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

• Off-label use of drugs, devices, or other agents: None
• Data from IRB-approved human research is not presented

2

I have the following financial interests or relationships to disclose: Disclosure code No financial relationships N

Financial and Other Disclosures

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

Age of onset: 60 y 35- 45 y

Sporadic Inherited

Multifocal bilateral Germline mutations Variable penetrance Usually in multiple close relatives Extrarenal manifestations Single unilateral Somatic mutations Frequency: 96% 4%

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 9q/16p AML, Renal cysts, Papillary, clear cell,

• ncocytoma

HLRCC FH 1q Heterogenous, predominantly papillary RCC type 2-like Hereditary paraganglioma- pheochromoctyoma syndrome SDHB (A,C,D) SDH-deficient RCC Hereditary sickle cell hemoglobinopathy and medullary RCC b-globin Medullary RCC Cowden syndrome PTEN 10q Clear cell, papillary, chromophobe RCC Hyperparathyroidism-jaw tumor syndrome HRPT2 1q MEST, papillary RCC, Wilms BAP1 cancer syndrome BAP1 3p Clear cell RCC Constitutional chromosome 3 translocation RCC Unknown chromosome 3 Clear cell RCC

Multiple Clear Cell RCC in Von Hippel-Lindau Disease

• Multiple tumors and

cysts

• Retinal or CNS

(cerebellar) hemangioblastomas

• Renal cysts (up to

1000)

• Clear cell RCC (up to

600) in 40-60%

Hemangioblastoma Pheochromocytoma

Endolymphatic sac tumor

Renal cell carcinoma

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)

VHL+/-

VHL germline mutation Multiple renal cysts

Deletion on 3p, somatic mutation, or silencing of VHL gene VHL-/- VHL-/- Additional mutations

Multiple clear 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

Papillary type-1 histology Multifocal (>100) bilateral 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

• RCC with

angioleiomyomatous stroma (RAT-like)

• Chromophobe RCC
• Eosinophilic macrocystic

RCC Young et al, AJSP 2014

• TSC-associated papillary

RCC

• Hybrid oncocytic tumors
• Unclassified 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 personal/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