Hereditary RCC Evgeny Yakirevich, MD, DSc Department of Pathology - PowerPoint PPT Presentation

Hereditary RCC Evgeny Yakirevich, MD, DSc Department of Pathology Lifespan Academic Medical Center Alpert Medical School at Brown University Providence, RI, USA

Financial and Other Disclosures • Off-label use of drugs, devices, or other agents: None • Data from IRB-approved human research is not presented I have the following financial interests or Disclosure code relationships to disclose: No financial relationships N 2

Outline • Definition of hereditary RCC • Old and new hereditary RCC • Characteristic renal and extrarenal features of hereditary RCC, morphology and molecular alterations • Role of pathology in genetic testing

Hereditary RCC • Defined as the presence of a single cancer or constellation of tumor types in >1 first-degree or second degree family member • Inherited through the passage of germline mutations • These mutations are specific for each hereditary RCC syndrome • Inherited in autosomal dominant manner

Hereditary RCC • Familial RCC (2004 WHO classification) • Described with corresponding histologic subtypes in 2016 WHO classification • Display characteristic histologies and genomic alterations • Some have specific extrarenal manifestations • Recognition and diagnosis is important for patients and relatives at risk

Sporadic versus Inherited Kidney Cancer Frequency: 96% 4% Inherited Sporadic Age of onset: 60 y 35- 45 y Multifocal bilateral Single unilateral Germline mutations Somatic mutations Variable penetrance Usually in multiple close relatives Extrarenal manifestations

Hereditary RCC Syndromes Syndromes Gene Histologic type VHL disease VHL 3p Clear cell RCC Hereditary papillary RCC MET 7q Papillary RCC type 1 BHD syndrome BHD 17p Hybrid oncocytic/chromophobe RCC TSC TSC1 / TSC2 AML, Renal cysts, Papillary, clear cell, 9q/16p oncocytoma HLRCC FH 1q Heterogenous, predominantly papillary RCC type 2-like Hereditary paraganglioma- SDHB ( A,C,D ) SDH-deficient RCC pheochromoctyoma syndrome b -globin Hereditary sickle cell Medullary RCC hemoglobinopathy and medullary RCC Cowden syndrome PTEN 10q Clear cell, papillary, chromophobe RCC Hyperparathyroidism-jaw tumor HRPT2 1q MEST, papillary RCC, Wilms syndrome BAP1 cancer syndrome BAP1 3p Clear cell RCC Constitutional chromosome 3 Unknown Clear cell RCC translocation RCC chromosome 3

Multiple Clear Cell RCC in Von Hippel-Lindau Disease Hemangioblastoma • Multiple tumors and cysts Endolymphatic • Retinal or CNS sac tumor (cerebellar) hemangioblastomas • Renal cysts (up to 1000) Pheochromocytoma • Clear cell RCC (up to Renal cell carcinoma 600) in 40-60% Multiple renal cysts

Von Hippel-Lindau Disease Multiple renal cysts and clear cell RCCs Przybycin Adv Anat Pathol 2013

Von Hippel-Lindau Disease is Caused by Germline Mutations in the VHL Gene (3p25.3) Deletion on 3p, somatic mutation, or Additional silencing of mutations VHL gene VHL +/- VHL -/- VHL -/- VHL germline Multiple renal Multiple clear mutation cysts cell RCCs

Hereditary Papillary Renal Cell Carcinoma (HPRCC) • Germline activating mutations in Met protooncogene (7q31) • Tumors: selective duplication of mutant allele in chromosome 7 • High penetrance (67% develop RCC by age 60) • No extrarenal manifestations

Activation Mutations in MET Oncogene (7q) in HPRCC Tyrosine kinase

HPRCC Multifocal (>100) bilateral Papillary type-1 histology tumors

Birt-Hogg-Dube Syndrome is Caused by Mutations in BHD Gene • Benign skin tumors Fibrofolliculoma • Pulmonary cysts • Renal cell tumors (15- 35%) ( Chromophobe RCC, oncocytoma, hybrid oncocytic tumors) • BHD gene chr 17 • Protein folliculin

Tuberous Sclerosis Complex • Germline mutations in TSC1 and TSC2 • Tumors in the brain, eye, skin, and kidney • Variable penetrance • Large number of patients without a prior family history • Renal tumors in 80-85% – Angiomyolipoma (in 80% of TSC) – RCC in 2-4%, also in children and young adults – Eosinophilic renal cysts

Types of RCC in TSC Guo et al, AJSP 2014 Young et al, AJSP 2014 • RCC with • TSC-associated papillary angioleiomyomatous RCC stroma (RAT-like) • Hybrid oncocytic tumors • Chromophobe RCC • Unclassified RCC • Eosinophilic macrocystic RCC Female predominance Concurrent AML in majority Eosinophilic renal cysts in the background

New Hereditary RCC in 2016 WHO Classification • Clear cell renal cell carcinoma • Multilocular cystic renal neoplasm of low malignant potential • Papillary renal cell carcinoma • Hereditary leiomyomatosis and renal cell carcinoma (HLRCC)-associated renal cell carcinoma • Chromophobe renal cell carcinoma • Collecting duct carcinoma • Renal medullary carcinoma • MiT Family translocation renal cell carcinomas • Succinate dehydrogenase (SDH) deficient renal cell carcinoma • Mucinous tubular and spindle cell carcinoma • Renal cell carcinoma, unclassified • Papillary adenoma • Oncocytoma

Hereditary Leiomyomatosis and Renal Cell Carcinoma (HLRCC)-associated Renal Cell Carcinoma • Multiple cutaneous and uterine leiomyomas

HLRCC-associated RCC • RCC (1/3 of patients) – Median age 39 years – Solitary – Aggressive, metastatic at the time of diagnosis • Germline mutation in Fumarate Hydratase ( FH ) gene on 1q42 • Loss of FH by IHC

HLRCC-associated RCC • Typically papillary histology (but is not considered now type 2 papillary RCC) • Variety of patterns described: – Tubular – Tubulocystic – Solid – Cystic – Collecting duct carcinoma-like – Mixed patterns

HLRCC-associated RCC

HLRCC-associated RCC

FH IHC

Succinate Dehydrogenase (SDH)- deficient RCC • SDH is a mitochondrial enzyme critical to the Krebs cycle with 4 subunits (A, B, C, and D) • SDH-deficient RCC is defined by morphology and loss of IHC expression of SDHB • When any one of the SDH subunits (A,B,C,or D) shows double hit inactivation, the entire complex becomes unstable and SDHB expression is lost

SDHB IHC

Succinate Dehydrogenase (SDH)-deficient RCC • Rare – 0.1%-0.2% of all RCC • Typically young adults – Median age 35 yrs • Male:Female 1.8:1 • 30% of patients have p ersonal/family history of – RCC – Pheochromocytoma/Paraganglioma – Gastrointestinal stromal tumor (GIST)

Succinate Dehydrogenase (SDH)-deficient RCC • The majority are low-grade eosinophilic tumors • Usually indolent • Variant morphology is described (papillary, collecting duct, clear cell) • Metastatic rate of 11% at long-term follow- up

Cytoplasmic inclusions

SDH-deficient RCC is Highly Hereditary • To date virtually all patients with SDH- deficient RCC have been shown to harbor germline mutation in SDHB (most common, 80%), C , D, or A genes • All cases should be considered syndromic and genetic testing should be offered • Clinical screening and follow-up for paraganglioma, GIST, and recurrent or metachronous kidney tumor • Patients with germline SDHB mutation have a 14% lifetime risk of RCC

Conclusions • Some hereditary kidney tumors share morphology and genomic alterations with sporadic counterparts • Some have distinct histology, immunophenotype and genomic alterations • Pathologists may recognize suspicious hereditary tumors and triage for genetic testing based on clinical features, histology and IHC findings