Pheochromocytoma differential diagnosis

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ahmad Al Maradni, M.D. [2] Mohammed Abdelwahed M.D[3]

Overview

Pheochromocytoma must be differentiated from other causes of paroxysmal hypertension including severe paroxysmal hypertension (pseudopheochromocytoma), panic disorder, factitious hypertension, carcinoid syndrome, migraine headache, hyperthyroidism, renovascular hypertension, hypoglycemia, labile hypertension (White coat hypertension), stroke, compression of the lateral medulla, seizures, baroreflex failure and drugs.

Differentiating pheochromocytoma from other diseases

Pheochromocytoma must be differentiated from other causes of paroxysmal hypertension. The differentials include:

Disease	Symptoms	Signs	Investigations
Pheochromocytoma[1][4]	Features of sympathetic nervous systemhyperactivity and include: Palpitations (especially in epinephrine producing tumors) Anxiety  Sweating Headaches (90 % of patients) Paroxysmal attacks of hypertension May be asymptomatic (incidentally discovered in MEN syndrome patients)	Tachycardia Hypertension, including paroxysmal (sporadic, episodic) high blood pressure, which sometimes can be more difficult to detect. Orthostatic hypotension	High-risk patients: Plasma fractionated metanephrines 24-hour urinary fractionated metanephrines, catecholamines Imaging studies (CT scan, MRI and  iodine-123-meta-iodobenzylguanidine or MIBG scintiscan) Low-risk patients: 24-hour urinary fractionated catecholamines and metanephrines
Pseudopheochromocytoma (idiopathic)	Paroxysmal activation of the sympathetic system may cause: Emotional distress Acute onset of high blood pressure Headache Chest pain Nausea Palpitations Flushing Duration of attacks ranges from minutes to hours Physical symptoms occur before feeling fear	Hypertension Tachycardia	Increase in plasma catecholamines between and during attacks
Panic attacks	Paroxysms of increased sympathetic activity Episodes of fear or panic attacks Chest pain Headache Palpitations Flushing Response to antidepressants Fear precedes physical symptoms.	Patients look anxious Tachycardia Hypertension Sweating	Laboratory studies that can exclude medical disorders other than panic disorder include: Serum electrolytes Serum glucose Cardiac enzymes Urine toxicology screening
Labile hypertension (White coat hypertension)	No history of hypertension	Elevated blood pressure, tachycardia, and may be anxiety in a clinical setting but not in other settings[1]	Ambulatory blood pressure monitoring and patient self-measurement using a home blood pressure monitoring device are being increasingly used to differentiate patients with white coat hypertension from patients with true hypertension.
Hyperthyroidism	Weight loss Heat intolerance Tremors Palpitations Anxiety Increased bowel disturbances Shortness of breath	Goiter Skin flushing Proptosis Increased sensitivity of beta receptors in the heart to catecholamines due to an effect of thyroid hormones increase cardiac work and output Systolic hypertension	Low thyroid-stimulating hormone (TSH) High free thyroxine (T4) concentration High triiodothyronine (T3) concentration
Renovascular hypertension	Common in individuals < 30 years or > 55 years Abrupt onset of hypertension Accelerated hypertension that was previously well-controlled Refractory hypertension to 3 anti-hypertensive medications Headache Nausea Subconjunctival hemorrhage	Bruit can be heard over the abdomen	Duplex ultrasonography may be used as an initial screening tool for diagnosis of atherosclerotic renal artery stenosis Ultrasonography (might not be very accurate in obese patients or those with intestinal gas)[1]
Stroke and compression of lateral medulla (Lateral medullary syndrome)	Extensive unilateral infarction of the brain stem in the region of the nucleus tractus solitarius may result in partial baroreflex dysfunction, increased sympathetic activity, and neurogenic paroxysmal hypertension. Blurred vision or diplopia Weakness of bulbar muscles Respiratory dysfunction Nystagmus Dizziness	Difficulty sitting upright without support Hypotonia of the ipsilateral arm Ipsilateral decreased pain and temperature sensation in the face The corneal reflex is usually reduced in the ipsilateral eye Contralateral loss of pain and thermal sensation involving the body and limbs	CT shows mass compressing lateral medulla or infarction in the same area
Seizures	According to type; it may be focal or generalized, clinical or subclinical: Tonic-clonic seizure: Repetitive twitches of arm and legs Tongue bitting Loss of consciousness Symptoms occur suddenly and may persist Muscle tension or tightening that causes twisting of the body, head, arms, or legs Amnesia Mood changes (fear, panic, or laughter) Change in sensation of the skin over the arm, leg, or trunk Vision changes and light flashes Hallucinations Tasting a bitter or metallic flavor Complex partial seizure: Confused or dazed and Not be able to respond to questions or direction Absence seizure: Rapid blinking Few seconds of staring into space	Physical examination is important when central nervous system infection or hemorrhage are diagnostic possibilities A tongue bite or laceration in generalized tonic-clonic seizure	Abnormal electroencephalography: a positive test without a clinical presentation is called a sub-clinical seizure. Lumbar puncture is useful to exclude acute central nervous system infections. A neuroimaging study should be performed in all adults with a first seizure to evaluate structural brain abnormalities. Magnetic resonance imaging is preferred over computed tomography.
Carcinoid syndrome	Hypertensive crisis occurs with malignant carcinoid syndrome. Symptoms include: Severe chest pain Severe headache Confusion and blurred vision Nausea and vomiting Severe anxiety Shortness of breath Seizures Unresponsiveness	Cutaneous flushing Venous telangiectasia Diarrhea Bronchospasm Cardiac valvular lesions (tricuspid incompetence)	High urinary excretion of 5-HIAA High urinary excretion of serotonin High chromogranin concentration(Chromogranin(A, B, and C) are proteins that are stored and released with peptides and amines in a variety of neuroendocrine tissues) CT is recommended for evaluation of all patients with carcinoid tumors.
Migraine headaches	Prodrome: Occurs hours or days before a headache Aura Immediately precedes the headache Pain phase Also known as headache phase Postdrome phase	Conjunctival injection Horner's syndrome[1]  Adie's pupil [2]  Cranial/ cervical muscle tenderness  Bruit at neck and head for clinical signs of an arteriovenous malformation Photosensitivity	CT is indicated in patients with:[1][2] Abnormal physical examination: Increase of headache's frequency Poor coordination Focal neurologic signs Headaches awakening the patient at nigt[3][4] Atypical aura Sudden onset Lasting more than 1 hour Always on the same side With or without visual symptoms Migraine attacks that begin after 50 years of age CT is not indicated in: Patients with a diagnosis of a migraine in accordance with the criteria for migraine Differentiating a migraine from other primary headaches
Drugs	Sympathomimetic drugs that can induce symptoms simulating pheochromocytoma include: High-dose phenylpropanolamine Cocaine Amphetamines Lysergic acid diethylamide (LSD) Phenylcyclidine (PCP) Combination of a monoamine oxidase (MAO) inhibitor and ingestion of tyramine-containing foods.	Disturbed consciousness Nasal septum perforation in cocaine addiction Needle marks on the skin History of antidepressantintake	Urine toxicology screening
Baroreflex failure	Marked and frequent fluctuations in blood pressure, with both high and low readings. It is caused by hypofunctioning of baroreflexes that normally buffer blood pressure fluctuations. The disorder is usually a result of injury to carotid baroreceptors, with most patients reporting a history of neck irradiation or surgery. History of changes of heart rate during normal daily activities	Increase in blood pressure with standing. Profound orthostatic hypotension in the absence of an adequate heart rate increase. The hypotension is immediately reversible in the supine position. Determination of respiratory sinus arrhythmia, a Valsalva maneuver, and cold-pressor and handgrip testing, can be helpful to diagnose it. Baroreflex failure patients show a normal or even an increased pressor response to cold-pressor and handgrip testing. These responses are attenuated in patients with autonomic failure. Twenty-four–hour blood pressure monitor can be useful to demonstrate the large blood pressure fluctuations and the tracking of blood pressure and heart rate.	Neck CT scan

Pheochromocytoma must be differentiated from other adrenal tumors such as adrenocortical adenoma, adrenal metastasis, and Cushing's syndrome.

Differential Diagnosis	Clinical picture	Imagings	Laboratory tests
Adrenocortical carcinoma	Mass effect symptoms Symptoms related to excess glucocorticoid Symptoms related to excess mineralocorticoid Symptoms related to excess androgen or estrogen secretion	Irregular shape Non-homogeneous density because of central areas of low attenuation due to tumor necrosis Tumor calcification Diameter usually >4 cm Unilateral location High unenhanced CT attenuation values (>20 HU) Non-homogeneous enhancement on CT with intravenous contrast Delay in contrast medium washout (10 minutes after administration of contrast, an absolute contrast medium washout of less than 50 percent) Hypointensity compared with liver on T1 weighted MRI and high to intermediate signal intensity on T2 weighted MRI High standardized uptake value (SUV) on FDG-PET-CT study Evidence of local invasion or metastases	Adrenal androgens (DHEAS) Androstenedione Bioavailable testosterone should be measured in every patient. 17-hydroxyprogesterone Serum estradiol in men and postmenopausal women Cortisol level Fasting serum cortisol at 8 AM following a 1 mg dose of dexamethasone at bedtime
Adrenal adenoma	Symptoms related to excess glucocorticoid Symptoms related to excess mineralocorticoid	Round, homogeneous with sharp margination Unilateral with diameter less than 4 cm Low unenhanced CT attenuation values (<10 HU) Rapid contrast medium washout after administration of contrast An absolute contrast medium washout of more than 50 percent Chemical shift: evidence of lipid on MRI Isointensity with liver on both T1 and T2 weighted MRI sequences	Cortisol level Fasting serum cortisol at 8 AM following a 1 mg dose of dexamethasone at bedtime Renin (PRA) or plasma renin concentration (PRC): very low in patients with primary aldosteronism, usually less than 1 ng/mL per hour for PRA and usually undetectable for PRC
Cushing's syndrome	Rapid weight gain, particularly of the trunk and face with limbs sparing (central obesity) Proximal muscle weakness A round face often referred to as a "moon face" Excess sweating Headache	Imaging may show mass if presents	24-hour urine cortisol Midnight salivary cortisol Low-dose dexamethasone suppression test; high cortisol level after the dexamethasone test is suggestive of hypercortisolism.
Pheochromocytoma	Palpitations especially in epinephrine-producing tumors. Anxiety often resembling that of a panic attack Sweating Headaches occur in 90 % of patients. Paroxysmal attacks of hypertension but some patients have normal blood pressure. It may be asymptomatic and discovered incidentally after screening for MEN patients.	Increased attenuation on non-enhanced CT (>20 HU) Increased mass vascularity Delay in contrast medium washout (10 minutes after administration of contrast, an absolute contrast medium washout of less than 50 percent) High signal intensity on T2 weighted MRI Cystic and hemorrhagic changes Variable size and may be bilateral	Plasma fractionated metanephrines  24-hour urinary fractionated metanephrines
Adrenal metastasis	Symptoms and signs of primary malignancy especially lung cancer General constitutional symptoms: Fever Fatigue Weight loss	Irregular shape and non-homogeneous nature Tendency to be bilateral High un-enhanced CT attenuation values (>20 HU) and enhancement with intravenous contrast on CT Delay in contrast medium washout (10 minutes after administration of contrast, an absolute contrast medium washout of less than 50 percent) Isointensity or slightly less intense than the liver on T1 weighted MRI and high to intermediate signal intensity on T2 weighted MRI (representing an increased water content) Elevated standardized uptake value on FDG-PET scan

S.No.	Disease	Symptoms			Signs		Diagnosis			Comments
		Abdominal Pain	Hematuria	Headache	Abdominal mass	Abdominal tenderness	Ultrasonography	CT scan	Histology
1.	Wilms tumor	+	+	-	+	+	It is the best initial diagnostic study used in cases suspected with Wilms tumor. Ultrasonography can help identify the mass as a kidney mass. It can distinguish tumor mass from other causes of renal swelling like hydronephrosis. Doppler ultrasonography can help to detect invasion of renal vein and IVC by the tumor.	Findings on CT scan which can be suggestive of Wilms tumor include: Heterogeneous soft-tissue density masses These masses have frequent areas of calcification (~10%) and fat-density regions Lymph node metastasis CT scan of the renal mass can further reveal: Invasion of surrounding organs Thrombus in or occlusion of the renal vein and/or the inferior vena cava Abdominal lymph nodes and contralateral involvement	Wilms tumor has a triphasic appearance. It is comprised of 3 types of cells: Stromal Epithelial Blastemal All the 3 types are not required for the diagnosis of Wilms tumor. Primitive tubules and glomeruli are often seen comprised of neoplastic cells. Beckwith and Palmer reported in NWTS the different histopathologic types of Wilms tumor to categorize them based on prognosis. Spindled cell stroma surrounding abortive tubules and glomeruli is characteristic. The stroma may include: Striated muscle cartilage bone Fat tissue Fibrous tissue.
2.	Renal cell carcinoma	+	+	+/-	+	-	Ultrasound (US) may be helpful when CT scan results are equivocal. It is noteworthy to mention that not all renal cell carcinomas are detectable on ultrasound.	Both CT and MRI may be used to detect neoplastic masses that may define renal cell carcinoma or metastasis of the primary cancer. CT scan and use of intravenous (IV) contrast is generally used for work-up and follow-up of patients with renal cell carcinoma.	The histological pattern of renal cell carcinoma depends whether it is papillary, chromophobe or collecting duct renal cell carcinoma.
3.	Rhabdoid kidney disease	+	+	-	+	-	Ultrasound shows a complex cystic mass.	CT scan may be diagnostic of malignant rhabdoid tumor. Findings on CT scan suggestive of malignant rhabdoid tumor include a large, heterogenous, centrally located mass, which is lobulated with individual lobules separated by intervening areas of decreased attenuation, relating to either previous hemorrhage or necrosis. Enhancement is similarly heterogeneous. Calcification is relatively common, observed in 20-50% of cases and is typically linear and tends to outline tumor lobules.	Malignant rhabdoid tumor is characterized by the round blue tumor cells of high cellularity composed of atypical cells with eccentric nuclei, small nucleoli, and abundant amounts of eosinophilic cytoplasm with frequent mitotic figures.
4.	Polycystic kidney disease	+	+	+ (from hypertension)	+	-	Ultrasound may be helpful in the diagnosis of polycystic kidney disease. Findings on an ultrasound diagnostic of polycystic kidney disease include: At least three unilateral or bilateral cysts in patients 15 - 39 years old Atleast two cysts in each kidney in patients 40 - 59 years old Atleast four cysts in each kidney in patients 60 years of age or older	Renal CT scan may be helpful in the diagnosis of polycystic kidney disease. Findings on CT scan diagnostic of ADPKD include: Numerous renal cysts of varying size and shape with little intervening parenchyma with water attenuation and very thin wall. Reduction in sinus fat due to expansion of the cortex Occasional complex cysts with hyperdense appearance, with possible septations or calcifications Multiple homogeneous and hypoattenuating cystic lesions in the liver in patients with liver involvement	On microscopic histopathological analysis, interstitial fibrosis, tubular atrophy, thickening and lamellation of tubular basement membranes, microcysts and negative immunofluorescence for complement and immunoglobulin are characteristic findings of ADPKD.
5.	Pheochromocytoma	-	-	+ (as a part of the hypertension paroxysm)	-	-	CT is the preferred imaging modality for the diagnosis of pheochromocytoma.	The following findings may be observed on CT scan: Most common extra-adrenal locations are superior and inferior abdominal paraaortic areas, the urinary bladder, thorax, head, neck and pelvis. In sporadic pheochromocytoma, CT and MRI are good choices. The choice depends on availability and cost. In patients with the multiple endocrine neoplasia type 2 (MEN2) syndrome, CT may miss the tumors.	On microscopic pathology, Pheochromocytoma typically demonstrates a nesting (Zellballen) pattern on microscopy. This pattern is composed of well-defined clusters of tumor cells containing eosinophilic cytoplasm separated by fibrovascular stroma.
6.	Burkitt lymphoma	+/- (in non-endemic or sporadic form of the disease)	-	-	-	-	Abdominal ultrasonography may show splenomegaly and ascites.	Chest, abdomen, and pelvis CT scan may be helpful in the diagnosis of Burkitt's lymphoma but it is not done routinely.	On microscopic histopathological analysis, characteristic findings of Burkitt's lymphoma include: Medium-sized (~1.5-2x the size of a RBC) with uniform size ("monotonous") -- key feature (i.e. tumor nuclei size similar to that of histiocytes or endothelial cells) Round nucleus Small nucleoli Relatively abundant cytoplasm (basophilic) Brisk mitotic rate and apoptotic activity Cellular outline usually appears squared off "Starry-sky pattern": The stars in the pattern are tingible-body macrophages (macrophages containing apoptotic tumor cells. The tumour cells are the sky
7.	Intussusception	+	-	-	+/-	+	Ultrasound is the gold standard imaging modality used to diagnose intussusception Target or doughnut sign Edematous intussuscipien forms an external ring around the centrally located intussusceptum Target sign is usually seen in right lower quadrant Layers of intussusception forms pseudo-kidney appearance on the transverse view	CT scan may be helpful in the diagnosis of intussusception. CT scan maybe used when other image modalities like x-ray and ultrasound have not given positive results but suspicion of intussusception is high.	Intussusception occurs if there is an imbalance between the longitudinal and radial smooth muscle forces of intestine that maintain its normal structure. This imbalance leads to a segment of intestine to invaginate into another segment and cause entero-enteral intussusception. Etiology of intussusception is either idiopathic or pathologic (lead point).
8.	Hydronephrosis	+	+/-	-	-	+ (CVA tenderness in case of pyelonephritis)	Ultrasound allows for visualization of the ureters and kidneys and can be used to assess the presence of hydronephrosis and/or hydroureter.	In the case of renal colic (one sided loin pain usually accompanied by a trace of blood in the urine) the initial investigation is usually an intravenous urogram. This has the advantage of showing whether there is any obstruction of flow of urine causing hydronephrosis as well as demonstrating the function of the other kidney. Many stones are not visible on plain x ray or IVU but 99% of stones are visible on CT and therefore CT is becoming a common choice of initial investigation.	The kidney undergoes extensive dilation with atrophy and thinning of the renal cortex.
9.	Dysplastic kidney	N/A	N/A	N/A	N/A	N/A	MCDK is usually diagnosed by ultrasound examination before birth. Mass of non-communicating cysts of variable size. Unlike severe hydronephrosis, in which the largest cystic structure (the renal pelvis) lies in a central location and is surrounded by dilated calices, in multicystic dysplastic kidney the cyst distribution shows no recognizable pattern. Dysplastic, echogenic parenchyma may be visible between the cysts, but no normal renal parenchyma is seen.	MCKD can be discovered accidentally on CT scan. CT scan shows myltiple cysts with absence of renal parenchyma.	MCKD is the result of abnormal differentiation of the renal parenchyma.
10.	Pediatric Neuroblastoma	+	-	-	+/-	+/-	On ultrasound, neuroblastoma is characterized by a heterogeneous echogenicity due to the vascular, necrotic, and calcified content of the mass.	CT scan is the investigation of choice for the diagnosis of neuroblastoma. On CT scan, neuroblastoma is characterized by: Heterogeneous mass Calcification Necrosis Compression of the surrounding vessels Invasion of the psoas muscle or kidneys Swollen lymph nodes	On microscopic histopathological analysis the presence of round blue cells separated by thin fibrous septa are characteristic findings of neuroblastoma. Other findings of neuroblastoma on light microscopy may include: Homer-Wright rosettes (rosettes with a small meshwork of fibers at the center) Neuropil-like stroma (paucicellular stroma with a cotton candy-like appearance) On electron microscopy neuroblastoma is characterized by: Dendritic processes with longitudinally oriented microtubules Membrane bound electron-dense granules that contain catecholamines Presence of desmosomes Absence of glycogen
11.	Pediatric Rhabdomyosarcoma	+	+/-	+/-	-	+/-		On CT scan, rhabdomyosarocma is characterized by: Soft tissue density Some enhancement with contrast Adjacent bony destruction (over 20% of cases)	Rhadbomyosarcoma has an appearance similar to the other round blue cell tumors such as Ewing sarcoma and small cell osteoblastoma.
12.	Mesoblastic nephroma	+	+	-	+	-	Ultrasound may be helpful in the diagnosis of mesoblastic nephroma. Mesoblastic nephroma may presents as a well-defined mass with low-level homogeneous echoes. The presence of concentric echogenic and hypoechoic rings can be a helpful diagnostic feature of mesoblastic nephroma.	CT scan may be helpful in the diagnosis of mesoblastic nephroma. Findings on CT scan suggestive of mesoblastic nephroma include: Solid hypoattenuating renal lesion Variable contrast enhancement No calcification	Classic mesoblastic nephroma Spindle cells in fascicles Infiltrative border Cellular mesoblastic nephroma Plump cells with vesicular nuclei Well-defined border Mitotically active Mixed mesoblastic nephroma Both classic pattern and cellular pattern areas are present	Most common renal tumor that occurs in 1st month of life