Paraganglioma & Pheochromocytoma Syndromes: Genetic Risk Assessment

Paraganglioma & Pheochromocytoma Syndromes: Genetic Risk Assessment 60 th Annual Spring Symposium for Houston Society of Clinical Pathologists Houston, TX April 6 th, 2019 Samuel Hyde, MMSc, CGC Certified Genetic Counselor Clinical Cancer Genetics University of Texas MD Anderson Cancer Center

Why Does This Matter? Horm Metab Res, 2012

Historically The 10% Rule for Pheochromocytoma & Paraganglioma 10% familial 10% extra-adrenal 10% malignant ~30-40% of all PCC/PGL are hereditary Eisenhofer et al Clin Biochem Rev 2017

(Very Brief) A & P Refresher Parasympathetic chain PGL Occur above the aortic arch, H&N typically non-functional glomus tumors (historically) Glomus jugular, vagal, jugulotympanicum, carotid body Sympathetic chain PGL Occur below the aortic arch Often functional (fight-orflight response regulation; catecholamine, metanephrines, dopamine) Extra-adrenal PGL, retroperitoneal PGL

Genetic Testing for Patients with PCC/PGL Pheochromocytomas/Paragangliomas represent a group of tumors with a HIGH hereditary burden (highest among hereditary benign and malignant neoplasms) Approximately 30-40% of all tumors associated with a germline mutation in a PCC/PGL predisposition gene This estimate increases with: Younger age (<40) Bilateral/multifocal tumors Malignant disease Family history of PCC/PGL Personal/family history consistent with syndromic presentation This estimate (may) decrease with: Older age (>50) Single, unilateral tumors particularly of H&N origin Intact SDHB immunohistochemistry

Genetic Testing for Patients with PCC/PGL Pheochromocytomas/Paragangliomas represent a group of tumors with a HIGH hereditary burden (highest among hereditary benign and malignant neoplasms) Approximately 30-40% of all tumors associated with a germline mutation in a PCC/PGL predisposition gene Current literature and professional guidelines generally support the recommendation that all patients with a PCC/PGL be offered genetic testing & several specifically recommend genetic counseling to aid these patients in their decision-making NCCN, Endocrine Society America, International Symposium on PCC/PGL Consistent with ASCO recommendation (>10% rule)

PCC/PGL Susceptibility Genes Welander, Soederkvist, Gimm (2011) Endocr-Related Cancer ***FH is not included here; has been associated with malignant PGL

Genetic Testing Options & Approaches (Endo Society Practice Guidelines, JCEM. 2014)

PCC/PGL Predisposition Syndromes Gene (Syndrome) Inheritance (all can exhibit RP & VE**) Risk for PCC/PGL SDHA AD Not well defined; few families/mutations known; H&N? SDHAF2 (PCC/PGL-2) AD paternal transmission Up to 100% for multiple H&N PGL (based on 1 large family study) SDHB (PCC/PGL-4) AD 80-100%; ~>20% malignant; abdomen & pelvis SDHC (PCC/PGL-3) AD Solitary H&N/thoracic PGL; rare PCC & abdominal PGL SDHD (PCC/PGL-1) AD paternal transmission Up to 90%; multiple H&N PGL; some increased risk for PCC; low rate of malignancy TMEM127 AD Unknown risk; unilateral/bilateral PCC; some PGL? MAX AD paternal transmission (?) Other manifestations Biallelic mutations cause Leigh s syndrome RCC, GIST, PTC ; Carney Stratakis syndrome (CSS) RCC, GIST; CSS RCC, GIST; CSS RCC Unknown risk; mostly PCC (bilateral); initial studies up to 30% malignant **Reduced penetrance & variable expressivity

Hereditary Syndromes with Significant PCC Risk Syndrome (gene) von Hippel-Lindau disease (VHL) Multiple Endocrine Neoplasia type 2A & 2B (RET) Neurofibromatosis (NF1) Primary manifestations RCC, PCC, pancreatic cysts/tumors, retinal & CNS hemangioblastomas, endolymphatic sac tumors, testicular cystadenomas, broad ligament tumors Medullary thyroid cancer, PCC, primary hyperparathyroidism (MEN2A only) Café au lait spots, axillary/inguinal freckling, cutaneous & plexiform neurofibromas, PCC, Lisch nodules, optic glioma Risk for PCC/PGL 10-20% risk for PCC; PGL have been reported; ~5% risk for malignancy Can be up to and/or greater than 50%; ~4% risk for malignancy Up to 13%; ~12% risk for malignancy **All autosomal dominant syndromes with variable expressivity Adrenal characteristics Often bilateral; mean age onset 30 years; can be one of earliest manifestations; low risk with Type 1 VHL mutations Often bilateral; highest risk with 634, 883, 918 mutations; lower risk with moderate risk mutations Average age onset 42 years (similar to gen pop); typically unilateral; NF1-associated HTN could be PCC or plexiform neurofibromas

A closer look at H&N PGL

H&N PGL Characteristics Most always nonfunctional (parasympathetic) <1-3% associated with catecholamine excess Carotid body most common location (60%) 30% middle ear PGL (jugulotympanic) 10% vagal PGL Rare laryngeal, sinonasal cavity PGL?Thyroid PGL Women > men Overall low risk of malignancy Presence of metastasis only way to designate malignant tumor Bilateral/multifocal PGL in ~25% cases (hereditary) Tx can include: observation, surgery, radiation therapy Williams MD Head Neck Pathol 2017

H&N PGL Characteristics Smith JD et al Laryngoscope Investig Otolarngol 2017 20 year experience from Univ of Michigan (194 patients) Mean age of dx: 52 years (±16) 63% women 24 patients with multifocal PPGL and/or metastases (panel B) SDHD>SDHB>SDHC Single mutations in SDHA, SDHAF2, NF1 100% of SCP, multifocal or metastatic HNPGL, and bilateral CBP had germline SDHx mutation

Germline Testing in H&N PGL Zhu WD et al Euro J Med Genet 2015 germline testing in HNPGL patients without family history of PPGL 31% had germline mutation (8/26) SDHD>SDHB>SDHAF2 Sridhara SK et al J Neurol Surg B Skull Base 2013 Germline SDHA/AF2/B/C/D testing indicated in all cases of even apparently sporadic HNPGL 1 reported case of tympanic PGL in TMEM127 mutation carrier (Bausch B et al JAMA Oncology 2017) No known cases of HNPGL in MAX mutation carriers (Pheo predominance) Germline VHL, RET and NF1 testing highly unlikely to yield mutation in the case of apparently sporadic HNPGL

SDHB/C/D Penetrance Compared (Andrews KA J Med Genet 2018) SDHB = 21.8% (95% CI 15.2-27.9%) SDHC = 25% (0-57%) SDHD = 43.2% (25.4-56.7%) Non-probands only; lifetime

SDHD The p.p81l mutation (Andrews KA J Med Genet 2018)

Immunohistochemistry in PCC/PGL SDHB IHC can be used to screen PCC/PGL for germline SDHx mutations SDHA IHC also available SDHB IHC stains for the entire mitochondrial complex Not specific for SDHB subunit SDHA IHC is specific for the SDHA subunit Muth A et al J Internal Med 2018

SDH Complex in Hypoxia Nat Review Cancer 2005 Lukyanova Open Journal Endocr and Metabolic Disease 2013

SDH Complex Inactivation SDH complex is inactivated due to germline mutation succinate accumulates and activates HIF-α pathway Pacak et al JCO 2013

SDHB IHC in PCC/PGL Retained SDHB expression in sporadic PGL Williams MD Head Neck Pathol 2017 SDHB expression loss in PGL associated with germline SDHx mutation

SDHB IHC in PCC/PGL 1) van Nederveen FH et al Lancet Oncol 2009 SDHB IHC in 220 tumors (175 retrospective cases associated with known germline mutation; 45 prospective accompanied by germline testing) SDHB expression loss 102/102 PCC/PGL associated with germline mutation Retained expression 65/65 PCC/PGL associated with MEN2, VHL, and NF1 47/53 (89%) PCC/PGL with no germline mutation showed SDHB expression Overall: Sensitivity 100% (95% CI 87-100) Specificity 84% (60-97)

SDHB IHC in PCC/PGL 2) Gill AJ et al Human Pathology 2010 SDHB IHC on 58 tumors with known germline mutation status (positive, negative, weak diffuse) 12/12 PGL associated with germline SDHx mutation showed weak diffuse or negative staining 9/10 VHL, MEN2 or NFI-associated tumors showed positive staining (1 VHL tumor = weak diffuse) 34/36 mutation negative PGL showed positive staining

SDHA IHC in PCC/PGL 4) Korpershoek E et al JCEM 2011 Evaluate significance of SDHA IHC in identifying patients with germline SDHA mutations SDHA IHC in 316 PCC/PGL 7 tumors showed SDHA expression loss (also showed SDHB expression loss) 4/6 patients with SDHA deficient PCC/PGL tested had germline SDHA mutation SDHB/C/D-associated tumors showed expression of SDHA Overall, suggest that the SDHB complex is degraded (?) with any SDHx mutation SDHA loss only if germline SDHA mutation

Case Example

IHC Conclusions IHC is not a replacement for germline genetic testing in any case at any time SDHB expression loss only screens for mutations in the SDHx complex, not a specific gene SDHA expression loss would highly suggest germline SDHA mutation, but still not perfect Rarity of SDHA germline mutations low yield False positives and false negatives happen, so be cautious when interpreting these results (Santi R et al Anticancer Research 2017) SDHB IHC can be useful in other tumors (RCC, GIST) SDHB/A IHC only screens for SDHx mutations, does not account for MAX, TMEM127, VHL, RET, etc. Particularly important for PCC and PGL below H&N

Summary All patients with PCC/PGL regardless of location, age of dx, family hx, IHC status, etc. should be referred for genetic counseling (or offered germline genetic testing) Personalized risk assessment based on location, family hx, IHC status, etc. should be conducted Unlikely to dramatically change genetic testing strategy Genetic testing critically important to inform extent of future screening/surveillance for the patient and the patient s family members

Samuel Hyde, MMSc, CGC Certified Genetic Counselor Clinical Cancer Genetics smhyde@mdanderson.org Questions?