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  1. SENIOR TALK Pratima Sood, M.D.

  2. CASE PRESENTATION 19 y.o man presents with episodic mild headaches that resolve spontaneously. Two months before presentation, the headaches became more severe and frequent, occurring almost daily, and were accompanied by throbbing chest pain, sweating, dizziness, and palpitations. During episodes of severe headache, BP was >235/135 mmHg. PMHx: Hypertension PSHx: None SHx: Denies tobacco, EtOH, or IVDA FHx: Father had HTN in 50s; Mother had migraines ALLERGIES: NKDA MEDS: Lisinopril

  3. CASE PRESENTATION Vital Signs: T: 36.6, BP 140/70 mmHg, HR 72 Physical Exam: GEN: NAD; AAO x3; Appears well HEENT: Carotid upstrokes were bounding CV: Cardiac apical impulse was prominent CHEST: CTAB ABD: Soft; NT/ND; BS+ EXT: No C/C/E ECG: PR interval 128msec, nonspecific ST-segment and T-wave abnormalities with prominent voltage.

  4. CASE PRESENTATION Lab studies are all WNL, except phosphorus level was 4.8 mg per dL; Serum and urine tox screen were negative. CT scan of head without contrast showed no abnormalities. CT scan of abdomen and pelvis with oral contrast was unremarkable. Renal MRI scan showed a well-demarcated mass, 3 x 2.4 x 2.2cm in the hilum of the right kidney. The right kidney had two renal arteries, the upper artery appeared normal, lower artery compressed by the mass.

  5. Thyrotoxicosis Hyperthyroidism Carcinoid tumor Essential hypertension Glomerulonephritis; Renovascular HTN Meds (MAOIs, decongestants, PCP, LSD, Cocaine, Sympathomimetics) Anxiety attack Hypoglycemia Insulinoma Paroxysmal SVT Subarachnoid hemorrhage Pheochromocytoma DIFFERENTIAL DIAGNOSIS • Common differential diagnosis seen in patients with tachycardia, tremor, palpitations, and hypermetabolism include:


  7. PHEOCHROMOCYTOMA Rare catecholamine-secreting tumor derived from chromaffin cells of adrenal medulla. PARAGANGLIOMAS ("extra-adrenal pheochromocytomas") are tumors that arise from sympathetic paraganglia . Rarely in locations as the thorax, bladder, or brain.

  8. INTRODUCTION • Occur in people of all races, less frequently in African-Americans. • Occur with equal frequency in males and females. • Peak incidence between third and fifth decade of life. • 10% occur in children; 50% of pheochromocytomas are solitary intra-adrenal, 25% are present bilaterally, and 25% are extra-adrenal.

  9. INTRODUCTION • Characterized by “Rule of Tens”: • 10% of cases are not associated with hypertension • 10% of cases are extra-adrenal, and of those about 10% of cases are extra-abdominal • 10% of cases occur in children. • 10% of cases the tumor involves both adrenal glands (bilateral adrenal tumors tend to occur more frequently in familial cases). • 10% of cases have metastatic disease noted around the time of diagnosis.

  10. INTRODUCTION • Found in less than 0.3% of hypertensive individuals. • Incidence is two cases per million. However, in autopsy cases, the incidence of pheochromocytoma is 250–1300 cases per million, indicating that most cases are not diagnosed. • Occur in familial syndromes: MEN 2A and 2B, Neurofibromatosis (von Recklinghausen disease), and VHL disease.

  11. MEN 2A (SIPPLE SYNDROME) • Medullary thyroid carcinoma • Hyperparathyroidism • Pheochromocytoma • Hirschsprung disease • Over 95% of cases of MEN 2A are associated with mutations in the ret proto-oncogene (encodes tyrosine kinase receptor involved in the regulation of cell growth and differentiation).

  12. MEN 2B • Medullary thyroid carcinoma • Pheochromocytoma • Mucosal neurofibromatosis • Intestinal ganglioneuromatosis • Hirschsprung disease • Marfanoid body habitus • Germline missense mutation in tyrosine kinase domain of ret proto-oncogene present in 95% of patients.

  13. VON HIPPEL-LINDAU DISEASE • Pheochromocytoma • Retinal hemangiomas • Cerebellar hemangioblastoma • Renal cell carcinoma • Renal and pancreatic cysts • Epididymal cystadenomas • Germline mutations VHL suppressor gene located on chromosome 3

  14. NEUROFIBROMATOSIS • also known as VON RECKLINGHAUSEN DISEASE • Congenital anomalies (often benign tumors) of skin, nervous system, bones, and endocrine glands. • 1% of patients with neurofibromatosis found to have pheochromocytomas, but as many as 5% of patients with pheochromocytomas found to have neurofibromatosis.

  15. CLINICAL SYMPTOMS The classic triad of symptoms consists of EPISODIC headache, sweating, and tachycardia in association with severe hypertension. Can also include: Tremor Nausea Weakness Anxiety, sense of doom Epigastric and/or flank pain Constipation Weight Loss

  16. CLINICAL SIGNS • Hypertension • Postural hypotension (from volume contraction) • Hypertensive retinopathy • Pallor • Fever • Tremor • Neurofibromas

  17. CLINICAL SIGNS • Café au lait spots: light to dark brown patches of cutaneous pigmentation that vary from 1-10 mm usually in the axillae and intertriginous areas (groin). • Tachyarrhythmias • Cardiomyopathy • Pulmonary Edema • Ileus

  18. LABORATORY FINDINGS • Fractionated metanephrines and catecholamines in a 24-hour urine collection. • Fractionated plasma free metanephrines. • 24-hour urinary VMA excretion has poor diagnostic sensitivity and specificity compared to 24-hour urinary fractionated metanephrines.

  19. LABORATORY FINDINGS • Plasma metanephrine: sensitivity ~96%, specificity ~85%: • High-risk patients (MEN 2A or 2B, VHL disease or neurofibromatosis, family history of pheochromocytoma). • 24-hour urinary collection for catecholamines and metanephrines: sensitivity ~87.5%, specificity ~ 99.7% • Lower risk patients (flushing spells, poorly controlled hypertension, or adrenal incidentalomas).

  20. LABORATORY FINDINGS • Factors misleading catecholamine or metanephrine results are drugs, medical conditions, certain foods. • Drugs (Acetaminophen, Amphetamines, Bronchodilators, Buspirone, Captopril, Cocaine, Cimetidine, Codeine, Decongestants, Ephedrine, Fenfluramine, Isoproterenol, Levodopa, Labetalol, Metoclopramide, NTG, Phenoxybenzamine, TCA antidepressants). • Conditions (ALS, Carcinoid, Eclampsia, vigorous exercise, GBS, Hypoglycemia, lead poisoning, MI, brain lesions, Acute Porphyria, Psychosis, Quadrplegia, Renal Failure). • Foods (Bananas, Caffeine, Peppers)

  21. LABORATORY FINDINGS • Rule out familial syndromes as MEN 2A or 2B. • Serum intact PTH, Ca to r/o Primary Hyperparathyroidism • Serum calcitonin • Screen for mutations in ret proto-oncogene • Opthalmology consult to r/o retinal angiomas, brain MRI for cerebellar hemangioblastomas for VHL disease • CT scan of kidney and pancreas to r/o cysts

  22. IMAGING • MRI has ~100% sensitivity in detecting adrenal and extra-adrenal pheochromocytomas. • CT has 85-95% accuracy detecting adrenal masses 1cm or greater: • Noncontrast CT followed by CT scan using nonionic contrast reduces the risk of catecholamine release from a pheochromocytoma. • IV contrast can precipitate hypertensive crisis, esp. in patients whose hypertension is uncontrolled. • Glucagon can provoke hypertensive crisis, therefore, should not be used during scanning.

  23. IMAGING • I-123 labeled MIBG (metaiodobenzylguanidine) used when CT or MRI does not show a tumor, but biochemically pheochromocytoma is confirmed. • Somatostatin receptor analog indium-111 used to visualize pheochromocytomas that do not concentrate MIBG. • PET detects tumors using 18F-deoxyglucose or 18F-dopamine and can demonstrate tumors not visible on MIBG.

  24. MRI

  25. CT

  26. COMPLICATIONS • Severe HTN; Catecholamine induced cardiomyopathy, heart failure, CV collapse, cardiac arrhythmia. • Acute Respiratory Distress Syndrome • Hypertensive crises with sudden blindness or CVA. • Decongestant meds, fluoxetine, SSRIs may induce hypertensive paroxysms and death. • After tumor removal, severe hypotension from spontaneous infarction or hemorrhage of tumor and shock, renal failure or MI may occur.

  27. TREATMENT • Alpha blockade with phenoxybenzamine 7-10 days preoperatively to allow for expansion of blood volume; Initially 10mg q12hrs, increasing every 3 days. Usual dose is 40-120mg daily. • CCB (nifedipine or nicardipine) better tolerated than alpha blockers. • Beta blocker only after alpha blockers; Unopposed alpha stimulation can precipitate hypertensive crisis. Labetalol is avoided (assoc. with post-op hypotension). • Volume expansion with high sodium diet and IV saline may be initiated in absence of CHF.

  28. TREATMENT • Laparoscopic removal of tumor. • IV phentolamine (rapid acting alpha-adrenergic antagonist). • IV beta-blocker, IV nicardipine, IV nitroprusside used to normalize BP. • Autotransfusion of 1-2 units blood at 12 hours pre-op plus intra-op volume reduces post-resection hypotension caused by densitization of vascular alpha-1 receptor. • Inoperable/metastatic tumors, metyrosine reduces catecholamine synthesis (SE: crystalluria). Combo therapy (cyclophosphamide, vincristine, dacarbazine) or high dose I-131 MIBG used for metastatic pheochromocytomas.

  29. PROGNOSIS • Good prognosis with smaller, benign pheochromocytomas • Malignancy more likely for paragangliomas and pheochromocytoma >7cm. • 5 year survival rate of 44% after surgery in pts with metastatic pheochromocytoma and paraganglioma. Pts. with primary tumor resection and I-123 MIBG treatment have 5 year survival rate of 75%.

  30. Young, WF Jr. Pheochromocytoma: 1926-1993. Trends in Endocrinology and Metabolism, vol 4, Elsevier Science, Inc 1993. p 122.

  31. SELF-ASSESSMENT 36 y.o man is evaluated for headache & palpitations. He is anxious, tremulous, & diaphoretic. BP is 198/106, HR is 110. Hypertension has been suboptimally controlled with HCTZ, diltiazem, and lisinopril. He frequently experiences similar episodic headache and diaphoresis, during which his BP is alarmingly high. Propranolol worsened their frequency and severity. Which of the following tests would be most appropriate next step in management of this patient? • Serum catecholamines • Serum potassium • Insulin-like growth factor 1 • Fractionated plasma metanephrines • 24-hour urine collection for cortisol

  32. SELF-ASSESSMENT 42 y.o man is evaluated for an anterior neck mass. He has a family history of thyroid cancer and hyperparathyroidism. BP is 147/85, HR is 88; has a 3-cm right thyroid nodule and bilateral anterior cervical lymphadenopathy. Cardiac exam reveals a 2/6 systolic ejection murmur. Labs show serum TSH of 1.4, calcium of 10.6, and microscopic hematuria. FNA of the nodule suggests medullary thyroid cancer. Which of the following tests is the most appropriate next test in the evaluation of this patient? • Serum calcitonin level • Repeat BX with immunostaining for calcitonin • Serum PTH level • Urine metanephrines • Urine calcium, phosphate, citrate

  33. SELF-ASSESSMENT 45 y.o woman with hypertension refractory to therapy with maximal doses of a diuretic, ACEIs, and CCBs is found to have markedly elevated fractionated plasma metanephrines. A 24-hour urine collection for metanephrines contains three times the normal daily excretion for a hypertensive patient. Which of the following is the most appropriate next step in the evaluation of this patient? • CT scan of abdomen, with view of adrenal glands • Plasma catecholamines • Glucagon stimulation test • MRI of the adrenal glands • Met-iodo benzguanidine (MIBG) scan

  34. SELF-ASSESSMENT 22 y.o woman presents for screening because of a family history of medullary thyroid carcinoma. PE reveals BP 155/105, a 1-cm left thyroid mass. She has no mucosal neuromas. Lab studies: Calcium 10.9; Phos 2.6; Chloride 108; Intact PTH 52; Calcitonin 350 Urine calcium excretion 382 mg/24 h; Urine catecholamines excretion 281 µg/24h Which of the following is the most appropriate next step in management? • Oral bisphosphonate • Surgery to remove parathyroid adenoma • Surgery to remove pheochromocytoma • Surgery to remove three and a half parathyroid gland • Surgery to remove a medullary thyroid carcinoma

  35. SELF-ASSESSMENT 38 y.o woman is found to have a 3-cm heterogeneous mass in the right adrenal gland during evaluation for abdominal discomfort. Plasma fractionated metanephrines are twice the upper limit of normal. 24hour urine collection for metanephrines contains 2.5 times the normal daily excretion. Pheochromocytoma is suspected and laparoscopic adrenalectomy is planned within the next 14 to 21 days. BP is 206/110, and HR is 104. Which of the following would be indicated first before surgery? • Carvedilol therapy • Blood transfusion • Fine-needle aspiration of the mass • Phenoxybenzamine therapy

  36. REFERENCES • Beard CM, Sheps SG, Kurland LT, et al. Occurrence of pheochromocytoma in Rochester, Minnesota, 1950 through 1979. Mayo Clin Proc. Dec 1983;58(12):802-4. • Bravo EL, Gifford RW Jr. Current concepts. Pheochromocytoma: diagnosis, localization and management. N Engl J Med. Nov 15 1984;311(20):1298-303. • Bravo EL, Gifford RW Jr. Pheochromocytoma. Endocrinol Metab Clin North Am. Jun 1993;22(2):329-41. • Kudva YC, Sawka AM, Young WF Jr. Clinical review 164: The laboratory diagnosis of adrenal pheochromocytoma: the Mayo Clinic experience. J Clin Endocrinol Metab. Oct 2003;88(10):4533-9. • Lenders JW, Keiser HR, Goldstein DS, et al. Plasma metanephrines in the diagnosis of pheochromocytoma. Ann Intern Med. Jul 15 1995;123(2):101-9. • Wong C, Yu R. Preoperative preparation for pheochromocytoma resection: physician survey and clinical practice. Exp Clin Endocrinol Diabetes. Jul 16 2009. • • Medical Diagnosis & Treatment • MedStudy 12th Edition • MKSAP14