Pheochromocytoma Update Quan-Yang Duh Professor of Surgery - PDF document

Pheochromocytoma Update Quan-Yang Duh Professor of Surgery University of California, San Francisco Advances in Endocrine Metabolism PG Course, UCSF, March 19, 2016 Nothing to Declare Page 1 1

Pheochromocytoma: Work up & Management ◆ Presentation ◆ Hereditary PPGL (pheo/paraganglioma) ◆ Diagnostic Testing ◆ Imaging ◆ Preop Preparation ◆ Laparoscopic Resection ◆ Pheo Crisis Pheochromocytoma and Paraganglioma: 2014 Endocrine Society Clinical Practice Guideline Jacques W.M. Lenders, Quan-Yang Duh, Graeme Eisenhofer, Anne-Paule Gimenez- Roqueplo, M. Hassan Murad, Mitsuhide Naruse, Karel Pacak, William F. Young, Jr. Endocrine Society Practice Guidelines: pheochromocytoma/paraganglioma Lenders JW, et al. J Clin Endocrinol Metab. 2014 Jun;99(6):1915-42. Page 2 2

An American President, a German Teenager, a Canadian Nun, and an Appalachian Family Feud Which is proven true? ◆ Lincoln MEN 2B ◆ Eisenhower Pheochromocytoma ◆ Kennedy Adrenal Insufficiency Page 3 3

Which is proven true? ◆ Lincoln MEN 2B ◆ Eisenhower Pheochromocytoma ◆ Kennedy Adrenal Insufficiency John G Sotos: The Physical Lincoln, 2008. Messerli FH, et al: The President and Pheochromocytoma, Am J Cardiol 99:1325-9, 2007 ◆ “wide swings in President’s BP”, “headache”, 8 MI’s ◆ 1.5 cm left adrenal pheo Messerli FH, et al: Am J Cardiol 99:1325-9, 2007 Page 4 4

Pheochromocytoma: 1 st description (Felix Frankel, Freiburg, 1886) ◆ Minna Roll, age 18. died in1884. ◆ 1 yr intermittent palpitation, anxiety, vertigo, headache, vomiting, constipation. ◆ Pale, “goiter”, tachycardia, chest pain. ◆ Died from circulatory failure 9 days after adm. ◆ Autopsy showed bilateral adrenal tumors (“sarcoma” & “angiosarcoma”), cardiac hypertrophy Felix Frankel 1886, CA Cancer J Clin 1984;34:93-106. Neumann HP, et al. NEJM 2007; 357:1311-5 Pheochromocytoma: Minna Roll had MEN 2A ◆ ret c634w mutation found in 4 affected relatives Neumann HP, et al. NEJM 2007; 357:1311-5 Page 5 5

Family Tree of Minna Roll Neumann HPH, et al. NEJM 2007; 357:1311-5 Pheochromocytoma: 1 st successful operations ◆ Cesar Roux (Lausanne) Feb 25, 1926 § Madame S, 33 yo, 2 years of nausea/vertigo § 13 cm R adrenal pheo resected § Well for at least 18 months ◆ Charles Mayo (Rochester) Oct 9, 1926 § Mother Joachim Vauthey JN, et al Surgery. 1992;112:946-50 Mayo CH: JAMA 1927; 89:1047-50 Van Heerden JA, Am J Surg. 1982;144:277-9 Page 6 6

Pheochromocytoma: 1 st successful operations in the US ◆ Charles Mayo (Rochester) operated on Mother Joachim on Oct 9, 1926 – 30 yo Ursuline nun from Chattam, Ontario – 18 months of episodic N/V/HA. – Adm’d June 3, 1926, paroxysmal HTN (300/160) – 6 cm left adrenal tumor “enucleated and packed”, op time 1 hr 4 min. Discharged in December. – No further symptoms, taught music at convent. – Died from “coronary thrombosis” at age 48 Mayo CH: JAMA 1927; 89:1047-50 Van Heerden JA, Am J Surg. 1982;144:277-9 Page 7 7

Hatfield & McCoy: A family feud fueled by pheo? Atuk NO, et al, J Clin Endocrin Metab 1998, 83:117-120 HOUSE, MD (Princeton-Plainsboro Teaching Hospital) ◆ Season 2 episode 1 – “acceptance” – Clarence, a prisoner on death row – Pheo as potential cause for his rage ◆ Season 4 episode 2 – “the right stuff” – Greta, an air force captain training to be an astronaut – Diagnosed with VHL and pheo Page 8 8

Grey’s Anatomy (Seattle Grace Mercy West Hospital) ◆ Season 7 episode 10 – Dr. Teddy Altman (cardiac surgeon) married Henry Burton (who has VHL) so he can have health insurance to have his adrenalectomy for pheochromocytoma ◆ Season 8 episode 9 – Henry died intraoperatively from a bleeding malignant pulmonary carcinoid tumor. Pheochromocytoma: Presentation Autopsy Eisenhower Crisis Minna Roll Classic Mother Joachim, Madame S Genetic McCoy, Minna Roll Incidentaloma Page 9 9

Case: young man with chest pain ◆ 30 year-old man seen in ER for “rule out MI” – Chest tightness, tachycardia, coughing, for 3 months – Sweating and sense of impending doom ◆ PMH – Diabetic for 3 years, on insulin 20 u each morning – Anxiety disorder – Tremor since age 14 ◆ Family History – Father died of MI at age 49 ◆ BP 160/95, P 125 ◆ MI ruled out. Treated with propranolol 20 mg BID Case: young man with chest pain ◆ Non-contrast CT ◆ L adre tumor, heterogen. ◆ 13 cm x 8 cm x 6.5 cm ◆ FNA suggested Page 10 10

Case: young man with chest pain Neck exam found a ◆ palpable 1.4 cm right jugular node Ultrasound also found non- ◆ palpable thyroid nodules 1.3x1.1x0.9 cm on the right and 1.7x1.0x0.9 cm on the left. Plasma calcitonin 1138 pg/ ◆ mL (nl < 10). Ret 634+. Pheochromocytoma/UCSF: Clinical Presentation UCSF, Jan 1994 - June 2009 102 patients (50 men, age 47 ± 16), 108 operations (5 bilateral) ◆ Classical (41%) – HTN w/HA, sweating, palp. ◆ Incidentaloma (33%) ◆ “Pheo crisis” (14%) – multisystem organ failure ◆ Screening for familial syndromes (7%) ◆ Prior operation elsewhere (4%) Shen WT et al, Arch Surg. 2010 Sep;145(9):893-7 Page 11 11

Pheochromocytoma No longer a “10% tumor” (30-35% familial, 15-20% malignant) Pheochromocytoma/Paraganglioma familial syndromes, UCSF ◆ 15/102 (15%) patients had familial syndromes: – 8 MEN-2A – 3 von-Hippel Lindau (VHL) – 2 neurofibromatosis type 1 (NF1) – 1 each MEN-2B, Osler-Weber-Rendu, SDHB ◆ Routine genetic counseling /screening started only recently Shen WT et al, Arch Surg. 2010 Sep;145(9):893-7 Page 12 12

Pheochromocytoma: Germ-line Mutations are Common ◆ Excluded those with known syndromes ◆ Overall 24% (66/271) had mutations – 30 VHL, 13 RET, 11 SDHD, 12 SDHB ◆ If multifocal, 84% ◆ If < 18 year-old, 59% ◆ If Extra-adrenal, 93% Neumann et al: NEJM 346: 1459, 2002 Clinically Guided Genetic Screening: Italian Pheochromocytoma Network ◆ 501 patients, for MEN2, VHL, PGL, NF1 ◆ Germline mutation found in 32.1% ◆ 11.6% for single tumor and no family history ◆ 38.8% if multiple or recurrence. ◆ 91.2% if positive family history. ◆ 100% if has associated syndromic lesions. Mannelli M, et al: JCEM 94:1541-1547, 2009 Page 13 13

Succinate Dehydrogenase (SDH) Subunits Mutations ◆ SDHB: abdm extra-adrenal; malignancy ◆ SDHD: adreanl; head & neck; multiple Neumann et al: JAMA 292:943, 2004 Succinate Dehydrogenase “Mitochondrial tumor-suppresser genes” ◆ SDHx: subunit ABCD ◆ Complex II of ETC mitochondria ◆ TCA (glycolysis) cycle ◆ SDHx dysfunction or mutation increases ROS and succinate Gottlieb E, Tomlinson IPM: Nature Rerviews Cancer 5:857-866, 2005 Page 14 14

Pheo/PGL Germ-line Mutations ◆ RET ◆ VHL ◆ NF1 ◆ TMEM127 ◆ MAX ◆ HIF2A ◆ SDHx (A,B,C,D,FA2) Crona J, et al: JCEM 98:E1266-1271, 2013 Dahia PLM: JCEM 98:2679-2681, 2013 Pheo/PGL Genetic Testing ◆ All patients with pheo/PGL should be referred for genetic testing/counselling. (1 ⏐⊕⊕⊕ O). ◆ Priority and sequence depends on syndromic features, family history, age at diagnosis, multifocal and metastatic presentation, tumor location and biochemical phenotype – Malignant pheo – Test for SDHB – All paraganglioma – Test for SDHx Endocrine Society Practice Guidelines: pheochromocytoma/paraganglioma Lenders JW, et al. J Clin Endocrinol Metab. 2014 Jun;99(6):1915-42. Page 15 15

Diagnosis of Pheochromocytoma Biochemical Diagnosis of Pheochromocytoma: Which test is best? ◆ Plasma metanephrines – Best negative predictive v ❖ More false positives ❖ Screen familial disease ◆ Urinary metanephrines – Best positive predictive v ❖ Fewer false positives ❖ All other patients ◆ (CT/MRI characteristics) Lenders et al: JAMA 287: 1427, 2002 Page 16 16

Pheo/PGL Biochemical Diagnosis ◆ Pheos (vs. nerve) ↑ COMT ↓ MAO – Catechols (COMT) → met/normet – Catechols (MAO) → DHPG ◆ Plasma free normetanephrine & metanephrine most sensitive. – Best if done supine, rest > 30 min ◆ Urinary fractionated metanephrines more specific Eisenhoefer G, et al. Kindney International 67:668-77, 2005 Lenders JW, et al. J Clin Endocrinol Metab. 2014 Jun;99(6):1915-42. Drugs interfere with Diagnosis of PPGL ◆ Acetaminophen ◆ Benzodiazepines ◆ Buspirone ◆ Catecholamines and related drugs ◆ Diuretics ◆ Levodopa ◆ Sympathomimetics ◆ Tricyclic antidepressants ◆ Vasodilators Neary NM, et al: NEJM 364:2268-70, 2011 Westphal SA: Am J Med Sci 329: 18-21, 2005 Page 17 17

Italian Society of Endocrinology Retrospective Multicenter Study ◆ 26 centers, 1980-1995, questionnaire ◆ 1004 pts, age 58 (15-86), 420 men, 3 (0.5-25) cm – 85% non-functioning, 15% functioning – 9.2% subclinical Cushing’s – 4.2% pheochromocytomas – 1.6% aldosteronoma ◆ 380 operated – 52% adenoma, 11% pheo – 12% carcinoma, 3/42 < 4 cm F Mantero, et al (Ancona): JCEM 2000;85:637-44. A Angeli, et al (Torino) Horm Res. 1997;47:279-83 . Swedish Prospective Multicenter Study for Adrenal Incidentaloma ◆ 381 patients, 33 hospitals, 1996-2001 – 164 men, 217 women, age 64 (18-84), 3 (1-20) cm ◆ Operative criteria: – > 3-4 cm or hypersecreting hormone ◆ 85/381 (22%) operated – 20 (5%) hypersecreting benign tumors (15 pheos) – 14 (4%) malignant (10 adrenal cortical ca) ❖ 10 (4-16) cm B Bulow & B Ahren (Lund): J Intern Med. 2002;252:239-46. Page 18 18