Incidentaloma differential diagnosis

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

Overview

Adrenal incidentaloma must be differentiated from other diseases that cause adrenal masses such as adrenal adenoma, adrenocortical carcinoma, Cushing's syndrome, pheochromocytoma, metastasis, and other causes of bilateral adrenal masses.

Differentiating different causese of Incidentaloma

• The cause of adrenal incidentaloma commonly include adrenal adenoma, sub-clinical Cushing's syndrome, pheochromocytoma, and adrenocortical carcinoma. These causes can be differentiated from each other as follows:

Differential Diagnosis	Clinical picture	Imagings	Laboratory tests
Adrenal adenoma	Symptoms related to excess glucocorticoid Symptoms related to excess mineralocorticoid	Round and homogeneous density, smooth contour and sharp margination Diameter less than 4 cm, unilateral location Low unenhanced CT attenuation values (<10 HU) Rapid contrast medium washout (10 minutes after administration of contrast, an absolute contrast medium washout of more than 50 percent) Isointensity with liver on both T1 and T2 weighted MRI sequences Chemical shift: evidence of lipid on MRI	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
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 Inhomogeneous 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) Inhomogeneous 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 post-menopausal women Cortisol level Fasting serum cortisol at 8 AM following a 1 mg dose of dexamethasone at bedtime
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 Mid-night 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.[3] Anxiety often resembling that of a panic attack Sweating Headaches occurs 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 nonenhanced 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 inhomogeneous nature Tendency to be bilateral High unenhanced 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) Iso-intensity 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

Differential diagnosis of Cushing's disease from other diseases

The table below summarizes the findings that differentiate Cushing's disease from other conditions that may cause hypertension, hyperandrogenism, and obesity. Facial plethora, skin changes, osteoporosis, nephrolithiasis and neuropsychiatric conditions should raise the concern for Cushing's syndrome.

Conditions Causes Associated features Diagnostic approach Cushing's syndrome Iatrogenic Pituitary adenoma Adrenal tumor Adrenal hyperplasia Ectopic ACTH secretion Obesity Hypertension PCOS/hyperandrogenism Oligomenorrhea/hypogonadism Osteoporosis Myopathy/cutaneous wasting Neuropsychiatric problems Kidney stones 24-hour urine cortisol Midnight salivary cortisol Low dose dexamethasone challenge test CRH stimulation High dose dexamethasone test MRI brain CT/MRI adrenals Pseudo-Cushing's syndrome Obesity Alcoholism Depression HIV Obesity Hypertension PCOS/hyperandrogenism Oligomenorrhea/hypogonadism Urinary free cortisol Midnight salivary cortisol Low dose dexamethasone challenge test Glucose tolerance test Loperamide test Metabolic syndrome X Familial/genetic Obesity Insulin resistance Obesity Hypertension PCOS/hyperandrogenism Oligomenorrhea/hypogonadism Dyslipidemia Diabetes/Glucose intolerance Waist circumference Low-density lipoproteins High-density lipoproteins Glucose tolerance test Fasting blood sugar HbA1c Differentiating pheochromocytoma from other diseases Pheochromocytoma must be differentiated from other causes of paroxysmal hypertension. The differentials include: Disease Symptoms Signs Investigations Pheochromocytoma The symptoms of a pheochromocytoma are those of sympathetic nervous systemhyperactivity and include:[1] 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)[1] Low-risk patients: 24-hour urinary fractionated catecholamines and metanephrines[4] Pseudopheochromocytoma (idiopathic) Paroxysmal activation of the sympathetic system causing: 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 with tired attitude 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 neuro-imaging 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 night[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 References