techniques (e.g., timing, three-dimensional treatment planning, and dose fractionation). Current Clinical Trials Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

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[PUBMED Abstract] Spiro SG, James LE, Rudd RM, et al.: Early compared with late radiotherapy in combined modality treatment for limited disease small-cell lung cancer: a London Lung Cancer Group multicenter randomized clinical trial and meta-analysis. J Clin Oncol 24 (24): 3823-30, 2006. [PUBMED Abstract] De Ruysscher D, Pijls-Johannesma M, Vansteenkiste J, et al.: Systematic review and meta-analysis of randomised, controlled trials of the timing of chest radiotherapy in patients with limited-stage, small-cell lung cancer. Ann Oncol 17 (4): 543-52, 2006. [PUBMED Abstract] Giaccone G, Dalesio O, McVie GJ, et al.: Maintenance chemotherapy in small-cell lung cancer: long-term results of a randomized trial. European Organization for Research and Treatment of Cancer Lung Cancer Cooperative Group. J Clin Oncol 11 (7): 1230-40, 1993. 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[PUBMED Abstract] Sculier JP, Paesmans M, Bureau G, et al.: Randomized trial comparing induction chemotherapy versus induction chemotherapy followed by maintenance chemotherapy in small-cell lung cancer. European Lung Cancer Working Party. J Clin Oncol 14 (8): 2337-44, 1996. [PUBMED Abstract] Fried DB, Morris DE, Poole C, et al.: Systematic review evaluating the timing of thoracic radiation therapy in combined modality therapy for limited-stage small-cell lung cancer. J Clin Oncol 22 (23): 4837-45, 2004. [PUBMED Abstract] Kubota K, Hida T, Ishikura S, et al.: Etoposide and cisplatin versus irinotecan and cisplatin in patients with limited-stage small-cell lung cancer treated with etoposide and cisplatin plus concurrent accelerated hyperfractionated thoracic radiotherapy (JCOG0202): a randomised phase 3 study. Lancet Oncol 15 (1): 106-13, 2014. 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[PUBMED Abstract] Le Péchoux C, Dunant A, Senan S, et al.: Standard-dose versus higher-dose prophylactic cranial irradiation (PCI) in patients with limited-stage small-cell lung cancer in complete remission after chemotherapy and thoracic radiotherapy (PCI 99-01, EORTC 22003-08004, RTOG 0212, and IFCT 99-01): a randomised clinical trial. Lancet Oncol 10 (5): 467-74, 2009. [PUBMED Abstract] Le Péchoux C, Laplanche A, Faivre-Finn C, et al.: Clinical neurological outcome and quality of life among patients with limited small-cell cancer treated with two different doses of prophylactic cranial irradiation in the intergroup phase III trial (PCI99-01, EORTC 22003-08004, RTOG 0212 and IFCT 99-01). Ann Oncol 22 (5): 1154-63, 2011. [PUBMED Abstract] Wolfson AH, Bae K, Komaki R, et al.: Primary analysis of a phase II randomized trial Radiation Therapy Oncology Group (RTOG) 0212: impact of different total doses and schedules of prophylactic cranial irradiation on chronic neurotoxicity and quality of life for patients with limited-disease small-cell lung cancer. Int J Radiat Oncol Biol Phys 81 (1): 77-84, 2011. [PUBMED Abstract] Johnson BE, Patronas N, Hayes W, et al.: Neurologic, computed cranial tomographic, and magnetic resonance imaging abnormalities in patients with small-cell lung cancer: further follow-up of 6- to 13-year survivors. J Clin Oncol 8 (1): 48-56, 1990. [PUBMED Abstract] Laukkanen E, Klonoff H, Allan B, et al.: The role of prophylactic brain irradiation in limited stage small cell lung cancer: clinical, neuropsychologic, and CT sequelae. Int J Radiat Oncol Biol Phys 14 (6): 1109-17, 1988. 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Extensive-Stage SCLC Treatment

Standard Treatment Options for Patients With Extensive-Stage SCLC Combination chemotherapy Radiation therapy Treatment Options Under Clinical Evaluation Current Clinical Trials Standard Treatment Options for Patients With Extensive-Stage SCLC Standard treatment options for patients with extensive-stage small-cell lung cancer (SCLC) include the following:

Combination chemotherapy. Radiation therapy. Thoracic radiation therapy for patients who respond to chemotherapy. Prophylactic cranial irradiation (PCI). Combination chemotherapy Chemotherapy for patients with extensive-stage disease (ED) SCLC is commonly given as a two-drug combination of platinum and etoposide in doses associated with at least moderate toxic effects (as in limited-stage [LD] SCLC).[1] Cisplatin is associated with significant toxic effects and requires fluid hydration, which can be problematic in patients with cardiovascular disease. Carboplatin is active in SCLC, is dosed according to renal function, and is associated with less nonhematological toxic effects.

Other regimens appear to produce similar survival outcomes but have been studied less extensively or are in less common use.

Table 2. Combination Chemotherapy For Extensive-Stage SCLC Standard treatment Etoposide + cisplatin Etoposide + carboplatin Other regimens Cisplatin + irinotecan Ifosfamide + cisplatin + etoposide Cyclophosphamide + doxorubicin + etoposide Cyclophosphamide + doxorubicin + etoposide + vincristine Cyclophosphamide + etoposide + vincristine Cyclophosphamide + doxorubicin + vincristine Doses and schedules used in current programs yield overall response rates of 50% to 80% and complete response rates of 0% to 30% in patients with ED.[2,3][Level of evidence: 1iiA]

Intracranial metastases from small cell carcinoma may respond to chemotherapy as readily as metastases in other organs.[4,5]

Evidence (standard regimens):

Two meta-analyses evaluating the role of platinum combinations versus nonplatinum combinations have been published. A Cochrane analysis did not identify a difference in 6-, 12-, or 24-month survival.[6] A meta-analysis of 19 trials published between 1981 and 1999 showed a significant survival advantage for patients receiving platinum-based chemotherapy compared with those not receiving a platinum agent.[3][Level of evidence: 1iiA] The Hellenic Oncology Group conducted a phase III trial comparing cisplatin and etoposide with carboplatin plus etoposide.[7] The median survival was 11.8 months in the cisplatin arm and 12.5 months in carboplatin-treated patients.[7][Level of evidence: 1iiA] Although this difference was not statistically significant, the trial was underpowered to prove equivalence of the two treatment regimens in patients with either LD or ED. Evidence (other combination chemotherapy regimens):

Irinotecan. Five trials and two meta-analyses have evaluated the combination of etoposide and cisplatin versus irinotecan and cisplatin. Only one of the trials showed the superiority of the irinotecan and cisplatin combination.[8][Level of evidence: 1iiA] Subsequent trials and the meta-analyses support that the regimens provide equivalent clinical benefit with differing toxicity profiles.[9-14][Level of evidence: 1iiA] Irinotecan and cisplatin regimens led to less grade 3 to 4 anemia, neutropenia, and thrombocytopenia but more grade 3 to 4 vomiting and diarrhea than etoposide and cisplatin regimens. Treatment-related deaths were comparable between the two groups. Topotecan. In a randomized trial of 784 patients, the combination of oral topotecan given with cisplatin for 5 days was not found to be superior to etoposide and cisplatin.[15] The 1-year survival rate was 31% (95% confidence interval [CI], 27%–36%) and was deemed to be noninferior, as the difference of -0.03 met the predefined criteria of no more than 10% absolute difference in 1-year survival.[15][Level of evidence: 1iiA] Paclitaxel. No consistent survival benefit has resulted from the addition of paclitaxel to etoposide and cisplatin.[16,17] Evidence (duration of treatment):

The optimal duration of chemotherapy is not clearly defined, but no obvious improvement in survival occurs when the duration of drug administration exceeds 6 months.[7,18,19] No clear evidence is available from reported data from randomized trials that maintenance chemotherapy will improve survival duration.[20-22][Level of evidence: 1iiA] However, a meta-analysis of 14 published, randomized trials assessing the benefit of duration/maintenance therapy reported an odds ratio of 0.67 for both 1- and 2-year overall survival (OS) of 0.67 (95% CI, 0.56–0.79; P < .001 for 1-year OS and 0.53–0.86; P < .001 for 2-year OS). This corresponded to an increase of 9% in 1-year OS and 4% in 2-year OS.[23][Level of evidence: 1iiA] Evidence (dose intensification):

The role of dose intensification in patients with SCLC remains unclear.[24-28] Early studies showed that under-treatment compromised outcome and suggested that early dose intensification may improve survival.[24,25] A number of clinical trials have examined the use of colony-stimulating factors to support dose-intensified chemotherapy in SCLC.[26-34] These studies have yielded conflicting results. Four studies have shown that a modest increase in dose intensity (25%–34%) was associated with a significant improvement in survival with no compromise in quality of life (QOL).[26-29][Level of evidence: 1iiA] Two of three studies that examined combinations of the variables of interval, dose per cycle, and number of cycles showed no advantage.[29-32][Level of evidence: 1iiA] The European Organization for Research and Treatment of Cancer trial (EORTC-08923) reported a randomized comparison of standard-dose cyclophosphamide, doxorubicin, and etoposide given every 3 weeks for five cycles versus intensified treatment given at 125% of the dose every 2 weeks for four cycles with granulocyte colony-stimulating factor (G-CSF) support.[32] The median dose intensity delivered was 70% higher in the experimental arm; the median cumulative dose was similar in both arms. There was no difference between treatment groups in median or 2-year survival. A randomized, phase III trial compared ifosfamide, cisplatin, and etoposide (ICE), which was given every 4 weeks, with twice weekly ICE with G-CSF and autologous blood support.[33] Despite achieving a relative dose intensity of 1.84 in the dose-accelerated arm, there was no difference in response rate (88% vs. 80%, respectively), median survival (14.4 vs. 13.9 months, respectively), or 2-year survival (19% vs. 22%, respectively) for dose-dense treatment compared with standard treatment.[33][Level of evidence: 1iiA] Patients who received dose-dense treatment spent less time on treatment and had fewer episodes of infection. A randomized, phase II study of identical design reported a significantly better median survival for the dose-dense arm (29.8 vs. 17.4 months, respectively; P = .02) and 2-year survival (62% vs. 36%, respectively; P = .05).[34] However, given the small study size (only 70 patients), these results should be viewed with caution. Factors influencing treatment with chemotherapy Performance status More patients with ED SCLC have greatly impaired performance status at the time of diagnosis than patients with LD. Such patients have a poor prognosis and tolerate aggressive chemotherapy or combined-modality therapy poorly. Single-agent intravenous, oral, and low-dose biweekly regimens have been developed for these patients.[30,35-41]

Prospective, randomized studies have shown that patients with a poor prognosis who are treated with conventional regimens live longer than those treated with the single-agent, low-dose regimens or abbreviated courses of therapy. A study comparing chemotherapy every 3 weeks with treatment given as required for symptom control showed an improvement in QOL in those patients receiving regular treatment.[38][Level of evidence: 1iiDii]

Other studies have tested intensive one-drug or two-drug regimens. A study conducted by the Medical Research Council demonstrated similar efficacy for an etoposide plus vincristine regimen and a four-drug regimen.[39] The latter regimen was associated with a greater risk of toxic effects and early death but was superior with respect to palliation of symptoms and psychological distress.[39][Level of evidence: 1iiC] Studies comparing a convenient oral treatment with single-agent oral etoposide versus combination therapy showed that the overall response rate and OS were significantly worse in the oral etoposide arm.[35,40][Level of evidence: 1iiA]

Age Subgroup analyses of phase II and phase III trials of SCLC patients by age showed that myelosuppression and doxorubicin-induced cardiac toxic effects were more severe in older patients than in younger patients and that the incidence of treatment-related death tended to be higher in older patients.[41] About 80% of older patients, however, received optimal treatment, and their survival was comparable with that of younger patients. The standard chemotherapy regimens for the general population could be applied to older patients in good general condition (i.e., performance status of 0–1, normal organ function, and no comorbidity). There is no evidence of a difference in response rate, disease-free survival (DFS), or OS in older patients compared with younger patients.

Radiation therapy Radiation therapy to sites of metastatic disease unlikely to be immediately palliated by chemotherapy, especially brain, epidural, and bone metastases, is a standard treatment option for patients with ED SCLC. Brain metastases are treated with whole-brain radiation therapy.

Chest radiation therapy is sometimes given for superior vena cava syndrome, but chemotherapy alone, with radiation reserved for nonresponding patients, is appropriate initial treatment. (Refer to the PDQ summary on Cardiopulmonary Syndromes for more information.)

Thoracic radiation therapy for patients who respond to chemotherapy Patients with ED treated with chemotherapy who have achieved a response can be considered for thoracic radiation therapy.

Evidence (thoracic radiation therapy):

A randomized trial of 498 patients who responded after receiving four to six cycles of chemotherapy compared thoracic radiation therapy with 30 Gy in 10 fractions versus no radiation therapy. All patients received PCI.[42][Level of evidence: 1iiA] OS was the primary study endpoint and not statistically different between the two groups at 1 year (33% for the thoracic radiation therapy group vs. 28% for the control group, P = .066). However, in a secondary analysis, 2-year OS was 13% in the thoracic radiation group (95% CI, 9–19) versus 3% in the control group (95% CI, 2–8; P = .004). The OS during the entire course of follow-up was not reported. Thoracic radiation therapy resulted in 6-month progression-free survival (PFS) of 24% in the thoracic radiation group (95% CI, 19–30) versus 7% in the control group (95% CI, 4–11; P = .001). Intrathoracic recurrences, both isolated (19.8% vs. 46.0%) and in combination with recurrences at other sites (43.7% vs. 79.8%), were reduced by approximately 50%. Thoracic radiation therapy was well tolerated. PCI Patients with ED treated with chemotherapy who have achieved a response can be considered for administration of PCI.

Evidence (PCI):

A randomized trial of 286 patients who responded after four to six cycles of chemotherapy compared PCI with no further therapy.[43][Level of evidence: 1iiD The cumulative risk of brain metastases within 1 year was 14.6% in the radiation group (95% CI, 8.3–20.9) and 40.4% in the control group (95% CI, 32.1– 48.6). Radiation was associated with an increase in median DFS from 12.0 weeks to 14.7 weeks and in median OS from 5.4 months to 6.7 months after randomization. The 1-year survival rate was 27.1% (95% CI, 19.4–35.5) in the radiation group and 13.3% (95% CI, 8.1–19.9) in the control group.[43] Radiation had side effects but did not have a clinically significant effect on global health status.[43] Only 29% of the randomly assigned patients had brain imaging at diagnosis.[44] Combination chemotherapy and radiation therapy Combination chemotherapy plus chest radiation therapy does not appear to improve survival compared with chemotherapy alone in patients with ED SCLC.

Treatment Options Under Clinical Evaluation Treatment options under clinical evaluation for patients with ED SCLC include the following:

New drug regimens. Alternative drug doses and schedules. Current Clinical Trials Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References Okamoto H, Watanabe K, Kunikane H, et al.: Randomised phase III trial of carboplatin plus etoposide vs split doses of cisplatin plus etoposide in elderly or poor-risk patients with extensive disease small-cell lung cancer: JCOG 9702. Br J Cancer 97 (2): 162-9, 2007. [PUBMED Abstract] Roth BJ, Johnson DH, Einhorn LH, et al.: Randomized study of cyclophosphamide, doxorubicin, and vincristine versus etoposide and cisplatin versus alternation of these two regimens in extensive small-cell lung cancer: a phase III trial of the Southeastern Cancer Study Group. J Clin Oncol 10 (2): 282-91, 1992. [PUBMED Abstract] Pujol JL, Carestia L, Daurès JP: Is there a case for cisplatin in the treatment of small-cell lung cancer? A meta-analysis of randomized trials of a cisplatin-containing regimen versus a regimen without this alkylating agent. Br J Cancer 83 (1): 8-15, 2000. 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N Engl J Med 346 (2): 85-91, 2002. [PUBMED Abstract] Hanna N, Bunn PA Jr, Langer C, et al.: Randomized phase III trial comparing irinotecan/cisplatin with etoposide/cisplatin in patients with previously untreated extensive-stage disease small-cell lung cancer. J Clin Oncol 24 (13): 2038-43, 2006. [PUBMED Abstract] Lara PN Jr, Natale R, Crowley J, et al.: Phase III trial of irinotecan/cisplatin compared with etoposide/cisplatin in extensive-stage small-cell lung cancer: clinical and pharmacogenomic results from SWOG S0124. J Clin Oncol 27 (15): 2530-5, 2009. [PUBMED Abstract] Schmittel A, Sebastian M, Fischer von Weikersthal L, et al.: A German multicenter, randomized phase III trial comparing irinotecan-carboplatin with etoposide-carboplatin as first-line therapy for extensive-disease small-cell lung cancer. Ann Oncol 22 (8): 1798-804, 2011. [PUBMED Abstract] Zatloukal P, Cardenal F, Szczesna A, et al.: A multicenter international randomized phase III study comparing cisplatin in combination with irinotecan or etoposide in previously untreated small-cell lung cancer patients with extensive disease. Ann Oncol 21 (9): 1810-6, 2010. [PUBMED Abstract] Jiang J, Liang X, Zhou X, et al.: A meta-analysis of randomized controlled trials comparing irinotecan/platinum with etoposide/platinum in patients with previously untreated extensive-stage small cell lung cancer. J Thorac Oncol 5 (6): 867-73, 2010. [PUBMED Abstract] Guo S, Liang Y, Zhou Q: Complement and correction for meta-analysis of patients with extensive-stage small cell lung cancer managed with irinotecan/cisplatin versus etoposide/cisplatin as first-line chemotherapy. J Thorac Oncol 6 (2): 406-8; author reply 408, 2011. [PUBMED Abstract] Eckardt JR, von Pawel J, Papai Z, et al.: Open-label, multicenter, randomized, phase III study comparing oral topotecan/cisplatin versus etoposide/cisplatin as treatment for chemotherapy-naive patients with extensive-disease small-cell lung cancer. J Clin Oncol 24 (13): 2044-51, 2006. [PUBMED Abstract] Mavroudis D, Papadakis E, Veslemes M, et al.: A multicenter randomized clinical trial comparing paclitaxel-cisplatin-etoposide versus cisplatin-etoposide as first-line treatment in patients with small-cell lung cancer. Ann Oncol 12 (4): 463-70, 2001. [PUBMED Abstract] Niell HB, Herndon JE 2nd, Miller AA, et al.: Randomized phase III intergroup trial of etoposide and cisplatin with or without paclitaxel and granulocyte colony-stimulating factor in patients with extensive-stage small-cell lung cancer: Cancer and Leukemia Group B Trial 9732. J Clin Oncol 23 (16): 3752-9, 2005. [PUBMED Abstract] Spiro SG, Souhami RL, Geddes DM, et al.: Duration of chemotherapy in small cell lung cancer: a Cancer Research Campaign trial. Br J Cancer 59 (4): 578-83, 1989. [PUBMED Abstract] Bleehen NM, Girling DJ, Machin D, et al.: A randomised trial of three or six courses of etoposide cyclophosphamide methotrexate and vincristine or six courses of etoposide and ifosfamide in small cell lung cancer (SCLC). I: Survival and prognostic factors. Medical Research Council Lung Cancer Working Party. Br J Cancer 68 (6): 1150-6, 1993. [PUBMED Abstract] Giaccone G, Dalesio O, McVie GJ, et al.: Maintenance chemotherapy in small-cell lung cancer: long-term results of a randomized trial. European Organization for Research and Treatment of Cancer Lung Cancer Cooperative Group. J Clin Oncol 11 (7): 1230-40, 1993. [PUBMED Abstract] Sculier JP, Paesmans M, Bureau G, et al.: Randomized trial comparing induction chemotherapy versus induction chemotherapy followed by maintenance chemotherapy in small-cell lung cancer. European Lung Cancer Working Party. J Clin Oncol 14 (8): 2337-44, 1996. [PUBMED Abstract] Schiller JH, Adak S, Cella D, et al.: Topotecan versus observation after cisplatin plus etoposide in extensive-stage small-cell lung cancer: E7593--a phase III trial of the Eastern Cooperative Oncology Group. J Clin Oncol 19 (8): 2114-22, 2001. [PUBMED Abstract] Bozcuk H, Artac M, Ozdogan M, et al.: Does maintenance/consolidation chemotherapy have a role in the management of small cell lung cancer (SCLC)? A metaanalysis of the published controlled trials. Cancer 104 (12): 2650-7, 2005. [PUBMED Abstract] Cohen MH, Creaven PJ, Fossieck BE Jr, et al.: Intensive chemotherapy of small cell bronchogenic carcinoma. Cancer Treat Rep 61 (3): 349-54, 1977 May-Jun. [PUBMED Abstract] Arriagada R, Le Chevalier T, Pignon JP, et al.: Initial chemotherapeutic doses and survival in patients with limited small-cell lung cancer. N Engl J Med 329 (25): 1848-52, 1993. [PUBMED Abstract] Fukuoka M, Masuda N, Negoro S, et al.: CODE chemotherapy with and without granulocyte colony-stimulating factor in small-cell lung cancer. Br J Cancer 75 (2): 306-9, 1997. [PUBMED Abstract] Woll PJ, Hodgetts J, Lomax L, et al.: Can cytotoxic dose-intensity be increased by using granulocyte colony-stimulating factor? A randomized controlled trial of lenograstim in small-cell lung cancer. J Clin Oncol 13 (3): 652-9, 1995. [PUBMED Abstract] Steward WP, von Pawel J, Gatzemeier U, et al.: Effects of granulocyte-macrophage colony-stimulating factor and dose intensification of V-ICE chemotherapy in small-cell lung cancer: a prospective randomized study of 300 patients. J Clin Oncol 16 (2): 642-50, 1998. [PUBMED Abstract] Thatcher N, Girling DJ, Hopwood P, et al.: Improving survival without reducing quality of life in small-cell lung cancer patients by increasing the dose-intensity of chemotherapy with granulocyte colony-stimulating factor support: results of a British Medical Research Council Multicenter Randomized Trial. Medical Research Council Lung Cancer Working Party. J Clin Oncol 18 (2): 395-404, 2000. [PUBMED Abstract] James LE, Gower NH, Rudd RM, et al.: A randomised trial of low-dose/high-frequency chemotherapy as palliative treatment of poor-prognosis small-cell lung cancer: a Cancer research Campaign trial. Br J Cancer 73 (12): 1563-8, 1996. [PUBMED Abstract] Pujol JL, Douillard JY, Rivière A, et al.: Dose-intensity of a four-drug chemotherapy regimen with or without recombinant human granulocyte-macrophage colony-stimulating factor in extensive-stage small-cell lung cancer: a multicenter randomized phase III study. J Clin Oncol 15 (5): 2082-9, 1997. [PUBMED Abstract] Ardizzoni A, Tjan-Heijnen VC, Postmus PE, et al.: Standard versus intensified chemotherapy with granulocyte colony-stimulating factor support in small-cell lung cancer: a prospective European Organization for Research and Treatment of Cancer-Lung Cancer Group Phase III Trial-08923. J Clin Oncol 20 (19): 3947-55, 2002. [PUBMED Abstract] Lorigan P, Woll PJ, O'Brien ME, et al.: Randomized phase III trial of dose-dense chemotherapy supported by whole-blood hematopoietic progenitors in better-prognosis small-cell lung cancer. J Natl Cancer Inst 97 (9): 666-74, 2005. [PUBMED Abstract] Buchholz E, Manegold C, Pilz L, et al.: Standard versus dose-intensified chemotherapy with sequential reinfusion of hematopoietic progenitor cells in small cell lung cancer patients with favorable prognosis. J Thorac Oncol 2 (1): 51-8, 2007. [PUBMED Abstract] Girling DJ: Comparison of oral etoposide and standard intravenous multidrug chemotherapy for small-cell lung cancer: a stopped multicentre randomised trial. Medical Research Council Lung Cancer Working Party. Lancet 348 (9027): 563-6, 1996. [PUBMED Abstract] Murray N, Grafton C, Shah A, et al.: Abbreviated treatment for elderly, infirm, or noncompliant patients with limited-stage small-cell lung cancer. J Clin Oncol 16 (10): 3323-8, 1998. [PUBMED Abstract] Westeel V, Murray N, Gelmon K, et al.: New combination of the old drugs for elderly patients with small-cell lung cancer: a phase II study of the PAVE regimen. J Clin Oncol 16 (5): 1940-7, 1998. [PUBMED Abstract] Earl HM, Rudd RM, Spiro SG, et al.: A randomised trial of planned versus as required chemotherapy in small cell lung cancer: a Cancer Research Campaign trial. Br J Cancer 64 (3): 566-72, 1991. [PUBMED Abstract] Randomised trial of four-drug vs less intensive two-drug chemotherapy in the palliative treatment of patients with small-cell lung cancer (SCLC) and poor prognosis. Medical Research Council Lung Cancer Working Party. Br J Cancer 73 (3): 406-13, 1996. [PUBMED Abstract] Souhami RL, Spiro SG, Rudd RM, et al.: Five-day oral etoposide treatment for advanced small-cell lung cancer: randomized comparison with intravenous chemotherapy. J Natl Cancer Inst 89 (8): 577-80, 1997. [PUBMED Abstract] Sekine I, Yamamoto N, Kunitoh H, et al.: Treatment of small cell lung cancer in the elderly based on a critical literature review of clinical trials. Cancer Treat Rev 30 (4): 359-68, 2004. [PUBMED Abstract] Slotman BJ, van Tinteren H, Praag JO, et al.: Use of thoracic radiotherapy for extensive stage small-cell lung cancer: a phase 3 randomised controlled trial. Lancet 385 (9962): 36-42, 2015. [PUBMED Abstract] Slotman B, Faivre-Finn C, Kramer G, et al.: Prophylactic cranial irradiation in extensive small-cell lung cancer. N Engl J Med 357 (7): 664-72, 2007. [PUBMED Abstract] Shivnani AT: Prophylactic cranial irradiation in small-cell lung cancer. N Engl J Med 357 (19): 1977; author reply 1978, 2007. [PUBMED Abstract]

Staging

Staging Systems Several staging systems have been proposed for small cell lung cancer (SCLC). These staging systems include the following:

American Joint Committee on Cancer (AJCC) Tumor, Node, and Metastasis (TNM).[1] Veterans Administration Lung Study Group (VALG).[2] International Association for the Study of Lung Cancer (IASLC).[3] Limited-Stage Disease No universally accepted definition of this term is available. Limited-stage disease (LD) SCLC is confined to the hemithorax of origin, the mediastinum, or the supraclavicular nodes, which can be encompassed within a tolerable radiation therapy port.

Patients with pleural effusion, massive pulmonary tumor, and contralateral supraclavicular nodes have been both included within and excluded from LD by various groups.

Extensive-Stage Disease Extensive-stage disease (ED) SCLC has spread beyond the supraclavicular areas and is too widespread to be included within the definition of LD. Patients with distant metastases (M1) are always considered to have ED.[3,4]

IASLC-AJCC TNM Staging System The AJCC TNM defines LD as any T, except for T3-4, due to multiple lung nodules that do not fit in a tolerable radiation field, any N, and M0.[1] This corresponds to TNM stages I to IIIB. Extensive disease is TNM stage IV with distant metastases (M1) including malignant pleural effusions.[3,4]

The IASLC conducted an analysis of clinical TNM staging for SCLC using the sixth edition of the AJCC TNM staging system for lung cancer. Survivals for patients with clinical stages I and II disease are significantly different from those for patients with stage III disease with N2 or N3 involvement.[3] Patients with pleural effusion have an intermediate prognosis between LD and ED with hematogenous metastases and will be classified as having M1 disease (or ED). Application of the TNM system will not change how patients are managed; however, the analysis suggests that, in the context of clinical trials in LD, accurate TNM staging and stratification may be important.[3]

Staging Evaluation Staging procedures for SCLC are important to distinguish patients with disease limited to their thorax from those with distant metastases. At the time of initial diagnosis, approximately two-thirds of patients with SCLC have clinical evidence of metastases; most of the remaining patients have clinical evidence of extensive nodal involvement in the hilar, mediastinal, and sometimes supraclavicular regions.

Determining the stage of cancer allows an assessment of prognosis and a determination of treatment, particularly when chest radiation therapy or surgical excision is added to chemotherapy for patients with LD. If ED is confirmed, further evaluation should be individualized according to the signs and symptoms unique to the individual patient. Standard staging procedures include the following:

A thorough physical examination. Routine blood counts and serum chemistries. Chest and upper abdominal computed tomography (CT) scanning. A radionuclide bone scan. A brain magnetic resonance imaging scan or CT scan. Bone marrow aspirate or biopsy in selected patients in which treatment would change based on the results. The role of positron emission tomography (PET) is still under study. SCLC is fluorine F 18-fludeoxyglucose (18F-FDG) avid at the primary site and at metastatic sites. PET may be used in staging patients with SCLC who are potential candidates for the addition of thoracic radiation therapy to chemotherapy, as PET may lead to upstaging or downstaging of patients and to alteration of radiation fields resulting from the identification of additional sites of nodal metastases.

Evidence (18F-FDGPET):

In a study of 120 patients with LD SCLC or ED SCLC, ten patients were upstaged and three patients were downstaged.[5] PET was more sensitive and specific than CT scans for nonbrain distant metastases. In a small series of 24 patients with LD by conventional staging, two patients were upstaged to ED.[2] Unsuspected nodal metastases were documented in 25% of patients, which altered the radiation plan in these patients. At this time, sensitivity, specificity, and positive- or negative-predictive value of PET scanning and its enhancement of staging accuracy are uncertain. References Lung. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 253-70. Bradley JD, Dehdashti F, Mintun MA, et al.: Positron emission tomography in limited-stage small-cell lung cancer: a prospective study. J Clin Oncol 22 (16): 3248-54, 2004. [PUBMED Abstract] Shepherd FA, Crowley J, Van Houtte P, et al.: The International Association for the Study of Lung Cancer lung cancer staging project: proposals regarding the clinical staging of small cell lung cancer in the forthcoming (seventh) edition of the tumor, node, metastasis classification for lung cancer. J Thorac Oncol 2 (12): 1067-77, 2007. [PUBMED Abstract] Ihde D, Souhami B, Comis R, et al.: Small cell lung cancer. Lung Cancer 17 (Suppl 1): S19-21, 1997. [PUBMED Abstract] Brink I, Schumacher T, Mix M, et al.: Impact of [18F]FDG-PET on the primary staging of small-cell lung cancer. Eur J Nucl Med Mol Imaging 31 (12): 1614-20, 2004. [PUBMED Abstract]

Pathologic classification

Before initiating treatment of a patient with small cell lung cancer (SCLC), an experienced lung cancer pathologist should review the pathologic material.

Pathologic Classification The current classification of subtypes of SCLC includes the following:[1]

Small cell carcinoma. Combined small cell carcinoma (i.e., SCLC combined with neoplastic squamous and/or glandular components). SCLC arising from neuroendocrine cells forms one extreme of the spectrum of neuroendocrine carcinomas of the lung.

Neuroendocrine tumors include the following:

Low-grade typical carcinoid. Intermediate-grade atypical carcinoid. High-grade neuroendocrine tumors including large-cell neuroendocrine carcinoma (LCNEC) and SCLC. Because of differences in clinical behavior, therapy, and epidemiology, these tumors are classified separately in the World Health Organization (WHO) revised classification. The variant form of SCLC called mixed small cell/large cell carcinoma was not retained in the revised WHO classification. Instead, SCLC is now described with only one variant, SCLC combined, when at least 10% of the tumor bulk is made of an associated non-small cell component.

SCLC presents as a proliferation of small cells with the following morphological features:[2]

Scant cytoplasm. Ill-defined borders. Finely granular "salt and pepper" chromatin. Absent or inconspicuous nucleoli. Frequent nuclear molding. A high mitotic count. Combined small cell carcinoma includes a mixture of small cell and large cell or any other non-small cell component. Any cases showing at least 10% of SCLC are diagnosed as combined SCLC, and SCLC is limited to tumors with pure SCLC histology. SCLC associated with LCNEC is diagnosed as SCLC combined with LCNEC.

Nearly all SCLC are immunoreactive for keratin, thyroid transcription factor 1, and epithelial membrane antigen. Neuroendocrine and neural differentiation result in the expression of dopa decarboxylase, calcitonin, neuron-specific enolase, chromogranin A, CD56 (also known as nucleosomal histone kinase 1 or neural-cell adhesion molecule), gastrin-releasing peptide, and insulin-like growth factor 1. One or more markers of neuroendocrine differentiation can be found in approximately 75% of SCLC.[3]

Although preinvasive and in situ malignant changes are frequently found in patients with non-small cell lung cancer, these findings are rare in patients with SCLC.[4]

References Travis WD, Colby TV, Corrin B, et al.: Histological typing of lung and pleural tumours. 3rd ed. Berlin: Springer-Verlag, 1999. Brambilla E, Travis WD, Colby TV, et al.: The new World Health Organization classification of lung tumours. Eur Respir J 18 (6): 1059-68, 2001. [PUBMED Abstract] Guinee DG Jr, Fishback NF, Koss MN, et al.: The spectrum of immunohistochemical staining of small-cell lung carcinoma in specimens from transbronchial and open-lung biopsies. Am J Clin Pathol 102 (4): 406-14, 1994. [PUBMED Abstract] Kumar V, Abbas A, Fausto N, eds.: Robins and Cotran Pathologic Basis of Disease. 7th ed. Philadelphia, Pa: Elsevier Inc, 2005.

Radiation therapy

Depending on the stage of small cell lung cancer (SCLC) and other factors, radiation therapy might be used in several situations:

In limited stage SCLC, radiation therapy can be given at the same time as chemotherapy (chemo) to treat the tumor and lymph nodes in the chest. Giving chemo and radiation together is called concurrent chemoradiation. The radiation may be started with the first or second cycle of chemo. Radiation can also be given after the chemo is finished. This is sometimes done for patients with extensive stage disease, or it can be used for people with limited stage disease who have trouble getting chemotherapy and radiation at the same time (as an alternative to chemoradiation). SCLC often spreads to the brain. Radiation can be given to the brain to help lower the chances of problems from cancer spread there. This is called prophylactic cranial irradiation. This is most often used to treat people with limited stage SCLC, but it can also help some people with extensive stage SCLC. Radiation can be used to shrink tumors to relieve (palliate) symptoms of lung cancer such as pain, bleeding, trouble swallowing, cough, shortness of breath, and problems caused by spread to other organs such as the brain. Types of radiation therapy The type of radiation therapy most often used to treat SCLC is called external beam radiation therapy (EBRT). It delivers radiation from outside the body and focuses it on the cancer.

Before treatments start, your radiation team will take careful measurements to find the correct angles for aiming the radiation beams and the proper dose of radiation. This planning session, called simulation, usually includes getting imaging tests such as CT scans.

Treatment is much like getting an x-ray, but the radiation is more intense. The procedure itself is painless. Each treatment lasts only a few minutes, although the setup time – getting you into place for treatment – usually takes longer.

Most often, radiation as part of the initial treatment for SCLC is given once or twice daily, 5 days a week, for 3 to 7 weeks. Radiation to relieve symptoms and prophylactic cranial radiation are given for shorter periods of time, typically less than 3 weeks.

In recent years, newer EBRT techniques have been shown to help doctors treat lung cancers more accurately while lowering the radiation exposure to nearby healthy tissues. These include:

Three-dimensional conformal radiation therapy (3D-CRT): 3D-CRT uses special computer programs to precisely map the location of the tumor(s). Radiation beams are shaped and aimed at the tumor(s) from several directions, which makes it less likely to damage normal tissues.

Intensity modulated radiation therapy (IMRT): IMRT is an advanced form of 3D therapy. It uses a computer-driven machine that moves around the patient as it delivers radiation. Along with shaping the beams and aiming them at the tumor from several angles, the intensity (strength) of the beams can be adjusted to limit the dose reaching nearby normal tissues. This technique is used most often if tumors are near important structures such as the spinal cord. Many major cancer centers now use IMRT.

A variation of IMRT is called volumetric modulated arc therapy (VMAT). It uses a machine that delivers radiation quickly as it rotates once around the body. Each treatment is given over just a few minutes.

Possible side effects of radiation therapy If you are going to get radiation therapy, it’s important to ask your doctor beforehand about the possible side effects so that you know what to expect. Common side effects of radiation therapy can include:

Skin changes in the area being treated, which can range from mild redness to blistering and peeling Hair loss (in the area where the radiation enters the body) Fatigue (tiredness) Nausea and vomiting Loss of appetite and weight loss Most of these side effects go away after treatment, but some can last a long time. When chemotherapy is given with radiation, the side effects are often worse.

Radiation therapy to the chest may damage your lungs, which might cause a cough, problems breathing, and shortness of breath. These usually improve after treatment is over, although sometimes they may not go away completely.

Your esophagus, which is in the middle of your chest, may be exposed to radiation, which could cause a sore throat and trouble swallowing during or shortly after treatment. This might make it hard to eat anything other than soft foods or liquids for a while.

Radiation therapy to large areas of the brain can sometimes cause memory loss, fatigue, headaches, trouble thinking, or reduced sexual desire. Usually these symptoms are minor compared with those caused by cancer that has spread to the brain, but they can affect your quality of life.

Surgery

The feasibility of surgery depends on the stage of small cell carcinoma at diagnosis. In small cell carcinoma of the lung (SCCL), surgery should only be considered among patients with clinical stage I (T1-2, N0). Postoperative chemotherapy with or without radiation therapy is recommended based on the presence or absence of lymph node involvement.

Surgery

• Surgery should only be considered among patients with clinical stage I (T1-2, N0). Given that the majority of patients are not diagnosed with clinical stage I (T1-2,N0), surgery is rarely performed among SCCL patients.
• Before a patient is considered for surgical resection of the tumor, investigation for occult nodal involvement by either mediastinoscopy or mediastinal node dissection should be performed.
• Post-operative palliative treatment following surgery includes:
  • Chemotherapy if there is no nodal involvement
  • Chemotherapy PLUS radiation therapy if there is nodal involvement
  • Prophylactic cranial irradiation is recommended among patients who undergo complete resection of the tumor, as long as their performance status is good and they do not have any neurological cognitive impairment.

Overview

There are no MRI findings associated with small cell carcinoma. However, a MRI may be helpful in the diagnosis of complications of small cell carcinoma, which include brain metastasis

MRI

• There are no MRI findings associated with small cell carcinoma. However, a MRI may be helpful in the diagnosis of complications of small cell carcinoma, which include:
  • Brain metastasis

Overview CT SCLC

Chest CT scan, preferably with intravenous contrast administration, may be helpful in the diagnosis of small cell carcinoma. Findings on CT scan suggestive of small cell carcinoma include hilar mass, mediastinal involvement, numerous lymphadenopathy, direct infiltration of adjacent structures, necrosis and hemorrhage. Small cell carcinoma of the lung is the most common cause of SVC obstruction, due to both compression/thrombosis and/or direct infiltration 2. All patients with confirmed diagnosis of SCLC by histopathological findings should undergo a CT scan of the abdomen for staging purposes. CT scan of the abdomen helps identify metastasis to organs, such as the liver or the adrenal glands. Brain imaging is also mandatory for staging; however, brain MRI is preferred over brain CT scan due to its superior sensitivity for the detection of brain metastasis. In addition, when limited stage small cell lung cancer is suspected, PET CT scan should be performed.

CT

Chest CT scan, preferably with intravenous contrast administration, may be helpful in the diagnosis of small cell carcinoma. Findings on CT scan suggestive of small cell carcinoma include:

• Hilar mass
• Mediastinal involvement
• Numerous lymphadenopathy
• Direct infiltration of adjacent structures
• Necrosis
• Hemorrhage
• Small cell carcinoma of the lung is the most common cause of SVC obstruction, due to both compression/thrombosis and/or direct infiltration 2.
• CT is used to stage small cell lung cancer.
• CT scan of the abdomen helps identify metastasis to organs, such as the liver or the adrenal glands.
• Brain imaging is also mandatory for staging; however, brain MRI is preferred over brain CT scan due to its superior sensitivity for the detection of brain metastasis.
• PET CT scan should be performed if limited stage small cell lung cancer is suspected.

Pathology SCLC

Small cell carcinoma is considered a neuroendocrine tumour of the lung. It arises from the bronchial mucosa. Local invasion occurs in the submucosa with subsequent invasion of peribronchial connective tissue. Cells are small, oval, with scant cytoplasm and a high mitotic count.

It is the most common lung cancer subtype to produce necrosis, superior vena cava (SVC) infiltration/SVC obstruction, and paraneoplastic syndromes (see bronchogenic carcinoma).

Location

Approximately 90-95% of SCLCs occur centrally, and usually arising in a lobar or main bronchus 3.

Small cell lung cancer X rays

Small cell carcinoma of Lung

Chest x-ray: Small cell carcinoma of the lung. Antero-posterior view, Case courtesy of A.Prof Frank Gaillard, via,Radiopaedia.org

Chest x-ray: Small cell carcinoma of the lung.Case courtesy of Dr Henry Knipe, via, Radiopaedia.org

Lung cancer

Surgery

If investigations confirm lung cancer, CT scan and often positron emission tomography (PET) are used to determine whether the disease is localised and amenable to surgery or whether it has spread to the point where it cannot be cured surgically.

Blood tests and spirometry (lung function testing) are also necessary to assess whether the patient is well enough to be operated on. If spirometry reveals poor respiratory reserve (often due to chronic obstructive pulmonary disease), surgery may be contraindicated.

Surgery itself has an operative death rate of about 4.4%, depending on the patient's lung function and other risk factors.[1] Surgery is usually only an option in non-small cell lung carcinoma limited to one lung, up to stage IIIA. This is assessed with medical imaging (computed tomography, positron emission tomography). A sufficient pre-operative respiratory reserve must be present to allow adequate lung function after the tissue is removed.

Pulmonary Reserve The American College of Chest Physicians established clinical practice guidelines for the physiologic evaluation of patients with lung cancer being considered for resectional surgery.[2] The preoperative physiologic assessment should include a cardiac evaluation and spirometry to measure the FEV1 and carbon monoxide diffusion capacity (DLCO). Depending on these results the patients can be stratified into different risk groups and further testing may be required or surgery can be initiated. Pulmonary reserve is measured by spirometry. The minimum forced vital capacity (FVC) for pneumonectomy in men is 2 liters. The minimum for lobectomy is 1.5 liters. In women, the minimum FVC values for pneumonectomy and lobectomy are 1.75 liters and 1.25 liters respectively.[3]

Surgery

Procedures include wedge resection (removal of part of a lobe), lobectomy (one lobe), bilobectomy (two lobes) or pneumonectomy (whole lung). In patients with adequate respiratory reserve, lobectomy is the preferred option, as this minimizes the chance of local recurrence. If the patient does not have enough functional lung for this, wedge resection may be performed.[4] Radioactive iodine brachytherapy at the margins of wedge excision may reduce recurrence to that of lobectomy.[5]

Also, many times during lung cancer surgery, the doctor will remove some of the lymph nodes to test for cancer. If the lymph nodes test positive for cancer then that is indicative of the disease spreading beyond the lung. There will most likely be subsequent treatments to help eliminate the remaining cancer.

Patient Selection Not all patients are suitable for operation. The stage, location and cell type are important limiting factors. In addition, patients who are very ill with a poor performance status or who have inadequate pulmonary reserve would be unlikely to survive. Even with careful selection, the overall operative death rate is about 4.4%.[1]

Stage "Stage" refers to the degree of spread of the cancer.

See non-small cell lung cancer staging

In non-small cell lung cancer, stages IA, IB, IIA, and IIB are suitable for surgical resection.[6] Stages IIIA, IIIB, and IV tend to involve the spreading out of the cancer. In that case chemotherapy or radiation is usually deemed the appropriate action to take because surgery will not adequately solve the diseased lungs.

Types of Surgery Lobectomy (removal of a lobe of the lung) Pneumonectomy (removal of an entire lung) Wedge resection Sleeve resection

Overview

Surgery is the best treatment option of lung cancer for patients with resectable tumors. The feasibility of surgery depends on the stage of lung cancer at the time of diagnosis.

Indications

• Surgical intervention is not recommended for the management of [disease name].

OR

• Surgery is not the first-line treatment option for patients with [disease name]. Surgery is usually reserved for patients with either:
  • [Indication 1]
  • [Indication 2]
  • [Indication 3]
• The mainstay of treatment for [disease name] is medical therapy. Surgery is usually reserved for patients with either:
  • [Indication 1]
  • [Indication 2]
  • [Indication 3]

Surgery

• Surgery is the best treatment option of lung cancer for patients with resectable tumors.
• The feasibility of surgery depends on the stage of lung cancer at the time of diagnosis.
• The procedures for lung cancer imclude:
  • Wedge resection (removal of part of a lobe)
    • Wedge resection is performed in the patients who do not have adequate respiratory reserve.
    • Radioactive iodine brachytherapy at the margins of wedge resection may reduce recurrence to that of lobectomy.
  • Lobectomy (one lobe)
    • Lobectomy is the preferred option for patients with adequate respiratory reserve because it reduces the chances of local recurrence.
  • Bilobectomy (two lobes)
  • Pneumonectomy (whole lung)

Lung Cancer Differential

Condition/disease	Signs/symptoms	Tests
Pneumonia/bronchitis	Typical symptoms include fever, cough, dyspnea, and chest pain; recurrent pneumonia or bronchitis in a smoker or former smoker should raise the suspicion of lung cancer	CXR is the first test performed; CT imaging can be helpful to evaluate pulmonary masses that might not be well visualised with chest x-ray; bronchoscopy can also be used to assess for endobronchial lesions or to biopsy suspicious pulmonary masses
Carcinoid tumor	Often asymptomatic with normal physical examination; may cause cough, dyspnea, hemoptysis, unilateral wheezing, or post-obstructive pneumonia if the tumor is endobronchial or compressing the central bronchi	CT chest: 80% of carcinoid tumors appear as an endobronchial nodule and 20% as a parenchymal nodule, with smooth, rounded borders and is highly vascularized; flexible bronchoscopy shows raised, pink, vascular, lobulated lesions; endobronchial forceps biopsy is usually required for pathology to be diagnostic; bronchial brushings, sputum specimens, and lavage fluid rarely provide sufficient tissue for a conclusive diagnosis
Metastatic cancer from a non-thoracic primary site	Signs and symptoms depend on the location of the primary tumor and distant disease and may include pain, weight loss, malaise, cough, dyspnea, clubbing, or focal wheezing; physical findings may be present depending on the location and extent of the disease	CT chest shows one or multiple nodules of variable sizes from diffuse micronodular opacities (miliary) to well-defined masses, lesions are often irregular and in the periphery of the lower lung zones; CT/MRI head, CT abdomen and pelvis: extrapulmonary cancers that commonly metastasis to the lung include melanoma, thyroid carcinoma, esophageal cancer; ovarian cancer; sarcomas; and adenocarcinomas of the colon, breast, kidney, and testis; PET-FDG scan shows increased uptake in both primary and distant sites, certain metastatic lesions, such as renal cell carcinoma, have a lower probability of 18-fluorodeoxyglucose (FDG) uptake; CT-guided transthoracic needle aspiration (TTNA) can reveal characteristic malignant cells, pneumothorax complicates 20% to 30% of TTNA procedures, the choice between bronchoscopy and TTNA is based on lesion size, location, risks, and local expertise; biopsy during flexible bronchoscopy and biopsy may show characteristic malignant cells, bronchoscopy has a 100% yield for endobronchial lesions (which are extremely rare in metastatic deposits from other primary tumors)
Infectious granuloma	History may include travel to endemic areas, pet/animal exposures, and specific leisure activities (e.g., caving); may feature cough, dyspnea, hemoptysis, weight loss, fever, joint aches, skin lesions, and night sweats, or no symptoms; many possible causes: Histoplasma capsulatum, Mycobacterium tuberculosis, Coccidioides immitis, Cryptococcus neoformans, Aspergillus, Pseudallescheria boydii, Fusarium species, zygomycetes, and others; non-specific skin findings may be seen in atypical mycobacteria and cryptococcosis; lymphadenopathy may be present with active disease	CT-guided TTNA can be used for diagnostic sampling, pneumothorax complicates 20% to 30% of TTNA procedures, the choice between bronchoscopy and TTNA is based on lesion size, location, risks, and local expertise; CT chest typically shows lesions <2 cm diameter and round with smooth borders, old granulomatous disease may feature central, laminated, or diffuse calcification pattern, mediastinal lymphadenopathy without calcifications is sometimes present, nodules from angioinvasive fungi (e.g., Aspergillus, Pseudallescheria boydii, Fusarium species, and zygomycetes) may demonstrate the "halo sign" (ground-glass opacity surrounding the nodule), occasionally, calcifications can be seen in the spleen or liver; fungal serologies: positive during active infection; flexible bronchoscopy and biopsy can sometimes provide sample for identification and culture and sensitivity of organism; PET: usually negative (<2.5 standardised uptake values), may be positive in active infectious processes
Sarcoidosis	Cough, dyspnea, fatigue weight loss, fever, night sweats, rash, eye pain, photophobia blurred vision, and red eye; pulmonary examination is usually unrevealing; can affect any organ, so physical findings depend on specific organs affected; skin lesions including maculopapular eruptions, subcutaneous nodular lesions, and red-purple skin lesions	CT chest: mediastinal adenopathy often present with sarcoid. Sarcoid nodules have predilection for upper zones, although can be located throughout the lung; flexible bronchoscopy and biopsy can demonstrate presence of non-caseating granulomas; CT-guided TTNA can provide access to material from some lesions inaccessible to flexible bronchoscopy; laboratory markers: ACE elevation may be seen in sarcoidosis but is non-specific
Rheumatoid arthritis	Arthralgias, pain, skin nodules, pleural effusions, pleuritis, joint pain, and deformity	CT chest typically shows lung nodule 3 mm to 7 cm, predominantly in peripheral upper and mid-lung zones, may show cavitation; flexible bronchoscopy and biopsy shows rheumatoid necrobiotic nodule, necrobiotic nodules demonstrate a central zone of eosinophilic fibrinoid necrosis surrounded by palisading fibroblasts, the nodule often centered on necrotic inflamed blood vessels; laboratory markers: patients with lung nodules due to rheumatoid arthritis frequently have high levels of rheumatoid factor, although seronegative cases have been reported
Wegener's granulomatosis	Cough, chest pain, dyspnea, hemoptysis, rhinorrhoea, epistaxis, ear/sinus pain, hoarseness, fever, fatigue, anorexia, weight loss, palpable purpura, painful ulcers, uveitis, upper airway inflammation, and sinus pain	CT chest shows solitary or multiple lung nodules, airways are frequently affected; Flexible bronchoscopy or CT-guided TTNA may show necrotising granulomatous inflammation; laboratory markers: anti-neutrophil cytoplasmic antibody (ANCA), ANCA testing results depend on the extent and severity of the disease
Arteriovenous malformation	Dyspnea is uncommon, may cause hemoptysis, pulmonary bruit, arteriovenous communications, or hemorrhagic telangiectasia in the skin, mucous membranes, and other organs, cyanosis and finger clubbing may be present, eurological symptoms from cerebral aneurysms, cerebral emboli	CT chest shows round or oval nodule(s) with feeding artery and draining vein often identified, most common in lower lobes, multiple lesions in 30% of cases, usually round or oval, ranging from 1 cm to several cm in diameter; pulmonary angiography confirms presence and location of AVMs, identifies feeding arterial and venous structures, in cases of significant hemoptysis, pulmonary angiogram is combined with bronchial artery embolisation; ABG analysis may show decreased pO2 and decreased oxygen saturation when AV flow is severe., in cases of severe systemic AVMs, chronic hypoxemia may cause polycythemia
Amyloidosis	Weight loss, paresthesias, dyspnea, and fatigue are the most common symptoms associated with amyloidosis and are common to all systemic forms; weight loss of >9 kg is common; small vessel involvement can cause jaw or limb claudication, and rarely angina; amyloid purpura is present in about 1 in 6 patients, typically peri-orbital; eyelid petechiae are common; hepatomegaly >5 cm below the right costal margin is seen in 10% of patients and splenomegaly is usually of modest degree	CT chest shows lung involvement characterised by focal pulmonary nodules, tracheobronchial lesions, or diffuse alveolar deposits; serum immunofixation shows presence of monoclonal protein; urine immunofixation shows presence of monoclonal protein; immunoglobulin free light chain assay shows abnormal kappa to lambda ratio
Bronchiolitis obliterans organizing pneumonia (BOOP)	Normally presents as a flu-like illness followed by a second illness lasting 1 to 4 months, with low-grade fever, non-productive cough, malaise, dyspnea, and weight loss; sometimes features pleuritic chest pain and hemoptysis; in most patients, auscultation reveals fine, dry lung crackles; finger clubbing is unusual	CT chest typical features include: patchy "ground-glass" opacities in a sub-pleural and/or peribronchovascular distribution; thickening of bronchial walls and cylindrical dilation; 3 to 5 mm diameter centrilobular nodules or other ill-defined nodules, mediastinal lymphadenopathy, pleural effusions; pulmonary function tests typically show a restrictive pattern; bronchoalveolar lavage (BAL shows a mixed cell pattern, with an increase in lymphocytes, neutrophils, eosinophils, mast cells, foamy macrophages, and occasional plasma cells, CD4+/CD8+ cell ratio is decreased, the ratio of lymphocytes to CD8+ cells is significantly increased; transbronchial lung biopsy in combination with BAL can be a useful approach, prior to possible open biopsy; open lung biopsy is often required for a definitive diagnosis
Pulmonary tuberculosis	Cough longer than 2 to 3 weeks, discolored or bloody sputum, night sweats, weight loss, loss of appetite, and/or pleuritic chest pain	Chest x-ray: primary disease commonly presents as middle and lower lung zone infiltrates, ipsilateral adenopathy, atelectasis from airway compression, and pleural effusion can be seen, reactivation-type (post-primary) pulmonary TB usually involves apical and/or posterior segment of right upper lobe, apicoposterior segment of left upper lobe, or superior segment of either lower lobe, with or without cavitation, as disease progresses it spreads to other segments/lobes; sputum smear: positive for acid-fast bacilli (AFB), sputum may be spontaneously expectorated or induced, and at least 3 specimens should be collected (minimum 8 hours apart, including an early morning specimen, which is the best way to detect Mycobacterium tuberculosis), organisms other than M. tuberculosis, especially on-tuberculous mycobacteria (e.g., M. kansasii and M. avium , may be positive for AFB stain; nucleic acid amplification tests (NAAT): positive for M. tuberculosis DNA or RNA amplification tests for rapid diagnosis, may be used on sputum or any sterile body fluid
Non-Hodgkin's lymphoma (NHL)	Aggressive NHL may present with fever, drenching night sweats, malaise, weight loss, cough, shortness of breath, abdominal discomfort, headache, change in mental status, dizziness, ataxia, pleural effusion, lymphadenopathy, pallor, purpura, jaundice, hepatomegaly, splenomegaly, skin nodules, and abnormal neurological examination, low-grade NHL patients often minimally symptomatic or asymptomatic	CT chest: frequently anterior mediastinum, can determine if mass is cystic or solid and whether it contains calcium or fat, contrast enhancement provides information concerning vascularisation of the mass and relationship to adjacent structures; FBC with differential: shows thrombocytopenia, pancytopenia; Blood smear: shows nucleated red blood cells, giant platelets; lymph node biopsy with immunohistochemistry: shows characteristic cells, preferably obtain excisional or core biopsy to provide information on lymph node architecture; mediastinoscopy: used to sample mediastinal nodes
Hodgkin's lymphoma	Predominantly a disease of young adults; most patients present with a several-month history of persistent adenopathy, most commonly of the cervical chain	Plain chest x-ray: typically shows mediastinal mass/large mediastinal adenopathy; PET scan: involved sites appear fluorodeoxyglucose (FDG)-avid (bright) with PET imaging; lymph node biopsy with immunohistochemistry: the Hodgkin's cell can be a characteristic Reed-Sternberg cell, or one of its variants, such as the lacunar cell in the nodular sclerosis subtype; in nodular lymphocyte-predominant Hodgkin's lymphoma, the characteristic cell is the lymphocytic and histiocytic (L&H) cell, also referred to as a popcorn cell
Thymoma/thymic carcinoma	Approximately 30% of patients with thymoma are asymptomatic at the time of diagnosis; may also present with cough, chest pain, signs of upper airway congestion, superior vena cava syndrome, dysphagia, or hoarseness; may have features of paraneoplastic syndromes associated with thymoma including myasthenia gravis, polymyositis, lupus erythematosus, rheumatoid arthritis, thyroiditis, and Sjogren's syndrome; about 30% of patients have symptoms suggestive of myasthenia gravis (e.g., ptosis, double vision)	Plain chest x-ray: in 50% of the patients, thymomas are detected by chance with plain-film chest radiography; CT chest: 90% occur in anterior mediastinum; Positron emission tomography (PET): may be of value in determining malignancy and extramediastinal involvement; pre-operative biopsy: indicated if there are atypical features or if imaging suggests invasive tumor and patient is under consideration for induction therapy
Bronchogenic cyst	Usually diagnosed in infancy and childhood, although 50% are diagnosed after 15 years of age; Approximately 50% of patients are asymptomatic; in adults, chest pain (often pleuritic) and dysphagia (due to esophageal compression) are the most common symptoms; may also feature recurrent cough and chest infection/pneumonia, superior vena cava syndrome, tracheal compression, and pneumothorax	Two-view chest radiography: typically shows a sharply demarcated spherical mass of variable size, most commonly located in the middle mediastinum around the carina, can appear as a solid tumor or show air-fluid level if cyst is infected or contains secretions; CT chest: frequently middle mediastinum, typically at level of the mediastinum, calcifications may also be seen; MRI: frequently middle mediastinum, typically at level of the mediastinum, T2-weighted images show a homogeneous mass of moderate-to-bright intensity, on T1-weighted images, lesions may vary in intensity depending on protein content of the cyst
Tracheal tumors	Common symptoms include dyspnea, cough, hemoptysis, wheeze, and stridor; less commonly, hoarseness and dysphagia may be present	Plain chest radiographs are generally insensitive for detection of tracheal tumors, clues that may indicate the presence of a tracheal tumour include abnormal calcification, tracheal narrowing, post-obstructive pneumonia, and/or atelectasis; helical CT enables accurate calculation of tumor volumes and can help differentiate mucosal lesions from submucosal lesions; MRI can be useful in assessing extension into surrounding tissue and vascular anatomy; bronchoscopy allows direct visualisation, opportunity for biopsy, and potential for laser treatment
Thyroid mass	Symptoms and signs depend on size of mass; may be visible/palpable as lump on anterior aspect of neck; may present with dysphagia, hoarseness, difficulty breathing, and pain in neck or throat; may also be signs and symptoms of hyper- or hypothyroidism depending on the nature of the mass	Laboratory testing should include thyroid function panel, with TSH, free T4, free T3; I-123 thyroid scan is ordered for patients with overt or subclinical hyperthyroidism a hyperfunctioning (hot) nodule is almost always benign, most nodules are hypofunctioning (cold) (most of these are benign, but malignant nodules are also cold); ultrasound and doppler can be used to define dimensions of thyroid nodules and solid/cystic component(s), features suspicious of malignancy include microcalcifications, a more tall-than-wide shape, hypervascularity, marked hypoechogenicity, or irregular margins, it can also guide fine-needle aspiration, which can reveal malignant cells or cyst fluid; CT neck can evaluate cervical lymph nodes in cases of medullary thyroid cancer, and extension of the scan into the chest can help evaluate a retrosternal thyroid mass

Other conditions that can be mistaken for lung cancer including the following:

• Pneumomediastinum
• Empyema
• Abscess
• Pneumothorax (tension and traumatic)
• Pleural effusion
• Pneumothorax
• Superior Vena Cava Syndrome

Differential Diagnosis

Lung cancer must be differentiated from other cavitary lung lesions.

Causes of lung cavities	Differentiating Features	Differentiating radiological findings	Diagnosis confirmation
Malignancy (Primary lung cancer)	Elderly male or female Chronic smokers Presents with a low-grade fever, absence of leukocytosis, systemic complaints weight loss, fatigue Absence of factors that predispose to gastric content aspiration, no response to antibiotics within 10 days Hemoptysis is commonly associated with bronchogenic carcinoma	A coin-shaped lesion with thick wall(>15mm) is seen on CXR with less ground glass opacities Bronchoalveolar lavage cytology shows malignant cells	Biopsy of lung
Pulmonary Tuberculosis	Mostly in endemic areas Symptoms include productive cough, night sweats, fever, and weight loss	CXR and CT demonstrates cavities in the upper lobe of the lung	Sputum smear positive for acid-fast bacilli and nucleic acid amplification tests (NAAT) is used on sputum or any sterile fluid for rapid diagnosis and is positive for mycobacteria.
Necrotizing Pneumonia	Any age group Acute, fulminant life threating complication of prior infection >100.4 °F fever, with hemodynamic instability Worsening pneumonia-like symptoms	CXR demonstrates multiple cavitary lesions Pleural effusion and empyema are common findings	CBC is positive for causative organism
Loculated empyema	Children and elderly are at risk Pleuritic chest pain, dry cough, fever with chills Dullness to percussion decreased breath sounds, and reduced vocal resonance on examination	Empyema appears lenticular in shape and has a thin wall with smooth luminal margins	Thoracocentesis
Granulomatosis with polyangiitis (Wegener's)	Women are more commonly effected than man Kidneys are also involved Upper respiratory tract symptoms, perforation of nasal septum, chronic sinusitis, otitis media, mastoiditis. Lower respiratory tract symptoms (e.g. hemoptysis, cough, dyspnea) Renal symptoms, hematuria, red cell casts	Pulmonary nodules with cavities and infiltrates are a frequent manifestation on CXR	Positive for P-ANCA Biopsy of the tissue involved shows necrotizing granulomas
Rheumatoid nodule	Elderly females of 40-50 age group Manifestation of rheumatoid arthritis Presents with other systemic symptoms including symmetric arthritis of the small joints of the hands and feet with morning stiffness are common manifestations	Pulmonary nodules with cavitation are located in the upper lobe (Caplan syndrome) on X-ray	Positive for both rheumatoid factor and anticyclic citrullinated peptide antibody.
Sarcoidosis	More common in African-American females Often asymptomatic except for enlarged lymph nodes Associated with restrictive lung disease Erythema nodosum Lupus pernio (skin lesions on face resembling lupus) Bell palsy Epithelioid granulomas containing microscopic Schaumann and asteroid bodies	On CXR bilateral adenopathy and coarse reticular opacities are seen CT of the chest demonstrates extensive hilar and mediastinal adenopathy Additional findings on CT include fibrosis (honeycomb, linear, or associated with bronchial distortion), pleural thickening, and ground-glass opacities.	Biopsy of lung shows non-caseating granuloma
Bronchiolitis obliterans (Cryptogenic organizing pneumonia)	Rare condition and mimics asthma, pneumonia and emphysema It is caused by drug or toxin exposure, autoimmune diseases, viral infections, or radiation injury People working in industries are at high risk Presents with fever, cough, wheezing, and shortness of breath over weeks to months	Common appearance on CT is patchy consolidation,often accompanied by ground-glass opacities and nodules.	Biopsy of the lung Pulmonary function tests demonstrate low fev1/fvc
Langerhans cell Histiocytosis	Exclusively afflicts smokers, with a peak age of onset of between 20 and 40 years Clinical presentation varies, but symptoms generally include months of dry cough, fever, night sweats, and weight loss Skin is involved in 80% of the cases, scaly erythematous rash is typical	Thin-walled cystic cavities are the usual radiographic manifestation, observed in over 50% of patients by either CXR or CT scans.	Biopsy of the lung

PBC USG

There are no ultrasound findings associated with primary biliary cirrhosis. However, the ultrasound is mandatory for liver and biliary tree for all cholestatic patients for the differentiation of intrahepatic from extrahepatic cholestasis.

• The ultrasound findings may include:
  • Cholestasis
  • Abdominal lymphadenopathy

Ultrasound examination of the liver and biliary tree is obligatory in all cholestatic patients in order to differentiate intrahepatic from extrahepatic . When the biliary system appears normal and serum AMA are present, no further radiologic workup is necessary. , particularly in the hilar region of the liver, is seen in 80% of patients with PBC

PBC CT

• Findings on CT scan suggestive of advanced primary biliary cirrhosis include:
  • Small heterogeneously attenuating liver
  • Varices
  • Splenomegaly
  • Lymphadenopathy
• Findings on CT scan suggestive of less advanced disease include:
  • Enlarged or normal size liver
  • Smooth contour liver
  • Little atrophy
  • Lacelike fibrosis
  • Regenerative nodules
  • Varices
  • Ascites
  • Lymphadenopathy

Synonoms

• Solitary hyperplastic nodule
• Hepatic hamartoma
• Focal cirrhosis
• Hamartomatous cholangiohepatoma
• Hepatic pseudotumor

Historical Perspective

• In early 1900s,Focal nodular hyperplasia was first described.
• Between 1918-1982,96.625 autopsy studies were conducted out of which 8 percent of nonhemangiomatous lesions were focal nodular hyperplasia.
• In 1994,Working party of the world congresses of gastroenterology suggested a standardized terminology of nodular hepatic lesions that placed Focal noduldar carcinoma in the group of regenerative nodules, as opposed to dysplastic or neoplastic nodules.

Differentiating Focal nodular hyperplasia from Other diseases

Focal nodular hyperplasia must be differentiated from:

• Hepatocellular carcinoma
• Cholangiocarcinoma
• Pancreatic carcinoma
• Liver hemangioma
• Liver abscess
• Cirrhosis
• Inflammatory lesions

Abbreviations: RUQ= Right upper quadrant of the abdomen, LUQ= Left upper quadrant, LLQ= Left lower quadrant, RLQ= Right lower quadrant, LFT= Liver function test, SIRS= Systemic inflammatory response syndrome, ERCP= Endoscopic retrograde cholangiopancreatography, IV= Intravenous, N= Normal, AMA= Anti mitochondrial antibodies, LDH= Lactate dehydrogenase, GI= Gastrointestinal, CXR= Chest X ray, IgA= Immunoglobulin A, IgG= Immunoglobulin G, IgM= Immunoglobulin M, CT= Computed tomography, PMN= Polymorphonuclear cells, ESR= Erythrocyte sedimentation rate, CRP= C-reactive protein, TS= Transferrin saturation, SF= Serum Ferritin, SMA= Superior mesenteric artery, SMV= Superior mesenteric vein, ECG= Electrocardiogram

Disease	Clinical manifestations													Diagnosis		Comments
	Symptoms									Signs
	Abdominal Pain	Fever	Rigors and chills	Nausea or vomiting	Jaundice	Constipation	Diarrhea	Weight loss	GI bleeding	Hypo- tension	Guarding	Rebound Tenderness	Bowel sounds	Lab Findings	Imaging
Focal nodular hyperplasia	Diffuse	±	−	−	±	−	−	+	+	−	−	−	Normal	Normal Liver function tests Normal AFP Minor elevations of Aspartate Alanine aminotransferase Alkaline phosphatase Gamma glutamyl transpeptidase	Us Multiphasic helical CT scan	Open biopsy if diagnosis can not be established
Hepatocellular carcinoma/Metastasis	RUQ	+	−	+	+	+	+	+	+	+	−	+	Normal Hyperactive if obstruction present	High levels of AFP in serum Abnormal liver function tests Thrombocytopenia	US CT MRI Liver biopsy	Other symptoms: Splenomegaly Variceal bleeding Ascites Spider nevi Asterixis
Cholangiocarcinoma	RUQ	+	−	+	+	−	−	+	−	−	−	+	Normal	Elevated CA 19-9 Increased amylase / lipase Increased stool fat content	Contrast-enhanced ultrasound CT scan Calcification Pseudocyst Dilation of main pancreatic duct MRI	Predisposes to pancreatic cancer
Pancreatic carcinoma	MidEpigastric	−	−	+	+	+	−	+	−	−	−	+	Normal	↑ Alkaline phosphatase ↑ serum bilirubin ↑ gamma-glutamyl transpeptidase ↑ CA 19-9	MDCT with PET/CT MRI EUS	Skin manifestations may include: Bullous pemphigoid Cicatricial pemphigoid Migratory superficial thrombophlebitis (classic Trousseau's syndrome) Pancreatic panniculitis
Disease	Abdominal Pain	Fever	Rigors and chills	Nausea or vomiting	Jaundice	Constipation	Diarrhea	Weight loss	GI bleeding	Hypo- tension	Guarding	Rebound Tenderness	Bowel sounds	Lab Findings	Imaging	Comments
Gallbladder cancer	Midepigastric	−	−	+	+	−	+	+	−	−	−	−	Normal	↑ Alkaline phosphatase ↑ CA 19-9	US CT MRI
Liver hemangioma	Intermittent RUQ	−	−	+	+	−	−	−	−	−	−	−	Normal	Abnormal LFTs	US Single-photon emission computerized tomography(SPECT) MRI	US will reveal hypoechoic lesions
Liver abscess	RUQ	+	−	+	+	−	−	+	−	−	−	−	Normal	Hypoalbuminemia Abnormal liver function tests	US CT
Cirrhosis	RUQ+Bloating	+	−	+	+	−	−	+	−	−	−	−	Normal	Hypoalbuminemia Prolonged PT Abnormal LFTs Hyponatremia Thrombocytopenia	US Nodular, shrunken liver Ascites	Stigmata of liver disease Cruveilhier- Baumgarten murmur
Inflammatory lesions	RUQ	±	−	+	+	−	−	−	−	−	−	−	Normal	Hypoalbuminemia Prolonged PT Abnormal LFTs Hyponatremia Thrombocytopenia	US Nodular,shrunken or coarse liver	Stigmata of liver disease

Focal Nodular Hyperplasia

FNH is typically benign, and usually no treatment is needed. Hemangiomas are the most common and are entirely benign. Treatment is unnecessary unless their expansion causes symptoms

Focal nodular hyperplasia (FNH) is a non-malignant hepatic tumor that is not of vascular origin. In one autopsy series of 96,625 patients, 8 percent of non-hemangiomatous lesions were FNH, representing 66 percent of all benign non-hemangiomatous lesions seen between 1918 and 1982 [1]. In large retrospective studies of patients referred for ultrasound and multidetector computed tomography, the prevalence of focal nodular hyperplasia was 0.2 percent and 1.6 percent, respectively [2,3].

FNH is seen in both sexes and throughout the age spectrum, although it is found predominantly in women (in a ratio of 8 or 9:1) between the ages of 20 and 50 years [4]. FNH comprises up to 2 percent of liver tumors in children [5].

This topic review will focus on the pathogenesis, clinical manifestations and management of FNH. An approach to patients presenting with a focal liver lesion is discussed separately. (See "Solid liver lesions: Differential diagnosis and evaluation".)

PATHOGENESIS — FNH has various labels: solitary hyperplastic nodule, hepatic hamartoma, focal cirrhosis, hamartomatous cholangiohepatoma, and hepatic pseudotumor. This profusion of terms epitomizes the confusion surrounding our understanding of the pathogenesis of the many conditions in which nodules of benign appearing hepatocytes are found. The International Working Party of the World Congresses of Gastroenterology proposed a standardized nomenclature in 1994, which placed FNH in the group of regenerative nodules, as opposed to dysplastic or neoplastic nodules [6]. This fits well with our current understanding of the pathogenesis of FNH. The contention that this lesion is non-neoplastic has been bolstered by the reported polyclonal origin of the hepatocytes [7], although this is disputed by others [8].

Previously considered to be a hamartoma, a neoplasm, a response to ischemia or other injury, or a focal area of regeneration, FNH is now generally accepted to be a hyperplastic (regenerative) response to hyperperfusion by the characteristic anomalous arteries found in the center of these nodules [4,9,10]. Whether vascular injury is also involved is less clear, but FNH is occasionally supplied primarily by portal venous blood due to thrombosis of the anomalous central artery [11].

The association of FNH with hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu disease [12]) and hepatic hemangiomas strengthens the hypothesis that FNH is a congenital vascular anomaly. Two pathology studies found cavernous hemangiomas in 6.5 and 2.3 percent of patients with FNH [13,14] and an imaging study, using ultrasound and dynamic CT, found that 23 percent of FNH patients had associated hemangiomas [15]. Multiple FNH lesions have also been noted in association with hemihypertrophy and vascular malformations (Klippel-Trénaunay-Weber syndrome) [16]. FNH with similar clinical and radiographic features has been documented in identical twins supporting a role of congenital vascular anomalies in its pathogenesis and a possible genetic predisposition to the disease [17].

PATHOLOGY — FNH is most often solitary (80 to 95 percent), and usually less than 5 cm in diameter. Only 3 percent are larger than 10 cm, although FNH as large as 19 cm have been reported [1,13,18]. It has a sharp margin with no capsule and may be pedunculated. The characteristic finding is the presence of a central stellate scar (picture 1) containing an inappropriately large artery with multiple branches radiating through the fibrous septa to the periphery. These branches divide the mass into multiple small nodules or cords of normal appearing hepatocytes (picture 2). The scar-like tissues within FNH nodules are composed of abnormally large portal tracts including large feeding arteries, portal veins, and bile ducts [10].

The arteries drain into adjacent hepatic veins. This radiating, branching pattern produces the spoke and wheel image typically seen on angiography. Although normal bile ducts are absent, bile ductules derived from hepatocyte metaplasia are usually prominent, traveling along the fibrous septa (picture 3). Sinusoids and Kupffer cells are typically present, distinguishing it from hepatocellular adenoma (HA), which usually lacks bile ducts and Kupffer cells [1,13,14,18,19]. The minimal microscopic criteria for the diagnosis of classical FNH are nodular architecture, abnormal vessels, and proliferation of bile ductules [13]. Lymphocyte infiltration, canalicular bile plugs, copper deposition, and feathery degeneration of hepatocytes may suggest cholestasis and/or inactive cirrhosis. Irregular intimal fibrosis or hypertrophy of the media may be seen in large arteries and veins, at times even occluding the lumen [13,14,19]. When present, portal veins are dilated and/or stenotic [10].

Non-classical variants — Non-classical forms of FNH lack either the typical nodular architecture or vascular malformations, but always contain bile ductular proliferation. They almost always lack the characteristic central scar [13]. Three variants have been recognized:

●The most common of these, the telangiectatic type, often presents with multiple FNH. In addition to the lack of a central scar, the mass is characterized by the absence of nodular architecture and the presence of single, quite regular plates of hepatocytes separated by sinusoids fed directly by anomalous arteries [13,20]. The risk of bleeding appears to be similar to the risk observed in patients with a hepatic adenoma [21].

●A mixed hyperplastic and adenomatous form may be difficult to distinguish from HA due to its subtle vascular and bile ductular findings [13,20].

●A third histologic variant consisting of FNH with cytologic atypia resembling dysplasia of large cell type has been proposed [13].

A comprehensive pathological study of 305 lesions failed to identify a macroscopic central stellate scar in 50 percent and noted non-classical histology in 20 percent of the lesions, most showing a telangiectatic variant [13]. The surprisingly high number of lesions without a central scar was almost exclusively due to the large number of masses that had non-classical histology. Ninety-five percent of those with non-classical histology did not have a scar, whereas only 18 percent of those with classical histology lacked a scar [13]. The overall prevalence and clinical significance of these variants remains to be determined.

DIAGNOSIS — The diagnosis of FNH is usually made by demonstrating its characteristic features on imaging tests and excluding other lesions. The latter can typically be accomplished by assessment of the context in which FNH is detected and by obtaining specific radiologic and laboratory testing (table 1). The differential diagnosis includes hepatic adenoma, hepatocellular carcinoma, fibrolamellar carcinoma, cirrhosis, large regenerative nodules, hemangioma, and hypervascular metastases. (See "Solid liver lesions: Differential diagnosis and evaluation".)

Symptoms — The majority of reports have found that symptoms or signs directly attributable to FNH are infrequent. Two-thirds to three-fourths of patients are identified incidentally [18], with the mass noted at the time of surgery, on an abdominal imaging study, or at autopsy. Unlike hepatic adenomas, FNH rarely presents with acute onset of hemorrhage, necrosis, or infarction [22,23].

However, symptomatic presentations have been described. In one series, for example, abdominal discomfort or a palpable liver mass was observed in 25 percent of 41 patients [24]. Another series that included 168 patients found that 60 percent had abdominal pain and 4 percent had an abdominal mass [13]. The high number of symptomatic patients in the second report probably reflects selection bias since all of the patients were identified from pathology specimens obtained at the time of surgical resection [13].

Laboratory tests — Liver tests are most often normal although minor elevations in aspartate and alanine aminotransferase, alkaline phosphatase and gamma glutamyl transpeptidase levels may be seen [13,14,24]. The alpha-fetoprotein is normal.

Imaging tests — A confident diagnosis can usually be made through a combination of imaging modalities; tissue diagnosis is usually not required.

Ultrasonography — Although often first identified on ultrasound examination, FNH is variably hyper, hypo, or isoechoic [24] and US is able to identify the central scar in only 20 percent of cases [25]. The ultrasound characteristics are difficult to distinguish from an adenoma or malignant lesions. Power Doppler ultrasound may help differentiate the arterial flow in FNH from the venous flow in HA [24,26,27].

Contrast-enhanced ultrasonography — Several reports have described improved characterization of focal liver lesions using contrast-enhanced ultrasonography compared with standard ultrasonography [28-30]. While the approach is not approved in the United States, it is available in other countries. Test characteristics compared with other imaging modalities remain incompletely defined, although emerging data suggest its ability for differentiation among solid liver lesions is comparable with MRI [31]. (See "Contrast-enhanced ultrasound for the evaluation of liver lesions".)

CT scan — A properly timed dynamic, triphasic, helical CT scan performed without contrast, and with contrast during the hepatic arterial and portal venous phases, will often be highly suggestive of the diagnosis [32,33]. The lesion may be hypo or isodense on non-contrast imaging with the central scar identified in one-third of patients. The lesion becomes hyperdense during the hepatic arterial phase due to the arterial origin of its blood supply (image 1). FNH is generally isodense during the portal venous phase, although the central scar may become hyperdense as contrast diffuses into the scar. While characteristic of FNH, a central scar may be present in the fibrolamellar variant of HCC. (See "Epidemiology, clinical manifestations, diagnosis, and treatment of fibrolamellar carcinoma", section on 'Imaging'.)

MRI — There may be little to distinguish FNH from normal liver on standard MRI, since it is composed of the same elements as normal liver. An isointense lesion is noted on T1-weighted images, while an isointense to slightly hyperintense mass appears on T2-weighted images (image 2 and image 3) [34]. The scar typically shows high signal intensity on T2-weighted images due to vessels or edema in the scar (image 3) [35]. Gadolinium infusion produces rapid enhancement of the FNH mass due to its arterial blood supply, producing a hyperintense lesion on early films (image 2). On delayed images it becomes more isointense with respect to normal liver. The central scar enhances on delayed imaging as contrast gradually diffuses into the fibrous center of the mass [36-39]. In one study, gadolinium enhanced MRI had a sensitivity and specificity of 70 and 98 percent, respectively [24].

A relatively new MR contrast agent has been introduced into clinical use. Unlike currently used gadolinium-based contrast agents for MRI, this agent, a Gd-BOPTA chelate of Gadobenate Dimeglumine, has a dual route of elimination, through both renal and hepatobiliary excretion (image 4). Thus, it can be useful for distinguishing hepatic adenomas from focal nodular hyperplasia. (See "Solid liver lesions: Differential diagnosis and evaluation".)

Angiography — Although angiography may reveal the diagnostic "spoked wheel" appearance of FNH, its use is rarely indicated [32,40,41].

ROLE OF ORAL CONTRACEPTIVES — FNH was first described in the early 1900s, long before the advent of oral contraceptives (OCPs). It is seen in men and children who do not use OCPs and its incidence remained steady after the introduction of OCPs in 1960, in sharp contrast to the dramatic rise in the incidence of HA with the widespread use of OCPs. Thus use of OCPs is not required for the development of FNH [42-44].

On the other hand, FNH may be responsive to estrogens [11]. Patients taking OCPs tend to have larger, more vascular tumors, have more symptoms, and reports of hemorrhage or rupture in patients with FNH have all occurred in patients taking OCPs [45-48]. However, the magnitude of the risk associated with OCPs is uncertain. In a study of 216 women with FNH, use of OCPs did not appear to influence the size or number of FNH lesions or size changes (which were rare) during follow-up for an average of two years [49]. A case control trial comparing 23 women with histologically confirmed FNH to 94 controls estimated the odds ratio of OCP use to be 2.8 (95% CI, 0.8 to 9.4) for those who had ever used OCPs and 4.5 (95% CI, 1.2 to 16.9) for those who had ≥3 years of use [50].

We generally do not insist that oral contraceptives and other estrogen containing preparations should be discontinued. However, it is reasonable to obtain a follow-up imaging study in 6 to 12 months in women who continue taking these drugs.

MANAGEMENT — The natural history of FNH is one of stability and lack of complications. Lesions generally do not change over time, although they occasionally become smaller [49,51-54]. However, as mentioned above, enlargement of FNH in the setting of OCPs and during pregnancy have been reported [55]. There is no evidence for malignant transformation of FNH [13,24,56,57].

Patients who are suspected of having FNH based upon the evaluation described above should be managed conservatively [24,35,49,51,52,54,58,59]. If a diagnosis remains unclear, a liver biopsy may be helpful, but may also be misleading since only resection will be definitive [60]. Follow-up studies at three and six months will often be sufficient to confirm the stability of the lesion and its benign nature, after which no long-term follow-up is required routinely. Surgery should be reserved for the rare, very symptomatic FNH lesion, and the highly suspicious lesion, which has eluded diagnosis by all other modalities.

We generally do not insist that oral contraceptives and other estrogen containing preparations should be discontinued. However, it is reasonable to obtain a follow-up imaging study in 6 to 12 months in women who continue taking these drugs. Small FNH do not appear to pose a significant risk to a successful pregnancy [49,61], although close observation is strongly recommended and resection may be prudent for large (>8 cm) FNH.

SUMMARY AND RECOMMENDATIONS

●Focal nodular hyperplasia (FNH) is a non-malignant hepatic tumor that is not of vascular origin. It is now generally accepted to be a hyperplastic (regenerative) response to hyperperfusion by the characteristic anomalous arteries found in the center of these nodules. (See 'Pathogenesis' above.)

●FNH is most often solitary (80 to 95 percent) and usually less than 5 cm in diameter. Only 3 percent are larger than 10 cm. (See 'Pathology' above.)

●The majority of reports have found that symptoms or signs directly attributable to FNH are infrequent. (See 'Symptoms' above.)

●The diagnosis of FNH is usually made by demonstrating its characteristic features on imaging tests and excluding other lesions. The latter can typically be accomplished by assessing the context in which FNH is detected and by obtaining specific radiologic and laboratory testing (table 1). (See 'Diagnosis' above and "Solid liver lesions: Differential diagnosis and evaluation".)

●The natural history of FNH is one of stability and a lack of complications. Thus, we suggest that patients who are suspected of having FNH based upon the evaluation described above be managed conservatively (Grade 2B). (See 'Management' above.)

●FNH may be responsive to exogenous estrogens. We generally do not insist that oral contraceptives and other estrogen-containing preparations should be discontinued. However, it is reasonable to obtain a follow-up imaging study in 6 to 12 months in women who continue taking these drugs. (See 'Role of oral contraceptives' above.)

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Histologic scoring of liver biopsy in focal nodular hyperplasia with atypical presentation. Hepatology 2002; 35:414. 61.Weimann A, Mössinger M, Fronhoff K, et al. Pregnancy in women with observed focal nodular hyperplasia of the liver. Lancet 1998; 351:1251.

HCC Differnetial Table

Abbreviations: RUQ= Right upper quadrant of the abdomen, LUQ= Left upper quadrant, LLQ= Left lower quadrant, RLQ= Right lower quadrant, LFT= Liver function test, SIRS= Systemic inflammatory response syndrome, ERCP= Endoscopic retrograde cholangiopancreatography, IV= Intravenous, N= Normal, AMA= Anti mitochondrial antibodies, LDH= Lactate dehydrogenase, GI= Gastrointestinal, CXR= Chest X ray, IgA= Immunoglobulin A, IgG= Immunoglobulin G, IgM= Immunoglobulin M, CT= Computed tomography, PMN= Polymorphonuclear cells, ESR= Erythrocyte sedimentation rate, CRP= C-reactive protein, TS= Transferrin saturation, SF= Serum Ferritin, SMA= Superior mesenteric artery, SMV= Superior mesenteric vein, ECG= Electrocardiogram

Disease	Clinical manifestations													Diagnosis		Comments
	Symptoms									Signs
	Abdominal Pain	Fever	Rigors and chills	Nausea or vomiting	Jaundice	Constipation	Diarrhea	Weight loss	GI bleeding	Hypo- tension	Guarding	Rebound Tenderness	Bowel sounds	Lab Findings	Imaging
Hepatocellular carcinoma/Metastasis	RUQ	+	−	+	+	+	+	+	+	+	−	+	Normal Hyperactive if obstruction present	High levels of AFP in serum Abnormal liver function tests Thrombocytopenia	US CT MRI Liver biopsy	Other symptoms: Splenomegaly Variceal bleeding Ascites Spider nevi Asterixis
Cholangiocarcinoma	RUQ	+	−	+	+	−	−	+	−	−	−	+	Normal	Elevated CA 19-9 Increased amylase / lipase Increased stool fat content	Contrast-enhanced ultrasound CT scan Calcification Pseudocyst Dilation of main pancreatic duct MRI	Predisposes to pancreatic cancer
Pancreatic carcinoma	MidEpigastric	−	−	+	+	+	−	+	−	−	−	+	Normal	↑ Alkaline phosphatase ↑ serum bilirubin ↑ gamma-glutamyl transpeptidase ↑ CA 19-9	MDCT with PET/CT MRI EUS	Skin manifestations may include: Bullous pemphigoid Cicatricial pemphigoid Migratory superficial thrombophlebitis (classic Trousseau's syndrome) Pancreatic panniculitis
Focal nodular hyperplasia	Diffuse	±	−	−	±	−	−	+	+	−	−	−	Normal	Normal Liver function tests Normal AFP Minor elevations of Aspartate Alanine aminotransferase Alkaline phosphatase Gamma glutamyl transpeptidase	Us Multiphasic helical CT scan	Open biopsy if diagnosis can not be established
Disease	Abdominal Pain	Fever	Rigors and chills	Nausea or vomiting	Jaundice	Constipation	Diarrhea	Weight loss	GI bleeding	Hypo- tension	Guarding	Rebound Tenderness	Bowel sounds	Lab Findings	Imaging	Comments
Gallbladder cancer	Midepigastric	−	−	+	+	−	+	+	−	−	−	−	Normal	↑ Alkaline phosphatase ↑ CA 19-9	US CT MRI
Liver hemangioma	Intermittent RUQ	−	−	+	+	−	−	−	−	−	−	−	Normal	Abnormal LFTs	US Single-photon emission computerized tomography(SPECT) MRI	US will reveal hypoechoic lesions
Liver abscess	RUQ	+	−	+	+	−	−	+	−	−	−	−	Normal	Hypoalbuminemia Abnormal liver function tests	US CT
Cirrhosis	RUQ+Bloating	+	−	+	+	−	−	+	−	−	−	−	Normal	Hypoalbuminemia Prolonged PT Abnormal LFTs Hyponatremia Thrombocytopenia	US Nodular, shrunken liver Ascites	Stigmata of liver disease Cruveilhier- Baumgarten murmur
Inflammatory lesions	RUQ	±	−	+	+	−	−	−	−	−	−	−	Normal	Hypoalbuminemia Prolonged PT Abnormal LFTs Hyponatremia Thrombocytopenia	US Nodular,shrunken or coarse liver	Stigmata of liver disease

Classification

Historical Perspective

Pathophysiology

Causes

Differentiating Splenic Rupture from Other Diseases

Epidemiology and Demographics

Risk Factors

Screening

Natural History, Complications and Prognosis

Diagnosis

Diagnostic Study of Choice

History and Symptoms

Physical Examination

Laboratory Findings

Electrocardiogram

X-Ray

MRI

Other Imaging Findings

Other Diagnostic Studies

Algorithms

Major molecular events in the pathogenesis of HCC

Genomic alterations

Epigenetic modifications

Growthfactor pathway alterations

Gene Mutations

Gene Amplification

DNA methylation micro RNA

Micro RNA

LNC RNA

Major Signaling pathways

•TERT promoter •TP53 •CTNNB1 •AXIN1 •AXIN2 •ATM •RPS6KA3 •JAK1 •IL6R •IL6ST •ARID1 •ARID2

•CCND1 •FGF19 •CDKNA2A •CDKNA2B •AXIN1 •IRF2 •MET

GSTP1 •E-Cadherin •CDKNA2 •RASSF1A •SOCS-3 •MIGMT

•MiR-155 •Mir-122 •Mir-224 •Mir-21

•HULC •HEIH •Dreh •MVIH •HOTAIR •MDIG •LINE1

•Wnt/β –catenin •Tyrosine kinase pathways EGF HGF/c-MET FGF VEGF •IGF •HIF •TGF β •Hedgehog

Elderly Male with jaundice from pancreatic cancer, By James Heilman, MD (Own work) [CC BY 3.0 (http://creativecommons.org/licenses/by/3.0)], via Wikimedia Commons

The incidence of HCC has almost tripled since the early 1980s in the United States where it is the fastest rising cause of cancer-related deaths1. According to population based Surveillance Epidemiology and End Results registry data, the overall HCC age adjusted incidence rates for liver and intrahepatic ducts cancer is as high as 8 per 100,000 underling population in 2010 (Fig. 1) of which at least 6 per 100,000 related to HCC. Men are at approximately three times higher risk than women. Asian men (i.e., Chinese, Korean, Filipino, and Japanese) have the highest age-adjusted incidence rates. However, the largest proportional increases have occurred among Hispanics followed by blacks and non-Hispanic whites, whereas the lowest proportional increases have occurred among Asians. In contrast to Asians/Pacific Islanders, HCC incidence rates are reported to be higher among Hispanics born in the United States than among foreign-born Hispanics2. HCC incidence rates have increased in each successive birth cohort born between 1900 and 19593 (Fig. 2). In addition, the age distribution of HCC patients has shifted to younger ages, with the greatest proportional increases among individuals 45–60 years old (Fig. 2). There is a south to north gradient in the incidence and mortality of HCC; Southern states including Texas, Louisiana, and Mississippi have some of the highest HCC incidence rates in the nation (Fig. 3). In one study, Texas Latino and especially South Texas Latinos had the highest age-adjusted HCC incidence rates (as high as 10.6/100,000)4.

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Normal versus Abnormal Barium study of esophagus with varices

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C. burnetii, the Q fever causing agent

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Gallery

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  Histopathology of a pancreatic endocrine tumor (insulinoma). Source:https://librepathology.org/wiki/Neuroendocrine_tumour_of_the_pancreas

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  Histopathology of a pancreatic endocrine tumor (insulinoma). Chromogranin A immunostain. Source:https://librepathology.org/wiki/Neuroendocrine_tumour_of_the_pancreas

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  Histopathology of a pancreatic endocrine tumor (insulinoma). Insulin immunostain. Source:https://librepathology.org/wiki/Neuroendocrine_tumour_of_the_pancreas

References

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [6]; Associate Editor(s)-in-Chief: Dildar Hussain, MBBS [7]

Kawasaki Disease

Overview

Kawasaki disease, also known as lymph node syndrome, mucocutaneous node disease, infantile polyarteritis and Kawasaki syndrome, is a poorly understood self-limited vasculitis that affects many organs, including the skin and mucous membranes, lymph nodes, blood vessel walls, and the heart. It does not seem to be contagious.It was first described in 1967 by Dr. Tomisaku Kawasaki in Japan. Kawasaki disease is predominantly a disease of young children, with 80% of patients younger than 5 years of age. Additional risk factors in the United States include Asian race and male sex. Kawasaki disease can cause vasculitic changes (inflammation of blood vessels) in the coronary arteries and subsequent coronary artery aneurysms. Common symptoms of kawasaki disease include high grade fever, red eyes, bright red and cracked lips, red mucous membranes in the mouth, strawberry tongue, white coating on the tongue or prominent red bumps (papillae) on the back of the tongue, red palms of the hands and the soles of the feet, swollen hands and feet, and rash. Intravenous Immunoglobulin (IVIG) and aspirin are indicated in kawasaki disease.

Historical Perspective

The Historical data on Kawasaki is described below:

• In 1961, Dr. Tomisaku Kawasaki saw his first case of Kawasaki disease.
• In 1967, Kawasaki published his first report of Kawasaki disease in Japanese.
• In 1960s, pathologist Noboru Tanaka and pediatrician Takajiro Yamamoto disputed the early assertion of Kawasaki that Kawasaki disease was a self-limited illness with no sequelae.
• In 1970, first Japanese nationwide survey of Kawasaki disease was conducted and 10 autopsy cases of sudden cardiac death after Kawasaki disease were documented.
• In 1973, at the University of Hawaii hospital, pathologist Eunice Larson, in collaboration with Benjamin Landing at the Los Angeles Children's Hospital, retrospectively established a diagnosis of Kawasaki disease in a 1971 autopsy case.
• In 1974, Tomisaku Kawasaki published the first English-language report of 50 patients with Kawasaki disease.
• By 1974, the link between Kawasaki disease and coronary artery vasuclitis was well established.
• In 1976, he first cases of Kawasaki disease outside of Japan were reported in Hawaii.
• In 1988, the Committee on infectious diseases of the American Academy of Pediatrics declared IVIG treatment as the recommended therapy for Kawasaki disease.
• In 2006 march, Kawasaki disease was mentioned in the television programs Nip/Tuck and Without a Trace In the episode All In of the TV series House, it was inexplicably mentioned as a possible diagnosis for a 6 year old boy that was admitted with bloody diarrhea and coordination problems, as well as an elderly woman with unexplained respiratory, cardiovascular and neural deficiencies. Maxie Jones, a fictional character on General Hospital suffers from it. According to John Travolta and Kelly Preston, their son Jett Travolta also suffers from the disease.

Classification

Pathophysiology

The exact pathogenesis of [disease name] is not fully understood.

OR

It is thought that [disease name] is the result of / is mediated by / is produced by / is caused by either [hypothesis 1], [hypothesis 2], or [hypothesis 3].

OR

[Pathogen name] is usually transmitted via the [transmission route] route to the human host.

OR

Following transmission/ingestion, the [pathogen] uses the [entry site] to invade the [cell name] cell.

OR

[Disease or malignancy name] arises from [cell name]s, which are [cell type] cells that are normally involved in [function of cells].

OR

The progression to [disease name] usually involves the [molecular pathway].

OR

The pathophysiology of [disease/malignancy] depends on the histological subtype.

Causes

• The Infectious agents which are thought to induce kawasaki disease are:
  • Parvovirus B19
  • Meningococcal septicemia
  • Adenovirus
  • Bacterial toxin–mediated superantigens
  • Cytomegalovirus
  • Epstein-Barr virus
  • Human lymphotropic virus infection
  • Klebsiella pneumoniae bacteremia
  • Mycoplasma pneumoniae
  • Mite-associated bacteria
  • Measles
  • Propionibacterium acnes
  • Parainfluenza type 3 virus
  • Rotavirus infection
  • Rickettsia species
  • Tick-borne diseases

Differentiating Kawasaki disease from other diseases

Different rash-like conditions can be confused with Kawasaki disease and are thus included in its differential diagnosis. The various conditions that should be differentiated from Kawasaki disease include:

Disease	Features
Kawasaki disease	Commonly presents with high and persistent fever, red mucous membranes in mouth, "strawberry tongue", swollen lymph nodes and skin rash in early disease, with peeling off of the skin of the hands, feet and genital area.
Impetigo	It commonly presents with pimple-like lesions surrounded by erythematous skin. Lesions are pustules, filled with pus, which then break down over 4-6 days and form a thick crust. It's often associated with insect bites, cuts, and other forms of trauma to the skin.
Insect bites	The insect injects formic acid, which can cause an immediate skin reaction often resulting in a rash and swelling in the injured area, often with formation of vesicles.
Measles	Commonly presents with high fever, coryza and conjunctivitis, with observation of oral mucosal lesions (Koplik's spots), followed by widespread skin rash.
Monkeypox	The presentation is similar to smallpox, although it is often a milder form, with fever, headache, myalgia, back pain, swollen lymph nodes, a general feeling of discomfort, and exhaustion. Within 1 to 3 days (sometimes longer) after the appearance of fever, the patient develops a papular rash, often first on the face. The lesions usually develop through several stages before crusting and falling off.
Rubella	Commonly presents with a facial rash which then spreads to the trunk and limbs, fading after 3 days, low grade fever, swollen glands, joint pains, headache and conjunctivitis. The rash disappears after a few days with no staining or peeling of the skin. Forchheimer's sign occurs in 20% of cases, and is characterized by small, red papules on the area of the soft palate.
Atypical measles	The symptoms commonly begin about 7-14 days after infection and present as fever, cough, coryza and conjunctivitis. Observation of Koplik's spots is also a characteristic finding in measles.
Coxsackievirus	The most commonly caused disease is the Coxsackie A disease, presenting as hand, foot and mouth disease. It may be asymptomatic or cause mild symptoms, or it may produce fever and painful blisters in the mouth (herpangina), on the palms and fingers of the hand, or on the soles of the feet. There can also be blisters in the throat or above the tonsils. Adults can also be affected. The rash, which can appear several days after high temperature and painful sore throat, can be itchy and painful, especially on the hands/fingers and bottom of feet.
Acne	It is typical of teenagers, usually appears on the face and upper neck, but the chest, back and shoulders may have acne as well. The upper arms can also have acne, but lesions found there are often keratosis pilaris, not acne. The typical acne lesions are comedones and inflammatory papules, pustules, and nodules. Some of the large nodules were previously called "cysts"
Syphilis	It commonly presents with gneralized systemic symptoms such as malaise, fatigue, headache and fever. Skin eruptions may be subtle and asymptomatic It is classically described as: Non-pruritic bilateral symmetrical mucocutaneous rash Non-tender regional lymphadenopathy Condylomata lata and Patchy alopecia.
Molluscum contagiosum	The lesions are commonly flesh-colored, dome-shaped, and pearly in appearance. They are often 1-5 millimeters in diameter, with a dimpled center. Generally not painful, but they may itch or become irritated. Picking or scratching the lesions may lead to further infection or scarring. In about 10% of the cases, eczema develops around the lesions. They may occasionally be complicated by secondary bacterial infections.
Mononucleosis	Common symptoms include low-grade fever without chills, sore throat, white patches on tonsils and back of the throat, muscle weakness and sometime extreme fatigue, tender lymphadenopathy, petechial hemorrhage and skin rash.
Toxic erythema	It is a common rash in infants, with clustered and vesicular appearance.
Rat-bite fever	It commonly presents with fever, chills, open sore at the site of the bite and rash, which may show red or purple plaques.
Parvovirus B19	The rash of fifth disease is typically described as "slapped cheeks," with erythema across the cheeks and sparing the nasolabial folds, forehead, and mouth.
Cytomegalovirus	The common symptoms include sore throat, swollen lymph nodes, fever, headache, fatigue, weakness, muscle pain and loss of appetite.
Scarlet fever	It commonly includes fever, punctate red macules on the hard and soft palate and uvula (Forchheimer's spots), bright red tongue with a "strawberry" appearance, sore throat and headache and lymphadenopathy.
Rocky Mountain spotted fever	The symptoms may include maculopapular rash, petechial rash, abdominal pain and joint pain.
Stevens-Johnson syndrome	The symptoms may include fever, sore throat and fatigue. Commonly presents ulcers and other lesions in the mucous membranes, almost always in the mouth and lips but also in the genital and anal regions. Those in the mouth are usually extremely painful and reduce the patient's ability to eat or drink. Conjunctivitis of the eyes occurs in about 30% of children. A rash of round lesions about an inch across, may arise on the face, trunk, arms and legs, and soles of the feet, but usually not on the scalp.
Varicella-zoster virus	It commonly starts as a painful rash on one side of the face or body. The rash forms blisters that typically scab over in 7-10 days and clears up within 2-4 weeks.
Chickenpox	It commonly starts with conjunctival and catarrhal symptoms and then characteristic spots appearing in two or three waves, mainly on the body and head, rather than the hands, becoming itchy raw pox (small open sores which heal mostly without scarring). Touching the fluid from a chickenpox blister can also spread the disease.
Meningococcemia	It commonly presents with rash, petechiae, headache, confusion, and stiff neck, high fever, mental status changes, nausea and vomiting.
Rickettsial pox	The first symptom is commonly a bump formed by a mite-bite, eventually resulting in a black, crusty scab. Many of the symptoms are flu-like including fever, chills, weakness and muscle pain but the most distinctive symptom is the rash that breaks out, spanning the person's entire body.
Meningitis	It commonly presents with headache, nuchal rigidity, fever, petechiae and altered mental status.

Disease	Epidemiology	Predisposing factors	Clinical features		Lab abnormalities
			Signs	Symptoms
Kawasaki disease	Occurs in children, usually age 1-4 years	Interaction of genetic and environmental factors, possibly including an infection in combination with genetic predisposition to an autoimmune mechanism (autoimmune vasculitis)	Non-suppurative, painless bilateral conjunctival inflammation (conjunctivitis), strawberry tongue (marked redness with prominent gustative papillae), deep transverse grooves across the nails may develop (Beau’s lines), lymphadenopathy present(acute, non-purulent, cervical), may lead to coronary artery aneurysms.	High and persistent fever that is not very responsive to normal treatment with acetaminophen or NSAIDs,  diffuse macular-papular erythematous rash	Liver function tests may show evidence of hepatic inflammation and low serum albumin levels, low hemoglobulin and age-adjusted hemoglobulin concentrations, thrombocytosis, anemia. Echocardiographic abnormalities, such as valvulitis (mitral or tricuspid regurgitation) and coronary artery lesions, are significantly more common in Kawasaki disease. Pyuria of uretheral origin.
Toxic shock syndrome	Occurs in both adults and children (9:1 female predominance)	Occurs in association with vaginitis during menstruation following tampon use (S. aureus); as a complication of soft tissue infections (S. pyogenes or GAS) or in females undergoing medical abortion (C. sordellii).	Hypotension, tachycardia, mucous membrane hyperemia (vaginal, oral, conjunctival)	Fever, diarrhea, vomiting, diffuse scarlantiform rash	Hyponatremia and uremia. Hepatic dysfunction (total bilirubin, serum asparate aminotransferase or serum alanine aminotransferase levels >2 times upper normal limit), leukocytosis with a polymorphonuclear shift to the left. Platelets < 100,000 per mm3 (thrombocytopenia), pyuria of renal origin.
Scarlet fever	Distributed equally among both genders. Most commonly affects children between five and fifteen years of age.	Occurs after streptococcal pharyngitis/tonsillitis	Pastia's sign (puncta and skin crease accentuation of the erythema), strawberry tongue, cervical lymphadenopathy may be present. Scarlet fever appears similar to Kawasaki's disease in some aspects, but lacks the eye signs or the swollen, red fingers and toes	Characteristic sandpaper-like rash which appears days after the illness begins (although the rash can appear before illness or up to 7 days later), rash may first appear on the neck, underarm, and groin	Leukocytosis with left shift and possibly eosinophilia a few weeks after convalescence. Anti-deoxyribonuclease B, antistreptolysin-O titers (antibodies to streptococcal extracellular products), antihyaluronidase, and antifibrinolysin may be positive.

Kawasaki disease must be differentiated from other causes of fever and rash in infants

Differential Diagnosis of Measles. Table adapted from CDC Pinkbook.

Disease	Agent	Typical Season	Typical Age	Prodrome	Fever	Duration of the rash (days)	Rash	Other Signs & Symptoms
Kawasaki disease	Unknown	Winter - Spring	< 5 years	3 days of abrupt fever	High; fever of 5 days is a diagnostic criteria	5 - 7	Erythematous, morbilliform, maculopapular or scarlatiniform, central distribution; erythematous, indurated palms and soles	Acute: dry, fissured and injected lips, strawberry tongue; irritability; cervical lymphadenopathy; conjunctival injection; peripheral edema; Subacute: finger-tip desquamation; Complications: arthritis, carditis
Measles	Paramyxovirus Measles virus	Winter - Spring	1 to 20 years	2-4 days of cough, conjunctivitis, and coryza	High	5 - 6	Erythematous, irregular size, maculopapular; starts on temples and behind ears; progresses down from face; fades to brownish	Koplik's spots: C blue-white papules (salt grains) on bright red mucosa opposite premolar teeth
Roseola Infantum (exanthem subitum)	Human herpes virus type 6	Any season	6 months to 2 years	None	High	1-2; it follows defervescence	Discrete erythematous macules, rarely involves face, begins as fever ends	Lymphadenopathy, irritability
Rubella	Togavirus	Spring	7 months to 29 years	0 - 4 days; mild malaise, fever; absent in children	Low grade	1 - 3	Discrete, rose-pink, diffuse, maculopapular; progresses downward from face, may change quickly	Arthralgia (usually in adults), tender posterior cervical and suboccipital lymphadenopathy, malaise, petechiae on soft palate
Scarlet Fever	ß-hemolytic streptococci	Winter	> 2 years	0 - 6 day, marked	Low to high	2 - 7	Scarlet "sunburn" with punctate papules "sandpaper", circumoral pallor, increased intensity in skin folds, blanches stars face/head, upper trunk and progresses downward	Sore throat, exudative tonsillitis, vomiting, abdominal pain, lmphadenopathy, white then red strawberry tongue
Erythema Infectiosum (Fifth Disease)	Human parvovirus type B19	Spring	5 - 10 years	None, usually in children, may occur in adults	None to low-grade	2 - 4	Starts as “slapped cheek”, maculopapular; progresses to reticular (lacy) pattern; can recur with environmental changes such as sunlight exposure	Arthralgia/arthritis in adults, adenopathy
Enterovirus	Echovirus Coxsackie virus	Summer - Fall	Mainly childhood	0 - 1 day fever and myalias	Low to high	1 - 5	Fine, pink, always affects face; variant is Boston exanthem (large ~ 1 cm, discrete maculopapules)	Sore throat, headache, malaise, no lymphadenopathy, gastroenteritis
Dengue Fever	Flavivirus Dengue virus types 1 - 4			None	High	1 - 5	Generalized maculopapular rash after defervescence; spares palms and soles	Headache, myalgia, abdominal pain, pharyngitis, vomiting
Drug induced rash	Many	Any	Any	Possible due to underlying illness	Possible	Varies	Typically diffuse but may be concentrated in diaper area, typically no progression, erythema multiform rash can progress over a few days	Possibly due to underlying illness or complications
Infectious Mononucleosis	Epstein-Barr Virus	None	10 - 30 years	2 - 5 days of malaise and fatigue	Low to high	2 - 7	Trunk and proximal extremities. Rash common if Ampicillin given	Pharyngitis, lymphadenopathy, splenomegaly, malaise
Pharyngoconjunctival Fever	Adenovirus types 2, 3, 4, 7, 7a	Winter - Spring	< 5 years		Low to high	3 - 5	Starts on face and spreads down to trunk and extremities	Sore throat, conjunctivitis, headache, anorexia

The following table is a list of differential diagnosis oral lesions presenting similar to measles:

Disease	Presentation	Risk Factors	Diagnosis	Affected Organ Systems	Important features	Picture
Coxsackie virus	Fever Sores in the mouth Rash with blisters Aches	Pregnancy immunodeficiency	History and Physical exam Throat swabs Swabs from the lesion Tzanck test	Oral cavity Skin	Symptomatic treatment	<figure-inline><figure-inline><figure-inline></figure-inline></figure-inline></figure-inline>
Chicken pox	Conjunctival symptoms Catarrhal symptoms Characteristic spots on the trunk appearing in two or three waves Itching	Pregnancy Premature infants born to susceptible mothers All infants born at less than 28 weeks gestation or who weigh ≤1000 grams Immunocompromised	History and physical exam PCR to detect VZV in skin lesions (vesicles, scabs, maculopapular lesions)	Oral cavity Skin	Sodium bicarbonate in baths or antihistamines for itching Paracetamol (acetaminophen) for fever Prednisolone is contraindicated	<figure-inline><figure-inline><figure-inline></figure-inline></figure-inline></figure-inline>
Measles	Fever Rash Cough Coryza (runny nose) Conjunctivitis (pink eye) Malaise Koplick spots in mouth	Unvaccinated individuals Crowded and/or unsanitary conditions Traveling to less developed and developing countries Immunocompromized Winter and spring seasons Born after 1956 and never fully vaccinated Health care workers	History and examination PCR for Measles-specific IgM antibody PCR for Measles RNA	Oral cavity Skin Respiratory tract Eyes Throat	Caused by Morbillivirus Primary site of infection is the respiratory epithelium of the nasopharynx Transmitted in respiratory secretions, via aerosol droplets containing virus particles	<figure-inline><figure-inline><figure-inline></figure-inline></figure-inline></figure-inline>
Herpangina	Sudden fever Sore throat and dysphagia- These can occur several hours(up to 24 hours), before the appearance of the enanthem. Vomiting Abdominal pain Myalgia Headache Pharyngeal lesions	Attendance at a kindergarten/child care center Contact with herpangina cases Residence in rural areas Overcrowding Poor hygiene Low socioeconomic status	Clincial diagnosis Pharyngeal viral and bacterial cultures can be taken to exclude HSV infection and streptococcal pharyngitis.	Skin Oral Cavity	Characteristic enanthem- Punctate macule which evolve over a period of 24 hours to 2-4mm erythematous papules which vesiculate, and then centrally ulcerate. The lesions are usually small in number, and evolve rapidly. The lesions are seen more commonly on the soft palate and uvula. The lesions can also be seen on the tonsils, posterior pharyngeal wall and the buccal mucosa.	Erythema, vesicles and ulcerating lesions in herpangina
Primary herpetic gingivoestomatitis	Pin-head vesicles rupture to form painful irregular ulcerations covered by yellow-grey membrane Severe pain Submandibular lymphadenopathy Halitosis It involves buccal mucosa, tongue, posterior pharynx, and gingival and palatal mucosa	Direct contact HIV infection	Tzanck test demonstrates multinucleated epithelial giant cells Viral culture is the gold standard for diagnosis Direct immunofluorescence	Oral cavity Mucous membranes	Ulcers are common on lips, gums, throat, front of tongue, inside of the cheeks and roof of the mouth Treatment is with antiviral agents such as Valacyclovir and Famciclovir	<figure-inline><figure-inline><figure-inline></figure-inline></figure-inline></figure-inline>

Koplik spots must be differentiated from other diseases causing oral lesions such as leukoplakia and herpes simplex virus infection.

Disease	Presentation	Risk Factors	Diagnosis	Affected Organ Systems	Important features	Picture
Diseases predominantly affecting the oral cavity
Oral Candidiasis	Dysphagia or odynophagia White patches on the mouth and tongue	Newborn babies Denture users Poorly controlled diabetes As a side effect of medication, most commonly having taken antibiotics. Inhaled corticosteroids for the treatment of lung conditions (e.g, asthma or COPD) may also result in oral candidiasis which may be reduced by regularly rinsing the mouth with water after taking the medication. People with poor nutrition, specifically vitamin A, iron and folate deficiencies. People with an immune deficiency (e.g. as a result of AIDS/HIV or chemotherapy treatment). Women undergoing hormonal changes, like pregnancy or those on birth control pills. Organ transplantation patients	Clinical diagnosis Confirmatory tests rarely needed	Localized candidiasis Oral and esophageal candidasis Candida vulvovaginitis Chronic mucocutaneous candidiasis Invasive candidasis Candidaemia Candida endocarditis Candida osteoarticular disease	Oral candidiaisis is a benign self limiting disease unless accompanied by immunosuppression.	Tongue infected with oral candidiasis - By James Heilman, MD - Own work, CC BY-SA 3.0, httpscommons.wikimedia.orgwindex.phpcurid=11717223.jpg
Herpes simplex oral lesions	Fever Sore throat Painful ulcers	Stress Recent URTI Female sex	Physical examination Viral culture Tzanck smear	Orofacial Infection Anogenital Infection Ocular Infection Herpes Encephalitis Neonatal Herpes Herpetic Whitlow Herpes Gladiatorum	The symptoms of primary HSV infection generally resolve within two weeks	Oral herpes simplex infection - By James Heilman, MD - Own work, CC BY-SA 3.0, httpscommons.wikimedia.orgwindex.phpcurid=19051042.jpg
Aphthous ulcers	Painful, red spot or bump that develops into an open ulcer	Being a female Between the ages of 10-40 Family history of aphthous ulcers	Physical examination Diagnosis of exclusion	Oral cavity	Self-limiting , Pain decreases in 7 to 10 days, with complete healing in 1 to 3 weeks	Apthous ulcer on the lower surface of the tongue - By Ebarruda - Own work, CC BY-SA 3.0, httpscommons.wikimedia.orgwindex.phpcurid=7903358
Squamous cell carcinoma	Non healing ulcer, nodule, indurated plaque or mass May involve skin, lips, inside the mouth, throat or esophagus	Chronic sun or UV exposure Fair skin Elderly age (>45 yrs) Male sex Smoking	Physical exam Biopsy	Oral Cavity Floor of mouth Lateral tongue Throat Esophagus	Malignant Can spread to TMJ Some times associated with leukoplakia	Squamous cell carcinoma - By Luca Pastore, Maria Luisa Fiorella, Raffaele Fiorella, Lorenzo Lo Muzio - http://www.plosmedicine.org/article/showImageLarge.action?uri=info%3Adoi%2F10.1371%2Fjournal.pmed.0050212.g001, CC BY 2.5, https://commons.wikimedia.org/w/index.php?curid=15252632
Leukoplakia	White leathery spots on the mucous membranes of the tongue and inside of the mouth Lateral borders of tongue	Atypical Tobacco use Chronic irritation Immunodeficiency Bloodroot (sanguinaria)	Physical exam Diagnosis of exclusion Biopsy	Vulvar lesions occur independent of oral lesions	Associated with HIV Persistant white spots Benign but can progress to carcinoma after almost 10 years Oral proliferative verrucous leukoplakia is an aggressive sub type with multiple lesions and higher conversion to warts or carcinoma	Leukoplakia - By Aitor III - Own work, Public Domain, https://commons.wikimedia.org/w/index.php?curid=9873087
Melanoma	A lesion with ABCD Asymmetry Border irregularity Color variation Diameter changes Bleeding from the lesion	UV radiations Genetic predisposition Old age Male gender Family or personal history of melanoma Multiple benign or atypical nevi	ABCD characteristics Bleeding or ulceration may show malignancy Serum LDH may be elevated in case of malignancy Biopsy	Can metastasize All UV radiation or sun exposed areas can be effected independently 1-2 to hundreds of granules	Neural crest cell derivative Development begins with disruption of nevus growth control Progression involves MAPK/ERK pathway N-RAS or BRAF oncogene also involved	Oral melanoma - By Emmanouil K Symvoulakis, Dionysios E Kyrmizakis, Emmanouil I Drivas, Anastassios V Koutsopoulos, Stylianos G Malandrakis, Charalambos E Skoulakis and John G Bizakis - Symvoulakis et al. Head & Face Medicine 2006 2:7 doi:10.1186/1746-160X-2-7 (Open Access), [1], CC BY-SA 2.0, https://commons.wikimedia.org/w/index.php?curid=9839811
Fordyce spots	Rice-like granules or spots Small, painless, raised, pale, red or white 1 to 3 mm in diameter	Greasy skin types Some rheumatic disorders Hereditary nonpolyposis colorectal cancer Lower gingiva (gums) Vestibular mucosa	Physical exam Small keratin-filled pseudocysts May be seen on incidental mucosal biopsy Biopsy not done for them primarily	Oral cavity Vermilion border of the lips Oral mucosa of the upper lip Buccal mucosa in the commissural region often bilaterally Genitals	Benign neoplasms with sebaceous features Visible sebaceous glands No surrounding mucosal change Several adjacent glands may coalesce into a larger cauliflower-like cluster	Fordyce spots - Por Perene - Obra do próprio, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=19772899
Burning mouth syndrome	Burning or tingling on the lips, tongue, or entire mouth	Nutritional deficiencies Chronic anxiety or depression Diabetes type 2 Menopause Oral thrush or dry mouth, or damaged nerves transmitting taste Female gender Menopause	Presentation Physical exam	Oral cavity	Pain typically is low in the morning and builds up over the day Low dosages of benzodiazepines, tricyclic antidepressants or anticonvulsants may be effective
Torus palatinus	Bony growth on midline of the hard palate Nodular mass covered with normal mucosa	Genetic predisposition Autosomal dominant	Physical exam Types Flat tori Spindle tori Nodular tori Lobular tori	Hard palate	More common in Asian and Inuit populations Twice more common in females Repeated trauma can cause bleeding Surgery may be required in symptomatic	Torus palatinus - By Photo taken by dozenist, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=846591
Diseases involving oral cavity and other organ systems
Behcet's disease	Painful mouth sores Acne like skin lesions Headache, fever, poor balance, disorientation Abdominal pain, diarrhea or bleeding Uveitis Joint swelling and joint pain Genital sores wit pain and scaring Aneurysms	Over active immune system	Physical examination	Mouth Genitals GIT Eye Joints Skin Vascular system Brain	Outbreaks of exaggerated inflammation Affects smaller blood vessels	Behcet's disease - By Ahmet Altiner MD, Rajni Mandal MD - http://dermatology.cdlib.org/1611/articles/18_2009-10-20/2.jpg, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=17863021
Crohn's disease	Chronic, episodic diarrhea or constipation Abdominal pain Vomiting Weight loss or weight gain	Smoking Whites and European Jews Hormonal contraception Diets high in microparticles, sweet, fatty or refined foods Industrialized country	Typical history and symptoms Skip lesions on biopsy Anti-Saccharomyces cerevisiae antibodies (ASCA) Anti-neutrophil cytoplasmic antibodies (ANCA)	Eyes Joints Skin	May lead to Obstructions Abscesses Free perforation Hemorrhage
Agranulocytosis	Fever or chills Frequent infections Unusual redness, pain, or swelling around a wound Mouth ulcers Abdominal pain Burning sensation when urinating Sore throat	Medications Cytotoxic chemotherapy Hematologic malignancies Autoimmune disorders	Neutropenia <100 cells per micro litre Eosinopenia Basopenia	Oral cavity Skin GIT Urinary system Conjunctiva	Immunocompromization Types Drug-induced Malignant Autoimmune
Syphilis	Chancre Regional lymphadenopathy	Multiple sexual partners Illicit drug use Unprotected sex Men who have sex with men Residence in highly prevalent areas HIV infection Presence of other STIs Previous history of STIs Intravenous drug use	Darkfield microscopy Non treponemal tests like VDRL and RPR test) Treponemal testsFTA-ABS tests, (TP-PA) assay, enzyme immunoassays, and chemiluminescence immunoassays)	Oral cavity Penis Cervix Labia Anal canal Rectum CNS CVS	Primary syphilis Chancre Secondary syphilis Condylomata lata Latent syphilis Asymptomatic Tertiary syphilis Gummas Neurosyphilis	oral syphilis - By CDC/Susan Lindsley - http://phil.cdc.gov/phil_images/20021114/34/PHIL_2385_lores.jpg, Public Domain, https://commons.wikimedia.org/w/index.php?curid=2134349
Coxsackie virus	Fever Sores in the mouth Rash with blisters Aches	Pregnancy immunodeficiency	History and Physical exam Throat swabs Swabs from the lesion Tzanck test	Oral cavity Skin	Symptomatic treatment	Coxsackie virus stomatitis - Adapted from Dermatology Atlas.
Chicken pox	Conjunctival symptoms Catarrhal symptoms Characteristic spots on the trunk appearing in two or three waves Itching	Pregnancy Premature infants born to susceptible mothers All infants born at less than 28 weeks gestation or who weigh ≤1000 grams Immunocompromised	History and physical exam PCR to detect VZV in skin lesions (vesicles, scabs, maculopapular lesions)	Oral cavity Skin	Sodium bicarbonate in baths or antihistamines for itching Paracetamol (acetaminophen) for fever Prednisolone is contraindicated	Chickenpox - By James Heilman, MD - Own work, CC BY-SA 4.0, https://commons.wikimedia.org/w/index.php?curid=52872565
Measles	Fever Rash Cough Coryza (runny nose) Conjunctivitis (pink eye) Malaise Koplick spots in mouth	Unvaccinated individuals Crowded and/or unsanitary conditions Traveling to less developed and developing countries Immunocompromized Winter and spring seasons Born after 1956 and never fully vaccinated Health care workers	History and examination PCR for Measles-specific IgM antibody PCR for Measles RNA	Oral cavity Skin Respiratory tract Eyes Throat	Caused by Morbillivirus Primary site of infection is the respiratory epithelium of the nasopharynx Transmitted in respiratory secretions, via aerosol droplets containing virus particles	Koplick spots (Measles) - By CDC - http://phil.cdc.gov/PHIL_Images/20040908/4f54ee8f0e5f49f58aaa30c1bc6413ba/6111_lores.jpg, Public Domain, https://commons.wikimedia.org/w/index.php?curid=824483

Epidemiology and Demographics

KS occurs worldwide, with the highest incidence in Japan, and it most often affects boys and younger children. KS may have a winter-spring seasonality, and community-wide outbreaks have been reported occasionally. In the continental United States, population-based and hospitalization studies have estimated an incidence of KS ranging from 9 to 19 per 100,000 children younger than 5 years of age. Approximately 4248 hospitalizations for KS, of which 3277 (77%) were for children under 5 years of age, were estimated among children younger than 18 years of age in the United States in the year 2000.

CDC uses hospital discharge data, a passive KS surveillance system, and special studies to describe the incidence and epidemiology of KS in the United States. The KS surveillance system has been maintained by CDC since 1976 and is based on voluntary reporting of KS cases by health care providers and local and state health authorities. A standardized case report form is used to collect information on patients.

For epidemiologic surveillance, CDC defines a case of KS as illness in a patient with fever of 5 or more days duration (or fever until the date of administration of intravenous immunoglobulin if it is given before the fifth day of fever), and the presence of at least 4 of the following 5 clinical signs:

• Rash
• Cervical lymphadenopathy (at least 1.5 cm in diameter)
• Bilateral conjuctival injection
• Oral mucosal changes
• Peripheral extremity changes.

Patients whose illness does not meet the above KS case definition but who have fever and coronary artery abnormalities are classified as having atypical or incomplete KS.

Incidence

By far, the highest incidence of Kawasaki disease occurs in Japan (175 per 100,000), though its incidence in the United States is increasing. Kawasaki disease is predominantly a disease of young children, with 80% of patients younger than 5 years of age. Additional risk factors in the United States include Asian race and male sex.

Risk Factors

Screening

Natural History, Complications, and Prognosis

Natural History

Complications

Prognosis

The cardiac complications are, by far, the most important aspect of the disease. Kawasaki disease can cause vasculitic changes (inflammation of blood vessels) in the coronary arteries and subsequent coronary artery aneurysms. These aneurysms can lead to myocardial infarction (heart attack) even in young children. Overall, about 10–18% of children with Kawasaki disease develop coronary artery aneurysms, with much higher prevalence among patients who are not treated early in the course of illness. Kawasaki disease is the most common cause of acquired heart disease among children in the United States.

With early treatment, rapid recovery from the acute symptoms can be expected and the risk of coronary artery aneurysms greatly reduced. Untreated, the acute symptoms of Kawasaki disease are self-limited (i.e. the patient will recover eventually), but the risk of coronary artery involvement is much greater. Overall, about 2% of patients die from complications of coronary vasculitis. Patients who have had Kawasaki disease should have an echocardiogram initially every few weeks, and then every 1–2 years to screen for progression of cardiac involvement.

It is also not uncommon that a relapse of symptoms may occur soon after initial treatment with IVIG. This usually requires re-hospitalization and retreatment. Treatment with IVIG can cause allergic and non-allergic acute reactions, aseptic meningitis, fluid overload and, rarely, other serious reactions. Aspirin may increase the risk of bleeding from other causes and may be associated with Reye's syndrome. Overall, life-threatening complications resulting from therapy for Kawasaki disease are exceedingly rare, especially compared with the risk of non-treatment.

Diagnosis

Diagnostic Criteria

Kawasaki disease is diagnosed clinically (by medical signs and symptoms), and there exists no specific laboratory test that can tell if someone has it. It is normally difficult to establish the diagnosis, especially early in the course of illness, and frequently children are not diagnosed until they have seen their doctor several times, or visited a number of different health care providers. Many other serious illnesses can cause similar symptoms, and must be considered in the differential diagnosis, including scarlet fever, toxic shock syndrome, and juvenile idiopathic arthritis.

Classically, five days of fever plus four of five diagnostic criteria must be met in order to establish the diagnosis.

The criteria are:

(1) Mucositis: erythema of the palatine mucosa, fissure erythematous lips, "strawberry tongue"

(2) Rash: Polymorphus, usually urticarial erythematous rash mainly in external extremities. The rash can spread to trunk

(3) Extremities changes: Edema of hand and feet, erythema of palms & soles, desquamation of fingertips

(4) Bilateral non-exudative conjuctival erythema

(5) Cervical lymphadenopathy for at least 15 milimeters

Many children, especially infants, eventually diagnosed with Kawasaki disease do not exhibit all of the above criteria. In fact, many experts now recommend treating for Kawasaki disease even if only three days of fever have passed and at least three diagnostic criteria are present, especially if other tests reveal abnormalities consistent with Kawasaki disease. In addition, the diagnosis can be made purely by the detection of coronary artery aneurysms in the proper clinical setting.

History and Symptoms

Kawasaki disease often begins with a high and persistent fever that is not very responsive to normal doses of acetaminophen or ibuprofen. The fever may persist steadily for up to two weeks and is normally accompanied by irritability. Affected children develop red eyes, red mucous membranes in the mouth, red cracked lips, a "strawberry tongue", iritis, keratic precipitates (detectable by an ophthalmologist but usually too small to be seen by the unaided eye), and swollen lymph nodes. Skin rashes occur early in the disease, and peeling of the skin in the genital area, hands, and feet (especially around the nails and on the palms and soles) may occur in later phases. Some of these symptoms may come and go during the course of the illness. If left untreated, the symptoms will eventually relent, but coronary artery aneurysms will not improve, resulting in a significant risk of death or disability due to myocardial infarction (heart attack). If treated in a timely fashion, this risk can be mostly avoided and the course of illness cut short.

• High-grade fever (greater than 39 °C or 102 °F; often as high as 40 °C or 104 °F) that normally lasts for more than a week if left untreated.
• Red eyes (conjunctivitis) without pus or drainage, also known as "conjunctival injection"
• Bright red, chapped, or cracked lips
• Red mucous membranes in the mouth
• Strawberry tongue, white coating on the tongue or prominent red bumps (papillae) on the back of the tongue
• Red palms of the hands and the soles of the feet
• Swollen hands and feet
• Rash which may take many forms, but not vesicular (blister-like), on the trunk
• Swollen lymph nodes (frequently only one lymph node is swollen), particularly in the neck area
• Joint pain (arthralgia) and swelling, frequently symmetrical
• Irritability
• Tachycardia (rapid heart beat)
• Peeling (desquamation) palms and soles (later in the illness); peeling may begin around the nails

AHA Scientific Statement on Kawasaki Disease

Recommendations for Cardiovascular Assessment for Diagnosis and Monitoring During the Acute Illness

Class I

"1. Echocardiography should be performed when the diagnosis of KD is considered, but unavailability or technical limitations should not delay treatment.(Level of Evidence: B) "

"2. Coronary arteries should be imaged, and quantitative assessment of luminal dimensions, normalized as Z scores adjusted for body surface, should be performed.(Level of Evidence: B) "

"3. For uncomplicated patients, echocardiog- raphy should be repeated both within 1 to 2 weeks and 4 to 6 weeks after treatment.(Level of Evidence: B) "

"4. For patients with important and evolving coronary artery abnormalities (Z score >2.5) detected during the acute illness, more fre- quent echocardiography (at least twice per week) should be performed until luminal dimensions have stopped progressing to determine the risk for and presence of thrombosis.(Level of Evidence: B) "

Class IIa

"1. To detect coronary artery thrombosis, it may be reasonable to perform echocardiography for patients with expanding large or giant aneurysms twice per week while dimensions are expanding rapidly and at least once weekly in the first 45 days of illness, and then monthly until the third month after illness onset, because the failure to escalate thromboprophylaxis in time with the rapid expansion of aneurysms is a primary cause of morbidity and mortality . (Level of Evidence: C) "

Physical Examination

A physical examination will demonstrate many of the features listed above.

Laboratory Findings

• There are no specific laboratory findings associated with [disease name].

• A [positive/negative] [test name] is diagnostic of [disease name].
• An [elevated/reduced] concentration of [serum/blood/urinary/CSF/other] [lab test] is diagnostic of [disease name].
• Other laboratory findings consistent with the diagnosis of [disease name] include [abnormal test 1], [abnormal test 2], and [abnormal test 3].

Blood tests

• Complete blood count (CBC) may reveal normocytic anemia and eventually thrombocytosis
• Erythrocyte sedimentation rate (ESR) will be elevated
• C-reactive protein (CRP) will be elevated
• Liver function tests may show evidence of hepatic inflammation and low serum albumin

Imaging Findings

Other Diagnostic Studies

Other tests (may or may not be performed)

• Electrocardiogram may show evidence of ventricular dysfunction or, occasionally, arrhythmia due to myocarditis
• Echocardiogram may show subtle coronary artery changes or, later, true aneurysms.
• Ultrasound or computerized tomography may show hydrops (enlargement) of the gallbladder
• Urinalysis may show white blood cells and protein in the urine (pyuria and proteinuria) without evidence of bacterial growth
• Lumbar puncture may show evidence of aseptic meningitis
• Angiography was historically used to detect coronary artery aneurysms and remains the gold standard for their detection, but is rarely used today unless coronary artery aneurysms have already been detected by echocardiography.

Treatment

Medical Therapy

Intravenous Immunoglobulin (IVIG) and aspirin are indicated in the treatment of Kawasaki Disease. It is imperative that treatment be started as soon as the diagnosis is made to prevent damage to the coronary arteries. Except for Kawasaki disease and a couple of other indications, aspirin is otherwise normally not recommended for children due to its association with Reye's syndrome. Children with Kawasaki disease should be hospitalized.

• 1. Initial treatment

• Preferred regimen: IVIG 2 g/kg single infusion within the first 7-10 days of illness AND Aspirin 80-100 mg/kg/day qid , reduce the aspirin dose after the child has been afebrile for 48 to 72 hours, then begin low-dose aspirin (3 to 5 mg/kg/day) and maintain it until the patient shows no evidence of coronary changes by 6 to 8 weeks after the onset of illness
• Note (1): Other clinicians continue highdose aspirin until day 14 of illness and 48 to 72 hours after fever cessation
• Note (2): For children who develop coronary abnormalities, aspirin may be continued indefinitely

• 2. Treatment of Patients Who Failed to Respond to Initial Therapy (persistent or recrudescent fever ≥ 36 hours after completion of the initial IVIG infusion)

• Preferred regimen: IVIG 2 g/kg q24h for 1-3 days OR Methylprednisolone 30 mg/kg IV for 2-3 hours q24h for 1-3 days

AHA Scientific Statement on Kawasaki Disease

Recommendations for Initial Treatment With Intravenous Immunoglobulin (IVIG) and Asetil Salisilat Acid (ASA)

Class I

"1. Patients with complete KD criteria and those who meet the algorithm criteria for incomplete KD should be treated with high-dose IVIG (2 g/kg given as a single intravenous infusion) within 10 days of illness onset but as soon as possible after diagnosis.(Level of Evidence: A) "

Class IIa

"1. It is reasonable to administer IVIG to children presenting after the 10th day of illness (ie, in whom the diagnosis was missed earlier) if they have either persistent fever without other explanation or coronary artery abnormalities together with ongoing systemic inflammation, as manifested by elevation of ESR or CRP (CRP >3.0 mg/dL). (Level of Evidence: B) "

"2. Administrationofmoderate-(30–50mg·kg−1·d−1) to high-dose (80–100 mg·kg−¹·d−¹) ASA is reasonable until the patient is afebrile, although there is no evidence that it reduces coronary artery aneurysms. (Level of Evidence: C) "

Class III

"1. IVIG generally should not be administered to patients beyond the tenth day of illness in the absence of fever, significant elevation of inflammatory markers, or coronary artery abnormalities . (Level of Evidence: C) "

"2. The ESR is accelerated by IVIG therapy and therefore should not be used to assess response to IVIG therapy. A persistently high ESR alone should not be interpreted as a sign of IVIG resistance. (Level of Evidence: C) "

Recommendations for Adjunctive Therapies for Primary Treatment

Class IIb

"1. Administration of a longer course of corticosteroids (eg, tapering over 2–3 weeks), together with IVIG 2 g/kg and ASA, may be considered for treatment of high-risk patients with acute KD, when such high risk can be identified in patients before initiation of treatment. (Level of Evidence: B) "

Class III

"1. Single-dose pulse methylprednisolone should not be administered with IVIG as routine primary therapy for patients with Kawasaki Disease. (Level of Evidence: B) "

Recommendations for Additional Therapy in the IVIG-Resistant Patient

Class IIa

"1. It is reasonable to administer a second dose of IVIG (2 g/kg) to patients with persistent or recrudescent fever at least 36 hours after the end of the first IVIG infusion. (Level of Evidence: B) "

Class IIb

"1. Administration of high-dose pulse steroids (usually methylprednisolone 20–30 mg/kg intravenously for 3 days, with or without a subsequent course and taper of oral prednisone) may be considered as an alternative to a second infusion of IVIG or for retreatment of patients with KD who have had recurrent or recrudescent fever after additional IVIG. (Level of Evidence: B) "

"2. Administration of a longer (eg, 2–3 weeks) tapering course of prednisolone or prednisone, together with IVIG 2 g/kg and ASA, may be considered in the retreatment of patients with KD who have had recurrent or recrudescent fever after initial IVIG treatment. (Level of Evidence: B) "

"3. Administration of infliximab (5 mg/kg) may be considered as an alternative to a second infusion of IVIG or corticosteroids for IVIG-resistant patients. (Level of Evidence: C) "

"4. Administration of cyclosporine may be considered in patients with refractory KD in whom a second IVIG infusion, infliximab, or a course of steroids has failed. (Level of Evidence: C) "

"5. Administration of immunomodulatory monoclonal antibody therapy (except TNF-α block- ers), cytotoxic agents, or (rarely) plasma exchange may be considered in highly refractory patients who have failed to respond to a second infusion of IVIG, an extended course of steroids, or infliximab. (Level of Evidence: C) "

Recommendations for Treatment of Coronary Artery Thrombosis

Class I

"1. Coronary artery thrombosis with actual or impending occlusion of the arterial lumen should be treated with thrombolytic therapy or, in patients of sufficient size, by mechanical restoration of coronary artery blood flow at cardiac catheterization.(Level of Evidence: C) "

"2. Thrombolytic agents should be administered together with low-dose ASA and low-dose heparin, with careful monitoring for bleeding.(Level of Evidence: C) "

Class IIb

"1. Treatment of coronary artery thrombosis with substantial thrombus burden and high risk of occlusion with a combination of reduced-dose thrombolytic therapy and abciximab may be considered. (Level of Evidence: C) "

Risk-Stratified Recommendations for Long-Term Evaluation and Management

No Involvement (Z Score Always <2)

Class IIa

"1. It is reasonable to use echocardiographic coronary artery luminal dimensions converted to BSA-adjusted Z scores to determine risk stratification. (Level of Evidence: B) ". (Level of Evidence: C) "

Type and frequency of additional cardiology assessment (other cardiology testing)

Class IIa

"1. It is reasonable that no additional cardiology assessment be performed. (Level of Evidence: B) ". (Level of Evidence: C) "

Cardiovascular risk factor assessment and management

Class IIa

"1. It is reasonable to provide general counseling regarding healthy lifestyle and activity promotion at every visit; this may be provided by the primary care provider. (Level of Evidence: B) ". (Level of Evidence: C) "

"2. It is reasonable to assess blood pressure, fast- ing lipid profile, body mass index (and plot), waist circumference, dietary and activity assessment, and smoking at least once and ideally at least 1 year from the episode of acute KD; this may be performed by the primary care provider. (Level of Evidence: B) ". (Level of Evidence: C) "

Medical therapy (β-blockers, angiotensin-converting enzyme inhibitor [ACEI], statin)

Class III

"1. No additional medical therapy should be given. (Level of Evidence: C) "

Thromboprophylaxis

Class IIa

"1. It is reasonable to give low-dose ASA for up to 4 to 6 weeks after the episode of acute KD, which should be discontinued thereafter. (Level of Evidence: C) ". (Level of Evidence: C) "

Physical activity

Class IIa

"1. It is reasonable to provide physical activity counseling at every visit with no restrictions or precautions at any time. (Level of Evidence: B) ". (Level of Evidence: C) "

Reproductive counselling

Class IIa

"1. It is reasonable to provide age-appropriate counseling regarding contraception and pregnancy without modification. (Level of Evidence: B) ". (Level of Evidence: C) "

Dilation Only (Z Score ≥2 but <2.5, or a Decrease in Z Score During Follow-up ≥1)

Class IIa

"1. If luminal dimensions have returned to normal by 4 to 6 weeks after KD onset, it is reasonable to discharge the patient from cardiology care, although ongoing follow-up to 12 months may be considered. (Level of Evidence: B) ". (Level of Evidence: C) "

"2. If dilation remains present at 4 to 6 weeks after KD onset, then it is reasonable to continue follow-up to 12 months. If the luminal dimensions return to normal before then, it is reasonable to discharge the patient from ongoing cardiology care. (Level of Evidence: B) ". (Level of Evidence: C) "

"3. Resolution is expected within 1 year. If dilation persists at 1 year, consider whether this represents a dominant branch. If this is a probable explanation, then it is reasonable to discharge the patient from ongoing cardiology care, although ongoing follow-up every 2 to 5 years may be considered. Patients and families should be advised to remember that having had KD is part of the patient’s permanent medical history. (Level of Evidence: C) ". (Level of Evidence: C) "

Type and frequency of additional cardiology assessment (other cardiology testing)

Class IIa

"1. It is reasonable that no additional cardiology assessment be performed. (Level of Evidence: B) ". (Level of Evidence: C) "

Cardiovascular risk factor assessment and management

Class IIa

"1. It is reasonable to provide general counseling regarding healthy lifestyle and activity promotion at every visit; this may be provided by the primary care provider. (Level of Evidence: C) ". (Level of Evidence: C) "

"2. It is reasonable to assess blood pressure, fasting lipid profile, body mass index (and plot), waist circumference, dietary and activity assessment, and smoking at least once and ideally at least 1 year from the episode of acute KD; this may be performed by the primary care provider. (Level of Evidence: C) ". (Level of Evidence: C) "

Medical therapy (β-blockers, ACEI, statin)

Class III

"1. No additional medical therapy should be given. (Level of Evidence: C) "

Thromboprophylaxis

Class IIa

"1. It is reasonable to give low-dose ASA until 4 to 6 weeks after the acute episode, which should be discontinued thereafter. (Level of Evidence: C) ". (Level of Evidence: C) "

Physical activity

Class IIa

"1. It is reasonable to provide physical activity counseling at every visit with no restrictions or precautions at any time. (Level of Evidence: B) "

Reproductive counseling

Class IIa

"1. It is reasonable to provide age-appropriate counseling regarding contraception and pregnancy without modification. (Level of Evidence: B) "

Regression to Normal Z Score or Dilation Only

Frequency of cardiology assessment (to include history and physical examination, echocardiography, electrocardiography)

Class IIa

"1. It is reasonable to assess every 1 to 3 years. It is reasonable not to perform echocardiogra- phy unless there is evidence for inducible myocardial ischemia or the patient has symptoms suggestive of ischemia or signs suggestive of ventricular dysfunction. (Level of Evidence: B) "

Type and frequency of additional cardiology assessment (other cardiology testing)

Class IIa

"1. It is reasonable to assess for inducible myocardial ischemia (stress echocardiography, stress with MRI, stress NM perfusion imaging, PET) every 3 to 5 years or if the patient has symptoms suggestive of ischemia or signs suggestive of ventricular dysfunction. (Level of Evidence: B) "

Class IIb

"1. Further imaging with angiography (CT, MRI, invasive) may be considered only if there is evidence for inducible myocardial ischemia or ventricular dysfunction. (Level of Evidence: C) "

Cardiovascular risk factor assessment and management

Class IIa

"1. It is reasonable to provide general counseling regarding healthy lifestyle and activity promotion at every visit; this may additionally be provided by the primary care provider.(Level of Evidence: C) "

"2. It is reasonable to assess blood pressure, fasting lipid profile, body mass index (and plot), waist circumference, dietary and activity assessment, and smoking every 2 years; this may be performed by the primary care provider. It is reasonable to obtain a follow- up fasting lipid profile. (Level of Evidence: C) "

Medical therapy (β-blockers, ACEI, statin)

Class IIb

"1. Empirical statin therapy for non–lipid-lowering (pleiotropic) effects may be considered.(Level of Evidence: C) "

Class III

"1. Empirical treatment with β-blockers is not indicated.(Level of Evidence: C) "

Thromboprophylaxis

Class IIb

"1. Ongoing treatment with low-dose ASA may be considered, although it is reasonable to discontinue.(Level of Evidence: C) "

Class IIa

"1. Use of an alternative antiplatelet agent (eg, a thienopyridine such as clopidogrel) instead of ASA is reasonable if the patient is intol- erant or resistant to ASA.(Level of Evidence: C) "

Physical activity

Class IIa

"1. It is reasonable to provide physical activity counseling at every visit with no restrictions or precautions at any time .(Level of Evidence: C) "

Reproductive counselling

Class IIa

"1. It is reasonable to provide age-appropriate counseling regarding contraception and pregnancy without modification.(Level of Evidence: B) "

Medium Aneurysms (Z Score ≥5 to <10, With an Absolute Luminal Dimension <8 mm)

Current or Persistent Medium Aneurysms

Frequency of cardiology assessment (to include history and physical examination, echocardiography, electrocardiography)

Class IIa

"1. It is reasonable to provide physical activity counseling at every visit with no restrictions or precautions at any time .(Level of Evidence: B) "

Type and frequency of additional cardiology assessment (other cardiology testing)

Class IIa

"1. It is reasonable to assess for inducible myo- cardial ischemia (stress echocardiography, stress with MRI, stress NM perfusion imaging, PET) every 1 to 3 years or if the patient has symptoms suggestive of ischemia or signs suggestive of ventricular dysfunction.(Level of Evidence: B) "

Class IIb

"1. Further imaging with angiography (CT, MRI, invasive) may be considered for periodic sur- veillance every 2 to 5 years.(Level of Evidence: C) "

Cardiovascular risk factor assessment and management

Class IIa

"1. It is reasonable to provide general counseling regarding healthy lifestyle and activity promotion at every visit; this may additionally be provided by the primary care provider.(Level of Evidence: C) "

"2. It is reasonable to assess blood pressure, fasting lipid profile, body mass index (and plot), waist circumference, dietary and activity assessment, and smoking at least once and ideally at least 1 year from the episode of acute KD; this may be performed by the primary care provider. It is reasonable to obtain a follow-up fasting lipid profile.(Level of Evidence: C) "

Medical therapy (β-blockers, ACEI, statin)

Class IIb

"1. Empirical statin therapy for non–lipid-lowering (pleiotropic) effects may be considered.(Level of Evidence: C) "

Class III

"1. Empirical treatment with β-blockers is not indicated.(Level of Evidence: C) "

Thromboprophylaxis

Class I

"1. Patients should be treated with low-dose ASA.(Level of Evidence: C) "

Class IIa

"1. Use of an alternative antiplatelet agent (eg, a thienopyridine such as clopidogrel) instead of ASA is reasonable if the patient is intoler- ant or resistant to ASA.(Level of Evidence: C) "

Class IIb

"1. Additional patient and coronary artery characteristics may be considered in decision making regarding intensification of thromboprophylaxis.(Level of Evidence: C) "

"2. Dual-antiplatelet therapy with an additional antiplatelet agent (eg, a thienopyridine such as clopidogrel) may be considered.(Level of Evidence: C) "

Class III

"1. Use of anticoagulation (warfarin, LMWH) is not indicated.(Level of Evidence: C) "

Physical activity

Class I

"1. For patients taking dual-antiplatelet therapy, activities involving a risk of bodily contact, trauma, or injury should be restricted or modified.(Level of Evidence: B) "

Class IIa

"1. It is reasonable to provide physical activity counseling at every visit without restrictions or precautions. Participation in competitive sports or high-intensity activities should be guided by results from testing for inducible myocardial ischemia or exercise-induced arrhythmias.(Level of Evidence: C) "

Reproductive counselling

Class IIa

"1. It is reasonable to discourage use of oral contraceptive drugs that increase thrombosis risk, to recommend that pregnancy be supervised by a multidisciplinary team including a cardiologist, and to alter thromboprophylaxis management during pregnancy and delivery.(Level of Evidence: B) "

Regression to Small Aneurysms

Frequency of cardiology assessment (to include history and physical examination, echocardiography, electrocardiography)

Class IIa

"1. Ongoing follow-up assessment every year is reasonable.(Level of Evidence: B) "

Type and frequency of additional cardiology assessment (other cardiology testing)

Class IIa

"1. It is reasonable to assess for inducible myocardial ischemia (stress echocardiography, stress with MRI, stress NM perfusion imaging, PET) every 2 to 3 years or if the patient has symptoms suggestive of ischemia or signs suggestive of ventricular dysfunction.(Level of Evidence: B) "

Class IIb

"1. Further imaging with angiography (CT, MRI, invasive) may be considered for periodic surveillance every 3 to 5 years.(Level of Evidence: C) "

Cardiovascular risk factor assessment and management

Class IIa

"1. It is reasonable to provide general counseling regarding healthy lifestyle and activity promotion at every visit; this may additionally be provided by the primary care provider.(Level of Evidence: C) "

"2. It is reasonable to assess blood pressure, fasting lipid profile, body mass index (and plot), waist circumference, dietary and activ- ity assessment, and smoking every year; this may be performed by the primary care provider. It is reasonable to obtain a follow- up fasting lipid profile.(Level of Evidence: C) "

Medical therapy (β-blockers, ACEI, statin)

Class IIb

"1. Empirical statin therapy for non–lipid-lowering (pleiotropic) effects may be considered.(Level of Evidence: C) "

Class III

"1. Empirical treatment with β-blockers is not indicated.(Level of Evidence: C) "

Thromboprophylaxis

Class I

"1. Patients should be treated with low-dose ASA.(Level of Evidence: C) "

Class IIa

"1. Use of an alternative antiplatelet agent (eg, a thienopyridine such as clopidogrel) instead of ASA is reasonable if the patient is intolerant or resistant to ASA.(Level of Evidence: C) "

Class IIb

"1. Dual-antiplatelet therapy with an additional antiplatelet agent (eg, a thienopyridine such as clopidogrel) may be considered.(Level of Evidence: C) "

"2. Additional patient and coronary artery characteristics may be considered in decision making regarding intensification or discontinuation of thromboprophylaxis.(Level of Evidence: C) "

Class III

"1. Use of anticoagulation is not indicated.(Level of Evidence: C) "

Physical activity

Class I

"1. For patients taking dual-antiplatelet therapy, activities involving a risk of bodily contact, trauma, or injury should be restricted or modified.(Level of Evidence: B) "

Class IIa

"1. It is reasonable to provide physical activity counseling at every visit without restrictions or precautions. Participation in competitive sports or high-intensity activities should be guided by results from testing for inducible myocardial ischemia or exercise-induced arrhythmias.(Level of Evidence: C) "

Reproductive counselling

Class IIa

"1. It is reasonable to discourage use of oral contraceptive drugs that increase thrombo- sis risk, to recommend that pregnancy be supervised by a multidisciplinary team includ- ing a cardiologist, and to alter thromboprophylaxis management during pregnancy and delivery.(Level of Evidence: B) "

Regression to Normal Z Score or Dilation Only

Frequency of cardiology assessment (to include history and physical examination, echocardiography, electrocardiography)

Class IIb

"1. It is reasonable to discourage use of oral contraceptive drugs that increase thrombo- sis risk, to recommend that pregnancy be supervised by a multidisciplinary team includ- ing a cardiologist, and to alter thromboprophylaxis management during pregnancy and delivery.(Level of Evidence: B) "

Type and frequency of additional cardiology assessment (other cardiology testing)

Class IIa

"1. It is reasonable to assess for inducible myocardial ischemia (stress echocardiography, stress with MRI, stress NM perfusion imaging, PET) every 2 to 4 years or if the patient has symptoms suggestive of ischemia or signs suggestive of ventricular dysfunction.(Level of Evidence: B) "

"2. It is reasonable to perform no further imaging with angiography (CT, MRI, invasive) in the absence of evidence of inducible myocardial ischemia. (Level of Evidence: C) "

Cardiovascular risk factor assessment and management

Class IIa

"1. It is reasonable to provide general counseling regarding healthy lifestyle and activity promotion at every visit; this may additionally be provided by the primary care provider.(Level of Evidence: C) "

"2. It is reasonable to assess blood pressure, fasting lipid profile, body mass index (and plot), waist circumference, dietary and activ- ity assessment, and smoking every 2 years; this may be performed by the primary care provider. It is reasonable to obtain a follow- up fasting lipid profile.(Level of Evidence: C) "

Medical therapy (β-blockers, statin)

Class IIb

"1. Empirical statin therapy for non–lipid-lowering (pleiotropic) effects may be considered.(Level of Evidence: C) "

Class III

"1. Empirical treatment with β-blockers is not indicated.(Level of Evidence: C) "

Thromboprophylaxis

Class IIa

"1. It is reasonable to continue treatment with low-dose ASA.(Level of Evidence: C) "

"2. Use of an alternative antiplatelet agent (eg, a thienopyridine such as clopidogrel) instead of ASA is reasonable if the patient is intolerant or resistant to ASA.(Level of Evidence: C) "

Class IIb

"1. Use of an additional antiplatelet agent (eg, a thienopyridine such as clopidogrel) is not recommended except in the presence of inducible myocardial ischemia.(Level of Evidence: C) "

"2. Additional patient and coronary artery characteristics may be considered in decision making regarding intensification or discontinuation of thromboprophylaxis.(Level of Evidence: C) "

Class III

"1. Use of anticoagulation (warfarin/LMWH) is not indicated.(Level of Evidence: C) "

Physical activity

Class IIa

"1. It is reasonable to provide physical activity counseling at every visit without restrictions or precautions. Participation in competitive sports or high-intensity activities should be guided by results from testing for inducible myocardial ischemia or exercise-induced arrhythmias.(Level of Evidence: C) "

Reproductive counselling

Class IIa

"1. It is reasonable to provide age-appropriate counseling regarding contraception and pregnancy without modification.(Level of Evidence: B) "

Large and Giant Aneurysms (Z Score ≥10 or Absolute Dimension ≥8 mm)

Frequency of cardiology assessment (to include history and physical examination, echocardiography, electrocardiography)

Class IIa

"1. It is reasonable to assess patients at 1, 2, 3, 6, 9, and 12 months after the episode of acute KD in the first year and every 3 to 6 months thereafter.(Level of Evidence: C) "

Type and frequency of additional cardiology assess- ment (other cardiology testing)

Class IIa

"1. It is reasonable to assess for inducible myocardial ischemia (stress echocardiography, stress with MRI, stress NM perfusion imaging, PET) every 6 to 12 months or if the patient has symptoms suggestive of ischemia or signs suggestive of ventricular dysfunction.(Level of Evidence: B) "

Class IIb

"1. Further imaging with angiography (CT, MRI, invasive) may be considered for diagnostic and prognostic purposes during the first year and may be considered for periodic surveillance every 1 to 5 years thereafter.(Level of Evidence: C) "

Cardiovascular risk factor assessment and management

Class IIa

"1. It is reasonable to provide general counseling regarding healthy lifestyle and activity promotion at every visit; this may additionally be provided by the primary care provider.(Level of Evidence: C) "

Class IIa

"1. It is reasonable to assess blood pressure, body mass index (and plot), waist circumference, dietary and activity assessment, and smoking every 6 to 12 months; this may be performed by the primary care provider. It is reasonable to obtain a fasting lipid profile during follow- up.(Level of Evidence: C) "

Medical therapy (β-blockers, ACEI, statin)

Class IIb

"1. Empirical statin therapy for non–lipid-lowering (pleiotropic) effects may be considered.(Level of Evidence: C) "

"2. Empirical treatment with β-blockers may be considered .(Level of Evidence: C) "

Thromboprophylaxis

Class I

"1. Patients should be treated with low-dose ASA.(Level of Evidence: C) "

Class IIa

"1. Use of an alternative antiplatelet agent (eg, a thienopyridine such as clopidogrel) instead of ASA is reasonable if the patient is intolerant or resistant to ASA.(Level of Evidence: C) "

"2. Use of warfarin to achieve a target international normalized ratio of 2 to 3 is reasonable.(Level of Evidence: B) "

"3. Use of LMWH to achieve target anti-factor Xa levels of 0.5 to 1.0 U/mL is reasonable as an alternative to warfarin.(Level of Evidence: C) "

Class IIb

"1. Use of an additional antiplatelet agent (eg, a thienopyridine such as clopidogrel) may be considered together with ASA and warfarin/ LMWH (triple therapy) for thromboprophylaxis in the setting of very extensive or distal coronary artery aneurysms, or if there is a history of coronary artery thrombosis.(Level of Evidence: C) "

"2. Additional patient and coronary artery characteristics (Table 9) may be considered in decision making regarding adjustments to strategy for thromboprophylaxis.(Level of Evidence: C) "

Physical activity

Class I

"1. Activities involving a risk of bodily contact, trauma, or injury should be restricted or modified if the patient is on dual-antiplatelet or anticoagulation therapy.(Level of Evidence: B) "

Class IIa

"1. It is reasonable to provide physical activity counseling at every visit without restrictions or precautions. Participation in competitive sports or high intensity activities should be guided by results from testing for inducible myocardial ischemia or exercise-induced arrhythmias.(Level of Evidence: C) "

Reproductive counselling

Class IIa

"1. It is reasonable to discourage use of oral contraceptive drugs that increase thrombosis risk, to recommend that pregnancy be super- vised by a multidisciplinary team including a cardiologist, and to alter thromboprophylaxis management during pregnancy and delivery.(Level of Evidence: B) "

Regression to Medium Aneurysms

Frequency of cardiology assessment (to include history and physical examination, echocardiography, electrocardiography)

Class IIa

"1. It is reasonable to assess the patient every 6 to 12 months.(Level of Evidence: C) "

Type and frequency of additional cardiology assessment (other cardiology testing)

Class IIa

"1. It is reasonable to assess for inducible myocardial ischemia (stress echocardiography, stress with MRI, stress NM perfusion imaging, PET) every year or if the patient has symptoms suggestive of ischemia or signs suggestive of ventricular dysfunction.(Level of Evidence: B) "

Class IIb

"1. Further imaging with angiography (CT, MRI, invasive) may be considered for periodic surveillance every 2 to 5 years.(Level of Evidence: C) "

Cardiovascular risk factor assessment and management

Class IIa

"1. It is reasonable to provide general counseling regarding healthy lifestyle and activity promotion at every visit; this may additionally be provided by the primary care provider.(Level of Evidence: C) "

"2. It is reasonable to assess blood pressure, body mass index (and plot), waist circumference, dietary and activity assessment, and smoking every year; this may be performed by the primary care provider. It is reason- able to obtain a follow-up fasting lipid profile.(Level of Evidence: C) "

Medical therapy (β-blockers, ACEI, statin)

Class IIb

"1. Empirical statin therapy for non–lipid-lowering (pleiotropic) effects may be considered.(Level of Evidence: C) "

"2. Empirical treatment with β-blockers may be considered.(Level of Evidence: C) "

Thromboprophylaxis

Class I

"1. Patients should be treated with low-dose ASA.(Level of Evidence: C) "

Class IIa

"1. Use of an alternative antiplatelet agent (eg, a thienopyridine such as clopidogrel) instead of ASA is reasonable if the patient is intolerant or resistant to ASA.(Level of Evidence: C) "

"2. Discontinuation of anticoagulation (warfarin/ LMWH) and substitution with an additional antiplatelet agent (eg, a thienopyridine such as clopidogrel) is reasonable.(Level of Evidence: C) "

Class IIb

"1. Additional patient and coronary artery characteristics may be considered in decision making regarding adjustments to strategy for thromboprophylaxis.(Level of Evidence: C) "

Class III

"1. Use of anticoagulation (warfarin, LMWH) is not indicated.(Level of Evidence: C) "

Physical activity

Class I

"1. Activities involving a risk of bodily contact, trauma, or injury should be restricted or modified for patients on dual-antiplatelet or anticoagulation therapy.(Level of Evidence: B) "

Class IIa

"1. It is reasonable to provide physical activity counseling at every visit without restrictions or precautions. Participation in competitive sports or high-intensity activities should be guided by results from testing for inducible myocardial ischemia or exercise-induced arrhythmias.(Level of Evidence: C) "

Reproductive counselling

Class IIa

"1. It is reasonable to discourage use of oral contraceptive drugs that increase thrombosis risk, to recommend that pregnancy be super- vised by a multidisciplinary team including a cardiologist, and to alter thromboprophylaxis management during pregnancy and delivery.(Level of Evidence: B) "

Regression to Small Aneurysms

Frequency of cardiology assessment (to include history and physical examination, echocardiography, electrocardiography)

Class IIa

"1. It is reasonable to assess the patient every 6 to 12 months.(Level of Evidence: C) "

Type and frequency of additional cardiology assessment (other cardiology testing)

Class IIa

"1. It is reasonable to assess for inducible myocardial ischemia (stress echocardiography, stress with MRI, stress NM perfusion imaging, PET) every 1 to 2 years or if the patient has symptoms suggestive of ischemia or signs suggestive of ventricular dysfunction.(Level of Evidence: B) "

Class IIb

"1. Further imaging with angiography (CT, MRI, invasive) may be considered for periodic surveillance every 2 to 5 years.(Level of Evidence: C) "

Cardiovascular risk factor assessment and management

Class IIa

"1. It is reasonable to provide general counseling regarding healthy lifestyle and activity promotion at every visit; this may additionally be provided by the primary care provider.(Level of Evidence: C) "

"2. It is reasonable to assess blood pressure, body mass index (and plot), waist circumference, dietary and activity assessment, and smoking every year; this may be performed by the primary care provider. It is reason- able to obtain a follow-up fasting lipid profile.(Level of Evidence: C) "

Medical therapy (β-blockers, ACEI, statin)

Class IIb

"1. Empirical statin therapy for non–lipid-lowering (pleiotropic) effects may be considered.(Level of Evidence: C) "

"2. Empirical treatment with β-blockers may be considered.(Level of Evidence: C) "

"3. Discontinuation of additional medical therapy may be considered.(Level of Evidence: C) "

Thromboprophylaxis

Class I

"1. Patients should be treated with low-dose ASA.(Level of Evidence: C) "

Class IIa

"1. Use of an alternative antiplatelet agent (eg, a thienopyridine such as clopidogrel) instead of ASA is reasonable if the patient is intolerant or resistant to ASA.(Level of Evidence: C) "

Class IIb

"1. Additional patient and coronary artery char- acteristics may be considered in decision making regarding adjustments to strategy for thromboprophylaxis.(Level of Evidence: C) "

Class III

"1. Anticoagulation or dual-antiplatelet therapy is not indicated.(Level of Evidence: C) "

Physical activity

Class I

"1. For patients on anticoagulation or dual-antiplatelet therapy, activities involving a risk of bodily contact, trauma, or injury should be restricted or modified.(Level of Evidence: B) "

Class IIa

"1. It is reasonable to provide physical activity counseling at every visit without restrictions or precautions. Participation in competitive sports or high-intensity activities should be guided by results from testing for inducible myocardial ischemia or exercise-induced arrhythmias.(Level of Evidence: C) "

Reproductive counselling

Class IIa

"1. It is reasonable to provide age-appropriate counseling regarding contraception. It is reasonable to recommend that pregnancy be supervised by a multidisciplinary team including a cardiologist and to alter thromboprophylaxis management during pregnancy and delivery.(Level of Evidence: B) "

Regression to Normal Z Score or Dilation Only

Frequency of cardiology assessment (to include history and physical examination, echocardiography, electrocardiography)

Class IIa

"1. It is reasonable to assess the patient every 1 to 2 years. Not performing routine 2D echocardiography may be considered unless there is evidence for inducible myocardial ischemia or the patient has symptoms suggestive of ischemia or signs suggestive of ventricular dysfunction.(Level of Evidence: C) "

Type and frequency of additional cardiology assessment (other cardiology testing)

Class IIa

"1. It is reasonable to assess for inducible myocardial ischemia (stress echocardiography, stress with MRI, stress NM perfusion imaging, PET) every 2 to 5 years or if the patient has symptoms suggestive of ischemia or signs suggestive of ventricular dysfunction.(Level of Evidence: B) "

Cardiovascular risk factor assessment and management

Class IIa

"1. It is reasonable to provide general counseling regarding healthy lifestyle and activity promotion at every visit; this may additionally be provided by the primary care provider.(Level of Evidence: C) "

"2. It is reasonable to assess blood pressure, body mass index (and plot), waist circumference, dietary and activity assessment, and smoking every 2 years; this may be performed by the primary care provider. It is reasonable to obtain a follow-up fasting lipid profile as per the Expert Panel guidelines.(Level of Evidence: C) "

Medical therapy (β-blockers, ACEI, statin)

Class IIb

"1. Empirical statin therapy for non–lipid-lowering (pleiotropic) effects may be considered.(Level of Evidence: C) "

Class III

"1. Empirical treatment with β-blockers is not indicated.(Level of Evidence: C) "

Thromboprophylaxis

Class IIa

"1. It is reasonable to continue treatment with low-dose ASA.(Level of Evidence: C) "

"2. Use of an alternative antiplatelet agent (eg, a thienopyridine such as clopidogrel) instead of ASA is reasonable if the patient is intol- erant or resistant to ASA.(Level of Evidence: C) "

Class IIb

"1. Additional patient and coronary artery characteristics may be considered in decision making regarding intensification or discontinuation of thromboprophylaxis.(Level of Evidence: C) "

Class III

"1. Use of anticoagulation (warfarin/LMWH) or dual-antiplatelet therapy is not indicated.(Level of Evidence: C) "

Physical activity

Class I

"1. For patients on anticoagulation or dual-anti- platelet therapy, activities involving a risk of bodily contact, trauma, or injury should be restricted or modified.(Level of Evidence: B) "

Class IIa

"1. It is reasonable to provide physical activity counseling at every visit without restrictions or precautions. Participation in competitive sports or high-intensity activities should be guided by results from testing for inducible myocardial ischemia or exercise-induced arrhythmias.(Level of Evidence: C) "

Reproductive counselling

Class IIa

"1. It is reasonable to provide age-appropriate counseling regarding contraception. It is reasonable to recommend that pregnancy be supervised by a multidisciplinary team including a cardiologist and to alter thrombo- prophylaxis management during pregnancy and delivery.(Level of Evidence: B) "

Recommendations for Testing for Inducible Ischemia

Class IIa

"1. It is reasonable to use stress echocardiography or CMRI, NM MPI, or PET for assessment of inducible myocardial ischemia. Note: The general principle is to minimize risk to the patient, particularly cumulative radiation dose, and this should guide selection of testing modality based on patient and institutional characteristics(Level of Evidence: B) "

Class III

"1. Exercise treadmill electrocardiographic testing alone should not be used for assessment for inducible myocardial ischemia.(Level of Evidence: C) "

Recommendation for Assessment of Patients With Inducible Myocardial Ischemia

Class I

"1. Patients with evidence of inducible myocardial ischemia on testing should undergo invasive coronary angiography.(Level of Evidence: B) "

Recommendations for Indications for Mechanical Revascularization

Class I

"1. Adult patients with remote history of KD presenting with STEMI should be referred emergently for coronary angiography for determination of best means of flow restoration in the culprit artery.(Level of Evidence: C) "

"2. Revascularization should be performed in KD patients with stable angina and high-risk coronary anatomy including left main CAD, multi- vessel coronary disease with reduction in LV function, multivessel coronary disease with diabetes mellitus, or high-risk noninvasive ischemia testing.(Level of Evidence: C) "

"3. Revascularization should be performed for patients with non–ST-segment elevation and coronary anatomy amenable to revascularization on coronary angiography.(Level of Evidence: C) "

Class IIa

"1. Revascularization for patients with stable angina and symptoms refractory to maximal medical therapy is reasonable. (Level of Evidence: C) "

Class IIb

"1. Revascularization for KD patients with silent ischemia and ischemia involving >10% of LV mass may be considered. (Level of Evidence: C) "

Class III

"1. Revascularization should be avoided in KD patients in the acute/subacute phase of the illness with STEMI attributable to acute thrombotic occlusion of an aneurysm.(Level of Evidence: C) "

Recommendations for Modes of Revascularization

Class I

"1. CABG is preferred to PCI in KD patients with left main CAD, multivessel CAD with reduced LV function, multivessel CAD with lesions not amenable to PCI, and multivessel CAD in diabetic patients.(Level of Evidence: B) "

"2. CABG is preferred to PCI in older children and adults with KD and multivessel involvement .(Level of Evidence: C) "

"3. CABG should be performed with bilateral internal thoracic arterial grafts where possible.(Level of Evidence: B) "

"4. PCI is preferred in patients with single-vessel or focal multivessel disease amenable to PCI.(Level of Evidence: C) "

"5. RA and stents should be used in PCI of calcified lesions.(Level of Evidence: C) "

Class IIa

"1. The use of multivessel PCI is reasonable for KD patients with focal lesions amenable to PCI. (Level of Evidence: C) "

"2. The use of DESs during PCI is reasonable for KD patients who do not require long- term anticoagulation. (Level of Evidence: C) "

"3. The use of IVUS is reasonably indicated during PCI in KD patients to ensure adequate stent sizing and deployment. (Level of Evidence: C) "

Class IIb

"1. Multivessel PCI may be considered for patients who are acceptable CABG candidates but prefer to avoid CABG, provided the risks and benefits of both approaches are discussed with and understood by the patient. (Level of Evidence: C) "

"2. The use of DESs during PCI may be considered for KD patients who require anti- coagulation, provided the bleeding risk of the patient is acceptable. (Level of Evidence: C) "

Class III

"1. Stand-alone balloon angioplasty should not be used for PCI in KD patients with coronary obstructions.(Level of Evidence: C) "

Recommendation for Cardiac Transplantation

Class IIa

"1. The use of multivessel PCI is reasonable for KD patients with focal lesions amenable to PCI. (Level of Evidence: C) "

Surgery

Prevention

AHA Scientific Statement on Kawasaki Disease

Recommendations for Prevention of Thrombosis During the Acute Illness

Class I

"1. Low-dose ASA (3–5 mg·kg−¹·d−¹) should be administered to patients without evidence of coronary artery changes until 4 to 6 weeks after onset of illness.(Level of Evidence: C) "

Class IIa

"1. For patients with rapidly expanding coronary artery aneurysms or a maximum Z score of ≥10, systemic anticoagulation with LMWH or warfarin (international normalized ratio target 2.0–3.0) in addition to low dose ASA is reasonable. (Level of Evidence: B) "

Class IIb

"1. For patients at increased risk of thrombosis, for example, with large or giant aneurysms (≥8 mm or Z score ≥10) and a recent history of coronary artery thrombosis, “triple therapy” with ASA, a second antiplatelet agent, and anticoagulation with warfarin or LMWH may be considered. (Level of Evidence: C) "

Class III

"1. Ibuprofen and other non steroidal anti-inflammatory drugs with known or potential involvement of cyclooxygenase pathway may be harmful in patients taking ASA for its antiplatelet effects. (Level of Evidence: B) "

Recommendations for Risk Stratification of Coronary Artery Abnormalities

Class IIa

"1. It is reasonable to use echocardiographic coronary artery luminal dimensions converted to BSA-adjusted Z scores to determine risk stratification. (Level of Evidence: B) "

"2. It is reasonable to incorporate both maximal and current coronary artery involvement in risk stratification. (Level of Evidence: C) "

"3. It is reasonable to incorporate the presence of additional features other than coronary artery luminal dimensions into decisions regarding risk stratification. (Level of Evidence: C) "

INTRODUCTION — Kawasaki disease (KD, previously called mucocutaneous lymph node syndrome) is one of the most common vasculitides of childhood [1]. KD also occurs rarely in adults. It is typically a self-limited condition, with fever and manifestations of acute inflammation lasting for an average of 12 days without therapy [2]. However, complications such as coronary artery (CA) aneurysms, depressed myocardial contractility and heart failure, myocardial infarction, arrhythmias, and peripheral arterial occlusion may develop and lead to significant morbidity and mortality. (See "Cardiovascular sequelae of Kawasaki disease: Clinical features and evaluation".)

The clinical manifestations and diagnosis of KD are discussed in this review. The epidemiology, etiology, treatment, and complications of KD, including cardiac sequelae, are presented separately. Incomplete (atypical) KD and unique features in infants and adults are also reviewed separately. (See "Kawasaki disease: Epidemiology and etiology" and "Kawasaki disease: Initial treatment and prognosis" and "Cardiovascular sequelae of Kawasaki disease: Clinical features and evaluation" and "Incomplete (atypical) Kawasaki disease" and "Kawasaki disease: Complications".)

CLINICAL MANIFESTATIONS — The clinical features of KD reflect widespread inflammation of primarily medium-sized muscular arteries. Diagnosis is based upon evidence of systemic inflammation (eg, fever) in association with signs of mucocutaneous inflammation. The characteristic bilateral nonexudative conjunctivitis, erythema of the lips and oral mucosa, rash, extremity changes, and cervical lymphadenopathy typically develop after a brief nonspecific prodrome of respiratory or gastrointestinal symptoms [3-8] (see 'Other findings' below). These characteristic clinical signs are the basis for the diagnostic criteria for KD (table 1) [9].

Oral mucous membrane findings are seen in approximately 90 percent of cases of KD, polymorphous rash in 70 to 90 percent, extremity changes in 50 to 85 percent, ocular changes in >75 percent, and cervical lymphadenopathy in 25 to 70 percent [7,10-12].

These findings are often not present at the same time, and there is no typical order of appearance. As an example, some patients have only developed fever and cervical lymphadenopathy by the time of admission (so-called KD with isolated cervical lymphadenopathy, KDiL) [13]. In one case series, these patients tended to be older and to have a more severe course, with increased risk of coronary artery (CA) disease and lack of response to intravenous immune globulin (IVIG). Thus, repeated histories and physical examinations are important both for making a timely diagnosis of KD in children who fail to meet diagnostic criteria, as well as for appropriate consideration of alternative diagnoses. (See 'Diagnosis' below.)

Fever — An elevated body temperature is the most consistent manifestation of KD. Fever is minimally responsive to antipyretic agents, and it typically remains above 38.5ºC (101.3ºF) during most of the illness. On the other hand, fever may be intermittent and may be missed by parents who use tympanic, temporal, axillary, or similar temperature measurement methods that are less reliable than oral or rectal methods. Thus, the diagnosis should be considered in all children with prolonged, unexplained fever ≥5 days but should still be considered in seemingly afebrile children who have other findings consistent with KD. (See "Incomplete (atypical) Kawasaki disease".)

Conjunctivitis — Bilateral nonexudative conjunctivitis is present in more than 90 percent of patients. A predominantly bulbar injection typically begins within days of the onset of fever, and the eyes often have a brilliant erythema, which characteristically spares the limbus (picture 1). Children also are frequently photophobic. In addition, anterior uveitis may develop in up to 70 percent of children with ocular findings [12,14]; therefore, slit-lamp examination may be helpful in ambiguous cases. The presence of uveitis provides further evidence for the diagnosis of KD since it is more commonly seen in KD than in other diseases with similar presentations. (See "Uveitis: Etiology, clinical manifestations, and diagnosis".)

Mucositis — Mucositis often becomes evident as KD progresses. Cracked, red lips (picture 2) and a strawberry tongue (picture 3) are characteristic. The latter is a result of sloughing of filiform papillae and denuding of the inflamed glossal tissue. These manifestations of oral mucositis may occur singly, in a very mild form, or not at all. Discrete oral lesions, such as vesicles or ulcers, and tonsillar exudate are suggestive of a disease process other than KD [6].

Rash — The cutaneous manifestations of KD are polymorphous. The rash usually begins during the first few days of illness, typically as perineal erythema and desquamation, followed by macular, morbilliform, or targetoid skin lesions of the trunk and extremities. Vesicular or bullous lesions generally are not observed, but KD may trigger a psoriasiform eruption in children not previously recognized to have psoriasis [15-18]. Patients may also have redness or crust formation at the site of Bacille Calmette-Guérin (BCG) inoculation. This finding is more useful for increasing the level of suspicion for KD in countries where BCG vaccine is routinely given. (See 'Diagnosis' below.)

Extremity changes — Changes in the extremities are generally the last manifestation to appear. Children develop an indurated edema of the dorsum of their hands and feet (picture 4) and a diffuse erythema of their palms and soles.

The convalescent phase of KD is often characterized by sheet-like desquamation that begins in the periungual region of the hands and feet (picture 5) and by linear nail creases (Beau's lines). The prevalence of periungual desquamation in patients with KD has been reported to vary from 68 to 98 percent [19].

Lymphadenopathy — Cervical lymphadenopathy is the least consistent feature of KD, absent in as many as one-half to three-quarters of children with the disease [11]. When present, lymphadenopathy tends to primarily involve the anterior cervical nodes overlying the sternocleidomastoid muscles [20]. Often, only a single, large node is palpable, although ultrasound imaging of the neck typically reveals numerous discrete nodes arranged like a bunch of grapes [21].

Diffuse lymphadenopathy or other signs of reticuloendothelial involvement (eg, splenomegaly) should prompt a search for alternative diagnoses. (See 'Differential diagnosis' below.)

Cardiovascular findings — Cardiovascular findings are not part of the diagnostic criteria, but they support the diagnosis since most conditions that mimic KD do not involve the heart. Cardiac manifestations during the first week to 10 days of illness may include tachycardia out of proportion to the degree of fever, gallop sounds, and muffled heart tones [2]. With improved echocardiographic techniques and use of Z-scores for determining CA diameter, approximately 30 percent of patients with KD are found to have CA dilatation at diagnosis [22,23]. Frank aneurysms are usually not seen until after day 10 of illness. Severely ill patients, particularly young infants, may develop fusiform aneurysms of the brachial arteries that are easily palpable or visible in the axillae. In addition, young infants may have cold, pale, or cyanotic digits of the hands and feet due to reduced perfusion. Gangrene may, in rare cases, cause loss of fingers or toes during this acute period. The cardiac complications associated with KD are discussed in detail separately. (See "Kawasaki disease: Complications", section on 'Cardiac complications' and "Cardiovascular sequelae of Kawasaki disease: Clinical features and evaluation".)

Arthritis — Arthritis is not included in the diagnostic criteria but has been reported in 7.5 to 25 percent of patients with KD [24,25]. The prevalence of arthritis was 7.5 percent in a retrospective Canadian study of 414 consecutive patients diagnosed with KD [24]. The large joints (ie, knee, ankle, and hip) were primarily involved. Oligoarticular involvement (arthritis of four or fewer joints) occurred in 16 patients and polyarticular involvement (arthritis of five or more joints) in 15 patients. With only very rare exceptions, the arthritis is self-limited and nondeforming. Patients with arthritis were more likely to have increased levels of inflammatory markers (C-reactive protein [CRP] or erythrocyte sedimentation rate [ESR]) and neutrophils. Otherwise, there were no differences in clinical features, response to therapy, or clinical outcomes between patients with or without arthritis.

Other findings — The following nonspecific symptoms commonly occur in children within the first 10 days before diagnosis of KD but are not included in the diagnostic criteria [2,5]:

●Diarrhea, vomiting, or abdominal pain – 61 percent

●Irritability – 50 percent (older children with KD may present more with lethargy than irritability)

●Vomiting alone – 44 percent

●Cough or rhinorrhea – 35 percent

●Decreased intake – 37 percent

●Joint pain – 15 percent

LABORATORY FINDINGS — No laboratory studies are included among the diagnostic criteria for typical KD. However, certain findings may support the diagnosis of KD, particularly in incomplete cases [1] (see 'Diagnosis' below and "Incomplete (atypical) Kawasaki disease", section on 'Laboratory tests'):

●Systemic inflammation is characteristic of KD. Typical manifestations include elevation of acute-phase reactants (eg, C-reactive protein [CRP] or erythrocyte sedimentation rate [ESR]), thrombocytosis that generally develops after the seventh day of illness, leukocytosis, and a left-shift (increased immature neutrophils) in the white blood cell (WBC) count.

CRP elevations resolve well before ESR. However, patients with more severe disease can have persistently high levels of CRP for weeks. Treatment with intravenous immune globulin (IVIG) usually raises the ESR, so this lab marker should not be measured after a child receives IVIG. On the other hand, control of inflammation by IVIG accelerates the decrease in CRP, making this a more useful marker of disease activity in a treated child.

Ferritin is another acute-phase reactant that is elevated in inflammatory conditions such as KD, usually less than five times the upper limit of normal. Much higher values, typically >5000 ng/mL, are seen in macrophage activation syndrome (MAS), a serious but rare complication of KD. Elevations of that magnitude are essentially diagnostic of MAS in the setting of KD. (See "Kawasaki disease: Complications", section on 'Macrophage activation syndrome' and "Clinical features and diagnosis of hemophagocytic lymphohistiocytosis", section on 'Rheumatologic disorders/MAS'.)

Lymphocyte numbers typically drop during the acute phase of KD, then rise dramatically during convalescence. Early in the course of disease, a complete blood count with a lymphocytic rather than neutrophilic preponderance is more suggestive of a viral illness. (See 'Differential diagnosis' below.)

Platelet counts generally rise by the second week of illness and may reach 1,000,000/mm3 (reactive thrombocytosis) in the most severe cases. In some studies, the degree of thrombocytosis correlates with the risk of coronary artery (CA) changes in KD. On the other hand, rare children with KD develop thrombocytopenia due to a consumptive coagulopathy. These patients are at significantly increased risk of morbidity and mortality, particularly the development of CA abnormalities [26]. (See "Kawasaki disease: Complications", section on 'Cardiac complications'.)

Thrombocytopenia, high triglycerides, low sodium, elevated liver function tests, and monocytes/macrophages in cerebral spinal fluid (CSF) can all be signs of subclinical MAS and may warrant further diagnostic testing. (See "Kawasaki disease: Complications", section on 'Macrophage activation syndrome'.)

●Children with KD often present with a normocytic, normochromic anemia. Hemoglobin concentrations more than two standard deviations below the mean for age are noted in one-half of patients within the first two weeks of illness (table 2).

●Urinary microscopy commonly reveals WBCs [27]. Pyuria can be of urethral origin and therefore may be missed on urinalyses obtained by bladder tap or catheterization [28]. The WBCs are not polymorphonuclear leukocytes and therefore are not detected by dipstick tests for leukocyte esterase. Thus, children with suspected KD should have a clean voided or bagged urine specimen collected for microscopic examination in order to detect this characteristic feature.

●In one retrospective series of 259 patients, 45 percent had at least one abnormal liver function test [29]. In a case-control series, approximately 30 percent of 280 patients with KD had mild-to-moderate elevation of transaminases (eg, serum alanine aminotransferase >50 units/L) [6]. The reason for this transaminitis is unclear. In addition, a minority of children develop obstructive jaundice from hydrops of the gallbladder.

●CSF may display a mononuclear pleocytosis without hypoglycorrhachia (decreased CSF glucose) or elevation of CSF protein. In a retrospective review, 46 of 520 children with KD underwent lumbar puncture [30]. In this subset of patients, 39 percent had elevated CSF WBC counts. The median count was 22.5 cells/mm3 with 6 percent neutrophils and 92 percent mononuclear cells, although cell counts as high as 320/mm3 with up to 79 percent neutrophils were reported.

●Similarly, arthrocentesis of involved joints typically demonstrates a pleocytosis, with 125,000 to 300,000 WBCs/mm3, primarily neutrophils [31].

●Children with KD develop significant perturbations in serum lipid profiles, including elevated triglycerides and low-density lipoproteins, and depressed high-density lipoproteins [2,32-34], as is often observed in a variety of infectious and inflammatory conditions. A return to normal generally occurs within weeks or months following IVIG therapy, though abnormalities may persist for years in untreated children [33].

●Hyponatremia (serum sodium <135 mEq/L) may be seen and is associated with an increased risk of CA aneurysms [35].

DIAGNOSIS — Diagnosis of KD according to the criteria established by Tomisaku Kawasaki in 1967 [36] requires the presence of fever lasting ≥5 days, combined with at least four of the five following physical findings, without an alternative explanation (table 1) [1,2,37]:

●Bilateral bulbar conjunctival injection (picture 1)

●Oral mucous membrane changes, including injected or fissured lips (picture 2), injected pharynx, or strawberry tongue (picture 3)

●Peripheral extremity changes, including erythema of palms or soles, edema of hands or feet (acute phase) (picture 4), and periungual desquamation (convalescent phase) (picture 5)

●Polymorphous rash

●Cervical lymphadenopathy (at least one lymph node >1.5 cm in diameter)

Redness or crust formation at the site of Bacille Calmette-Guérin (BCG) inoculation is also suggested as a useful sign in several diagnostic guidelines [2,9]. In one series of 15,524 patients with KD and a history of BCG vaccination, 50 percent had this finding compared with none of the 53 children admitted with respiratory syncytial virus or rotavirus infection who served as the control group [38].

As with all clinical criteria, these are imperfect guidelines with less than 100 percent sensitivity and specificity. In addition, Dr. Kawasaki published his guidelines before cardiac involvement was recognized in this disease, so they were never intended to identify children at risk for developing coronary artery (CA) abnormalities. Thus, it is not surprising that at least 10 percent of children who develop CA aneurysms never meet criteria for KD [39]. Children who do not meet the criteria may have an incomplete form of KD. An algorithmic approach can help identify such cases (algorithm 1) [2]. (See "Incomplete (atypical) Kawasaki disease".)

Rash and conjunctival injection are seen with many illnesses, but other KD features, such as red, cracked lips and redness and swelling of the hands and feet, are unusual in the illnesses in the differential diagnosis and should increase the suspicion for KD. (See 'Differential diagnosis' below.)

Laboratory evaluation — As noted above, Dr. Kawasaki identified the first 50 cases of "mucocutaneous lymph node syndrome" on the basis of clinical findings rather than laboratory or imaging studies [36]. Thus, no laboratory values are included in the classical diagnostic criteria, but they nonetheless may support a diagnosis of KD in ambiguous cases. In fact, some laboratory tests are explicitly included in the algorithm for diagnosis of atypical KD (algorithm 1) [2]. (See "Incomplete (atypical) Kawasaki disease", section on 'Laboratory tests'.)

The following blood tests are typically obtained on children in whom a diagnosis of KD is being considered:

●Complete blood counts with differential white blood cell (WBC) counts

●Liver function tests including aspartate transaminase (AST), alanine transaminase (ALT), and albumin

●C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR)

●Urinalysis

Elevated WBC and platelet counts, transaminases, and acute-phase reactants, as well as anemia and pyuria, are suggestive of KD.

In addition, when specific mimics of KD are strongly suspected, studies that are more specific for these alternative diagnoses may help confirm the diagnosis. These can include rapid viral testing (eg, adenovirus), serologic testing for leptospirosis and other bacterial infections, and blood cultures.

Echocardiography — Echocardiography should be performed in all patients with KD as soon as the diagnosis is suspected in order to establish a baseline for longitudinal follow-up (algorithm 1). Pretreatment CA diameters establish a baseline for assessment of treatment efficacy and longitudinal follow-up. In addition, initial CA diameter is a factor in identifying patients at high risk of developing a coronary aneurysm and therefore warranting augmentation of initial intravenous immune globulin (IVIG) therapy (see "Kawasaki disease: Complications", section on 'Risk factors for coronary artery aneurysms'). Finally, CA diameters are useful for identifying patients who should be treated with IVIG despite failing to meet classical diagnostic criteria for KD. Echocardiography evaluation for KD is discussed in greater detail separately. (See "Cardiovascular sequelae of Kawasaki disease: Clinical features and evaluation", section on 'Initial evaluation' and "Incomplete (atypical) Kawasaki disease", section on 'Echocardiography'.)

DIFFERENTIAL DIAGNOSIS — KD is most commonly confused with infectious exanthems of childhood [2,40,41]. Early in the course, KD is often mistaken for more routine childhood illnesses, such as viral gastroenteritis, viral upper respiratory tract infection, or pneumonia, depending upon the other presenting symptoms, such as vomiting or cough. Concurrent viral infections are common, and, therefore, the presence of respiratory symptoms or positive respiratory viral polymerase chain reaction (PCR) testing does not exclude the diagnosis of KD [42]. Meningitis is sometimes suspected due to irritability.

Infectious diseases and other mimics of KD may have the following clinical features not commonly found in KD [2]:

●Exudative conjunctivitis (eg, adenovirus)

●Exudative pharyngitis (eg, streptococcal pharyngitis)

●Discrete intraoral lesions (eg, Koplik spots in measles)

●Bullous or vesicular rash (eg, Stevens-Johnson syndrome)

●Generalized lymphadenopathy (eg, Epstein-Barr virus [EBV] infection)

The presence of any of these findings and/or the absence of fever should suggest a diagnosis other than KD. Of note, concurrent infections (both viral and bacterial) are common in patients with KD, found in up to 33 percent of children in one study [43]. In this review of 129 consecutive children seen with KD in Toronto, infection at the time of diagnosis did not affect response to therapy or outcome. In any event, diagnosis of an infectious condition does not preclude a concurrent diagnosis of KD.

The differential diagnosis of KD includes (table 3):

●Measles, echovirus, adenovirus [44], and EBV – These viral illnesses may share many of the signs of mucocutaneous inflammation, but they typically have less evidence of systemic inflammation and generally lack the extremity changes seen in KD. (See "Measles: Clinical manifestations, diagnosis, treatment, and prevention" and "Enterovirus and parechovirus infections: Clinical features, laboratory diagnosis, treatment, and prevention" and "Pathogenesis, epidemiology, and clinical manifestations of adenovirus infection" and "Clinical manifestations and treatment of Epstein-Barr virus infection".)

●Toxin-mediated illnesses, especially group A streptococcal infections (eg, scarlet fever and toxic shock syndrome) – These usually lack the ocular and articular involvement typical of KD, though patients with staphylococcal toxic shock syndrome occasionally have conjunctival erythema. Patients with toxic shock often have generalized edema. The edema is rarely confined to the hands and feet. Patients with scarlet fever may have periungual desquamation. (See "Epidemiology, clinical manifestations, and diagnosis of streptococcal toxic shock syndrome" and "Staphylococcal toxic shock syndrome" and "Group A streptococcal (Streptococcus pyogenes) bacteremia in children", section on 'Clinical manifestations'.)

●Rocky Mountain spotted fever and leptospirosis – Headache and gastrointestinal complaints typically are prominent features of these infections. (See "Clinical manifestations and diagnosis of Rocky Mountain spotted fever" and "Epidemiology, microbiology, clinical manifestations, and diagnosis of leptospirosis".)

●Drug reactions such as Stevens-Johnson syndrome or serum sickness – These may mimic KD but with subtle differences in the ocular and mucosal manifestations, and laboratory markers of inflammation are generally normal or only mildly elevated. (See "Stevens-Johnson syndrome and toxic epidermal necrolysis: Pathogenesis, clinical manifestations, and diagnosis".)

●Systemic juvenile idiopathic arthritis – Children with this condition generally lack the conjunctival and oral findings of KD. Lymphadenopathy also is generalized, and it may be accompanied by splenomegaly, unlike in KD. (See "Systemic juvenile idiopathic arthritis: Clinical manifestations and diagnosis".)

Delayed diagnosis — Treatment with intravenous immune globulin (IVIG) within the first 10 days of illness reduces the prevalence of coronary artery (CA) aneurysms fivefold compared with children not treated with IVIG [45,46]. Thus, it is desirable to diagnose KD as soon as possible after the onset of symptoms in order to initiate treatment and reduce the risk of CA lesions [47]. However, timely identification is challenging because the diagnosis is based upon nonspecific clinical signs and there is no definitive diagnostic test. Thus, the clinicians in a medical facility with the most experience taking care of patients with KD should be consulted as early in the course of the evaluation of suspected KD as possible. These clinicians may include pediatric rheumatologists, infectious disease specialists, cardiologists, and/or hospitalists, depending upon the institution.

In a retrospective study of 562 patients diagnosed with KD at eight North American centers, 92 cases (16 percent) were diagnosed after the first 10 days of illness (ie, late diagnosis) [48]. Predictors of a delay in diagnosis of KD included age below six months, clinical presentation of incomplete KD, greater distance from a tertiary center, and variability between clinical centers. In contrast, socioeconomic status was not associated with a delay in diagnosis.

These findings suggest that practice variation in confirming a diagnosis of KD may in part contribute to a delayed diagnosis. The results of this study underscore the need for a high index of suspicion of KD, especially in young infants and patients who present with incomplete KD, in order to identify and treat patients in a timely manner. (See "Incomplete (atypical) Kawasaki disease".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Kawasaki disease".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topic (see "Patient education: Kawasaki disease (The Basics)")

SUMMARY

●Kawasaki disease (KD, also called mucocutaneous lymph node syndrome) is one of the most common vasculitides of childhood. KD occurs only rarely in adults. It is typically a self-limited condition, with fever and manifestations of acute inflammation lasting for an average of 12 days without therapy. (See 'Introduction' above.)

●KD is characterized by systemic inflammation manifested by fever and mucocutaneous involvement, including bilateral nonexudative conjunctivitis, erythema of the lips and oral mucosa, rash, extremity changes, and cervical lymphadenopathy (table 1). These findings are often not present at the same time. Thus, repeated histories and physical examinations are important in making a timely diagnosis of KD in children with fever and signs of mucocutaneous inflammation. (See 'Clinical manifestations' above.)

●No laboratory studies are included among the diagnostic criteria for typical KD. However, the presence of compatible laboratory features strongly supports the diagnosis. (See 'Laboratory findings' above and "Incomplete (atypical) Kawasaki disease", section on 'Laboratory tests'.)

●The diagnosis of KD according to classical criteria requires the presence of fever ≥5 days, combined with at least four of the other five signs of mucocutaneous inflammation, without any other explanation (table 1). Additional clinical and laboratory features are often used to guide diagnosis in children who have fewer than five criteria for KD (incomplete KD). (See 'Diagnosis' above and "Incomplete (atypical) Kawasaki disease".)

●KD is most commonly confused with infectious exanthems of childhood. The presence of clinical features not commonly found in KD, including exudative conjunctivitis, exudative pharyngitis, discrete intraoral lesions, bullous or vesicular rash, splenomegaly, and/or generalized lymphadenopathy, suggest another diagnosis (table 3). Nonetheless, KD is sufficiently pleomorphic that none of these findings can definitively exclude the diagnosis. Children with KD can have concurrent infections, particularly with viruses circulating in the community at the time of their diagnosis. (See 'Differential diagnosis' above.)

Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES Burns JC, Glodé MP. Kawasaki syndrome. Lancet 2004; 364:533. McCrindle BW, Rowley AH, Newburger JW, et al. Diagnosis, Treatment, and Long-Term Management of Kawasaki Disease: A Scientific Statement for Health Professionals From the American Heart Association. Circulation 2017; 135:e927. Morens DM, Anderson LJ, Hurwitz ES. National surveillance of Kawasaki disease. Pediatrics 1980; 65:21. Huang GY, Ma XJ, Huang M, et al. Epidemiologic pictures of Kawasaki disease in Shanghai from 1998 through 2002. J Epidemiol 2006; 16:9. Baker AL, Lu M, Minich LL, et al. Associated symptoms in the ten days before diagnosis of Kawasaki disease. J Pediatr 2009; 154:592. Burns JC, Mason WH, Glode MP, et al. Clinical and epidemiologic characteristics of patients referred for evaluation of possible Kawasaki disease. United States Multicenter Kawasaki Disease Study Group. J Pediatr 1991; 118:680. Ozdemir H, Ciftçi E, Tapisiz A, et al. Clinical and epidemiological characteristics of children with Kawasaki disease in Turkey. J Trop Pediatr 2010; 56:260. Cai Z, Zuo R, Liu Y. Characteristics of Kawasaki disease in older children. Clin Pediatr (Phila) 2011; 50:952. Ayusawa M, Sonobe T, Uemura S, et al. Revision of diagnostic guidelines for Kawasaki disease (the 5th revised edition). Pediatr Int 2005; 47:232. Fukushige J, Takahashi N, Ueda Y, Ueda K. Incidence and clinical features of incomplete Kawasaki disease. Acta Paediatr 1994; 83:1057. Sung RY, Ng YM, Choi KC, et al. Lack of association of cervical lymphadenopathy and coronary artery complications in Kawasaki disease. Pediatr Infect Dis J 2006; 25:521. Germain BF, Moroney JD, Guggino GS, et al. Anterior uveitis in Kawasaki disease. J Pediatr 1980; 97:780. Nomura Y, Arata M, Koriyama C, et al. A severe form of Kawasaki disease presenting with only fever and cervical lymphadenopathy at admission. J Pediatr 2010; 156:786. Smith LB, Newburger JW, Burns JC. Kawasaki syndrome and the eye. Pediatr Infect Dis J 1989; 8:116. Eberhard BA, Sundel RP, Newburger JW, et al. Psoriatic eruption in Kawasaki disease. J Pediatr 2000; 137:578. Kishimoto S, Muneuchi J, Takahashi Y, et al. Psoriasiform skin lesion and supprative acrodermatitis associated with Kawasaki disease followed by the treatment with infliximab: a case report. Acta Paediatr 2010; 99:1102. Ergin S, Karaduman A, Demirkaya E, et al. Plaque psoriasis induced after Kawasaki disease. Turk J Pediatr 2009; 51:375. Liao YC, Lee JY. Psoriasis in a 3-month-old infant with Kawasaki disease. Dermatol Online J 2009; 15:10. Wang S, Best BM, Burns JC. Periungual desquamation in patients with Kawasaki disease. Pediatr Infect Dis J 2009; 28:538. April MM, Burns JC, Newburger JW, Healy GB. Kawasaki disease and cervical adenopathy. Arch Otolaryngol Head Neck Surg 1989; 115:512. Kanegaye JT, Van Cott E, Tremoulet AH, et al. Lymph-node-first presentation of Kawasaki disease compared with bacterial cervical adenitis and typical Kawasaki disease. J Pediatr 2013; 162:1259. Dominguez SR, Anderson MS, El-Adawy M, Glodé MP. Preventing coronary artery abnormalities: a need for earlier diagnosis and treatment of Kawasaki disease. Pediatr Infect Dis J 2012; 31:1217. Printz BF, Sleeper LA, Newburger JW, et al. Noncoronary cardiac abnormalities are associated with coronary artery dilation and with laboratory inflammatory markers in acute Kawasaki disease. J Am Coll Cardiol 2011; 57:86. Gong GW, McCrindle BW, Ching JC, Yeung RS. Arthritis presenting during the acute phase of Kawasaki disease. J Pediatr 2006; 148:800. Melish ME. Kawasaki syndrome: a 1986 perspective. Rheum Dis Clin North Am 1987; 13:7. Nofech-Mozes Y, Garty BZ. Thrombocytopenia in Kawasaki disease: a risk factor for the development of coronary artery aneurysms. Pediatr Hematol Oncol 2003; 20:597. Shike H, Kanegaye JT, Best BM, et al. Pyuria associated with acute Kawasaki disease and fever from other causes. Pediatr Infect Dis J 2009; 28:440. Watanabe T, Abe Y, Sato S, et al. Sterile pyuria in patients with Kawasaki disease originates from both the urethra and the kidney. Pediatr Nephrol 2007; 22:987. Eladawy M, Dominguez SR, Anderson MS, Glodé MP. Abnormal liver panel in acute kawasaki disease. Pediatr Infect Dis J 2011; 30:141. Dengler LD, Capparelli EV, Bastian JF, et al. Cerebrospinal fluid profile in patients with acute Kawasaki disease. Pediatr Infect Dis J 1998; 17:478. Hicks RV, Melish ME. Kawasaki syndrome. Pediatr Clin North Am 1986; 33:1151. Salo E, Pesonen E, Viikari J. Serum cholesterol levels during and after Kawasaki disease. J Pediatr 1991; 119:557. Newburger JW, Burns JC, Beiser AS, Loscalzo J. Altered lipid profile after Kawasaki syndrome. Circulation 1991; 84:625. Cabana VG, Gidding SS, Getz GS, et al. Serum amyloid A and high density lipoprotein participate in the acute phase response of Kawasaki disease. Pediatr Res 1997; 42:651. Nakamura Y, Yashiro M, Uehara R, et al. Use of laboratory data to identify risk factors of giant coronary aneurysms due to Kawasaki disease. Pediatr Int 2004; 46:33. Kawasaki T. [Acute febrile mucocutaneous syndrome with lymphoid involvement with specific desquamation of the fingers and toes in children]. Arerugi 1967; 16:178. Centers for Disease Control. Kawasaki disease — New York. MMWR Morb Mortal Wkly Rep 1980; 29:61. Uehara R, Igarashi H, Yashiro M, et al. Kawasaki disease patients with redness or crust formation at the Bacille Calmette-Guérin inoculation site. Pediatr Infect Dis J 2010; 29:430. Sundel RP. Update on the treatment of Kawasaki disease in childhood. Curr Rheumatol Rep 2002; 4:474. Yanagihara R, Todd JK. Acute febrile mucocutaneous lymph node syndrome. Am J Dis Child 1980; 134:603. Barron KS. Kawasaki disease in children. Curr Opin Rheumatol 1998; 10:29. Turnier JL, Anderson MS, Heizer HR, et al. Concurrent Respiratory Viruses and Kawasaki Disease. Pediatrics 2015; 136:e609. Benseler SM, McCrindle BW, Silverman ED, et al. Infections and Kawasaki disease: implications for coronary artery outcome. Pediatrics 2005; 116:e760. Jaggi P, Kajon AE, Mejias A, et al. Human adenovirus infection in Kawasaki disease: a confounding bystander? Clin Infect Dis 2013; 56:58. Furusho K, Kamiya T, Nakano H, et al. High-dose intravenous gammaglobulin for Kawasaki disease. Lancet 1984; 2:1055. Newburger JW, Takahashi M, Burns JC, et al. The treatment of Kawasaki syndrome with intravenous gamma globulin. N Engl J Med 1986; 315:341. Newburger JW, Takahashi M, Gerber MA, et al. Diagnosis, treatment, and long-term management of Kawasaki disease: a statement for health professionals from the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease, Council on Cardiovascular Disease in the Young, American Heart Association. Pediatrics 2004; 114:1708. Minich LL, Sleeper LA, Atz AM, et al. Delayed diagnosis of Kawasaki disease: what are the risk factors? Pediatrics 2007; 120:e1434.

Obstructive lung disease DD

Obstructive lung disease

Diseases		Clinical manifestations										Diagnosis
		Symptoms					Signs					Lab findings	PFT				Imaging			Gold standard	Other features
		Cough	Dyspnea	Hemoptysis	Fever	Weight loss	Cyanosis	Clubbing	JVD	Peripheral edema	Auscultation		ABGs	FEV1/FVC	TLC	DLCO
																	CXR	CT scan	Other tests
Asthma	Stable Asthma	+	+	−	−	−	−	−	−	−	Wheeze Rhonchi	↑IgE	Normal	↓FEV1 FEV1:FVC =<0.7	↑TLC	Normal/↑DLCO	Pulmonary hyperinflation	Extensive air trapping	Bronchoprovocation testing Peak expiratory flow measurement	Physical Exam Spirometry	Associated with: Allergic rhinitis GERD and obesity can mimic asthma
	Status Asthmaticus	+	+	-	±	-	-	-	+	-	Wheeze Absent or ↓Breath sounds	↑TLC ↑Glucose	↑PCO2 ↓PO2	↓FEV1:FVC < 30% of predictive value	↑TLC	↑DLCO	Pulmonary hyperinflation Atypical presentation	-	Peak expiratory flow<50% of baseline	Clinical diagnosis	Pulses paradoxus
COPD	Chronic bronchitis	+	+	±	+	−	−	−	−	−	Wheeze Rhonchi Egophony Rales ↓Bronchial breath sounds(present in consolidation)	↑Procalcitonin	Normal	↓FEV1	↑TLC	Normal	Thickening of the bronchial walls in the lower lobes	Thickening of the bronchial walls in the lower lobes	Microbiological testing is done in cases of: Influenza Pertusis	Clinical diagnosis Chest radiograph	Secondary to URTI
	Emphysema	+	+	–	+	+	+	+	–	–	Expiratory wheeze Hyperinflation	↓alpha-1 antitrypsin deficency	Respiratory alkalosis Metabolic acidosis	↓FEV1	↑TLC	–	Flattening of the diaphragm Vertical heart	Small subpleural collections of gas Centriacinar emphysema Panacinar emphysema Paraseptal emphysema	Pulse oximetry	Physical Exam Spirometery	Barrel Chest
Bronchiolitis		+	+	−	+	−	−	−	−	–	Wheeze Crackles		Normal	↓	↑TLC	↓DLCO	Bronchovascular markings	Air trapping Bronchial wall thickening	Bronchoscopy Lung biopsy	Thoracoscopic lung biopsy	Can be associated with: Organ transplantation
Bronchiectasis		+	+	+	+	–	+	+	–	–	Rhonchi Wheeze Crackles	↑Neutrophils		↓FEV1:FVC	↑TLC	↓DLCO	Tram track opacities	Signet-ring sign Airway dilation	Flexible bronchoscopy	HRCT	Chronic productive cough
Heart failure		+	+	–	–	–	+	–	+	+	S3 gallop Wheeze Rales	↑Pro-BNP ↑Troponin Anemia Hyponatremia ↑BUN ↑Creatinine	Respiratory alkalosis		Normal TLC	Normal	Bat wing appearance Cardiomegaly Pulmonary congestion Pulmonary interstitial edema Pleural effusion		MRI Cardiac catheterization Exercise testing Ambulatory ECG monitoring
Tuberculosis		+	+	+	+	+	–	–	–	–	Diminished breath sounds Rhonchi Wheeze	↑ESR ↑C-reactive protein Normocytic anemia Hypercalcemia			↑TLC	Normal	Upper lobe infiltrate Upper lobe cavitation Hilar adenopathy Solitary nodules Pleural effusion Mediastinal lymphadenopathy Fibrotic leisons Distortion of the lung parenchyma	Centrilobular 2 to 4 mm nodules Branching linear lesions Patchy small lower lobe infiltrates	Interferon gamma release assay Sputum smear positive for AFB Nucleic acid amplification test	Culture for AFB	Night Sweats Chest pain Fatigue Anorexia
Lymphangioleiomyomatosis		+	+	+(<5%)	-	-	-	+(rare)	-	+	Wheeze Hyperinflation Absent or ↓Breath sounds	↑Vascular endothelial growth factor-D	Respiratory acidosis in severe disease	↓FEV1:FVC	Normal TLC	↓DLCO	Ground glass appearance Interstetial pulmonary edema Septal thickening	Pulmonary cyst Pnuemothorax Pleural masses Pleural thickening Mediastianl lymphadenopathy Pleural effusion	VQ Scan PET Scan Advanced lymphatic imaging	Surgical lung biopsy	Chylothorax(most common lymphatic manifestation) Chyloperitonium Renalangiomyolipoma
Cystic fibrosis		+	+	+	+	-	+	+	-	-	Crackles	Sweat Chloride test: >60 mEq/L	↑PCO2 ↓PO2	↓FEV1:FVC	↑TLC	↓ In severe lung impairment	Hyperinflation Peribronchial thickening Bilateral infiltrates		↑Nasal potential difference measurement test	HRCT	Meconium ileus Volvulus Malabsorption

SCLC

SCLC accounts for approximately 15% of bronchogenic carcinomas.

At the time of diagnosis, approximately 30% of patients with SCLC will have tumors confined to the hemithorax of origin, the mediastinum, or the supraclavicular lymph nodes. These patients are designated as having limited-stage disease (LD).[1] Patients with tumors that have spread beyond the supraclavicular areas are said to have extensive-stage disease (ED).

SCLC is more responsive to chemotherapy and radiation therapy than other cell types of lung cancer; however, a cure is difficult to achieve because SCLC has a greater tendency to be widely disseminated by the time of diagnosis.

Incidence and Mortality The overall incidence and mortality rates of SCLC in the United States have decreased during the past few decades.[2]

Estimated new cases and deaths from lung cancer (SCLC and non-small cell lung cancer [NSCLC] combined) in the United States in 2018:[3]

New cases: 234,030. Deaths: 154,050. Risk Factors Increasing age is the most important risk factor for most cancers. Other risk factors for lung cancer include:

Current or history of tobacco use: cigarettes, pipes, and cigars.[4] Exposure to cancer-causing substances in secondhand smoke.[5,6] Occupational exposure to asbestos, arsenic, chromium, beryllium, nickel, and other agents.[7] Radiation exposure from any of the following: Radiation therapy to the breast or chest.[8] Radon exposure in the home or workplace.[9] Medical imaging tests, such as computed tomography (CT) scans.[10] Atomic bomb radiation.[11] Living in an area with air pollution.[12-14] Family history of lung cancer.[15] Human immunodeficiency virus infection.[16] Beta carotene supplements in heavy smokers.[17,18] Clinical Features Lung cancer may present with symptoms or be found incidentally on chest imaging. Symptoms and signs may result from the location of the primary local invasion or compression of adjacent thoracic structures, distant metastases, or paraneoplastic phenomena. The most common symptoms at presentation are worsening cough, shortness of breath, and dyspnea. Other presenting symptoms include the following:

Chest pain. Hoarseness. Malaise. Anorexia. Weight loss. Hemoptysis. Symptoms may result from local invasion or compression of adjacent thoracic structures, such as compression involving the esophagus causing dysphagia, compression involving the laryngeal nerves causing hoarseness, or compression involving the superior vena cava causing facial edema and distension of the superficial veins of the head and neck. Symptoms from distant metastases may also be present and include neurological defect or personality change from brain metastases or pain from bone metastases.

Infrequently, patients with SCLC may present with symptoms and signs of one of the following paraneoplastic syndromes:

Inappropriate antidiuretic hormone secretion. Cushing syndrome from secretion of adrenocorticotropic hormone. Paraneoplastic cerebellar degeneration. Lambert-Eaton myasthenic syndrome.[2] Physical examination may identify enlarged supraclavicular lymphadenopathy, pleural effusion or lobar collapse, unresolved pneumonia, or signs of associated disease such as chronic obstructive pulmonary disease.

Diagnosis Treatment options for patients are determined by histology, stage, and general health and comorbidities of the patient. Investigations of patients with suspected SCLC focus on confirming the diagnosis and determining the extent of the disease.

The procedures used to determine the presence of cancer include the following:

History. Physical examination. Routine laboratory evaluations. Chest x-ray. Chest CT scan with infusion of contrast material. Biopsy. Before a patient begins lung cancer treatment, an experienced lung cancer pathologist must review the pathologic material. This is critical because SCLC, which responds well to chemotherapy and is generally not treated surgically, can be confused on microscopic examination with NSCLC.[19] Immunohistochemistry and electron microscopy are invaluable techniques for diagnosis and subclassification, but most lung tumors can be classified by light microscopic criteria.

(Refer to the Staging Evaluation section in the Stage Information for SCLC section of this summary for more information about tests and procedures used for staging.)

Prognosis and Survival Regardless of stage, the current prognosis for patients with SCLC is unsatisfactory despite improvements in diagnosis and therapy made during the past 25 years. Without treatment, SCLC has the most aggressive clinical course of any type of pulmonary tumor, with median survival from diagnosis of only 2 to 4 months. About 10% of the total population of SCLC patients remains free of disease during the 2 years from the start of therapy, which is the time period during which most relapses occur. Even these patients, however, are at risk of dying from lung cancer (both small and non-small cell types).[20] The overall survival at 5 years is 5% to 10%.[1,20-22]

An important prognostic factor for SCLC is the extent of disease. Patients with LD have a better prognosis than patients with ED. For patients with LD, median survival of 16 to 24 months and 5-year survivals of 14% with current forms of treatment have been reported.[1,21,23,24] Patients diagnosed with LD who smoke should be encouraged to stop smoking before undergoing combined-modality therapy because continued smoking may compromise survival.[25]

Improved long-term survival in patients with LD has been shown with combined-modality therapy.[24,26][Level of evidence: 1iiA] Although long-term survivors have been reported among patients who received either surgery or chemotherapy alone, chemotherapy combined with thoracic radiation therapy (TRT) is considered the standard of care.[27] Adding TRT increases absolute survival by approximately 5% over chemotherapy alone.[26,28] The optimal timing of TRT relative to chemotherapy has been evaluated in multiple trials and meta-analyses with the weight of evidence suggesting a small benefit to early TRT.[1,29,30][Level of evidence: 1iiA]

In patients with ED, median survival of 6 to 12 months is reported with currently available therapy, but long-term disease-free survival is rare.

Prophylactic cranial radiation prevents central nervous system recurrence and can improve survival in patients with good performance status who have had a complete response or a very good partial response to chemoradiation in LD or chemotherapy in ED.[31,32][Level of evidence: 1iiA]

Thoracic radiation may also improve long-term outcomes for these patients.[33]

All patients with this type of cancer may appropriately be considered for inclusion in clinical trials at the time of diagnosis. Information about ongoing clinical trials is available from the NCI website.

References Murray N, Coy P, Pater JL, et al.: Importance of timing for thoracic irradiation in the combined modality treatment of limited-stage small-cell lung cancer. The National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 11 (2): 336-44, 1993. [PUBMED Abstract] Govindan R, Page N, Morgensztern D, et al.: Changing epidemiology of small-cell lung cancer in the United States over the last 30 years: analysis of the surveillance, epidemiologic, and end results database. J Clin Oncol 24 (28): 4539-44, 2006. [PUBMED Abstract] American Cancer Society: Cancer Facts and Figures 2018. Atlanta, Ga: American Cancer Society, 2018. Available onlineExit Disclaimer. Last accessed January 5, 2018. Alberg AJ, Ford JG, Samet JM, et al.: Epidemiology of lung cancer: ACCP evidence-based clinical practice guidelines (2nd edition). Chest 132 (3 Suppl): 29S-55S, 2007. [PUBMED Abstract] Tulunay OE, Hecht SS, Carmella SG, et al.: Urinary metabolites of a tobacco-specific lung carcinogen in nonsmoking hospitality workers. Cancer Epidemiol Biomarkers Prev 14 (5): 1283-6, 2005. [PUBMED Abstract] Anderson KE, Kliris J, Murphy L, et al.: Metabolites of a tobacco-specific lung carcinogen in nonsmoking casino patrons. Cancer Epidemiol Biomarkers Prev 12 (12): 1544-6, 2003. [PUBMED Abstract] Straif K, Benbrahim-Tallaa L, Baan R, et al.: A review of human carcinogens--part C: metals, arsenic, dusts, and fibres. Lancet Oncol 10 (5): 453-4, 2009. [PUBMED Abstract] Friedman DL, Whitton J, Leisenring W, et al.: Subsequent neoplasms in 5-year survivors of childhood cancer: the Childhood Cancer Survivor Study. J Natl Cancer Inst 102 (14): 1083-95, 2010. [PUBMED Abstract] Gray A, Read S, McGale P, et al.: Lung cancer deaths from indoor radon and the cost effectiveness and potential of policies to reduce them. BMJ 338: a3110, 2009. [PUBMED Abstract] Berrington de González A, Kim KP, Berg CD: Low-dose lung computed tomography screening before age 55: estimates of the mortality reduction required to outweigh the radiation-induced cancer risk. J Med Screen 15 (3): 153-8, 2008. [PUBMED Abstract] Shimizu Y, Kato H, Schull WJ: Studies of the mortality of A-bomb survivors. 9. Mortality, 1950-1985: Part 2. Cancer mortality based on the recently revised doses (DS86). Radiat Res 121 (2): 120-41, 1990. [PUBMED Abstract] Katanoda K, Sobue T, Satoh H, et al.: An association between long-term exposure to ambient air pollution and mortality from lung cancer and respiratory diseases in Japan. J Epidemiol 21 (2): 132-43, 2011. [PUBMED Abstract] Cao J, Yang C, Li J, et al.: Association between long-term exposure to outdoor air pollution and mortality in China: a cohort study. J Hazard Mater 186 (2-3): 1594-600, 2011. [PUBMED Abstract] Hales S, Blakely T, Woodward A: Air pollution and mortality in New Zealand: cohort study. J Epidemiol Community Health 66 (5): 468-73, 2012. [PUBMED Abstract] Lissowska J, Foretova L, Dabek J, et al.: Family history and lung cancer risk: international multicentre case-control study in Eastern and Central Europe and meta-analyses. Cancer Causes Control 21 (7): 1091-104, 2010. [PUBMED Abstract] Shiels MS, Cole SR, Kirk GD, et al.: A meta-analysis of the incidence of non-AIDS cancers in HIV-infected individuals. J Acquir Immune Defic Syndr 52 (5): 611-22, 2009. [PUBMED Abstract] The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. The Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group. N Engl J Med 330 (15): 1029-35, 1994. [PUBMED Abstract] Omenn GS, Goodman GE, Thornquist MD, et al.: Effects of a combination of beta carotene and vitamin A on lung cancer and cardiovascular disease. N Engl J Med 334 (18): 1150-5, 1996. [PUBMED Abstract] Travis WD, Colby TV, Corrin B, et al.: Histological typing of lung and pleural tumours. 3rd ed. Berlin: Springer-Verlag, 1999. Johnson BE, Grayson J, Makuch RW, et al.: Ten-year survival of patients with small-cell lung cancer treated with combination chemotherapy with or without irradiation. J Clin Oncol 8 (3): 396-401, 1990. [PUBMED Abstract] Fry WA, Menck HR, Winchester DP: The National Cancer Data Base report on lung cancer. Cancer 77 (9): 1947-55, 1996. [PUBMED Abstract] Lassen U, Osterlind K, Hansen M, et al.: Long-term survival in small-cell lung cancer: posttreatment characteristics in patients surviving 5 to 18+ years--an analysis of 1,714 consecutive patients. J Clin Oncol 13 (5): 1215-20, 1995. [PUBMED Abstract] Turrisi AT 3rd, Kim K, Blum R, et al.: Twice-daily compared with once-daily thoracic radiotherapy in limited small-cell lung cancer treated concurrently with cisplatin and etoposide. N Engl J Med 340 (4): 265-71, 1999. [PUBMED Abstract] Jänne PA, Freidlin B, Saxman S, et al.: Twenty-five years of clinical research for patients with limited-stage small cell lung carcinoma in North America. Cancer 95 (7): 1528-38, 2002. [PUBMED Abstract] Videtic GM, Stitt LW, Dar AR, et al.: Continued cigarette smoking by patients receiving concurrent chemoradiotherapy for limited-stage small-cell lung cancer is associated with decreased survival. J Clin Oncol 21 (8): 1544-9, 2003. [PUBMED Abstract] Pignon JP, Arriagada R, Ihde DC, et al.: A meta-analysis of thoracic radiotherapy for small-cell lung cancer. N Engl J Med 327 (23): 1618-24, 1992. [PUBMED Abstract] Chandra V, Allen MS, Nichols FC 3rd, et al.: The role of pulmonary resection in small cell lung cancer. Mayo Clin Proc 81 (5): 619-24, 2006. [PUBMED Abstract] Warde P, Payne D: Does thoracic irradiation improve survival and local control in limited-stage small-cell carcinoma of the lung? A meta-analysis. J Clin Oncol 10 (6): 890-5, 1992. [PUBMED Abstract] Perry MC, Eaton WL, Propert KJ, et al.: Chemotherapy with or without radiation therapy in limited small-cell carcinoma of the lung. N Engl J Med 316 (15): 912-8, 1987. [PUBMED Abstract] Takada M, Fukuoka M, Kawahara M, et al.: Phase III study of concurrent versus sequential thoracic radiotherapy in combination with cisplatin and etoposide for limited-stage small-cell lung cancer: results of the Japan Clinical Oncology Group Study 9104. J Clin Oncol 20 (14): 3054-60, 2002. [PUBMED Abstract] Aupérin A, Arriagada R, Pignon JP, et al.: Prophylactic cranial irradiation for patients with small-cell lung cancer in complete remission. Prophylactic Cranial Irradiation Overview Collaborative Group. N Engl J Med 341 (7): 476-84, 1999. [PUBMED Abstract] Slotman B, Faivre-Finn C, Kramer G, et al.: Prophylactic cranial irradiation in extensive small-cell lung cancer. N Engl J Med 357 (7): 664-72, 2007. [PUBMED Abstract] Slotman BJ, van Tinteren H, Praag JO, et al.: Use of thoracic radiotherapy for extensive stage small-cell lung cancer: a phase 3 randomised controlled trial. Lancet 385 (9962): 36-42, 2015. [PUBMED Abstract]

Treatment options

Chemotherapy and radiation therapy have been shown to improve survival for patients with small cell lung cancer (SCLC).

Chemotherapy Chemotherapy improves the survival of patients with limited-stage disease (LD) or extensive-stage disease (ED), but it is curative in only a minority of patients.[1,2] Because patients with SCLC tend to develop distant metastases, localized forms of treatment, such as surgical resection or radiation therapy, rarely produce long-term survival.[3] With incorporation of current chemotherapy regimens into the treatment program, however, survival is prolonged, with at least a fourfold to fivefold improvement in median survival compared with patients who are given no therapy.

The combination of platinum and etoposide is the most widely used standard chemotherapeutic regimen.[4-6][Level of evidence: 1iiA] No consistent survival benefit has resulted from platinum versus nonplatinum combinations, increased dose intensity or dose density, altered mode of administration (e.g., alternating or sequential administration) of various chemotherapeutic agents, or maintenance chemotherapy.[7-12][Level of evidence: 1iiA]

Radiation Therapy SCLC is highly radiosensitive and thoracic radiation therapy improves survival of patients with LD and ED tumors.[13-16][Level of evidence: 1iiA] Prophylactic cranial ir (PCI) prevents central nervous system recurrence and may improve the long-term survival of patients with good performance status who have responded to chemoradiation therapy [17-19][Level of evidence: 1iiA] and offers palliation of symptomatic metastatic disease.

Treatment for patients with LD, ED, or recurrent SCLC is summarized in Table 1.

Table 1. Standard Treatment Options for Patients With SCLC Stage Standard Treatment Options ED = extensive-stage disease; LD = limited stage disease (LD) Chemotherapy and radiation therapy Combination chemotherapy alone Surgery followed by chemotherapy or chemoradiation therapy Prophylactic cranial irradiation (ED) Combination chemotherapy Radiation therapy Prophylactic cranial irradiation Recurrent disease Chemotherapy Palliative therapy Despite treatment advances, most patients with SCLC die of their tumor even with the best available therapy. Most of the improvements in the survival of patients with SCLC are attributable to clinical trials that have attempted to improve on the best available and most accepted therapy. Patient entry into such studies is highly desirable.

Information about ongoing clinical trials is available from the NCI website.

References Comis RL, Friedland DM, Good BC: Small-cell lung cancer: a perspective on the past and a preview of the future. Oncology (Huntingt) 12 (1 Suppl 2): 44-50, 1998. [PUBMED Abstract] Agra Y, Pelayo M, Sacristan M, et al.: Chemotherapy versus best supportive care for extensive small cell lung cancer. Cochrane Database Syst Rev (4): CD001990, 2003. [PUBMED Abstract] Prasad US, Naylor AR, Walker WS, et al.: Long term survival after pulmonary resection for small cell carcinoma of the lung. Thorax 44 (10): 784-7, 1989. [PUBMED Abstract] Johnson BE, Grayson J, Makuch RW, et al.: Ten-year survival of patients with small-cell lung cancer treated with combination chemotherapy with or without irradiation. J Clin Oncol 8 (3): 396-401, 1990. [PUBMED Abstract] Lassen U, Osterlind K, Hansen M, et al.: Long-term survival in small-cell lung cancer: posttreatment characteristics in patients surviving 5 to 18+ years--an analysis of 1,714 consecutive patients. J Clin Oncol 13 (5): 1215-20, 1995. [PUBMED Abstract] Fry WA, Menck HR, Winchester DP: The National Cancer Data Base report on lung cancer. Cancer 77 (9): 1947-55, 1996. [PUBMED Abstract] Ihde DC, Mulshine JL, Kramer BS, et al.: Prospective randomized comparison of high-dose and standard-dose etoposide and cisplatin chemotherapy in patients with extensive-stage small-cell lung cancer. J Clin Oncol 12 (10): 2022-34, 1994. [PUBMED Abstract] Arriagada R, Le Chevalier T, Pignon JP, et al.: Initial chemotherapeutic doses and survival in patients with limited small-cell lung cancer. N Engl J Med 329 (25): 1848-52, 1993. [PUBMED Abstract] Klasa RJ, Murray N, Coldman AJ: Dose-intensity meta-analysis of chemotherapy regimens in small-cell carcinoma of the lung. J Clin Oncol 9 (3): 499-508, 1991. [PUBMED Abstract] Elias AD, Ayash L, Frei E 3rd, et al.: Intensive combined modality therapy for limited-stage small-cell lung cancer. J Natl Cancer Inst 85 (7): 559-66, 1993. [PUBMED Abstract] Murray N, Livingston RB, Shepherd FA, et al.: Randomized study of CODE versus alternating CAV/EP for extensive-stage small-cell lung cancer: an Intergroup Study of the National Cancer Institute of Canada Clinical Trials Group and the Southwest Oncology Group. J Clin Oncol 17 (8): 2300-8, 1999. [PUBMED Abstract] Amarasena IU, Walters JA, Wood-Baker R, et al.: Platinum versus non-platinum chemotherapy regimens for small cell lung cancer. Cochrane Database Syst Rev (4): CD006849, 2008. [PUBMED Abstract] Pignon JP, Arriagada R, Ihde DC, et al.: A meta-analysis of thoracic radiotherapy for small-cell lung cancer. N Engl J Med 327 (23): 1618-24, 1992. [PUBMED Abstract] Warde P, Payne D: Does thoracic irradiation improve survival and local control in limited-stage small-cell carcinoma of the lung? A meta-analysis. J Clin Oncol 10 (6): 890-5, 1992. [PUBMED Abstract] Murray N, Coy P, Pater JL, et al.: Importance of timing for thoracic irradiation in the combined modality treatment of limited-stage small-cell lung cancer. The National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 11 (2): 336-44, 1993. [PUBMED Abstract] Slotman BJ, van Tinteren H, Praag JO, et al.: Use of thoracic radiotherapy for extensive stage small-cell lung cancer: a phase 3 randomised controlled trial. Lancet 385 (9962): 36-42, 2015. [PUBMED Abstract] Turrisi AT 3rd, Glover DJ: Thoracic radiotherapy variables: influence on local control in small cell lung cancer limited disease. Int J Radiat Oncol Biol Phys 19 (6): 1473-9, 1990. [PUBMED Abstract] Aupérin A, Arriagada R, Pignon JP, et al.: Prophylactic cranial irradiation for patients with small-cell lung cancer in complete remission. Prophylactic Cranial Irradiation Overview Collaborative Group. N Engl J Med 341 (7): 476-84, 1999. [PUBMED Abstract] Slotman B, Faivre-Finn C, Kramer G, et al.: Prophylactic cranial irradiation in extensive small-cell lung cancer. N Engl J Med 357 (7): 664-72, 2007. [PUBMED Abstract]

Limited-Stage SCLC Treatment

Standard Treatment Options for Patients With Limited-Stage SCLC Chemotherapy and radiation therapy Combination chemotherapy alone Surgery followed by chemotherapy or chemoradiation therapy PCI Neurologic sequelae Treatment options for older patients Treatment Options Under Clinical Evaluation Current Clinical Trials Standard Treatment Options for Patients With Limited-Stage SCLC Standard treatment options for patients with limited-stage small-cell lung cancer (SCLC) include the following:

Chemotherapy and radiation therapy. Combination chemotherapy alone. Surgery followed by chemotherapy or chemoradiation therapy. Prophylactic cranial irradiation (PCI). Chemotherapy and radiation therapy Combined-modality treatment with etoposide and cisplatin with thoracic radiation therapy (TRT) is the most widely used treatment for patients with limited-stage disease (LD) SCLC.

Evidence (combined modality treatment):

Survival. The following results have been reported in clinical trials: Mature results of prospective randomized trials suggest that combined-modality therapy produces a modest but significant improvement in survival of 5% at 3 years compared with chemotherapy alone.[1-3][Level of evidence: 1iiA] Clinical trials have consistently achieved median survivals of 18 to 24 months and 40% to 50% 2-year survival rates with less than a 3% treatment-related mortality.[3-7][Level of evidence: 1iiA] No consistent survival benefit has resulted from the following:[8-16] Increased dose intensity. Increased dose density. Administration of additional drugs or other (non–etoposide-containing) platinum-based combination regimens. Altered modes of administration of various chemotherapeutic agents. Maintenance chemotherapy. Length of treatment. The optimal duration of chemotherapy for patients with LD SCLC is not clearly defined, but no improvement exists in survival after the duration of drug administration exceeds 3 to 6 months. The preponderance of evidence available from randomized trials indicates that maintenance chemotherapy does not prolong survival for patients with LD SCLC.[8-15][Level of evidence: 1iiA] Dose and timing. The optimal dose and timing of TRT remain controversial. Multiple clinical trials and meta-analyses addressing the timing of TRT have been published, with the weight of evidence suggesting a small benefit to early TRT (i.e., TRT administered during the first or second cycle of chemotherapy administration).[3-6,8,9,15,17-20][Level of evidence: 1iiA] The amount of time from start to completion of TRT in LD SCLC may also effect overall survival (OS). In an analysis of four trials, the completion of therapy in less than 30 days was associated with an improved 5-year survival rate (relative risk, 0.62; 95% confidence interval, 0.49–0.80; P = .0003).[20][Level of evidence: 1iiA] Both once-daily and twice-daily chest radiation schedules have been used in regimens with etoposide and cisplatin. One randomized study showed a modest survival advantage in favor of twice-daily radiation therapy given for 3 weeks compared with once-daily radiation therapy to 45 Gy given for 5 weeks (26% vs. 16% at 5 years; P = .04).[17][Level of evidence: 1iiA] Esophagitis was increased with twice-daily treatment. Twice-daily radiation therapy has not been broadly adopted. Once-daily fractions to higher doses of greater than 60 Gy are feasible and commonly used; their clinical benefits are yet to be defined in phase III trials.[21-25][Level of evidence: 3iiiA] Combination chemotherapy alone Patients with a contraindication to radiation therapy could be treated with chemotherapy alone. Patients presenting with superior vena cava syndrome are treated immediately with combination chemotherapy, radiation therapy, or both, depending on the severity of presentation.[26,27] (Refer to the PDQ summary on Cardiopulmonary Syndromes for more information.)

Surgery followed by chemotherapy or chemoradiation therapy The role of surgery in the management of patients with SCLC is unproven. Small case series and population studies have reported favorable outcomes for the minority of LD patients with very limited disease, with small tumors pathologically confined to the lung of origin or the lung and ipsilateral hilar lymph nodes from surgical resection with adjuvant chemotherapy.[28-32][Level of evidence: 3iiiDii] Patients who have undergone surgery and then been diagnosed with SCLC generally receive adjuvant chemotherapy with or without radiation therapy. In patients who receive chemotherapy with radiation therapy, there is no improvement in survival with the addition of surgery.[32][Level of evidence: 3iiiDii] Given the absence of data from randomized trials, the role of surgery in the management of individual patients with SCLC must be considered, both in terms of potential benefit and risk from the surgical procedure.

Evidence (role of surgery):

A randomized study evaluating the role of surgery in addition to chemoradiation therapy enrolled 328 patients with LD SCLC and found no OS benefit with the addition of pulmonary resection.[33][Level of evidence: 1iiA] PCI Patients who have achieved a complete remission can be considered for administration of PCI. Patients whose cancer can be controlled outside the brain have a 60% actuarial risk of developing central nervous system (CNS) metastases within 2 to 3 years after starting treatment.[32,34,35] Most of these patients relapse only in their brain, and nearly all of those who relapse in their CNS die of their cranial metastases. The risk of developing CNS metastases can be reduced by more than 50% with the administration of PCI.[34]

Evidence (role of PCI):

A meta-analysis of seven randomized trials evaluating the value of PCI in patients in complete remission reported improvement in brain recurrence, disease-free survival, and OS with the addition of PCI. The 3-year OS was improved from 15% to 21% with PCI.[34][Level of evidence: 1iiA] A randomized study (RTOG-0212) of 720 patients with LD SCLC in complete remission after chemoradiation therapy demonstrated that standard-dose PCI (25 Gy in 10 fractions) was as effective as and less toxic than higher doses of brain radiation.[36] Randomized trials such as EORTC-22003-08004 (NCT00005062) showed that doses higher than 25 Gy in 10 daily fractions do not improve long-term survival.[36-38] Neurologic sequelae Retrospective studies have shown that long-term survivors of SCLC (>2 years from the start of treatment) have a high incidence of CNS impairment.[32,35,39-41] Prospective studies have shown that patients treated with PCI do not have significantly worse neuropsychological function than patients not treated.[41] Most patients with SCLC have neuropsychological abnormalities present before the start of PCI and have no detectable decline in their neurological status for as long as 2 years after the start of their PCI.[41] Patients treated for SCLC continue to have declining neuropsychologic function after 2 years from the start of treatment.[39-41] Additional neuropsychologic testing of patients beyond 2 years from the start of treatment will be needed before concluding that PCI does not contribute to the decline in intellectual function.

Treatment options for older patients The optimal therapeutic approach in older patients remains unclear. A population analysis showed that increasing age was associated with a decreased performance status and increased comorbidity.[42] Older patients were less likely to be treated with combined chemoradiation therapy, more intensive chemotherapy, and PCI. Older patients were also less likely to respond to therapy and had poorer survival outcomes. Whether this was a result of age and its associated comorbidities or suboptimal treatment delivery remains uncertain.

No specific phase III trial in older patients with LD SCLC has been reported; however, three secondary analyses of two cooperative group trials have been published evaluating outcomes in patients aged 70 years or older.[43-45] The survival outcomes for the older patients were identical to their younger counterparts in both trials. The older patients experienced more toxic effects, particularly hematologic, compared with younger patients. There was a significant increase in treatment-related mortality in the EST-3588 trial that compared etoposide and cisplatin with either once-daily or twice-daily radiation therapy (1% for patients aged <70 years vs. 10% for patients aged ≥70 years; P = .01).[44] Because the older patients enrolled in these phase III trials may not be representative of LD SCLC patients in the general population, caution must be exercised in extrapolating these results to the general population of older patients.

Treatment Options Under Clinical Evaluation Treatment options under clinical evaluation for patients with LD SCLC include the following:

New drug regimens. Surgical resection of the primary tumor. New radiation therapy schedules and techniques (e.g., timing, three-dimensional treatment planning, and dose fractionation). Current Clinical Trials Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

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[PUBMED Abstract] Le Péchoux C, Dunant A, Senan S, et al.: Standard-dose versus higher-dose prophylactic cranial irradiation (PCI) in patients with limited-stage small-cell lung cancer in complete remission after chemotherapy and thoracic radiotherapy (PCI 99-01, EORTC 22003-08004, RTOG 0212, and IFCT 99-01): a randomised clinical trial. Lancet Oncol 10 (5): 467-74, 2009. [PUBMED Abstract] Le Péchoux C, Laplanche A, Faivre-Finn C, et al.: Clinical neurological outcome and quality of life among patients with limited small-cell cancer treated with two different doses of prophylactic cranial irradiation in the intergroup phase III trial (PCI99-01, EORTC 22003-08004, RTOG 0212 and IFCT 99-01). Ann Oncol 22 (5): 1154-63, 2011. [PUBMED Abstract] Wolfson AH, Bae K, Komaki R, et al.: Primary analysis of a phase II randomized trial Radiation Therapy Oncology Group (RTOG) 0212: impact of different total doses and schedules of prophylactic cranial irradiation on chronic neurotoxicity and quality of life for patients with limited-disease small-cell lung cancer. Int J Radiat Oncol Biol Phys 81 (1): 77-84, 2011. [PUBMED Abstract] Johnson BE, Patronas N, Hayes W, et al.: Neurologic, computed cranial tomographic, and magnetic resonance imaging abnormalities in patients with small-cell lung cancer: further follow-up of 6- to 13-year survivors. J Clin Oncol 8 (1): 48-56, 1990. [PUBMED Abstract] Laukkanen E, Klonoff H, Allan B, et al.: The role of prophylactic brain irradiation in limited stage small cell lung cancer: clinical, neuropsychologic, and CT sequelae. Int J Radiat Oncol Biol Phys 14 (6): 1109-17, 1988. [PUBMED Abstract] Cull A, Gregor A, Hopwood P, et al.: Neurological and cognitive impairment in long-term survivors of small cell lung cancer. Eur J Cancer 30A (8): 1067-74, 1994. [PUBMED Abstract] Ludbrook JJ, Truong PT, MacNeil MV, et al.: Do age and comorbidity impact treatment allocation and outcomes in limited stage small-cell lung cancer? a community-based population analysis. Int J Radiat Oncol Biol Phys 55 (5): 1321-30, 2003. [PUBMED Abstract] Schild SE, Stella PJ, Geyer SM, et al.: The outcome of combined-modality therapy for stage III non-small-cell lung cancer in the elderly. J Clin Oncol 21 (17): 3201-6, 2003. [PUBMED Abstract] Yuen AR, Zou G, Turrisi AT, et al.: Similar outcome of elderly patients in intergroup trial 0096: Cisplatin, etoposide, and thoracic radiotherapy administered once or twice daily in limited stage small cell lung carcinoma. Cancer 89 (9): 1953-60, 2000. [PUBMED Abstract] Siu LL, Shepherd FA, Murray N, et al.: Influence of age on the treatment of limited-stage small-cell lung cancer. J Clin Oncol 14 (3): 821-8, 1996. [PUBMED Abstract]

Extensive-Stage SCLC Treatment

Standard Treatment Options for Patients With Extensive-Stage SCLC Combination chemotherapy Radiation therapy Treatment Options Under Clinical Evaluation Current Clinical Trials Standard Treatment Options for Patients With Extensive-Stage SCLC Standard treatment options for patients with extensive-stage small-cell lung cancer (SCLC) include the following:

Combination chemotherapy. Radiation therapy. Thoracic radiation therapy for patients who respond to chemotherapy. Prophylactic cranial irradiation (PCI). Combination chemotherapy Chemotherapy for patients with extensive-stage disease (ED) SCLC is commonly given as a two-drug combination of platinum and etoposide in doses associated with at least moderate toxic effects (as in limited-stage [LD] SCLC).[1] Cisplatin is associated with significant toxic effects and requires fluid hydration, which can be problematic in patients with cardiovascular disease. Carboplatin is active in SCLC, is dosed according to renal function, and is associated with less nonhematological toxic effects.

Other regimens appear to produce similar survival outcomes but have been studied less extensively or are in less common use.

Table 2. Combination Chemotherapy For Extensive-Stage SCLC Standard treatment Etoposide + cisplatin Etoposide + carboplatin Other regimens Cisplatin + irinotecan Ifosfamide + cisplatin + etoposide Cyclophosphamide + doxorubicin + etoposide Cyclophosphamide + doxorubicin + etoposide + vincristine Cyclophosphamide + etoposide + vincristine Cyclophosphamide + doxorubicin + vincristine Doses and schedules used in current programs yield overall response rates of 50% to 80% and complete response rates of 0% to 30% in patients with ED.[2,3][Level of evidence: 1iiA]

Intracranial metastases from small cell carcinoma may respond to chemotherapy as readily as metastases in other organs.[4,5]

Evidence (standard regimens):

Two meta-analyses evaluating the role of platinum combinations versus nonplatinum combinations have been published. A Cochrane analysis did not identify a difference in 6-, 12-, or 24-month survival.[6] A meta-analysis of 19 trials published between 1981 and 1999 showed a significant survival advantage for patients receiving platinum-based chemotherapy compared with those not receiving a platinum agent.[3][Level of evidence: 1iiA] The Hellenic Oncology Group conducted a phase III trial comparing cisplatin and etoposide with carboplatin plus etoposide.[7] The median survival was 11.8 months in the cisplatin arm and 12.5 months in carboplatin-treated patients.[7][Level of evidence: 1iiA] Although this difference was not statistically significant, the trial was underpowered to prove equivalence of the two treatment regimens in patients with either LD or ED. Evidence (other combination chemotherapy regimens):

Irinotecan. Five trials and two meta-analyses have evaluated the combination of etoposide and cisplatin versus irinotecan and cisplatin. Only one of the trials showed the superiority of the irinotecan and cisplatin combination.[8][Level of evidence: 1iiA] Subsequent trials and the meta-analyses support that the regimens provide equivalent clinical benefit with differing toxicity profiles.[9-14][Level of evidence: 1iiA] Irinotecan and cisplatin regimens led to less grade 3 to 4 anemia, neutropenia, and thrombocytopenia but more grade 3 to 4 vomiting and diarrhea than etoposide and cisplatin regimens. Treatment-related deaths were comparable between the two groups. Topotecan. In a randomized trial of 784 patients, the combination of oral topotecan given with cisplatin for 5 days was not found to be superior to etoposide and cisplatin.[15] The 1-year survival rate was 31% (95% confidence interval [CI], 27%–36%) and was deemed to be noninferior, as the difference of -0.03 met the predefined criteria of no more than 10% absolute difference in 1-year survival.[15][Level of evidence: 1iiA] Paclitaxel. No consistent survival benefit has resulted from the addition of paclitaxel to etoposide and cisplatin.[16,17] Evidence (duration of treatment):

The optimal duration of chemotherapy is not clearly defined, but no obvious improvement in survival occurs when the duration of drug administration exceeds 6 months.[7,18,19] No clear evidence is available from reported data from randomized trials that maintenance chemotherapy will improve survival duration.[20-22][Level of evidence: 1iiA] However, a meta-analysis of 14 published, randomized trials assessing the benefit of duration/maintenance therapy reported an odds ratio of 0.67 for both 1- and 2-year overall survival (OS) of 0.67 (95% CI, 0.56–0.79; P < .001 for 1-year OS and 0.53–0.86; P < .001 for 2-year OS). This corresponded to an increase of 9% in 1-year OS and 4% in 2-year OS.[23][Level of evidence: 1iiA] Evidence (dose intensification):

The role of dose intensification in patients with SCLC remains unclear.[24-28] Early studies showed that under-treatment compromised outcome and suggested that early dose intensification may improve survival.[24,25] A number of clinical trials have examined the use of colony-stimulating factors to support dose-intensified chemotherapy in SCLC.[26-34] These studies have yielded conflicting results. Four studies have shown that a modest increase in dose intensity (25%–34%) was associated with a significant improvement in survival with no compromise in quality of life (QOL).[26-29][Level of evidence: 1iiA] Two of three studies that examined combinations of the variables of interval, dose per cycle, and number of cycles showed no advantage.[29-32][Level of evidence: 1iiA] The European Organization for Research and Treatment of Cancer trial (EORTC-08923) reported a randomized comparison of standard-dose cyclophosphamide, doxorubicin, and etoposide given every 3 weeks for five cycles versus intensified treatment given at 125% of the dose every 2 weeks for four cycles with granulocyte colony-stimulating factor (G-CSF) support.[32] The median dose intensity delivered was 70% higher in the experimental arm; the median cumulative dose was similar in both arms. There was no difference between treatment groups in median or 2-year survival. A randomized, phase III trial compared ifosfamide, cisplatin, and etoposide (ICE), which was given every 4 weeks, with twice weekly ICE with G-CSF and autologous blood support.[33] Despite achieving a relative dose intensity of 1.84 in the dose-accelerated arm, there was no difference in response rate (88% vs. 80%, respectively), median survival (14.4 vs. 13.9 months, respectively), or 2-year survival (19% vs. 22%, respectively) for dose-dense treatment compared with standard treatment.[33][Level of evidence: 1iiA] Patients who received dose-dense treatment spent less time on treatment and had fewer episodes of infection. A randomized, phase II study of identical design reported a significantly better median survival for the dose-dense arm (29.8 vs. 17.4 months, respectively; P = .02) and 2-year survival (62% vs. 36%, respectively; P = .05).[34] However, given the small study size (only 70 patients), these results should be viewed with caution. Factors influencing treatment with chemotherapy Performance status More patients with ED SCLC have greatly impaired performance status at the time of diagnosis than patients with LD. Such patients have a poor prognosis and tolerate aggressive chemotherapy or combined-modality therapy poorly. Single-agent intravenous, oral, and low-dose biweekly regimens have been developed for these patients.[30,35-41]

Prospective, randomized studies have shown that patients with a poor prognosis who are treated with conventional regimens live longer than those treated with the single-agent, low-dose regimens or abbreviated courses of therapy. A study comparing chemotherapy every 3 weeks with treatment given as required for symptom control showed an improvement in QOL in those patients receiving regular treatment.[38][Level of evidence: 1iiDii]

Other studies have tested intensive one-drug or two-drug regimens. A study conducted by the Medical Research Council demonstrated similar efficacy for an etoposide plus vincristine regimen and a four-drug regimen.[39] The latter regimen was associated with a greater risk of toxic effects and early death but was superior with respect to palliation of symptoms and psychological distress.[39][Level of evidence: 1iiC] Studies comparing a convenient oral treatment with single-agent oral etoposide versus combination therapy showed that the overall response rate and OS were significantly worse in the oral etoposide arm.[35,40][Level of evidence: 1iiA]

Age Subgroup analyses of phase II and phase III trials of SCLC patients by age showed that myelosuppression and doxorubicin-induced cardiac toxic effects were more severe in older patients than in younger patients and that the incidence of treatment-related death tended to be higher in older patients.[41] About 80% of older patients, however, received optimal treatment, and their survival was comparable with that of younger patients. The standard chemotherapy regimens for the general population could be applied to older patients in good general condition (i.e., performance status of 0–1, normal organ function, and no comorbidity). There is no evidence of a difference in response rate, disease-free survival (DFS), or OS in older patients compared with younger patients.

Radiation therapy Radiation therapy to sites of metastatic disease unlikely to be immediately palliated by chemotherapy, especially brain, epidural, and bone metastases, is a standard treatment option for patients with ED SCLC. Brain metastases are treated with whole-brain radiation therapy.

Chest radiation therapy is sometimes given for superior vena cava syndrome, but chemotherapy alone, with radiation reserved for nonresponding patients, is appropriate initial treatment. (Refer to the PDQ summary on Cardiopulmonary Syndromes for more information.)

Thoracic radiation therapy for patients who respond to chemotherapy Patients with ED treated with chemotherapy who have achieved a response can be considered for thoracic radiation therapy.

Evidence (thoracic radiation therapy):

A randomized trial of 498 patients who responded after receiving four to six cycles of chemotherapy compared thoracic radiation therapy with 30 Gy in 10 fractions versus no radiation therapy. All patients received PCI.[42][Level of evidence: 1iiA] OS was the primary study endpoint and not statistically different between the two groups at 1 year (33% for the thoracic radiation therapy group vs. 28% for the control group, P = .066). However, in a secondary analysis, 2-year OS was 13% in the thoracic radiation group (95% CI, 9–19) versus 3% in the control group (95% CI, 2–8; P = .004). The OS during the entire course of follow-up was not reported. Thoracic radiation therapy resulted in 6-month progression-free survival (PFS) of 24% in the thoracic radiation group (95% CI, 19–30) versus 7% in the control group (95% CI, 4–11; P = .001). Intrathoracic recurrences, both isolated (19.8% vs. 46.0%) and in combination with recurrences at other sites (43.7% vs. 79.8%), were reduced by approximately 50%. Thoracic radiation therapy was well tolerated. PCI Patients with ED treated with chemotherapy who have achieved a response can be considered for administration of PCI.

Evidence (PCI):

A randomized trial of 286 patients who responded after four to six cycles of chemotherapy compared PCI with no further therapy.[43][Level of evidence: 1iiD The cumulative risk of brain metastases within 1 year was 14.6% in the radiation group (95% CI, 8.3–20.9) and 40.4% in the control group (95% CI, 32.1– 48.6). Radiation was associated with an increase in median DFS from 12.0 weeks to 14.7 weeks and in median OS from 5.4 months to 6.7 months after randomization. The 1-year survival rate was 27.1% (95% CI, 19.4–35.5) in the radiation group and 13.3% (95% CI, 8.1–19.9) in the control group.[43] Radiation had side effects but did not have a clinically significant effect on global health status.[43] Only 29% of the randomly assigned patients had brain imaging at diagnosis.[44] Combination chemotherapy and radiation therapy Combination chemotherapy plus chest radiation therapy does not appear to improve survival compared with chemotherapy alone in patients with ED SCLC.

Treatment Options Under Clinical Evaluation Treatment options under clinical evaluation for patients with ED SCLC include the following:

New drug regimens. Alternative drug doses and schedules. Current Clinical Trials Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References Okamoto H, Watanabe K, Kunikane H, et al.: Randomised phase III trial of carboplatin plus etoposide vs split doses of cisplatin plus etoposide in elderly or poor-risk patients with extensive disease small-cell lung cancer: JCOG 9702. Br J Cancer 97 (2): 162-9, 2007. [PUBMED Abstract] Roth BJ, Johnson DH, Einhorn LH, et al.: Randomized study of cyclophosphamide, doxorubicin, and vincristine versus etoposide and cisplatin versus alternation of these two regimens in extensive small-cell lung cancer: a phase III trial of the Southeastern Cancer Study Group. J Clin Oncol 10 (2): 282-91, 1992. [PUBMED Abstract] Pujol JL, Carestia L, Daurès JP: Is there a case for cisplatin in the treatment of small-cell lung cancer? A meta-analysis of randomized trials of a cisplatin-containing regimen versus a regimen without this alkylating agent. Br J Cancer 83 (1): 8-15, 2000. [PUBMED Abstract] Twelves CJ, Souhami RL, Harper PG, et al.: The response of cerebral metastases in small cell lung cancer to systemic chemotherapy. Br J Cancer 61 (1): 147-50, 1990. [PUBMED Abstract] Nugent JL, Bunn PA Jr, Matthews MJ, et al.: CNS metastases in small cell bronchogenic carcinoma: increasing frequency and changing pattern with lengthening survival. Cancer 44 (5): 1885-93, 1979. [PUBMED Abstract] Amarasena IU, Walters JA, Wood-Baker R, et al.: Platinum versus non-platinum chemotherapy regimens for small cell lung cancer. Cochrane Database Syst Rev (4): CD006849, 2008. [PUBMED Abstract] Controlled trial of twelve versus six courses of chemotherapy in the treatment of small-cell lung cancer. Report to the Medical Research Council by its Lung Cancer Working Party. Br J Cancer 59 (4): 584-90, 1989. [PUBMED Abstract] Noda K, Nishiwaki Y, Kawahara M, et al.: Irinotecan plus cisplatin compared with etoposide plus cisplatin for extensive small-cell lung cancer. N Engl J Med 346 (2): 85-91, 2002. [PUBMED Abstract] Hanna N, Bunn PA Jr, Langer C, et al.: Randomized phase III trial comparing irinotecan/cisplatin with etoposide/cisplatin in patients with previously untreated extensive-stage disease small-cell lung cancer. J Clin Oncol 24 (13): 2038-43, 2006. [PUBMED Abstract] Lara PN Jr, Natale R, Crowley J, et al.: Phase III trial of irinotecan/cisplatin compared with etoposide/cisplatin in extensive-stage small-cell lung cancer: clinical and pharmacogenomic results from SWOG S0124. J Clin Oncol 27 (15): 2530-5, 2009. [PUBMED Abstract] Schmittel A, Sebastian M, Fischer von Weikersthal L, et al.: A German multicenter, randomized phase III trial comparing irinotecan-carboplatin with etoposide-carboplatin as first-line therapy for extensive-disease small-cell lung cancer. Ann Oncol 22 (8): 1798-804, 2011. [PUBMED Abstract] Zatloukal P, Cardenal F, Szczesna A, et al.: A multicenter international randomized phase III study comparing cisplatin in combination with irinotecan or etoposide in previously untreated small-cell lung cancer patients with extensive disease. Ann Oncol 21 (9): 1810-6, 2010. [PUBMED Abstract] Jiang J, Liang X, Zhou X, et al.: A meta-analysis of randomized controlled trials comparing irinotecan/platinum with etoposide/platinum in patients with previously untreated extensive-stage small cell lung cancer. J Thorac Oncol 5 (6): 867-73, 2010. [PUBMED Abstract] Guo S, Liang Y, Zhou Q: Complement and correction for meta-analysis of patients with extensive-stage small cell lung cancer managed with irinotecan/cisplatin versus etoposide/cisplatin as first-line chemotherapy. J Thorac Oncol 6 (2): 406-8; author reply 408, 2011. [PUBMED Abstract] Eckardt JR, von Pawel J, Papai Z, et al.: Open-label, multicenter, randomized, phase III study comparing oral topotecan/cisplatin versus etoposide/cisplatin as treatment for chemotherapy-naive patients with extensive-disease small-cell lung cancer. J Clin Oncol 24 (13): 2044-51, 2006. [PUBMED Abstract] Mavroudis D, Papadakis E, Veslemes M, et al.: A multicenter randomized clinical trial comparing paclitaxel-cisplatin-etoposide versus cisplatin-etoposide as first-line treatment in patients with small-cell lung cancer. Ann Oncol 12 (4): 463-70, 2001. [PUBMED Abstract] Niell HB, Herndon JE 2nd, Miller AA, et al.: Randomized phase III intergroup trial of etoposide and cisplatin with or without paclitaxel and granulocyte colony-stimulating factor in patients with extensive-stage small-cell lung cancer: Cancer and Leukemia Group B Trial 9732. J Clin Oncol 23 (16): 3752-9, 2005. [PUBMED Abstract] Spiro SG, Souhami RL, Geddes DM, et al.: Duration of chemotherapy in small cell lung cancer: a Cancer Research Campaign trial. Br J Cancer 59 (4): 578-83, 1989. [PUBMED Abstract] Bleehen NM, Girling DJ, Machin D, et al.: A randomised trial of three or six courses of etoposide cyclophosphamide methotrexate and vincristine or six courses of etoposide and ifosfamide in small cell lung cancer (SCLC). I: Survival and prognostic factors. Medical Research Council Lung Cancer Working Party. Br J Cancer 68 (6): 1150-6, 1993. [PUBMED Abstract] Giaccone G, Dalesio O, McVie GJ, et al.: Maintenance chemotherapy in small-cell lung cancer: long-term results of a randomized trial. European Organization for Research and Treatment of Cancer Lung Cancer Cooperative Group. J Clin Oncol 11 (7): 1230-40, 1993. [PUBMED Abstract] Sculier JP, Paesmans M, Bureau G, et al.: Randomized trial comparing induction chemotherapy versus induction chemotherapy followed by maintenance chemotherapy in small-cell lung cancer. European Lung Cancer Working Party. J Clin Oncol 14 (8): 2337-44, 1996. [PUBMED Abstract] Schiller JH, Adak S, Cella D, et al.: Topotecan versus observation after cisplatin plus etoposide in extensive-stage small-cell lung cancer: E7593--a phase III trial of the Eastern Cooperative Oncology Group. J Clin Oncol 19 (8): 2114-22, 2001. [PUBMED Abstract] Bozcuk H, Artac M, Ozdogan M, et al.: Does maintenance/consolidation chemotherapy have a role in the management of small cell lung cancer (SCLC)? A metaanalysis of the published controlled trials. Cancer 104 (12): 2650-7, 2005. [PUBMED Abstract] Cohen MH, Creaven PJ, Fossieck BE Jr, et al.: Intensive chemotherapy of small cell bronchogenic carcinoma. Cancer Treat Rep 61 (3): 349-54, 1977 May-Jun. [PUBMED Abstract] Arriagada R, Le Chevalier T, Pignon JP, et al.: Initial chemotherapeutic doses and survival in patients with limited small-cell lung cancer. N Engl J Med 329 (25): 1848-52, 1993. [PUBMED Abstract] Fukuoka M, Masuda N, Negoro S, et al.: CODE chemotherapy with and without granulocyte colony-stimulating factor in small-cell lung cancer. Br J Cancer 75 (2): 306-9, 1997. [PUBMED Abstract] Woll PJ, Hodgetts J, Lomax L, et al.: Can cytotoxic dose-intensity be increased by using granulocyte colony-stimulating factor? A randomized controlled trial of lenograstim in small-cell lung cancer. J Clin Oncol 13 (3): 652-9, 1995. [PUBMED Abstract] Steward WP, von Pawel J, Gatzemeier U, et al.: Effects of granulocyte-macrophage colony-stimulating factor and dose intensification of V-ICE chemotherapy in small-cell lung cancer: a prospective randomized study of 300 patients. J Clin Oncol 16 (2): 642-50, 1998. [PUBMED Abstract] Thatcher N, Girling DJ, Hopwood P, et al.: Improving survival without reducing quality of life in small-cell lung cancer patients by increasing the dose-intensity of chemotherapy with granulocyte colony-stimulating factor support: results of a British Medical Research Council Multicenter Randomized Trial. Medical Research Council Lung Cancer Working Party. J Clin Oncol 18 (2): 395-404, 2000. [PUBMED Abstract] James LE, Gower NH, Rudd RM, et al.: A randomised trial of low-dose/high-frequency chemotherapy as palliative treatment of poor-prognosis small-cell lung cancer: a Cancer research Campaign trial. Br J Cancer 73 (12): 1563-8, 1996. [PUBMED Abstract] Pujol JL, Douillard JY, Rivière A, et al.: Dose-intensity of a four-drug chemotherapy regimen with or without recombinant human granulocyte-macrophage colony-stimulating factor in extensive-stage small-cell lung cancer: a multicenter randomized phase III study. J Clin Oncol 15 (5): 2082-9, 1997. [PUBMED Abstract] Ardizzoni A, Tjan-Heijnen VC, Postmus PE, et al.: Standard versus intensified chemotherapy with granulocyte colony-stimulating factor support in small-cell lung cancer: a prospective European Organization for Research and Treatment of Cancer-Lung Cancer Group Phase III Trial-08923. J Clin Oncol 20 (19): 3947-55, 2002. [PUBMED Abstract] Lorigan P, Woll PJ, O'Brien ME, et al.: Randomized phase III trial of dose-dense chemotherapy supported by whole-blood hematopoietic progenitors in better-prognosis small-cell lung cancer. J Natl Cancer Inst 97 (9): 666-74, 2005. [PUBMED Abstract] Buchholz E, Manegold C, Pilz L, et al.: Standard versus dose-intensified chemotherapy with sequential reinfusion of hematopoietic progenitor cells in small cell lung cancer patients with favorable prognosis. J Thorac Oncol 2 (1): 51-8, 2007. [PUBMED Abstract] Girling DJ: Comparison of oral etoposide and standard intravenous multidrug chemotherapy for small-cell lung cancer: a stopped multicentre randomised trial. Medical Research Council Lung Cancer Working Party. Lancet 348 (9027): 563-6, 1996. [PUBMED Abstract] Murray N, Grafton C, Shah A, et al.: Abbreviated treatment for elderly, infirm, or noncompliant patients with limited-stage small-cell lung cancer. J Clin Oncol 16 (10): 3323-8, 1998. [PUBMED Abstract] Westeel V, Murray N, Gelmon K, et al.: New combination of the old drugs for elderly patients with small-cell lung cancer: a phase II study of the PAVE regimen. J Clin Oncol 16 (5): 1940-7, 1998. [PUBMED Abstract] Earl HM, Rudd RM, Spiro SG, et al.: A randomised trial of planned versus as required chemotherapy in small cell lung cancer: a Cancer Research Campaign trial. Br J Cancer 64 (3): 566-72, 1991. [PUBMED Abstract] Randomised trial of four-drug vs less intensive two-drug chemotherapy in the palliative treatment of patients with small-cell lung cancer (SCLC) and poor prognosis. Medical Research Council Lung Cancer Working Party. Br J Cancer 73 (3): 406-13, 1996. [PUBMED Abstract] Souhami RL, Spiro SG, Rudd RM, et al.: Five-day oral etoposide treatment for advanced small-cell lung cancer: randomized comparison with intravenous chemotherapy. J Natl Cancer Inst 89 (8): 577-80, 1997. [PUBMED Abstract] Sekine I, Yamamoto N, Kunitoh H, et al.: Treatment of small cell lung cancer in the elderly based on a critical literature review of clinical trials. Cancer Treat Rev 30 (4): 359-68, 2004. [PUBMED Abstract] Slotman BJ, van Tinteren H, Praag JO, et al.: Use of thoracic radiotherapy for extensive stage small-cell lung cancer: a phase 3 randomised controlled trial. Lancet 385 (9962): 36-42, 2015. [PUBMED Abstract] Slotman B, Faivre-Finn C, Kramer G, et al.: Prophylactic cranial irradiation in extensive small-cell lung cancer. N Engl J Med 357 (7): 664-72, 2007. [PUBMED Abstract] Shivnani AT: Prophylactic cranial irradiation in small-cell lung cancer. N Engl J Med 357 (19): 1977; author reply 1978, 2007. [PUBMED Abstract]

Staging

Staging Systems Several staging systems have been proposed for small cell lung cancer (SCLC). These staging systems include the following:

American Joint Committee on Cancer (AJCC) Tumor, Node, and Metastasis (TNM).[1] Veterans Administration Lung Study Group (VALG).[2] International Association for the Study of Lung Cancer (IASLC).[3] Limited-Stage Disease No universally accepted definition of this term is available. Limited-stage disease (LD) SCLC is confined to the hemithorax of origin, the mediastinum, or the supraclavicular nodes, which can be encompassed within a tolerable radiation therapy port.

Patients with pleural effusion, massive pulmonary tumor, and contralateral supraclavicular nodes have been both included within and excluded from LD by various groups.

Extensive-Stage Disease Extensive-stage disease (ED) SCLC has spread beyond the supraclavicular areas and is too widespread to be included within the definition of LD. Patients with distant metastases (M1) are always considered to have ED.[3,4]

IASLC-AJCC TNM Staging System The AJCC TNM defines LD as any T, except for T3-4, due to multiple lung nodules that do not fit in a tolerable radiation field, any N, and M0.[1] This corresponds to TNM stages I to IIIB. Extensive disease is TNM stage IV with distant metastases (M1) including malignant pleural effusions.[3,4]

The IASLC conducted an analysis of clinical TNM staging for SCLC using the sixth edition of the AJCC TNM staging system for lung cancer. Survivals for patients with clinical stages I and II disease are significantly different from those for patients with stage III disease with N2 or N3 involvement.[3] Patients with pleural effusion have an intermediate prognosis between LD and ED with hematogenous metastases and will be classified as having M1 disease (or ED). Application of the TNM system will not change how patients are managed; however, the analysis suggests that, in the context of clinical trials in LD, accurate TNM staging and stratification may be important.[3]

Staging Evaluation Staging procedures for SCLC are important to distinguish patients with disease limited to their thorax from those with distant metastases. At the time of initial diagnosis, approximately two-thirds of patients with SCLC have clinical evidence of metastases; most of the remaining patients have clinical evidence of extensive nodal involvement in the hilar, mediastinal, and sometimes supraclavicular regions.

Determining the stage of cancer allows an assessment of prognosis and a determination of treatment, particularly when chest radiation therapy or surgical excision is added to chemotherapy for patients with LD. If ED is confirmed, further evaluation should be individualized according to the signs and symptoms unique to the individual patient. Standard staging procedures include the following:

A thorough physical examination. Routine blood counts and serum chemistries. Chest and upper abdominal computed tomography (CT) scanning. A radionuclide bone scan. A brain magnetic resonance imaging scan or CT scan. Bone marrow aspirate or biopsy in selected patients in which treatment would change based on the results. The role of positron emission tomography (PET) is still under study. SCLC is fluorine F 18-fludeoxyglucose (18F-FDG) avid at the primary site and at metastatic sites. PET may be used in staging patients with SCLC who are potential candidates for the addition of thoracic radiation therapy to chemotherapy, as PET may lead to upstaging or downstaging of patients and to alteration of radiation fields resulting from the identification of additional sites of nodal metastases.

Evidence (18F-FDGPET):

In a study of 120 patients with LD SCLC or ED SCLC, ten patients were upstaged and three patients were downstaged.[5] PET was more sensitive and specific than CT scans for nonbrain distant metastases. In a small series of 24 patients with LD by conventional staging, two patients were upstaged to ED.[2] Unsuspected nodal metastases were documented in 25% of patients, which altered the radiation plan in these patients. At this time, sensitivity, specificity, and positive- or negative-predictive value of PET scanning and its enhancement of staging accuracy are uncertain. References Lung. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 253-70. Bradley JD, Dehdashti F, Mintun MA, et al.: Positron emission tomography in limited-stage small-cell lung cancer: a prospective study. J Clin Oncol 22 (16): 3248-54, 2004. [PUBMED Abstract] Shepherd FA, Crowley J, Van Houtte P, et al.: The International Association for the Study of Lung Cancer lung cancer staging project: proposals regarding the clinical staging of small cell lung cancer in the forthcoming (seventh) edition of the tumor, node, metastasis classification for lung cancer. J Thorac Oncol 2 (12): 1067-77, 2007. [PUBMED Abstract] Ihde D, Souhami B, Comis R, et al.: Small cell lung cancer. Lung Cancer 17 (Suppl 1): S19-21, 1997. [PUBMED Abstract] Brink I, Schumacher T, Mix M, et al.: Impact of [18F]FDG-PET on the primary staging of small-cell lung cancer. Eur J Nucl Med Mol Imaging 31 (12): 1614-20, 2004. [PUBMED Abstract]

Pathologic classification

Before initiating treatment of a patient with small cell lung cancer (SCLC), an experienced lung cancer pathologist should review the pathologic material.

Pathologic Classification The current classification of subtypes of SCLC includes the following:[1]

Small cell carcinoma. Combined small cell carcinoma (i.e., SCLC combined with neoplastic squamous and/or glandular components). SCLC arising from neuroendocrine cells forms one extreme of the spectrum of neuroendocrine carcinomas of the lung.

Neuroendocrine tumors include the following:

Low-grade typical carcinoid. Intermediate-grade atypical carcinoid. High-grade neuroendocrine tumors including large-cell neuroendocrine carcinoma (LCNEC) and SCLC. Because of differences in clinical behavior, therapy, and epidemiology, these tumors are classified separately in the World Health Organization (WHO) revised classification. The variant form of SCLC called mixed small cell/large cell carcinoma was not retained in the revised WHO classification. Instead, SCLC is now described with only one variant, SCLC combined, when at least 10% of the tumor bulk is made of an associated non-small cell component.

SCLC presents as a proliferation of small cells with the following morphological features:[2]

Scant cytoplasm. Ill-defined borders. Finely granular "salt and pepper" chromatin. Absent or inconspicuous nucleoli. Frequent nuclear molding. A high mitotic count. Combined small cell carcinoma includes a mixture of small cell and large cell or any other non-small cell component. Any cases showing at least 10% of SCLC are diagnosed as combined SCLC, and SCLC is limited to tumors with pure SCLC histology. SCLC associated with LCNEC is diagnosed as SCLC combined with LCNEC.

Nearly all SCLC are immunoreactive for keratin, thyroid transcription factor 1, and epithelial membrane antigen. Neuroendocrine and neural differentiation result in the expression of dopa decarboxylase, calcitonin, neuron-specific enolase, chromogranin A, CD56 (also known as nucleosomal histone kinase 1 or neural-cell adhesion molecule), gastrin-releasing peptide, and insulin-like growth factor 1. One or more markers of neuroendocrine differentiation can be found in approximately 75% of SCLC.[3]

Although preinvasive and in situ malignant changes are frequently found in patients with non-small cell lung cancer, these findings are rare in patients with SCLC.[4]

References Travis WD, Colby TV, Corrin B, et al.: Histological typing of lung and pleural tumours. 3rd ed. Berlin: Springer-Verlag, 1999. Brambilla E, Travis WD, Colby TV, et al.: The new World Health Organization classification of lung tumours. Eur Respir J 18 (6): 1059-68, 2001. [PUBMED Abstract] Guinee DG Jr, Fishback NF, Koss MN, et al.: The spectrum of immunohistochemical staining of small-cell lung carcinoma in specimens from transbronchial and open-lung biopsies. Am J Clin Pathol 102 (4): 406-14, 1994. [PUBMED Abstract] Kumar V, Abbas A, Fausto N, eds.: Robins and Cotran Pathologic Basis of Disease. 7th ed. Philadelphia, Pa: Elsevier Inc, 2005.

Radiation therapy

Depending on the stage of small cell lung cancer (SCLC) and other factors, radiation therapy might be used in several situations:

In limited stage SCLC, radiation therapy can be given at the same time as chemotherapy (chemo) to treat the tumor and lymph nodes in the chest. Giving chemo and radiation together is called concurrent chemoradiation. The radiation may be started with the first or second cycle of chemo. Radiation can also be given after the chemo is finished. This is sometimes done for patients with extensive stage disease, or it can be used for people with limited stage disease who have trouble getting chemotherapy and radiation at the same time (as an alternative to chemoradiation). SCLC often spreads to the brain. Radiation can be given to the brain to help lower the chances of problems from cancer spread there. This is called prophylactic cranial irradiation. This is most often used to treat people with limited stage SCLC, but it can also help some people with extensive stage SCLC. Radiation can be used to shrink tumors to relieve (palliate) symptoms of lung cancer such as pain, bleeding, trouble swallowing, cough, shortness of breath, and problems caused by spread to other organs such as the brain. Types of radiation therapy The type of radiation therapy most often used to treat SCLC is called external beam radiation therapy (EBRT). It delivers radiation from outside the body and focuses it on the cancer.

Before treatments start, your radiation team will take careful measurements to find the correct angles for aiming the radiation beams and the proper dose of radiation. This planning session, called simulation, usually includes getting imaging tests such as CT scans.

Treatment is much like getting an x-ray, but the radiation is more intense. The procedure itself is painless. Each treatment lasts only a few minutes, although the setup time – getting you into place for treatment – usually takes longer.

Most often, radiation as part of the initial treatment for SCLC is given once or twice daily, 5 days a week, for 3 to 7 weeks. Radiation to relieve symptoms and prophylactic cranial radiation are given for shorter periods of time, typically less than 3 weeks.

In recent years, newer EBRT techniques have been shown to help doctors treat lung cancers more accurately while lowering the radiation exposure to nearby healthy tissues. These include:

Three-dimensional conformal radiation therapy (3D-CRT): 3D-CRT uses special computer programs to precisely map the location of the tumor(s). Radiation beams are shaped and aimed at the tumor(s) from several directions, which makes it less likely to damage normal tissues.

Intensity modulated radiation therapy (IMRT): IMRT is an advanced form of 3D therapy. It uses a computer-driven machine that moves around the patient as it delivers radiation. Along with shaping the beams and aiming them at the tumor from several angles, the intensity (strength) of the beams can be adjusted to limit the dose reaching nearby normal tissues. This technique is used most often if tumors are near important structures such as the spinal cord. Many major cancer centers now use IMRT.

A variation of IMRT is called volumetric modulated arc therapy (VMAT). It uses a machine that delivers radiation quickly as it rotates once around the body. Each treatment is given over just a few minutes.

Possible side effects of radiation therapy If you are going to get radiation therapy, it’s important to ask your doctor beforehand about the possible side effects so that you know what to expect. Common side effects of radiation therapy can include:

Skin changes in the area being treated, which can range from mild redness to blistering and peeling Hair loss (in the area where the radiation enters the body) Fatigue (tiredness) Nausea and vomiting Loss of appetite and weight loss Most of these side effects go away after treatment, but some can last a long time. When chemotherapy is given with radiation, the side effects are often worse.

Radiation therapy to the chest may damage your lungs, which might cause a cough, problems breathing, and shortness of breath. These usually improve after treatment is over, although sometimes they may not go away completely.

Your esophagus, which is in the middle of your chest, may be exposed to radiation, which could cause a sore throat and trouble swallowing during or shortly after treatment. This might make it hard to eat anything other than soft foods or liquids for a while.

Radiation therapy to large areas of the brain can sometimes cause memory loss, fatigue, headaches, trouble thinking, or reduced sexual desire. Usually these symptoms are minor compared with those caused by cancer that has spread to the brain, but they can affect your quality of life.

Surgery

The feasibility of surgery depends on the stage of small cell carcinoma at diagnosis. In small cell carcinoma of the lung (SCCL), surgery should only be considered among patients with clinical stage I (T1-2, N0). Postoperative chemotherapy with or without radiation therapy is recommended based on the presence or absence of lymph node involvement.

Surgery

• Surgery should only be considered among patients with clinical stage I (T1-2, N0). Given that the majority of patients are not diagnosed with clinical stage I (T1-2,N0), surgery is rarely performed among SCCL patients.
• Before a patient is considered for surgical resection of the tumor, investigation for occult nodal involvement by either mediastinoscopy or mediastinal node dissection should be performed.
• Post-operative palliative treatment following surgery includes:
  • Chemotherapy if there is no nodal involvement
  • Chemotherapy PLUS radiation therapy if there is nodal involvement
  • Prophylactic cranial irradiation is recommended among patients who undergo complete resection of the tumor, as long as their performance status is good and they do not have any neurological cognitive impairment.

MRI

Overview

There are no MRI findings associated with small cell carcinoma. However, a MRI may be helpful in the diagnosis of complications of small cell carcinoma, which include brain metastasis

MRI

• There are no MRI findings associated with small cell carcinoma. However, a MRI may be helpful in the diagnosis of complications of small cell carcinoma, which include:
  • Brain metastasis

CT

Overview CT SCLC

Chest CT scan, preferably with intravenous contrast administration, may be helpful in the diagnosis of small cell carcinoma. Findings on CT scan suggestive of small cell carcinoma include hilar mass, mediastinal involvement, numerous lymphadenopathy, direct infiltration of adjacent structures, necrosis and hemorrhage. Small cell carcinoma of the lung is the most common cause of SVC obstruction, due to both compression/thrombosis and/or direct infiltration 2. All patients with confirmed diagnosis of SCLC by histopathological findings should undergo a CT scan of the abdomen for staging purposes. CT scan of the abdomen helps identify metastasis to organs, such as the liver or the adrenal glands. Brain imaging is also mandatory for staging; however, brain MRI is preferred over brain CT scan due to its superior sensitivity for the detection of brain metastasis. In addition, when limited stage small cell lung cancer is suspected, PET CT scan should be performed.

CT

Chest CT scan, preferably with intravenous contrast administration, may be helpful in the diagnosis of small cell carcinoma. Findings on CT scan suggestive of small cell carcinoma include:

• Hilar mass
• Mediastinal involvement
• Numerous lymphadenopathy
• Direct infiltration of adjacent structures
• Necrosis
• Hemorrhage
• Small cell carcinoma of the lung is the most common cause of SVC obstruction, due to both compression/thrombosis and/or direct infiltration 2.
• CT is used to stage small cell lung cancer.
• CT scan of the abdomen helps identify metastasis to organs, such as the liver or the adrenal glands.
• Brain imaging is also mandatory for staging; however, brain MRI is preferred over brain CT scan due to its superior sensitivity for the detection of brain metastasis.
• PET CT scan should be performed if limited stage small cell lung cancer is suspected.

Pathology SCLC

Small cell carcinoma is considered a neuroendocrine tumour of the lung. It arises from the bronchial mucosa. Local invasion occurs in the submucosa with subsequent invasion of peribronchial connective tissue. Cells are small, oval, with scant cytoplasm and a high mitotic count.

It is the most common lung cancer subtype to produce necrosis, superior vena cava (SVC) infiltration/SVC obstruction, and paraneoplastic syndromes (see bronchogenic carcinoma).

Location

Approximately 90-95% of SCLCs occur centrally, and usually arising in a lobar or main bronchus 3.

Small cell lung cancer X rays

Small cell carcinoma of Lung

Chest x-ray: Small cell carcinoma of the lung. Antero-posterior view, Case courtesy of A.Prof Frank Gaillard, via,Radiopaedia.org

Chest x-ray: Small cell carcinoma of the lung.Case courtesy of Dr Henry Knipe, via, Radiopaedia.org

Lung cancer

Surgery

If investigations confirm lung cancer, CT scan and often positron emission tomography (PET) are used to determine whether the disease is localised and amenable to surgery or whether it has spread to the point where it cannot be cured surgically.

Blood tests and spirometry (lung function testing) are also necessary to assess whether the patient is well enough to be operated on. If spirometry reveals poor respiratory reserve (often due to chronic obstructive pulmonary disease), surgery may be contraindicated.

Surgery itself has an operative death rate of about 4.4%, depending on the patient's lung function and other risk factors.[1] Surgery is usually only an option in non-small cell lung carcinoma limited to one lung, up to stage IIIA. This is assessed with medical imaging (computed tomography, positron emission tomography). A sufficient pre-operative respiratory reserve must be present to allow adequate lung function after the tissue is removed.

Pulmonary Reserve The American College of Chest Physicians established clinical practice guidelines for the physiologic evaluation of patients with lung cancer being considered for resectional surgery.[2] The preoperative physiologic assessment should include a cardiac evaluation and spirometry to measure the FEV1 and carbon monoxide diffusion capacity (DLCO). Depending on these results the patients can be stratified into different risk groups and further testing may be required or surgery can be initiated. Pulmonary reserve is measured by spirometry. The minimum forced vital capacity (FVC) for pneumonectomy in men is 2 liters. The minimum for lobectomy is 1.5 liters. In women, the minimum FVC values for pneumonectomy and lobectomy are 1.75 liters and 1.25 liters respectively.[3]

Surgery

Procedures include wedge resection (removal of part of a lobe), lobectomy (one lobe), bilobectomy (two lobes) or pneumonectomy (whole lung). In patients with adequate respiratory reserve, lobectomy is the preferred option, as this minimizes the chance of local recurrence. If the patient does not have enough functional lung for this, wedge resection may be performed.[4] Radioactive iodine brachytherapy at the margins of wedge excision may reduce recurrence to that of lobectomy.[5]

Also, many times during lung cancer surgery, the doctor will remove some of the lymph nodes to test for cancer. If the lymph nodes test positive for cancer then that is indicative of the disease spreading beyond the lung. There will most likely be subsequent treatments to help eliminate the remaining cancer.

Patient Selection Not all patients are suitable for operation. The stage, location and cell type are important limiting factors. In addition, patients who are very ill with a poor performance status or who have inadequate pulmonary reserve would be unlikely to survive. Even with careful selection, the overall operative death rate is about 4.4%.[1]

Stage "Stage" refers to the degree of spread of the cancer.

See non-small cell lung cancer staging

In non-small cell lung cancer, stages IA, IB, IIA, and IIB are suitable for surgical resection.[6] Stages IIIA, IIIB, and IV tend to involve the spreading out of the cancer. In that case chemotherapy or radiation is usually deemed the appropriate action to take because surgery will not adequately solve the diseased lungs.

Types of Surgery Lobectomy (removal of a lobe of the lung) Pneumonectomy (removal of an entire lung) Wedge resection Sleeve resection

Overview

Surgery is the best treatment option of lung cancer for patients with resectable tumors. The feasibility of surgery depends on the stage of lung cancer at the time of diagnosis.

Indications

• Surgical intervention is not recommended for the management of [disease name].

OR

• Surgery is not the first-line treatment option for patients with [disease name]. Surgery is usually reserved for patients with either:
  • [Indication 1]
  • [Indication 2]
  • [Indication 3]
• The mainstay of treatment for [disease name] is medical therapy. Surgery is usually reserved for patients with either:
  • [Indication 1]
  • [Indication 2]
  • [Indication 3]

Surgery

• Surgery is the best treatment option of lung cancer for patients with resectable tumors.
• The feasibility of surgery depends on the stage of lung cancer at the time of diagnosis.
• The procedures for lung cancer imclude:
  • Wedge resection (removal of part of a lobe)
    • Wedge resection is performed in the patients who do not have adequate respiratory reserve.
    • Radioactive iodine brachytherapy at the margins of wedge resection may reduce recurrence to that of lobectomy.
  • Lobectomy (one lobe)
    • Lobectomy is the preferred option for patients with adequate respiratory reserve because it reduces the chances of local recurrence.
  • Bilobectomy (two lobes)
  • Pneumonectomy (whole lung)

Contraindications

References

Lung Cancer Differential

Condition/disease	Signs/symptoms	Tests
Pneumonia/bronchitis	Typical symptoms include fever, cough, dyspnea, and chest pain; recurrent pneumonia or bronchitis in a smoker or former smoker should raise the suspicion of lung cancer	CXR is the first test performed; CT imaging can be helpful to evaluate pulmonary masses that might not be well visualised with chest x-ray; bronchoscopy can also be used to assess for endobronchial lesions or to biopsy suspicious pulmonary masses
Carcinoid tumor	Often asymptomatic with normal physical examination; may cause cough, dyspnea, hemoptysis, unilateral wheezing, or post-obstructive pneumonia if the tumor is endobronchial or compressing the central bronchi	CT chest: 80% of carcinoid tumors appear as an endobronchial nodule and 20% as a parenchymal nodule, with smooth, rounded borders and is highly vascularized; flexible bronchoscopy shows raised, pink, vascular, lobulated lesions; endobronchial forceps biopsy is usually required for pathology to be diagnostic; bronchial brushings, sputum specimens, and lavage fluid rarely provide sufficient tissue for a conclusive diagnosis
Metastatic cancer from a non-thoracic primary site	Signs and symptoms depend on the location of the primary tumor and distant disease and may include pain, weight loss, malaise, cough, dyspnea, clubbing, or focal wheezing; physical findings may be present depending on the location and extent of the disease	CT chest shows one or multiple nodules of variable sizes from diffuse micronodular opacities (miliary) to well-defined masses, lesions are often irregular and in the periphery of the lower lung zones; CT/MRI head, CT abdomen and pelvis: extrapulmonary cancers that commonly metastasis to the lung include melanoma, thyroid carcinoma, esophageal cancer; ovarian cancer; sarcomas; and adenocarcinomas of the colon, breast, kidney, and testis; PET-FDG scan shows increased uptake in both primary and distant sites, certain metastatic lesions, such as renal cell carcinoma, have a lower probability of 18-fluorodeoxyglucose (FDG) uptake; CT-guided transthoracic needle aspiration (TTNA) can reveal characteristic malignant cells, pneumothorax complicates 20% to 30% of TTNA procedures, the choice between bronchoscopy and TTNA is based on lesion size, location, risks, and local expertise; biopsy during flexible bronchoscopy and biopsy may show characteristic malignant cells, bronchoscopy has a 100% yield for endobronchial lesions (which are extremely rare in metastatic deposits from other primary tumors)
Infectious granuloma	History may include travel to endemic areas, pet/animal exposures, and specific leisure activities (e.g., caving); may feature cough, dyspnea, hemoptysis, weight loss, fever, joint aches, skin lesions, and night sweats, or no symptoms; many possible causes: Histoplasma capsulatum, Mycobacterium tuberculosis, Coccidioides immitis, Cryptococcus neoformans, Aspergillus, Pseudallescheria boydii, Fusarium species, zygomycetes, and others; non-specific skin findings may be seen in atypical mycobacteria and cryptococcosis; lymphadenopathy may be present with active disease	CT-guided TTNA can be used for diagnostic sampling, pneumothorax complicates 20% to 30% of TTNA procedures, the choice between bronchoscopy and TTNA is based on lesion size, location, risks, and local expertise; CT chest typically shows lesions <2 cm diameter and round with smooth borders, old granulomatous disease may feature central, laminated, or diffuse calcification pattern, mediastinal lymphadenopathy without calcifications is sometimes present, nodules from angioinvasive fungi (e.g., Aspergillus, Pseudallescheria boydii, Fusarium species, and zygomycetes) may demonstrate the "halo sign" (ground-glass opacity surrounding the nodule), occasionally, calcifications can be seen in the spleen or liver; fungal serologies: positive during active infection; flexible bronchoscopy and biopsy can sometimes provide sample for identification and culture and sensitivity of organism; PET: usually negative (<2.5 standardised uptake values), may be positive in active infectious processes
Sarcoidosis	Cough, dyspnea, fatigue weight loss, fever, night sweats, rash, eye pain, photophobia blurred vision, and red eye; pulmonary examination is usually unrevealing; can affect any organ, so physical findings depend on specific organs affected; skin lesions including maculopapular eruptions, subcutaneous nodular lesions, and red-purple skin lesions	CT chest: mediastinal adenopathy often present with sarcoid. Sarcoid nodules have predilection for upper zones, although can be located throughout the lung; flexible bronchoscopy and biopsy can demonstrate presence of non-caseating granulomas; CT-guided TTNA can provide access to material from some lesions inaccessible to flexible bronchoscopy; laboratory markers: ACE elevation may be seen in sarcoidosis but is non-specific
Rheumatoid arthritis	Arthralgias, pain, skin nodules, pleural effusions, pleuritis, joint pain, and deformity	CT chest typically shows lung nodule 3 mm to 7 cm, predominantly in peripheral upper and mid-lung zones, may show cavitation; flexible bronchoscopy and biopsy shows rheumatoid necrobiotic nodule, necrobiotic nodules demonstrate a central zone of eosinophilic fibrinoid necrosis surrounded by palisading fibroblasts, the nodule often centered on necrotic inflamed blood vessels; laboratory markers: patients with lung nodules due to rheumatoid arthritis frequently have high levels of rheumatoid factor, although seronegative cases have been reported
Wegener's granulomatosis	Cough, chest pain, dyspnea, hemoptysis, rhinorrhoea, epistaxis, ear/sinus pain, hoarseness, fever, fatigue, anorexia, weight loss, palpable purpura, painful ulcers, uveitis, upper airway inflammation, and sinus pain	CT chest shows solitary or multiple lung nodules, airways are frequently affected; Flexible bronchoscopy or CT-guided TTNA may show necrotising granulomatous inflammation; laboratory markers: anti-neutrophil cytoplasmic antibody (ANCA), ANCA testing results depend on the extent and severity of the disease
Arteriovenous malformation	Dyspnea is uncommon, may cause hemoptysis, pulmonary bruit, arteriovenous communications, or hemorrhagic telangiectasia in the skin, mucous membranes, and other organs, cyanosis and finger clubbing may be present, eurological symptoms from cerebral aneurysms, cerebral emboli	CT chest shows round or oval nodule(s) with feeding artery and draining vein often identified, most common in lower lobes, multiple lesions in 30% of cases, usually round or oval, ranging from 1 cm to several cm in diameter; pulmonary angiography confirms presence and location of AVMs, identifies feeding arterial and venous structures, in cases of significant hemoptysis, pulmonary angiogram is combined with bronchial artery embolisation; ABG analysis may show decreased pO2 and decreased oxygen saturation when AV flow is severe., in cases of severe systemic AVMs, chronic hypoxemia may cause polycythemia
Amyloidosis	Weight loss, paresthesias, dyspnea, and fatigue are the most common symptoms associated with amyloidosis and are common to all systemic forms; weight loss of >9 kg is common; small vessel involvement can cause jaw or limb claudication, and rarely angina; amyloid purpura is present in about 1 in 6 patients, typically peri-orbital; eyelid petechiae are common; hepatomegaly >5 cm below the right costal margin is seen in 10% of patients and splenomegaly is usually of modest degree	CT chest shows lung involvement characterised by focal pulmonary nodules, tracheobronchial lesions, or diffuse alveolar deposits; serum immunofixation shows presence of monoclonal protein; urine immunofixation shows presence of monoclonal protein; immunoglobulin free light chain assay shows abnormal kappa to lambda ratio
Bronchiolitis obliterans organizing pneumonia (BOOP)	Normally presents as a flu-like illness followed by a second illness lasting 1 to 4 months, with low-grade fever, non-productive cough, malaise, dyspnea, and weight loss; sometimes features pleuritic chest pain and hemoptysis; in most patients, auscultation reveals fine, dry lung crackles; finger clubbing is unusual	CT chest typical features include: patchy "ground-glass" opacities in a sub-pleural and/or peribronchovascular distribution; thickening of bronchial walls and cylindrical dilation; 3 to 5 mm diameter centrilobular nodules or other ill-defined nodules, mediastinal lymphadenopathy, pleural effusions; pulmonary function tests typically show a restrictive pattern; bronchoalveolar lavage (BAL shows a mixed cell pattern, with an increase in lymphocytes, neutrophils, eosinophils, mast cells, foamy macrophages, and occasional plasma cells, CD4+/CD8+ cell ratio is decreased, the ratio of lymphocytes to CD8+ cells is significantly increased; transbronchial lung biopsy in combination with BAL can be a useful approach, prior to possible open biopsy; open lung biopsy is often required for a definitive diagnosis
Pulmonary tuberculosis	Cough longer than 2 to 3 weeks, discolored or bloody sputum, night sweats, weight loss, loss of appetite, and/or pleuritic chest pain	Chest x-ray: primary disease commonly presents as middle and lower lung zone infiltrates, ipsilateral adenopathy, atelectasis from airway compression, and pleural effusion can be seen, reactivation-type (post-primary) pulmonary TB usually involves apical and/or posterior segment of right upper lobe, apicoposterior segment of left upper lobe, or superior segment of either lower lobe, with or without cavitation, as disease progresses it spreads to other segments/lobes; sputum smear: positive for acid-fast bacilli (AFB), sputum may be spontaneously expectorated or induced, and at least 3 specimens should be collected (minimum 8 hours apart, including an early morning specimen, which is the best way to detect Mycobacterium tuberculosis), organisms other than M. tuberculosis, especially on-tuberculous mycobacteria (e.g., M. kansasii and M. avium , may be positive for AFB stain; nucleic acid amplification tests (NAAT): positive for M. tuberculosis DNA or RNA amplification tests for rapid diagnosis, may be used on sputum or any sterile body fluid
Non-Hodgkin's lymphoma (NHL)	Aggressive NHL may present with fever, drenching night sweats, malaise, weight loss, cough, shortness of breath, abdominal discomfort, headache, change in mental status, dizziness, ataxia, pleural effusion, lymphadenopathy, pallor, purpura, jaundice, hepatomegaly, splenomegaly, skin nodules, and abnormal neurological examination, low-grade NHL patients often minimally symptomatic or asymptomatic	CT chest: frequently anterior mediastinum, can determine if mass is cystic or solid and whether it contains calcium or fat, contrast enhancement provides information concerning vascularisation of the mass and relationship to adjacent structures; FBC with differential: shows thrombocytopenia, pancytopenia; Blood smear: shows nucleated red blood cells, giant platelets; lymph node biopsy with immunohistochemistry: shows characteristic cells, preferably obtain excisional or core biopsy to provide information on lymph node architecture; mediastinoscopy: used to sample mediastinal nodes
Hodgkin's lymphoma	Predominantly a disease of young adults; most patients present with a several-month history of persistent adenopathy, most commonly of the cervical chain	Plain chest x-ray: typically shows mediastinal mass/large mediastinal adenopathy; PET scan: involved sites appear fluorodeoxyglucose (FDG)-avid (bright) with PET imaging; lymph node biopsy with immunohistochemistry: the Hodgkin's cell can be a characteristic Reed-Sternberg cell, or one of its variants, such as the lacunar cell in the nodular sclerosis subtype; in nodular lymphocyte-predominant Hodgkin's lymphoma, the characteristic cell is the lymphocytic and histiocytic (L&H) cell, also referred to as a popcorn cell
Thymoma/thymic carcinoma	Approximately 30% of patients with thymoma are asymptomatic at the time of diagnosis; may also present with cough, chest pain, signs of upper airway congestion, superior vena cava syndrome, dysphagia, or hoarseness; may have features of paraneoplastic syndromes associated with thymoma including myasthenia gravis, polymyositis, lupus erythematosus, rheumatoid arthritis, thyroiditis, and Sjogren's syndrome; about 30% of patients have symptoms suggestive of myasthenia gravis (e.g., ptosis, double vision)	Plain chest x-ray: in 50% of the patients, thymomas are detected by chance with plain-film chest radiography; CT chest: 90% occur in anterior mediastinum; Positron emission tomography (PET): may be of value in determining malignancy and extramediastinal involvement; pre-operative biopsy: indicated if there are atypical features or if imaging suggests invasive tumor and patient is under consideration for induction therapy
Bronchogenic cyst	Usually diagnosed in infancy and childhood, although 50% are diagnosed after 15 years of age; Approximately 50% of patients are asymptomatic; in adults, chest pain (often pleuritic) and dysphagia (due to esophageal compression) are the most common symptoms; may also feature recurrent cough and chest infection/pneumonia, superior vena cava syndrome, tracheal compression, and pneumothorax	Two-view chest radiography: typically shows a sharply demarcated spherical mass of variable size, most commonly located in the middle mediastinum around the carina, can appear as a solid tumor or show air-fluid level if cyst is infected or contains secretions; CT chest: frequently middle mediastinum, typically at level of the mediastinum, calcifications may also be seen; MRI: frequently middle mediastinum, typically at level of the mediastinum, T2-weighted images show a homogeneous mass of moderate-to-bright intensity, on T1-weighted images, lesions may vary in intensity depending on protein content of the cyst
Tracheal tumors	Common symptoms include dyspnea, cough, hemoptysis, wheeze, and stridor; less commonly, hoarseness and dysphagia may be present	Plain chest radiographs are generally insensitive for detection of tracheal tumors, clues that may indicate the presence of a tracheal tumour include abnormal calcification, tracheal narrowing, post-obstructive pneumonia, and/or atelectasis; helical CT enables accurate calculation of tumor volumes and can help differentiate mucosal lesions from submucosal lesions; MRI can be useful in assessing extension into surrounding tissue and vascular anatomy; bronchoscopy allows direct visualisation, opportunity for biopsy, and potential for laser treatment
Thyroid mass	Symptoms and signs depend on size of mass; may be visible/palpable as lump on anterior aspect of neck; may present with dysphagia, hoarseness, difficulty breathing, and pain in neck or throat; may also be signs and symptoms of hyper- or hypothyroidism depending on the nature of the mass	Laboratory testing should include thyroid function panel, with TSH, free T4, free T3; I-123 thyroid scan is ordered for patients with overt or subclinical hyperthyroidism a hyperfunctioning (hot) nodule is almost always benign, most nodules are hypofunctioning (cold) (most of these are benign, but malignant nodules are also cold); ultrasound and doppler can be used to define dimensions of thyroid nodules and solid/cystic component(s), features suspicious of malignancy include microcalcifications, a more tall-than-wide shape, hypervascularity, marked hypoechogenicity, or irregular margins, it can also guide fine-needle aspiration, which can reveal malignant cells or cyst fluid; CT neck can evaluate cervical lymph nodes in cases of medullary thyroid cancer, and extension of the scan into the chest can help evaluate a retrosternal thyroid mass

Other conditions that can be mistaken for lung cancer including the following:

• Pneumomediastinum
• Empyema
• Abscess
• Pneumothorax (tension and traumatic)
• Pleural effusion
• Pneumothorax
• Superior Vena Cava Syndrome

Differential Diagnosis

Lung cancer must be differentiated from other cavitary lung lesions.

Causes of lung cavities	Differentiating Features	Differentiating radiological findings	Diagnosis confirmation
Malignancy (Primary lung cancer)	Elderly male or female Chronic smokers Presents with a low-grade fever, absence of leukocytosis, systemic complaints weight loss, fatigue Absence of factors that predispose to gastric content aspiration, no response to antibiotics within 10 days Hemoptysis is commonly associated with bronchogenic carcinoma	A coin-shaped lesion with thick wall(>15mm) is seen on CXR with less ground glass opacities Bronchoalveolar lavage cytology shows malignant cells	Biopsy of lung
Pulmonary Tuberculosis	Mostly in endemic areas Symptoms include productive cough, night sweats, fever, and weight loss	CXR and CT demonstrates cavities in the upper lobe of the lung	Sputum smear positive for acid-fast bacilli and nucleic acid amplification tests (NAAT) is used on sputum or any sterile fluid for rapid diagnosis and is positive for mycobacteria.
Necrotizing Pneumonia	Any age group Acute, fulminant life threating complication of prior infection >100.4 °F fever, with hemodynamic instability Worsening pneumonia-like symptoms	CXR demonstrates multiple cavitary lesions Pleural effusion and empyema are common findings	CBC is positive for causative organism
Loculated empyema	Children and elderly are at risk Pleuritic chest pain, dry cough, fever with chills Dullness to percussion decreased breath sounds, and reduced vocal resonance on examination	Empyema appears lenticular in shape and has a thin wall with smooth luminal margins	Thoracocentesis
Granulomatosis with polyangiitis (Wegener's)	Women are more commonly effected than man Kidneys are also involved Upper respiratory tract symptoms, perforation of nasal septum, chronic sinusitis, otitis media, mastoiditis. Lower respiratory tract symptoms (e.g. hemoptysis, cough, dyspnea) Renal symptoms, hematuria, red cell casts	Pulmonary nodules with cavities and infiltrates are a frequent manifestation on CXR	Positive for P-ANCA Biopsy of the tissue involved shows necrotizing granulomas
Rheumatoid nodule	Elderly females of 40-50 age group Manifestation of rheumatoid arthritis Presents with other systemic symptoms including symmetric arthritis of the small joints of the hands and feet with morning stiffness are common manifestations	Pulmonary nodules with cavitation are located in the upper lobe (Caplan syndrome) on X-ray	Positive for both rheumatoid factor and anticyclic citrullinated peptide antibody.
Sarcoidosis	More common in African-American females Often asymptomatic except for enlarged lymph nodes Associated with restrictive lung disease Erythema nodosum Lupus pernio (skin lesions on face resembling lupus) Bell palsy Epithelioid granulomas containing microscopic Schaumann and asteroid bodies	On CXR bilateral adenopathy and coarse reticular opacities are seen CT of the chest demonstrates extensive hilar and mediastinal adenopathy Additional findings on CT include fibrosis (honeycomb, linear, or associated with bronchial distortion), pleural thickening, and ground-glass opacities.	Biopsy of lung shows non-caseating granuloma
Bronchiolitis obliterans (Cryptogenic organizing pneumonia)	Rare condition and mimics asthma, pneumonia and emphysema It is caused by drug or toxin exposure, autoimmune diseases, viral infections, or radiation injury People working in industries are at high risk Presents with fever, cough, wheezing, and shortness of breath over weeks to months	Common appearance on CT is patchy consolidation,often accompanied by ground-glass opacities and nodules.	Biopsy of the lung Pulmonary function tests demonstrate low fev1/fvc
Langerhans cell Histiocytosis	Exclusively afflicts smokers, with a peak age of onset of between 20 and 40 years Clinical presentation varies, but symptoms generally include months of dry cough, fever, night sweats, and weight loss Skin is involved in 80% of the cases, scaly erythematous rash is typical	Thin-walled cystic cavities are the usual radiographic manifestation, observed in over 50% of patients by either CXR or CT scans.	Biopsy of the lung

PBC USG

There are no ultrasound findings associated with primary biliary cirrhosis. However, the ultrasound is mandatory for liver and biliary tree for all cholestatic patients for the differentiation of intrahepatic from extrahepatic cholestasis.

• The ultrasound findings may include:
  • Cholestasis
  • Abdominal lymphadenopathy

Ultrasound examination of the liver and biliary tree is obligatory in all cholestatic patients in order to differentiate intrahepatic from extrahepatic . When the biliary system appears normal and serum AMA are present, no further radiologic workup is necessary. , particularly in the hilar region of the liver, is seen in 80% of patients with PBC

PBC CT

• Findings on CT scan suggestive of advanced primary biliary cirrhosis include:
  • Small heterogeneously attenuating liver
  • Varices
  • Splenomegaly
  • Lymphadenopathy
• Findings on CT scan suggestive of less advanced disease include:
  • Enlarged or normal size liver
  • Smooth contour liver
  • Little atrophy
  • Lacelike fibrosis
  • Regenerative nodules
  • Varices
  • Ascites
  • Lymphadenopathy

Synonoms

• Solitary hyperplastic nodule
• Hepatic hamartoma
• Focal cirrhosis
• Hamartomatous cholangiohepatoma
• Hepatic pseudotumor

Historical Perspective

• In early 1900s,Focal nodular hyperplasia was first described.
• Between 1918-1982,96.625 autopsy studies were conducted out of which 8 percent of nonhemangiomatous lesions were focal nodular hyperplasia.
• In 1994,Working party of the world congresses of gastroenterology suggested a standardized terminology of nodular hepatic lesions that placed Focal noduldar carcinoma in the group of regenerative nodules, as opposed to dysplastic or neoplastic nodules.

Differentiating Focal nodular hyperplasia from Other diseases

Focal nodular hyperplasia must be differentiated from:

• Hepatocellular carcinoma
• Cholangiocarcinoma
• Pancreatic carcinoma
• Liver hemangioma
• Liver abscess
• Cirrhosis
• Inflammatory lesions

Abbreviations: RUQ= Right upper quadrant of the abdomen, LUQ= Left upper quadrant, LLQ= Left lower quadrant, RLQ= Right lower quadrant, LFT= Liver function test, SIRS= Systemic inflammatory response syndrome, ERCP= Endoscopic retrograde cholangiopancreatography, IV= Intravenous, N= Normal, AMA= Anti mitochondrial antibodies, LDH= Lactate dehydrogenase, GI= Gastrointestinal, CXR= Chest X ray, IgA= Immunoglobulin A, IgG= Immunoglobulin G, IgM= Immunoglobulin M, CT= Computed tomography, PMN= Polymorphonuclear cells, ESR= Erythrocyte sedimentation rate, CRP= C-reactive protein, TS= Transferrin saturation, SF= Serum Ferritin, SMA= Superior mesenteric artery, SMV= Superior mesenteric vein, ECG= Electrocardiogram

Disease	Clinical manifestations													Diagnosis		Comments
	Symptoms									Signs
	Abdominal Pain	Fever	Rigors and chills	Nausea or vomiting	Jaundice	Constipation	Diarrhea	Weight loss	GI bleeding	Hypo- tension	Guarding	Rebound Tenderness	Bowel sounds	Lab Findings	Imaging
Focal nodular hyperplasia	Diffuse	±	−	−	±	−	−	+	+	−	−	−	Normal	Normal Liver function tests Normal AFP Minor elevations of Aspartate Alanine aminotransferase Alkaline phosphatase Gamma glutamyl transpeptidase	Us Multiphasic helical CT scan	Open biopsy if diagnosis can not be established
Hepatocellular carcinoma/Metastasis	RUQ	+	−	+	+	+	+	+	+	+	−	+	Normal Hyperactive if obstruction present	High levels of AFP in serum Abnormal liver function tests Thrombocytopenia	US CT MRI Liver biopsy	Other symptoms: Splenomegaly Variceal bleeding Ascites Spider nevi Asterixis
Cholangiocarcinoma	RUQ	+	−	+	+	−	−	+	−	−	−	+	Normal	Elevated CA 19-9 Increased amylase / lipase Increased stool fat content	Contrast-enhanced ultrasound CT scan Calcification Pseudocyst Dilation of main pancreatic duct MRI	Predisposes to pancreatic cancer
Pancreatic carcinoma	MidEpigastric	−	−	+	+	+	−	+	−	−	−	+	Normal	↑ Alkaline phosphatase ↑ serum bilirubin ↑ gamma-glutamyl transpeptidase ↑ CA 19-9	MDCT with PET/CT MRI EUS	Skin manifestations may include: Bullous pemphigoid Cicatricial pemphigoid Migratory superficial thrombophlebitis (classic Trousseau's syndrome) Pancreatic panniculitis
Disease	Abdominal Pain	Fever	Rigors and chills	Nausea or vomiting	Jaundice	Constipation	Diarrhea	Weight loss	GI bleeding	Hypo- tension	Guarding	Rebound Tenderness	Bowel sounds	Lab Findings	Imaging	Comments
Gallbladder cancer	Midepigastric	−	−	+	+	−	+	+	−	−	−	−	Normal	↑ Alkaline phosphatase ↑ CA 19-9	US CT MRI
Liver hemangioma	Intermittent RUQ	−	−	+	+	−	−	−	−	−	−	−	Normal	Abnormal LFTs	US Single-photon emission computerized tomography(SPECT) MRI	US will reveal hypoechoic lesions
Liver abscess	RUQ	+	−	+	+	−	−	+	−	−	−	−	Normal	Hypoalbuminemia Abnormal liver function tests	US CT
Cirrhosis	RUQ+Bloating	+	−	+	+	−	−	+	−	−	−	−	Normal	Hypoalbuminemia Prolonged PT Abnormal LFTs Hyponatremia Thrombocytopenia	US Nodular, shrunken liver Ascites	Stigmata of liver disease Cruveilhier- Baumgarten murmur
Inflammatory lesions	RUQ	±	−	+	+	−	−	−	−	−	−	−	Normal	Hypoalbuminemia Prolonged PT Abnormal LFTs Hyponatremia Thrombocytopenia	US Nodular,shrunken or coarse liver	Stigmata of liver disease

Focal Nodular Hyperplasia

FNH is typically benign, and usually no treatment is needed. Hemangiomas are the most common and are entirely benign. Treatment is unnecessary unless their expansion causes symptoms

Focal nodular hyperplasia (FNH) is a non-malignant hepatic tumor that is not of vascular origin. In one autopsy series of 96,625 patients, 8 percent of non-hemangiomatous lesions were FNH, representing 66 percent of all benign non-hemangiomatous lesions seen between 1918 and 1982 [1]. In large retrospective studies of patients referred for ultrasound and multidetector computed tomography, the prevalence of focal nodular hyperplasia was 0.2 percent and 1.6 percent, respectively [2,3].

FNH is seen in both sexes and throughout the age spectrum, although it is found predominantly in women (in a ratio of 8 or 9:1) between the ages of 20 and 50 years [4]. FNH comprises up to 2 percent of liver tumors in children [5].

This topic review will focus on the pathogenesis, clinical manifestations and management of FNH. An approach to patients presenting with a focal liver lesion is discussed separately. (See "Solid liver lesions: Differential diagnosis and evaluation".)

PATHOGENESIS — FNH has various labels: solitary hyperplastic nodule, hepatic hamartoma, focal cirrhosis, hamartomatous cholangiohepatoma, and hepatic pseudotumor. This profusion of terms epitomizes the confusion surrounding our understanding of the pathogenesis of the many conditions in which nodules of benign appearing hepatocytes are found. The International Working Party of the World Congresses of Gastroenterology proposed a standardized nomenclature in 1994, which placed FNH in the group of regenerative nodules, as opposed to dysplastic or neoplastic nodules [6]. This fits well with our current understanding of the pathogenesis of FNH. The contention that this lesion is non-neoplastic has been bolstered by the reported polyclonal origin of the hepatocytes [7], although this is disputed by others [8].

Previously considered to be a hamartoma, a neoplasm, a response to ischemia or other injury, or a focal area of regeneration, FNH is now generally accepted to be a hyperplastic (regenerative) response to hyperperfusion by the characteristic anomalous arteries found in the center of these nodules [4,9,10]. Whether vascular injury is also involved is less clear, but FNH is occasionally supplied primarily by portal venous blood due to thrombosis of the anomalous central artery [11].

The association of FNH with hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu disease [12]) and hepatic hemangiomas strengthens the hypothesis that FNH is a congenital vascular anomaly. Two pathology studies found cavernous hemangiomas in 6.5 and 2.3 percent of patients with FNH [13,14] and an imaging study, using ultrasound and dynamic CT, found that 23 percent of FNH patients had associated hemangiomas [15]. Multiple FNH lesions have also been noted in association with hemihypertrophy and vascular malformations (Klippel-Trénaunay-Weber syndrome) [16]. FNH with similar clinical and radiographic features has been documented in identical twins supporting a role of congenital vascular anomalies in its pathogenesis and a possible genetic predisposition to the disease [17].

PATHOLOGY — FNH is most often solitary (80 to 95 percent), and usually less than 5 cm in diameter. Only 3 percent are larger than 10 cm, although FNH as large as 19 cm have been reported [1,13,18]. It has a sharp margin with no capsule and may be pedunculated. The characteristic finding is the presence of a central stellate scar (picture 1) containing an inappropriately large artery with multiple branches radiating through the fibrous septa to the periphery. These branches divide the mass into multiple small nodules or cords of normal appearing hepatocytes (picture 2). The scar-like tissues within FNH nodules are composed of abnormally large portal tracts including large feeding arteries, portal veins, and bile ducts [10].

The arteries drain into adjacent hepatic veins. This radiating, branching pattern produces the spoke and wheel image typically seen on angiography. Although normal bile ducts are absent, bile ductules derived from hepatocyte metaplasia are usually prominent, traveling along the fibrous septa (picture 3). Sinusoids and Kupffer cells are typically present, distinguishing it from hepatocellular adenoma (HA), which usually lacks bile ducts and Kupffer cells [1,13,14,18,19]. The minimal microscopic criteria for the diagnosis of classical FNH are nodular architecture, abnormal vessels, and proliferation of bile ductules [13]. Lymphocyte infiltration, canalicular bile plugs, copper deposition, and feathery degeneration of hepatocytes may suggest cholestasis and/or inactive cirrhosis. Irregular intimal fibrosis or hypertrophy of the media may be seen in large arteries and veins, at times even occluding the lumen [13,14,19]. When present, portal veins are dilated and/or stenotic [10].

Non-classical variants — Non-classical forms of FNH lack either the typical nodular architecture or vascular malformations, but always contain bile ductular proliferation. They almost always lack the characteristic central scar [13]. Three variants have been recognized:

●The most common of these, the telangiectatic type, often presents with multiple FNH. In addition to the lack of a central scar, the mass is characterized by the absence of nodular architecture and the presence of single, quite regular plates of hepatocytes separated by sinusoids fed directly by anomalous arteries [13,20]. The risk of bleeding appears to be similar to the risk observed in patients with a hepatic adenoma [21].

●A mixed hyperplastic and adenomatous form may be difficult to distinguish from HA due to its subtle vascular and bile ductular findings [13,20].

●A third histologic variant consisting of FNH with cytologic atypia resembling dysplasia of large cell type has been proposed [13].

A comprehensive pathological study of 305 lesions failed to identify a macroscopic central stellate scar in 50 percent and noted non-classical histology in 20 percent of the lesions, most showing a telangiectatic variant [13]. The surprisingly high number of lesions without a central scar was almost exclusively due to the large number of masses that had non-classical histology. Ninety-five percent of those with non-classical histology did not have a scar, whereas only 18 percent of those with classical histology lacked a scar [13]. The overall prevalence and clinical significance of these variants remains to be determined.

DIAGNOSIS — The diagnosis of FNH is usually made by demonstrating its characteristic features on imaging tests and excluding other lesions. The latter can typically be accomplished by assessment of the context in which FNH is detected and by obtaining specific radiologic and laboratory testing (table 1). The differential diagnosis includes hepatic adenoma, hepatocellular carcinoma, fibrolamellar carcinoma, cirrhosis, large regenerative nodules, hemangioma, and hypervascular metastases. (See "Solid liver lesions: Differential diagnosis and evaluation".)

Symptoms — The majority of reports have found that symptoms or signs directly attributable to FNH are infrequent. Two-thirds to three-fourths of patients are identified incidentally [18], with the mass noted at the time of surgery, on an abdominal imaging study, or at autopsy. Unlike hepatic adenomas, FNH rarely presents with acute onset of hemorrhage, necrosis, or infarction [22,23].

However, symptomatic presentations have been described. In one series, for example, abdominal discomfort or a palpable liver mass was observed in 25 percent of 41 patients [24]. Another series that included 168 patients found that 60 percent had abdominal pain and 4 percent had an abdominal mass [13]. The high number of symptomatic patients in the second report probably reflects selection bias since all of the patients were identified from pathology specimens obtained at the time of surgical resection [13].

Laboratory tests — Liver tests are most often normal although minor elevations in aspartate and alanine aminotransferase, alkaline phosphatase and gamma glutamyl transpeptidase levels may be seen [13,14,24]. The alpha-fetoprotein is normal.

Imaging tests — A confident diagnosis can usually be made through a combination of imaging modalities; tissue diagnosis is usually not required.

Ultrasonography — Although often first identified on ultrasound examination, FNH is variably hyper, hypo, or isoechoic [24] and US is able to identify the central scar in only 20 percent of cases [25]. The ultrasound characteristics are difficult to distinguish from an adenoma or malignant lesions. Power Doppler ultrasound may help differentiate the arterial flow in FNH from the venous flow in HA [24,26,27].

Contrast-enhanced ultrasonography — Several reports have described improved characterization of focal liver lesions using contrast-enhanced ultrasonography compared with standard ultrasonography [28-30]. While the approach is not approved in the United States, it is available in other countries. Test characteristics compared with other imaging modalities remain incompletely defined, although emerging data suggest its ability for differentiation among solid liver lesions is comparable with MRI [31]. (See "Contrast-enhanced ultrasound for the evaluation of liver lesions".)

CT scan — A properly timed dynamic, triphasic, helical CT scan performed without contrast, and with contrast during the hepatic arterial and portal venous phases, will often be highly suggestive of the diagnosis [32,33]. The lesion may be hypo or isodense on non-contrast imaging with the central scar identified in one-third of patients. The lesion becomes hyperdense during the hepatic arterial phase due to the arterial origin of its blood supply (image 1). FNH is generally isodense during the portal venous phase, although the central scar may become hyperdense as contrast diffuses into the scar. While characteristic of FNH, a central scar may be present in the fibrolamellar variant of HCC. (See "Epidemiology, clinical manifestations, diagnosis, and treatment of fibrolamellar carcinoma", section on 'Imaging'.)

MRI — There may be little to distinguish FNH from normal liver on standard MRI, since it is composed of the same elements as normal liver. An isointense lesion is noted on T1-weighted images, while an isointense to slightly hyperintense mass appears on T2-weighted images (image 2 and image 3) [34]. The scar typically shows high signal intensity on T2-weighted images due to vessels or edema in the scar (image 3) [35]. Gadolinium infusion produces rapid enhancement of the FNH mass due to its arterial blood supply, producing a hyperintense lesion on early films (image 2). On delayed images it becomes more isointense with respect to normal liver. The central scar enhances on delayed imaging as contrast gradually diffuses into the fibrous center of the mass [36-39]. In one study, gadolinium enhanced MRI had a sensitivity and specificity of 70 and 98 percent, respectively [24].

A relatively new MR contrast agent has been introduced into clinical use. Unlike currently used gadolinium-based contrast agents for MRI, this agent, a Gd-BOPTA chelate of Gadobenate Dimeglumine, has a dual route of elimination, through both renal and hepatobiliary excretion (image 4). Thus, it can be useful for distinguishing hepatic adenomas from focal nodular hyperplasia. (See "Solid liver lesions: Differential diagnosis and evaluation".)

Angiography — Although angiography may reveal the diagnostic "spoked wheel" appearance of FNH, its use is rarely indicated [32,40,41].

ROLE OF ORAL CONTRACEPTIVES — FNH was first described in the early 1900s, long before the advent of oral contraceptives (OCPs). It is seen in men and children who do not use OCPs and its incidence remained steady after the introduction of OCPs in 1960, in sharp contrast to the dramatic rise in the incidence of HA with the widespread use of OCPs. Thus use of OCPs is not required for the development of FNH [42-44].

On the other hand, FNH may be responsive to estrogens [11]. Patients taking OCPs tend to have larger, more vascular tumors, have more symptoms, and reports of hemorrhage or rupture in patients with FNH have all occurred in patients taking OCPs [45-48]. However, the magnitude of the risk associated with OCPs is uncertain. In a study of 216 women with FNH, use of OCPs did not appear to influence the size or number of FNH lesions or size changes (which were rare) during follow-up for an average of two years [49]. A case control trial comparing 23 women with histologically confirmed FNH to 94 controls estimated the odds ratio of OCP use to be 2.8 (95% CI, 0.8 to 9.4) for those who had ever used OCPs and 4.5 (95% CI, 1.2 to 16.9) for those who had ≥3 years of use [50].

We generally do not insist that oral contraceptives and other estrogen containing preparations should be discontinued. However, it is reasonable to obtain a follow-up imaging study in 6 to 12 months in women who continue taking these drugs.

MANAGEMENT — The natural history of FNH is one of stability and lack of complications. Lesions generally do not change over time, although they occasionally become smaller [49,51-54]. However, as mentioned above, enlargement of FNH in the setting of OCPs and during pregnancy have been reported [55]. There is no evidence for malignant transformation of FNH [13,24,56,57].

Patients who are suspected of having FNH based upon the evaluation described above should be managed conservatively [24,35,49,51,52,54,58,59]. If a diagnosis remains unclear, a liver biopsy may be helpful, but may also be misleading since only resection will be definitive [60]. Follow-up studies at three and six months will often be sufficient to confirm the stability of the lesion and its benign nature, after which no long-term follow-up is required routinely. Surgery should be reserved for the rare, very symptomatic FNH lesion, and the highly suspicious lesion, which has eluded diagnosis by all other modalities.

We generally do not insist that oral contraceptives and other estrogen containing preparations should be discontinued. However, it is reasonable to obtain a follow-up imaging study in 6 to 12 months in women who continue taking these drugs. Small FNH do not appear to pose a significant risk to a successful pregnancy [49,61], although close observation is strongly recommended and resection may be prudent for large (>8 cm) FNH.

SUMMARY AND RECOMMENDATIONS

●Focal nodular hyperplasia (FNH) is a non-malignant hepatic tumor that is not of vascular origin. It is now generally accepted to be a hyperplastic (regenerative) response to hyperperfusion by the characteristic anomalous arteries found in the center of these nodules. (See 'Pathogenesis' above.)

●FNH is most often solitary (80 to 95 percent) and usually less than 5 cm in diameter. Only 3 percent are larger than 10 cm. (See 'Pathology' above.)

●The majority of reports have found that symptoms or signs directly attributable to FNH are infrequent. (See 'Symptoms' above.)

●The diagnosis of FNH is usually made by demonstrating its characteristic features on imaging tests and excluding other lesions. The latter can typically be accomplished by assessing the context in which FNH is detected and by obtaining specific radiologic and laboratory testing (table 1). (See 'Diagnosis' above and "Solid liver lesions: Differential diagnosis and evaluation".)

●The natural history of FNH is one of stability and a lack of complications. Thus, we suggest that patients who are suspected of having FNH based upon the evaluation described above be managed conservatively (Grade 2B). (See 'Management' above.)

●FNH may be responsive to exogenous estrogens. We generally do not insist that oral contraceptives and other estrogen-containing preparations should be discontinued. However, it is reasonable to obtain a follow-up imaging study in 6 to 12 months in women who continue taking these drugs. (See 'Role of oral contraceptives' above.)

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HCC Differnetial Table

Abbreviations: RUQ= Right upper quadrant of the abdomen, LUQ= Left upper quadrant, LLQ= Left lower quadrant, RLQ= Right lower quadrant, LFT= Liver function test, SIRS= Systemic inflammatory response syndrome, ERCP= Endoscopic retrograde cholangiopancreatography, IV= Intravenous, N= Normal, AMA= Anti mitochondrial antibodies, LDH= Lactate dehydrogenase, GI= Gastrointestinal, CXR= Chest X ray, IgA= Immunoglobulin A, IgG= Immunoglobulin G, IgM= Immunoglobulin M, CT= Computed tomography, PMN= Polymorphonuclear cells, ESR= Erythrocyte sedimentation rate, CRP= C-reactive protein, TS= Transferrin saturation, SF= Serum Ferritin, SMA= Superior mesenteric artery, SMV= Superior mesenteric vein, ECG= Electrocardiogram

Disease	Clinical manifestations													Diagnosis		Comments
	Symptoms									Signs
	Abdominal Pain	Fever	Rigors and chills	Nausea or vomiting	Jaundice	Constipation	Diarrhea	Weight loss	GI bleeding	Hypo- tension	Guarding	Rebound Tenderness	Bowel sounds	Lab Findings	Imaging
Hepatocellular carcinoma/Metastasis	RUQ	+	−	+	+	+	+	+	+	+	−	+	Normal Hyperactive if obstruction present	High levels of AFP in serum Abnormal liver function tests Thrombocytopenia	US CT MRI Liver biopsy	Other symptoms: Splenomegaly Variceal bleeding Ascites Spider nevi Asterixis
Cholangiocarcinoma	RUQ	+	−	+	+	−	−	+	−	−	−	+	Normal	Elevated CA 19-9 Increased amylase / lipase Increased stool fat content	Contrast-enhanced ultrasound CT scan Calcification Pseudocyst Dilation of main pancreatic duct MRI	Predisposes to pancreatic cancer
Pancreatic carcinoma	MidEpigastric	−	−	+	+	+	−	+	−	−	−	+	Normal	↑ Alkaline phosphatase ↑ serum bilirubin ↑ gamma-glutamyl transpeptidase ↑ CA 19-9	MDCT with PET/CT MRI EUS	Skin manifestations may include: Bullous pemphigoid Cicatricial pemphigoid Migratory superficial thrombophlebitis (classic Trousseau's syndrome) Pancreatic panniculitis
Focal nodular hyperplasia	Diffuse	±	−	−	±	−	−	+	+	−	−	−	Normal	Normal Liver function tests Normal AFP Minor elevations of Aspartate Alanine aminotransferase Alkaline phosphatase Gamma glutamyl transpeptidase	Us Multiphasic helical CT scan	Open biopsy if diagnosis can not be established
Disease	Abdominal Pain	Fever	Rigors and chills	Nausea or vomiting	Jaundice	Constipation	Diarrhea	Weight loss	GI bleeding	Hypo- tension	Guarding	Rebound Tenderness	Bowel sounds	Lab Findings	Imaging	Comments
Gallbladder cancer	Midepigastric	−	−	+	+	−	+	+	−	−	−	−	Normal	↑ Alkaline phosphatase ↑ CA 19-9	US CT MRI
Liver hemangioma	Intermittent RUQ	−	−	+	+	−	−	−	−	−	−	−	Normal	Abnormal LFTs	US Single-photon emission computerized tomography(SPECT) MRI	US will reveal hypoechoic lesions
Liver abscess	RUQ	+	−	+	+	−	−	+	−	−	−	−	Normal	Hypoalbuminemia Abnormal liver function tests	US CT
Cirrhosis	RUQ+Bloating	+	−	+	+	−	−	+	−	−	−	−	Normal	Hypoalbuminemia Prolonged PT Abnormal LFTs Hyponatremia Thrombocytopenia	US Nodular, shrunken liver Ascites	Stigmata of liver disease Cruveilhier- Baumgarten murmur
Inflammatory lesions	RUQ	±	−	+	+	−	−	−	−	−	−	−	Normal	Hypoalbuminemia Prolonged PT Abnormal LFTs Hyponatremia Thrombocytopenia	US Nodular,shrunken or coarse liver	Stigmata of liver disease

Classification

Historical Perspective

Pathophysiology

Causes

Differentiating Splenic Rupture from Other Diseases

Epidemiology and Demographics

Risk Factors

Screening

Natural History, Complications and Prognosis

Diagnosis

Diagnostic Study of Choice

History and Symptoms

Physical Examination

Laboratory Findings

Electrocardiogram

X-Ray

MRI

Other Imaging Findings

Other Diagnostic Studies

Algorithms

Major molecular events in the pathogenesis of HCC

Genomic alterations

Epigenetic modifications

Growthfactor pathway alterations

Gene Mutations

Gene Amplification

DNA methylation micro RNA

Micro RNA

LNC RNA

Major Signaling pathways

•TERT promoter •TP53 •CTNNB1 •AXIN1 •AXIN2 •ATM •RPS6KA3 •JAK1 •IL6R •IL6ST •ARID1 •ARID2

•CCND1 •FGF19 •CDKNA2A •CDKNA2B •AXIN1 •IRF2 •MET

GSTP1 •E-Cadherin •CDKNA2 •RASSF1A •SOCS-3 •MIGMT

•MiR-155 •Mir-122 •Mir-224 •Mir-21

•HULC •HEIH •Dreh •MVIH •HOTAIR •MDIG •LINE1

•Wnt/β –catenin •Tyrosine kinase pathways EGF HGF/c-MET FGF VEGF •IGF •HIF •TGF β •Hedgehog

Elderly Male with jaundice from pancreatic cancer, By James Heilman, MD (Own work) [CC BY 3.0 (http://creativecommons.org/licenses/by/3.0)], via Wikimedia Commons

The incidence of HCC has almost tripled since the early 1980s in the United States where it is the fastest rising cause of cancer-related deaths1. According to population based Surveillance Epidemiology and End Results registry data, the overall HCC age adjusted incidence rates for liver and intrahepatic ducts cancer is as high as 8 per 100,000 underling population in 2010 (Fig. 1) of which at least 6 per 100,000 related to HCC. Men are at approximately three times higher risk than women. Asian men (i.e., Chinese, Korean, Filipino, and Japanese) have the highest age-adjusted incidence rates. However, the largest proportional increases have occurred among Hispanics followed by blacks and non-Hispanic whites, whereas the lowest proportional increases have occurred among Asians. In contrast to Asians/Pacific Islanders, HCC incidence rates are reported to be higher among Hispanics born in the United States than among foreign-born Hispanics2. HCC incidence rates have increased in each successive birth cohort born between 1900 and 19593 (Fig. 2). In addition, the age distribution of HCC patients has shifted to younger ages, with the greatest proportional increases among individuals 45–60 years old (Fig. 2). There is a south to north gradient in the incidence and mortality of HCC; Southern states including Texas, Louisiana, and Mississippi have some of the highest HCC incidence rates in the nation (Fig. 3). In one study, Texas Latino and especially South Texas Latinos had the highest age-adjusted HCC incidence rates (as high as 10.6/100,000)4.

Video codes

Normal video

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Video in table

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Floating video

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Redirect

1. REDIRECTEsophageal web

synonym website

https://mq.b2i.sg/snow-owl/#!terminology/snomed/10743008

Image

Normal versus Abnormal Barium study of esophagus with varices

Image to the right

C. burnetii, the Q fever causing agent

Image and text to the right

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Gallery

• 

  Histopathology of a pancreatic endocrine tumor (insulinoma). Source:https://librepathology.org/wiki/Neuroendocrine_tumour_of_the_pancreas

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  Histopathology of a pancreatic endocrine tumor (insulinoma). Chromogranin A immunostain. Source:https://librepathology.org/wiki/Neuroendocrine_tumour_of_the_pancreas

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  Histopathology of a pancreatic endocrine tumor (insulinoma). Insulin immunostain. Source:https://librepathology.org/wiki/Neuroendocrine_tumour_of_the_pancreas

References