ACCME/Disclosures The USCAP requires that anyone in a position to influence or control the content of CME disclose any relevant financial relationship WITH COMMERCIAL INTERESTS which they or their spouse/partner have, or have had, within the past 12 months, which relates to the content of this educational activity and creates a conflict of interest. Dr. (INSERT NAME HERE) declares he/she has no conflict(s) of interest to disclose. OR Dr. (INSERT NAME HERE) declares affiliation with (INSERT AFFILIATION HERE) How Molecular Pathology Has Changed My Practice in Renal Neoplasia Pedram Argani, MD The Johns Hopkins Medical Institutions Baltimore, MD, USA [email protected] USCAP 2016 Renal Cell Carcinoma (RCC)-1997 • Clear cell • Papillary • Chromophobe • Collecting Duct – Medullary Renal Cell Carcinoma (RCC)-WHO 2016 • Clear cell RCC – Multilocular cystic renal neoplasm of low malignant potential • Papillary RCC • Hereditary leiomyomatosis RCC (HLRCC)-associated RCC • Chromophobe RCC • Collecting duct carcinoma • Renal medullary carcinoma • Mucinous tubular and spindle cell carcinoma • MiT family translocation RCC • Succinate dehydrogenase (SDH) deficient RCC • Tubulocystic RCC • Acquired cystic disease (ACD) associated RCC • Clear cell papillary RCC Two Common Problems in Renal Tumor Classification • RCC with Papillary Architecture and Clear Cells • Hard to Classify Eosinophilic Renal Neoplasms Case 1: 24 year old female with 3cm renal mass Renal Cell Carcinomas Which Often Have Papillary Architecture and Clear Cells • Clear cell RCC • Papillary RCC • Clear Cell Papillary RCC • Xp11 translocation RCC CLEAR CELL RCC CLEAR CELL RCC CLEAR CELL RCC: CA-IX PAPILLARY RCC PAPILLARY RCC: CK7 CLEAR CELL RCC PAPILLARY RCC Clear Cell Papillary RCC • 1-4% of RCC • Originally reported in ESRD but most sporadic • All typical cases have had benign outcome • Histology – Architecture: papillary, tubular – Cytology: clear sub nuclear cytoplasmlinear suprabasal low grade nuclei CLEAR CELL PAPILLARY RCC CLEAR CELL PAPILLARY RCC CK7 CA-IX CLEAR CELL PAPILLARY RCC MiT family Translocation RCC • Xp11 translocation RCC • t(6;11) RCC Xp11 translocation Renal Cell Carcinoma (RCC) • Definition – RCC with translocations involving Xp11 – Gene fusions involving TFE3 transcription factor • Diagnosis confirmed by – Nuclear labeling for TFE3 protein by IHC – TFE3 gene rearrangement by FISH • Often young patients – Median= 22 years – Comprise majority of pediatric RCC – Comprise 1-2% of adult RCC • Outcome similar to clear cell RCC – Stage and Age predict outcome Xp11 RCC CONFIRMED BY TFE3 BREAK-APART FISH Green WM et al. Am J Surg Pathol 2013;37:1150–1163 Cathepsin-K Immunoreactivity distinguishes Translocation RCC from other RCC Martignoni G et al. Mod Pathol 2009;22: 1016-1022 RCC with Papillary Architecture and Clear Cells CA-IX CK7 Cathepsin K Clear Cell RCC +++ - - Papillary RCC - +++ - Clear Cell Papillary RCC ++ +++ - Xp11 translocation RCC - - +/- Back to Our Case CK7- CA-IX- CATHEPSIN K- Diagnosis: Xp11 Translocation RCC with SFPQ-TFE3 Gene Fusion TFE3 BREAK-APART FISH SFPQ BREAK-APART FISH Johns Hopkins Cytogenetics Cristina Antonescu, MD Red, centromeric; green, telomeric Xp11 translocation RCC Fusion Age Translocation ASPL-TFE3 1-75 t(X;17)(p11.2;q25) PRCC-TFE3 2-69 t(X;1)(p11.2;q21) SFPQ-TFE3* 5-68 t(X;1)(p11.2;p34) NonO-TFE3* 29-51 inv(X)(p11.2;q12) CLTC-TFE3 14 t(X;17)(p11.2;q23) PARP14-TFE3 32 t(X;3)(p11.2;q23) DVL2-TFE3 73 t(X;17)(p11;p13) *typically show subnuclear vacuoles mimicking clear cell papillary RCC *typically Cathepsin K negative Am J Surg Pathol 2016, in press Hard to Classify Eosinophilic Renal Neoplasms Case 2: 54 year old female with 5cm renal mass Features Acceptable in Oncocytoma • Capsular invasion • Vascular invasion (rare) • Degenerative atypia Features that Exclude Oncocytoma • Well-Formed Papillae • Clear cells (non-focal) • Diffuse Cytokeratin 7 immunoreactivity • Wrinkly nuclei with well-preserved chromatin Renal Cell Carcinomas with Eosinophilic Cytoplasm • High Grade Clear Cell RCC • “Type 2” Papillary RCC • Eosinophilic Variant of Chromophobe RCC • Acquired Cystic Disease-Associated RCC (ACD-RCC) • Renal Medullary Carcinoma • VCL-ALK RCC • Collecting Duct Carcinoma • SHDB RCC • HLRCC-associated RCC • MiT family translocation RCC CLEAR CELL RCC CLEAR CELL RCC “type“Type II Papillary II Papillary RCC” RCC” “Type II Papillary RCC” • TCGA Study (NEJM 2015 Nov4 Epub) – At least 3 different entities genetically – 5% are actually MiT family Translocation RCC! • WHO 2016: “ may not in fact constitute a single well defined entity… but remains a useful morphologic descriptor ” Acquired Cystic Disease- Associated RCC (ACD-RCC) • Most common RCC in End Stage Renal Disease (36%), particularly in ACD (46%) • 50% multifocal, 20% bilateral Tickoo S et al. Am J Surg Pathol 2006;30: 141-153 ACD-RCC: Key Features • Cribriform/Sievelike Architecture – Intercellular and Intracellular Lumina • Eosinophilic Cytoplasm, Prominent Nucleolus • Intratumoral Oxalate Crystals ACD-RCC ACD-RCC Succinate Dehydrogenase Deficient RCC (SDH RCC) • Germline succinate dehydrogenase B mutations • PGL4 Syndrome – Pheochromocytoma – Paraganglioma – Type II GIST • Pediatric, Carney syndrome – Renal Neoplasms (14% lifetime risk) Barletta JA, Hornick JL. Adv Anat Pathol. 2012;19:193-203 SDHB RCC • Less than 0.6% of RCC • Typically young adults, 26% bilateral • Indolent course in most cases – Rare cases with aggressive histologic features metastasize – Can metastasize late (16, 30 years after resection) Gill AJ Am J Surg Pathol 2014;38: 1588-1602 Williamson SR Mod Pathol 2015;28: 80-94 SDHB RCC • Compact nests of eosinophilic cells • Vacuolated cytoplasm • Pale eosinophilic cytoplasmic inclusions – Giant mitochondria • Loss of SDHB protein by IHC SDHB RCC VACUOLES SDHB RCC INCLUSIONS SDHB IHC Hereditary Leiomyomatosis Renal Cell Carcinoma (HLRCC)- associated RCC Hereditary Leiomyomatosis Renal Cell Carcinoma (HLRCC) Syndrome • Autosomal Dominant • Germline mutations in Fumarate Hydratase gene (1q42) • Multiple Cutaneous and Uterine Leiomyomas – 50% of women have hysterectomy before age 30 • RCC – 1/3 of patients – Solitary – Aggressive HLRCC-associated RCC HLRCC-associated RCC HLRCC-associated RCC: IHC Markers • Aberrant succination of proteins S-(2-succinyl) cysteine (2 SC) IHC – Bardella C et al. J Pathol 2011;225: 4-11 – Chen YB et al. Am J Surg Pathol 2014;38: 627-637 • Loss of Fumarate Hydratase by IHC – Trypkov K et al. Am J Surg Pathol 2016, in press Renal Cell Carcinomas Associated with Sickle Cell Trait • Renal Medullary Carcinoma – Often rhabdoid morphology – Loss of INI1 expression – Poor prognosis • VCL-ALK RCC – Vacuolated Cytoplasm – INI1 intact – Prognosis unclear Renal Medullary Carcinoma VCL-ALK RCC Back to Our Case Additional Sections FUMARATE HYDRATASE Diagnosis: HLRCC-Associated RCC Hard to Classify Eosinophilic Renal Neoplasms • r/o Oncocytoma • Consider high grade clear cell RCC • Beware of type II PRCC • Clues – Young age: MiT family Translocation RCC – ESRD: ACD-RCC – Sickle Cell Trait: RMC, VCL-ALK RCC – Vacuoles, Inclusions: SDHB RCC – Prominent Nucleoli: HLRCC-associated RCC Arthur Purdy Stout Society March 13, 2016 How has molecular pathology changed my diagnostic surgical pathology practice? Renal Neoplasia Pedram Argani MD The Johns Hopkins Medical Institutions [email protected] I. Renal Cell Carcinomas (RCCs) with Clear Cells and Papillary Features Clear Cell RCC Clear cell RCC represents the most common RCC subtype, comprising approximately 60% of all renal tumors. The typical architecture is solid or acinar, with clear cells separated by hypervascular thin fibrous septa. The neoplastic cells of low nucleolar grade clear cell RCC (ISUP grade 1-2) typically have water-clear, virtually agranular cytoplasm. However, high nucleolar grade clear cell RCC typically has densely granular eosinophilic cytoplasm. Rarely, true cases of low grade clear cell RCC have well-developed papillae. In other low grade tumors, small papillae lined by clear cells protrude into cystic spaces. More commonly, high grade clear cell RCC with necrosis demonstrate pseudopapillae resulting from fragmentation of the acinar architecture. Additional sections of such tumors often show diagnostic lower grade acinar areas with clear cytoplasm. Clear cell RCC typically demonstrates strong immunoreactivity for cytokeratin Cam5.2, vimentin, CD10, EMA, RCC marker as well as PAX8 and/or PAX2. Additionally, diffuse membranous staining for CA-IX is present, reflecting inactivation of the von Hippel-Landau (VHL) gene and constitutive activation of the hypoxia-inducible-factor (HIF) pathway. Notably, clear cell RCCs are typically negative for both cytokeratin 7 (CK7) and α-methylacyl-CoA racemase (AMACR), though both may be focally positive, especially in higher grade tumors. CK7 may also label cystic areas. Cathepsin K is consistently negative. In summary, the most helpful morphologic clue for a clear cell RCC is hypervascular septa intimately associated with the neoplastic cells with transparent clear cytoplasm. Features further supporting the diagnosis are diffuse, strong, complete membranous CA-IX labeling and absence of CK7 labeling by IHC, as well as chromosome 3p loss by genetics. Papillary RCC Papillary RCC comprises 11-20% of renal tumors. In contrast to other RCC subtypes, papillary RCC is the more often multifocal (up to 45% of cases) and these typically are of independent origin. The prognosis is more favorable for papillary RCC than for clear cell RCC. Histologically,