5/1/2010. Genetic testing in patients with endocrine tumors. Genetic testing in Patients with Endocrine Tumors

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1 Genetic testing in patients with endocrine tumors Why? Jessica E. Gosnell MD Assistant Prof of Surgery April 30, 2010 Genetic testing in Patients with Tumors Indications & Interpretation Germline mutations common Avoid sudden death! (undiagnosed pheochromocytoma) Known genotype-phenotype relationships Guide surgical management of patient Diagnose disease in other affected endocrine organs Screen appropriate family members Offer prophylactic surgery Avoid screening in those without mutations 2 Genetic syndromes associated with endocrine tumors Multiple endocrine neoplasia von Hippel Lindau Neurofibromatosis Pheo/paraganglioma syndrome Cowden s Gardeners Carney complex Osler-Weber Rendu Genetic testing in patients with endocrine tumors Thyroid Medullary thyroid cancer Adrenal Pheochromocytoma Pancreas Islet cell tumors (pancreatic neuroendocrine tumors) Pituitary prolactinoma 3 4 1

2 Medullary thyroid cancer Most rare of the differentiated thyroid cancers but confers disproportionately high mortality Distinct embryology (C-cells) Associated with familial syndromes in up to 40% of cases (including apparent sporadic cases) Well described genetic mutation, which has essentially 100% penetrance of MTC RET (rearranged during transfection) proto-oncogene Encodes a receptor tyrosine kinase Loss of fx-> Hirschsprung s Gain of fx->mtc, MEN Chromosome 10 (21 exons) 5 6 Clinical features of MTC Genotype-phenotype correlations and risk levels MTC features Associated abnormalities Inheritance Genetic defect Sporadic MTC unifocal none None MEN-2A MEN-2B Multi-focal, bilateral Multi-focal, bilateral Primary HPT, pheochromocytoma, cutaneous lichen amyloidosis pheochromocytoma, mucosal neuromas, marfanoid habitus, megacolon AD AD Somatic mutations in RET 20% RET mutation RET mutation (ATA guidelines MTC 2009, Kloos et al. Thyroid ;19 (6):565) FMTC Multi-focal, bilateral none AD RET mutation 7 8 2

3 MTC: algorithm for clinical disease FNA diagnostic or suspicious for MTC: *Full H&P *Labs: Calcitonin, CEA, Ca, PTH RET mutation *Neck ultrasound *Exclude pheo -plasma free MN, MN or urinary N0 and calcitonin < 400 pg/ml N1 and calcitonin < 400 pg/ml *CT scan chest, neck and multiphase abd/pelvis M1 M0 *total tx *central LND *lateral LND for image or bx + *total tx *central LND *lateral LND for image or bx + *For minimal disease, consider thyroidectomy, for extensive disease, palliative neck operation, consider clinical trials 9 MTC: algorithm for preclinical diagnosis (RET+) Germline RET+ with normal thyroid exam: *Full H&P *Labs: Calcitonin, CEA, Ca, PTH *Neck ultrasound *Review specific codon -low, -intermediate -high risk Thyroid nodules <5mm, no LN mets and calcitonin < 40pg/ml (Kloos et al Thyroid 2009:19(6); ) No Go to clinical fig *total tx *central LND if clinically+ *lateral LND for image or bx + **low risk codon: prophylactic OR can be delayed >5yrs **intermediate prophylactic OR <5yrs ** high risk (MEN 2B) Prophylactic OR <1yrs, with CLND 10 Case: patient with newly diagnosed MTC 32yo woman Solitary left thyroid nodule FNA suggestive of MTC Calcitonin 128, CEA 6.4, calcium 9.1, urinary catecholamines normal Neck ultrasound: no suspicious lymph nodes RET positive Total thyroidectomy, bilateral central lymph node dissection C609y ATA risk level B PHPT minority Pheo rare

4 c609y kindred Pt s mother: RET + 54yo woman, hypothyroidism palpable L thyroid nodule Calcitonin 249, CEA 12, calcium 9.4, PTH 54, urinary catecholamines neg US: MNG, largest 1.2cm L lobe, no suspicious nodes Total tx, CLND Pt s aunt: RET + 49yo woman Normal exam Calcitonin 1667 CEA, Calcium, urinary catecholamines PENDING Multiphase CT scan brain, neck, chest, abd/pelvis PENDING Likely total tx, CLND,?lateral neck c609y kindred Pt s daughter: RET + 7yo Referred for evaluation Prophylactic Total tx Pt s son: 18 months Pt s son: RET + 5yo RET testing deferred Referred for evaluation Adrenal: Pheochromcytoma Neural crest derived tumors, secrete catecholamines Requires thoughtful perioperative management to avoid morbidity/death Benign or malignant Germline mutations common 20-25% (10% rule no longer applies!) (Bryant J et al. J Natl Cancer Inst. 2003;95: ) (Benn D et al. JCEM 2006;91: )

5 Hereditary pheochromocytoma/ paraganglioma syndromes MEN 1 MEN 2a, 2B von Hippel-Lindau Neurofibromatosis 1 Osler-Weber Rendu Paraganglioma syndromes (PGL 1-4) Hereditary pheochromocytoma/ paraganglioma von Hippel-Lindau AD (3p25-26) characterized by multiple hemangioblastomas, renal cell Ca, and pheochromocytoma Neurofibromatosis Type 1 (17q11.2) neurofibromas, café au lait spots, pheochromocytoma Type 2 (22q12) neurofibromas, acoustic neuromas Pheo/Paraganglioma syndrome caused by inherited mutations in the SDHD, SDHB and SDHC (chrom 11,1) leads to the development of multiple neuroendocrine tumors along the brain and spinal cord, and in the adrenal gland can be associated with GIST, kidney and thyroid cancer Osler-Weber Rendu multiple types, hemorrhagic telangiectasia Hereditary pheochromocytoma/ paraganglioma genes MENIN RET VHL NF 1 Succinate dehydrogenase genes (SDH) SDH D SDH B SDH C Succinate dehydrogenase SDHD head & neck paragangliomas Genetic imprinting (only at risk when inherited from father) SDHB Adrenal and extraadrenal, thorax and abdomen SDHC Rare, parasympathetic

6 Germline mutations in nonsyndromic pheochromocytoma Germline mutations in nonsyndromic pheochromocytoma NEJM 2002: 271 German and Polish patients 66 (24%) had mutations (30 VHL, 13 RET, 12 SDHB, 11 SDHD, 5 RET) 84% of patients with multifocal tumors, and 59% of patients with age of onset <18yrs, had hereditary disease JCEM 2009: Italian cohort of 501 patients Mutations detected in 32.1% Varied from 100% in pts with associated syndromic lesions, to 11.6% in pts with single tumor and no FH Well described genotype-phenotype relationship (Neumann et al. NEJM 2002;346(19):1463) (Mannelli et al. JCEM 2009;94(5):1541) Germline mutations in nonsyndromic pheochromocytoma JCEM 2006: Review of 12 studies: Bilateral or multicentric tumors -> VHL, RET Epi/metaneph -> RET first Norepi/Normetaneph -> VHL first Sympathetic paragangliomas 47% SDHB, SDHD Age <20 yrs 54% had hereditary disease, usually VHL mutation (Jimenez et al. JCEM 2006;91(8):2851) Pheochromocytoma: UCSF experience 500 adrenalectomies: 102 patients with pheochromocytoma underwent 108 operations form Jan 1994-June 2009 MEN-2A 8 MEN-2B 1 VHL 3 SDH-B 1 NF-1 2 Osler-Weber-Rendu 1 Total: 16 patients (Shen and Duh, PCS meeting, 2010)

7 AACE/AAES adrenal incidentaloma guidelines In light of the association between certain familial syndromes and the development of pheochromocytoma, patients diagnosed with pheochromocytomas at a young age or with multifocal or extra-adrenal disease should be screened with genetic testing for a RET mutation, mutations in the VHL gene, and subunits of the succinate dehydrogenase genes ( Practice Vol 15 (Supp 1) July/Aug 2009) Pancreatic islet cell tumors (pancreatic endocrine neoplasms) Rare tumors of the endocrine pancreas Functional Insulin, gastrin, glucagon, somatostatin, vasoactive intestinal peptide (VIP) Nonfunctional Age Inherited risk factors MEN 1 von Hippel-Lindau Tuberous sclerosis neurofibromatosis (Skogseid B et al. JCEM 1991;73:281) Multiple endocrine neoplasia I Syndrome characterized by development of multiple endocrine tumors Wermer s syndrome Parathyroid (95%), pituitary (30-50%), pancreatic islet (50-75%; insulinomas <30 yrs, gastrinomas> 30 yrs), adrenal cortical tumors (35-40%), thyroid tumors, carcinoid Rare < 1 in 20,000 patients Caused by germline mutations in the MENIN gene (11q13), a tumor suppressor gene Approximately 90% of those with family hx suggestive of MEN-1 will have positive genetic test (Burgess J et al. Arch Surg 1996;131:699) Pancreatic endocrine neoplasms Insulinoma Most common syndromic islet cell tumor Whipple s triad, 90% single tumor < 10% will have MEN-1 Gastrinoma (Zollinger-Ellison) 1:1000 pts with primary duodenal ulcer disease 75% sporadic, 25% associated with MEN-1 VIPoma (Verner-Morrison, WDHA) watery diarrhea, hypokalemia, achlorhydria, 5L/day Glucagonoma Severe dermatitis ( necrolytic migratory erythema ), diabetes, wt loss Somatostatinoma Least common, non-specific clinical features

8 Pituitary adenomas Prolactinomas most common (60%) In patients with MEN-1, pituitary tumors seen in 10-60% 14% incidence of MEN-1 in patients with prolactinomas Consider genetic testing in all patients with prolactinomas, especially in those with any other endocrine disease Conclusions Germline mutations common in patients with endocrine tumors Distinct genotype-phenotype relationships have been described that directly affect management decisions MTC, paraganglioma, pheochromocytoma, prolactinoma and patients with 2 or more endocrine tumors associated with MEN-1 should prompt: genetic testing appropriate testing of other endocrine organs consultation with genetic counselor Referral to tertiary care center? (Carty S et al Surgery 1998;124:1106) Selected references Medullary thyroid cancer: Management guidelines of the American Thyroid Association Kloos RT, Eng C, Evans DB, Francis GL, Gagel RF, Gharib H, Moley JF, Pacini F, Ringel MD, Schlumberger M and Wells SA Thyroid Volume 19, Number 6, 2009, pages American Association of Clinical Endocrinologists and American Association of Surgeons: Medical guidelines for the management of adrenal incidentalomas Zeiger MA, Thompson GB, Duh QY, Hamrahian AH, Angelos P, Elaraj D, Fishman E and Kharlip J Practice Volume 15 (Supp 1) July, August 2009, pages