Pheochromocytomas are associated with all of the following familial disorders EXCEPT?
Correct Answer: C
Pheochromocytomas are rare catecholamine-secreting neuroendocrine tumors that originate from chromaffin cells of the adrenal medulla. While the majority are sporadic neoplasms, up to 40% have the disease as part of a familial disorder. These familial disorders all exhibit autosomal dominant inheritance and include MEN2 (mutations in RET proto-oncogene), VHL syndrome (mutations in the VHL tumor suppressor gene), and NF1 (mutation sin the NF1 gene). HNPCC is a genetic condition that demonstrates autosomal dominant inheritance; however, it is not associated with pheochromocytomas.
Approximately 50% of patients with MEN2, 20% of patients with VHL, and 1% of patients with NF1 will have a pheochromocytoma. When compared with each other, MEN2 patients are often more symptomatic with higher incidences of hypertension and higher plasma metanephrine (epinephrine metabolite) concentrations. VHL patients have higher plasma normetanephrine (norepinephrine) concentrations than MEN2 patients. When pheochromocytomas are diagnosed in the setting of no known familial disorder, clinicians should monitor closely for findings such as retinal angiomas in VHL syndrome, a thyroid mass in MEN2, café au lait spots, and neurofibromas in NF1. Any of these findings or a family history of pheochromocytoma should warrant genetic testing for early diagnosis and management.
A 48-year-old female with family history of pheochromocytoma is undergoing laparoscopic nephrectomy for newly diagnosed renal cell carcinoma. The surgeons note an adrenal mass not previously seen on imaging, and manipulation of the kidney causes severe hypertension up to 225/135 mm Hg. The case is aborted, with the patient transferred to the intensive care unit for blood pressure management. In this scenario, which of the following biochemical testing is most recommended?
Correct Answer: D
Measuring plasma-fractionated metanephrines is the recommended first-line test when there is a high index of suspicion for pheochromocytoma. It has the highest sensitivity (96%-100%) and moderate specificity (85%-91%) among all biochemical testing for pheochromocytoma, with the highest area under the receiver operating characteristic curve. The nearly maximal negative predictive value of plasma free metanephrines suggests that pheochromocytoma can be ruled out when the test result is within the normal range. However, the falsepositive rate is high when the blood is not drawn per recommendation (i.e., supine with an indwelling cannula over 30 minutes). Since plasmafractionated metanephrines is associated with a high–false-positive rate, it should only be used when there is a high index of suspicion. The following scenarios warrant a high index of suspicion: family history of pheochromocytoma, genetic syndrome that is associated with pheochromocytoma (MEN2, VHL, NF1), prior resection of pheochromocytoma, or adrenal mass consistent with pheochromocytoma. The patient above had a family history of pheochromocytoma and an incidentally found adrenal mass, which qualify for a high index of suspicion and thus further confirmation with plasma-fractionated metanephrines.
24-hour urine-fractionated metanephrines is the recommended test for patients with low index of suspicion. It has a sensitivity of 92% to 98% and a specificity of 94% to 98% and thus less sensitive than plasma metanephrines but more specific. Measurement of plasma or urinary catecholamines is less sensitive than the aforementioned tests, likely due to the sporadic secretion of parent catecholamines compared to the continuous diffusion of intratumorally produced metanephrines into the circulation.
Which of the following is the appropriate management strategy of pheochromocytoma-associated hypertension?
Blood pressure management is critical in the preoperative management of pheochromocytoma prior to definitive treatment via surgical resection. α-adrenergic receptor blockade (particularly α1-mediated vasoconstriction) should be established prior to β-adrenoreceptor blockade, as unopposed αadrenergic receptor stimulation can cause a hypertensive crisis and place a patient at high risk for heart attack, stroke, and death.
Phenoxybenzamine is a long-acting, nonselective, noncompetitive αantagonist (α1 > α2) often used to control blood pressure prior to surgery. Phentolamine is an intravenous, rapid-acting, nonselective α-antagonist (α1 = α2) often used to control blood pressure perioperatively. While selective α1-blockers such as prazosin, terazosin, and doxazosin may offer a more favorable adverse effect profile, they are not used to prepare patients for surgery due to their incomplete α-blockade.
Once α-blockade is established, β-blockade should be initiated to treat or prevent tachycardia. Both noncardioselective β-blockers, such as propranolol, and cardioselective β-blockers, such as metoprolol, have been used for heart rate control prior to surgery. Esmolol is an intravenous, rapid, short-acting, β1-selective blocker often to control heart rate perioperatively.
Metyrosine is an oral medication which inhibits tyrosine hydroxylase, the rate-limiting step in catecholamine synthesis. It is often used for patients with malignant pheochromocytoma or in whom surgery is contraindicated. Of note, it can also be prescribed for patients with a pheochromocytoma who do not respond to phenoxybenzamine or phentolamine therapy, or as an adjunct to therapy.
Which of the following statements regarding neuroendocrine tumors is FALSE?
Correct Answer: B
Carcinoid syndrome is a paraneoplastic syndrome that occurs in approximately 5% of carcinoid tumors. It is caused by endogenous secretion of serotonin, histamine, prostaglandins, and kallikrein, an enzyme that catalyzes conversion of kininogen to bradykinin. These bioactive molecules cause a wide variety of symptoms, but the most notable are diarrhea (from serotonin), flushing (from histamine and bradykinin), wheezing (from histamine and bradykinin), and cardiac lesions (from serotonin-stimulated fibrogenesis). The liver inactivates many of these bioactive molecules, and thus, it is commonly thought that carcinoid syndrome only occurs with liver dysfunction or metastasis. This is not true, as several case reports describe carcinoid syndrome in the absence of liver metastases. Carcinoid tumors were found in the lungs, ovaries, and testis, and it is thought that carcinoid syndrome may arise in these situations because of the tumors draining directly into the systemic circulation, bypassing portal circulation and subsequent inactivation. Thus, one should consider the possibility of carcinoid syndrome in the absence of liver metastases.
Which of the following diagnostic tests is most appropriate for suspected carcinoid tumor?
Correct Answer: A
24-hour urinary excretion of 5-HIAA is the recommended test for suspected carcinoid tumor. 5-HIAA is the main metabolite of serotonin, and normal urinary excretion ranges from 2 to 8 mg/d, greater than 25 mg/d is diagnostic of a carcinoid tumor.
The test has high sensitivity (>90%) and high specificity (>90%) and is most useful in patients with primary midgut (jejunoileal, appendiceal, ascending colon) tumors which produce the highest levels of serotonin. Foregut (gastroduodenal, bronchus) and hindgut (transverse, descending, sigmoid, rectum, genitourinary) tumors rarely secrete serotonin and thus, 5-HIAA levels may not be elevated in the urine. False-positive results can occur with intake of acetaminophen, guaifenesin, ephedrine, methamphetamine, nicotine, caffeine, and tryptophan-/serotonin-rich foods such as spinach, eggplant, wine, and cheese. False negatives can occur with intake of ethanol, levodopa, methyldopa, monoamine oxidase inhibitors, aspirin, heparin, isoniazid, and fluoxetine.
24-hour urinary excretion of serotonin, plasma serotonin, and chromogranin assays is of interest but have not been validated in large clinical series. The sensitivities and specificities of these tests are not well established and inferior to the 24-hour urinary excretion of 5-HIAA and thus offer little diagnostic value and are not recommended.
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