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

Molecular Pathology of 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

• Molecular pathology of main histologic subtypes of

RCC:

– Clear cell RCC – Papillary RCC – Chromophobe RCC

• Molecular pathology of rare histologic subtypes of

RCC

– Collecting duct/Medullary – MiT family translocation carcinoma

• Molecular pathology of unclassified RCC

Most Common Histologic Types of RCC

• Clear cell renal cell carcinoma 70%
• Multilocular cystic renal neoplasm of low malignant potential
• Papillary renal cell carcinoma 15%
• Hereditary leiomyomatosis and renal cell carcinoma-associated renal cell carcinoma
• Chromophobe renal cell carcinoma 5%
• Collecting duct carcinoma
• Renal medullary carcinoma
• MiT Family translocation renal cell carcinomas
• Succinate dehydrogenase-deficient renal cell carcinoma
• Mucinous tubular and spindle cell carcinoma
• Tubulocystic renal cell carcinoma
• Acquired cystic disease associated renal cell carcinoma
• Clear cell papillary renal cell carcinoma
• Renal cell carcinoma, unclassified
• Papillary adenoma
• Oncocytoma

Clear Cell RCC

Clear cytoplasm – lipid, glycogen Prominent blood vessels

VHL and Chromatin Remodeling Genes Alterations in Clear Cell RCC

VHL+/+ Deletion on 3p VHL+/- VHL-/- Additional mutations Chromatin remodeling genes Somatic mutation or epigenetic silencing of VHL gene VHL-/-

PBRM1 SETD2 BAP1

• n 3p

KDM5C

Clear cell RCC

In 90% of sporadic cases

Abnormal VHL Protein Causes Accumulation

• f Hypoxia Inducible Factor-a (HIF-a)

PDGF TGF-a VEGF

TCEB1

TCEB1-mutated RCC

• 11 tumors with clear cell cytology from Sato

and TCGA (Hakimi et al 2015)

• Lack of 3p loss and VHL mutations
• Loss of chromosome 8 containing TCEB1
• Hotspot mutations in VHL-binding site Tyr79
• Thick fibromuscular bands
• Low grade and indolent behavior

RCC with Angioleiomyomatous stroma

Hakimi et al 2015

TCEB1-mutated RCC

Papillary RCC

• 15% of RCC
• Two histologic subtypes:

– Type 1 – Type 2 (not a single entity, but remains a useful morphologic descriptor)

• Subset with mixed histology

Papillary RCC Type 1 Papillary RCC Type 2

Multiplatform-Based Subtype Discovery in Papillary Renal-Cell Carcinoma

Type 2 papillary RCC – at least 3 different entities genetically

The Cancer Genome Atlas Research Network. N Engl J Med 2016, 374:135-45.

MET Alterations in Papillary Carcinoma

• 161 tumors in TCGA cohort

– 17% in type 1 – 2% in type 2

• 169 Advanced papillary RCC analyzed

by CGP at Foundation Medicine (Pal et al 2018)

– 33% in type 1 – 7% in type 2

Chromophobe RCC

• Hypodiploid DNA: -1,-

2,-6,-10,-13,-17,-21

(Multiple chromosomal losses)

• TP53 mutation (chr 17)

in 30%

• PTEN mutation (chr 10)

in 10%

• Folliculin (FLCN)

mutations are rare

Collecting Duct Carcinoma and Renal Medullary Carcinoma

Collecting Duct Carcinoma Renal Medullary Carcinoma Age 43-63 years 2-3 decade Association Sickle cell trait/disease Location Medulla Medulla; Right kidney Histology Infiltrative growth Desmoplastic stromal reaction Prognosis Poor Poor Molecular alterations NF2 (29%) SETD2 (24%) SMARCB1/INI1 (18%) SDKN2A (12%) Pal et al 2016 SMARCB1/INI1 inactivation (100%)

Renal Medullary Carcinoma

SMARCB1/(INI1) loss Infiltrating Necrosis Rhabdoid

MiT Family Translocation RCC

• MiT – Microphtalmia/TFE gene family

1) Xp11 translocation RCC (TFE3 fusion)

– Was included in 2004 WHO classification

2) t(6;11) RCC (MALAT1-TFEB fusion)

– New in 2016 WHO classification

MiT Family Translocation RCC

1) Xp11 Translocation RCC

• 40% of pediatric RCC
• 1.6-4% of adult RCC (overall adults>children)
• F>M (3.7:1)
• Survival is similar to clear cell RCC
• Children have a better prognosis than do

adults

• Adults often with advanced disease and

distant mets

Xp11 Translocation RCC

Xp11 Translocation RCC

Fusion Age Translocation ASPL-TFE3 PRCC-TFE3 SFPQ-TFE3* NONO-TFE3* CLTC-TFE3 PARP14-TFE3 DVL2-TFE3 1-75 2-69 5-68 29-51 14 32 73 t(X;17)(p11.2;q25 t(X;1)(p11.2;q21) t(X;1)(p11.2;p34) inv(X)(p11.2;q12) t(X;17)(p11.2;q23) t(X;3(p11.2;q23) t(X;17)(p11;p13)

*Typically show subnuclear vacuoles mimicking clear cell papillary RCC Argani AJSP 2016

Xp11 Translocation RCC SFPQ-TFE3

Argani AJSP 2016

Clear Cell Papillary RCC

IHC and Molecular Studies

• TFE3 IHC (nuclear) is the

most sensitive and specific (but highly fixation dependent)

• Cathepsin-K + in 60%
• FISH with TFE3 break-

apart probe

TFE3 Cathepsin-K

MiT Family Translocation RCC

2) t(6;11) Renal Cell Carcinoma

• MALAT1-TFEB gene fusion
• >50 reported cases
• Young adults, mean age 31y
• More indolent
• Biphasic low-grade morphology
• IHC: TFEB+ (highly fixation dependent),

MelanA and HMB45+, Cathepsin-K+

• TFEB break apart FISH

t(6;11) RCC: Biphasic morphology

TFEB-amplified RCC

• Recently described, not in 2016 WHO
• Aggressive
• Variable morphology
• First case Peckova et al in 2014
• 8 cases Argani et al AJSP 2016
• 9 cases Williamson et al AJSP 2017
• 11 cases Gupta et al Mod Pathol 2017

TFEB with VEGFA (6p21.1) co- amplification– potential for clinical management

Unclassified RCC

• Is not a distinct subtype of RCC
• Histology does not fit into any of the

recognized subtypes

• 62 unclassified RCC  molecular analysis

(Ying-Bei Chen, 2016)

– Recurrent somatic mutations in 76% cases in 29 genes, including

• NF2 (18%)
• SETD2 (18%)
• BAP1 (13%)
• KMT2C (10%)
• MTOR (8%)
• FH deficiency 6%
• ALK translocations 2%

Conclusions

• Histologic subtypes of RCC have

distinct molecular alterations from large deletions to point mutations and translocations

• Some molecular alterations (Xp11 and

t(6;11) translocations, INI-1 loss) are helpful diagnostic markers

• Molecular alterations could have

therapeutic implications