RENAL NEOPLASMS: NEW ENTITIES & DIFFICULT DIAGNOSES
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1 RENAL NEOPLASMS: NEW ENTITIES & DIFFICULT DIAGNOSES Cristina Magi-Galluzzi, MD, PhD Professor of Pathology Director of Anatomic Pathology
2 Kidney Tumors American Cancer Society Cancer Facts and Figures Estimated new cases: 61,560 - Estimated deaths of disease: 14,080 5 and 10 year relative survival rates: - 72% 62% 126% increase in incidence over last 50 years ~60% incidental; 2/3 diagnosed at local stage (5-year relative survival rate 92%) 2% associated with inherited syndromes
3 Renal Epithelial Neoplasms Several subtypes of renal neoplasms with unique histological features impacting prognosis and treatment have been described 2016 WHO classification based on: Histology & IHC Molecular features Cytogenetic findings Renal cell tumours Clear cell renal cell carcinoma Multilocular cystic renal neoplasm of low malignant potential Papillary renal cell carcinoma Hereditary leiomyomatosis and renal cell carcinomaassociated renal cell carcinoma Chromophobe renal cell carcinoma 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
4 Renal Cell Tumors WHO Tubulocystic renal cell carcinoma - Acquired cystic disease - associated renal cell carcinoma - Clear cell papillary renal cell carcinoma - MiT family translocation renal cell carcinomas - Hereditary leiomyomatosis and RCC - associated RCC - Succinate dehydrogenase deficiency- renal cell carcinoma - Thyroid-like follicular RCC - ALK translocation RCC - RCC with prominent (angio)leiomyomatous stroma - Multilocular cystic renal neoplasm of low malignant potential - Oncocytic PRCC is not a distinct entity - Hybrid oncocytic chromophobe RCC (subtype of CHRCC) - Epithelioid and epithelial cystic AML are variants of AML - MEST and CN-considered as spectrum of one entity - Synovial sarcoma was placed within sarcoma group New entities included in WHO 2016 Emerging/provisional entities in WHO 2016 Modifications from WHO 2004 to WHO 2016
5 Tubulocystic Renal Cell Carcinoma Rare tumor; M:F=7:1 Incidental finding in ½ Wide variation is size Well circumscribed,cystic Spongy bubble wrap
6 Tubulocystic Renal Cell Carcinoma
7 Tubulocystic Renal Cell Carcinoma Microscopic features: Cysts/tubules lined by single layer of cuboidal cells with eosinophilic to oncocytic cytoplasm Hobnail morphology Enlarged nuclei with prominent nucleoli Yang et al, AJSP, 2008
8 Tubulocystic Renal Cell Carcinoma IHC and cytogenetic profile: EMA, vimentin, PAX-8 + CK8, CK18, CK19 + CD10, AMACR, CK7 + HMWCK Clinical outcome: Most present at low stage Low potential for metastasis (~10%, to bone and liver) prominent nucleoli hobnail 8
9 Tubulocystic Renal Cell Carcinoma Some cases may display focal papillary pattern
10 Tubulocystic Renal Cell Carcinoma Clinical outcome: Most present at low stage (limited to kidney) Low potential for metastasis (~10%, to bone and liver) F/U available in 11/13 [mean 27 (1-90) months]: - 10 NED; 1 AWD (PRCC) Differential diagnosis: - Cystic nephroma (CN)/Mixed epithelial and stromal tumor (MEST) - Papillary RCC - Metastasis - Collecting duct carcinoma
11 End Stage Renal Disease (ESRD) ESRD patients are more prone to kidney neoplasm: % ESRD patients with ACKD are even more prone to develop carcinoma (incidence 3-7%, a risk ~100 times that of general population) 40% of tumors are classic clear cell, papillary or chromophobe RCC Majority (60%) are represented by 2 new subtypes: - Acquired cystic disease-associated RCC (36-46%) - Clear cell (tubulo)papillary RCC of end stage kidneys (23%) Tickoo et al. AJSP 2006
12 Acquired cystic disease-associated RCC (ACD-associated RCC) Occurs in kidneys with ACKD Often multifocal and bilateral Size range 1-8 cm Well-circumscribed; some have focally calcified capsule Hemorrhage and necrosis are common Many seem to arise in a cyst All patients on dialysis (8-11years) Tickoo et al. AJSP 2006; Sule et al. AJSP 2005
13 ACD-associated RCC Most common patterns: tubulocystic and papillary; solid, solid-alveolar, microcystic, macrocystic are also known tubulocystic pattern papillary pattern alveolar pattern
14 ACD-associated RCC Inter or intracellular microlumen formation leading to cribriform architecture Eosinophilic cells with large nuclei prominent nucleoli Frequent presence of intratumoral oxalate crystals
15 ACD-associated RCC IHC and cytogenetic profile: CK7, HMWCK, CAIX AMACR, CD57, vinculin + CD10 + (proximal tubular cell differentiation) Clinical outcome: - Relatively good prognosis (low grade, stage, metastatic rate than sporadic RCC) - Mostly indolent tumors - Has metastatic potential CK7 AMACR
16 Acquired Cystic Disease-Associated RCC: IHC and differential diagnosis PAX-8 CAIX CD10 HMWCK CK7 AMACR CD117 ACD-RCC Oncocytoma ESC-RCC HLRCC SDH-deficient RCC CK7 AMACR
17 Clear cell papillary renal cell carcinoma Low-stage, low-grade tumor Both in ACKD patients and sporadic 4 th most common type of RCC Usually present in 6 th decade Well circumscribed small tumors Frequently cystic (up to 90%) with a thick circumferential capsule (>70%); most cases have at least a partial capsule
18 Clear cell papillary renal cell carcinoma Tubulopapillary architecture with compressed tubules lined by clear cells Short papillae arising from cyst wall, lined by a single layer of cells with clear cytoplasm Prominent fibrotic stroma
19 Clear cell papillary renal cell carcinoma 19
20 Tubules/Acini Solid tubules Clear cell papillary renal cell carcinoma Branching acini 20 Clear cell ribbon
21 Clear cell papillary renal cell carcinoma Linear arrangement of nuclei away from basal aspect of cells Lacks vascular pattern typical of CCRCC
22 Clear cell papillary renal cell carcinoma IHC and cytogenetic profile: CK7, HMWCK + CAIX (cup-like) + AMACR, TFE3 CD10 usually - No LOH of 3p; no VHL mutation/methylation No chr. 7/17 trisomy or chr. Y loss Prognosis: Favorable; no reported cases of metastasis or death Most cases are stage pt1 CK7 AMACR 22
23 CCRCC with features of CCPRCC Williamson et al. AJSP 2015; Dhakal et al. AJSP 2016
24 MiT family translocation renal cell carcinomas Members of MiTF/TFE transcription factor family - MiTF, TFE3, TFEB, TFEC Xp11 translocation carcinoma (TFE3 gene fusions) t(6;11)(p21;q12) carcinoma (alpha-tfeb gene fusion) Both types of translocation result in overexpression of fusion gene products Activate transcription of similar genes in vitro Translocation RCC express proteins normally driven by MiTF which are not expressed in other RCCs - Melanocytic markers - Cathepsin K (Martignoni et al. Mod Pathol 2009)
25 Xp11 translocation renal cell carcinoma Gene fusions involving TFE3 transcription factor Typically young patients; range: yrs (median 22 yrs) Comprise most of pediatric RCC; 1-2% of adult RCC 10-15% of cases are association with prior chemotherapy Stage and age predict outcome Fusion partners Tumor Age Translocation ASPL-TFE3* RCC 1-75 t(x;17)(p11.2;q25) PRCC-TFE3 RCC 2-69 t(x;1)(p11.2;q21) SFPQ-TFE3 RCC 5-68 t(x;1)(p11.2;p34) NonO-TFE3 RCC 39 inv(x)(p11.2;q12) CLTC-TFE3 RCC 14 t(x;17)(p11.2;q23)
26 Xp11 translocation renal cell carcinoma ASPL-TFE3 RCC [t(x;17)(p11.2;q25)] - papillary structures lined with clear cells - abundant clear to eosinophilic cytoplasm - discrete cytoplasm membrane - prominent nucleoli - psammoma bodies associated with hyaline nodules are often present
27 Xp11 translocation renal cell carcinoma PRCC-TFE3 RCC [(X;1)(p11.2;q21)] - nested pattern with clear to eosinophilic cytoplasm - less abundant cytoplasm - less prominent psammoma bodies and hyaline nodules
28 ASPL-TFE3 vs. PRCC-TFE3 RCC Feature Nodal metastasis Distant mets at presentation ASPL-TFE3 (X;17) 75% (24/32) 20% (8/40) Cathepsin K IHC 0 (0/8) PRCC-TFE3 (X;1) 35% (5/14) 0 (0/26) 86% (12/14) p value p=0.02 p=0.02 p= Ellis CL et al. Mod Pathol. 2014;27:875-86
29 Xp11 translocation renal cell carcinoma IHC and cytogenetic profile: Vimentin, CD10, RCC + CK7 - Pan-CK, AE1/3, CAM5.2, EMA: weakly/focally + Chromosomal translocation detected by: - Nuclear labeling for TFE3 protein by IHC - TFE3 rearrangements by FISH TFE3 Magers et al. Arch Pathol Lab Med 2015
30 Xp11 RCC confirmed by TFE3 break-apart FISH
31 t(6;11)(p21;q12) renal cell carcinoma Alpha-TFEB Gene Fusion 49 genetically confirmed cases Ages 3-68 years (median 31) Female predominance Size usually up to 10 cm 4 metastases/tumor related deaths in limited follow up PAX8+ Often Cytokeratin -
32 t(6;11) renal cell carcinoma with biphasic pattern
33 t(6;11) RCC Resembling Xp11 translocation RCC!
34 t(6;11) renal cell carcinoma IHC profile: HMB45+, Melan A+ Mostly cathepsin K+, PAX-8 + OSCAR, AE1/AE3, CAM5.2 focally + EMA Chromosomal translocation detected by: - Nuclear labeling for TFEB protein by IHC - TFEB rearrangements by FISH Smith NE et al. AJSP 2014;38: CK TFEB
35 t(6;11) RCC confirmed by TFEB break-apart FISH AJSP 2012;136:
36 t(6;11) RCC confirmed by TFEB break-apart FISH 36
37 Cathepsin K IHC distinguishes translocation RCC from other RCC t(6;11) RCC 100% PRCC-TFE3 RCC (X;1) 86% ASPL-TFE3 RCC (X;17) 0% CCRCC, PRCC, ChRCC 0% t(6;11) Cathepsin K
38 TFEB amplified renal cell carcinoma Emerging entity Most cases show predominant papillary architecture with high-grade features and oncocytic phenotype Potentially aggressive subtypes of RCC Argani P et al. AJSP 2016; 40; Skala SL et al. Mod Pathol 2018; Gupta S. Mod Pathol 2017
39 Hereditary leiomyomatosis and renal cell carcinoma associated renal cell carcinoma Autosomal dominant syndrome Germline-inactivating mutation in FH gene (1q42.3-1q43), encoding enzyme fumarate hydratase Cutaneous and uterine smooth muscle tumors Unilateral renal tumors (4 th decade) resembling type 2 papillary RCC: - papillary, tubulopapillary, tubular, solid patterns - papillae lined by tall cells with abundant eosinophilic cytoplasm - enlarged nuclei with a prominent eosinophilic nucleolus surrounded by a clear halo High stage at presentation, poor clinical outcomes Merino et al, AJSP 2007
40 HLRCC Merino MJ et al. AJSP
41 HLRCC 41
42 HLRCC CAIX AMACR Variable IHC: CK7, CAIX AMACR, CD10 + CK7 CD10 Courtesy Dr. J Lopez, Bilbao
43 FH-deficient RCC sensitive & specific specific, not sensitive fumarate hydratase (FH) 2-succinocysteine (2SC)
44 FH-deficient RCC FH
45 Hereditary leiomyomatosis and renal cell carcinoma associated renal cell carcinoma Clinical features definitional for HLRCC: Multiple biopsy-proven cutaneous piloleiomyomas or 2 of the following minor criteria: - Surgical treatment for symptomatic uterine leiomyomas before age 40 - Type 2 papillary RCC before age 40-1 st degree family member who meets these criteria
46 Tubulocystic carcinoma with poorly differentiated foci (TC-PD): A frequent morphologic pattern of FH-deficient RCC (Smith SC et al. AJSP 2016) RCCs with TC-PD features are enriched for FH deficiency FH-deficient RCC proposed term for tumors with suggestive morphology and IHC where genetic confirmation is unavailable
47 Succinate dehydrogenase (SDH) - deficient RCC Germline mutations of genes encoding SDH subunits result in hereditary syndromes: - Pheochromocytoma/paraganglioma - GIST - Pituitary adenomas - RCC SDH-deficient RCC ~30% multifocal or bilateral Solid or focally cystic growth Uniform cytology; eosinophilic flocculent cytoplasm, intracytoplasmic vacuolations and inclusions
48 SDH - deficient RCC 48
49 SDH - deficient RCC 49
50 SDH - deficient RCC
51 Succinate dehydrogenase - deficient RCC 51
52 Succinate Dehydrogenase (SDH) Deficient - RCC: IHC and differential diagnosis SDH-deficient RCC SDHB PAX-8 EMA CD10 CK20 CK7 CD * *stains intratumoral mast cells Mutation analysis: - double-hit inactivation of SDH-related genes (75% involve SDHB) SDHA-deficient RCC (2 cases): - genetic alteration likely somatic SDHB Kumar R et al. BMC Urol. 2018
53 Succinate dehydrogenase (SDH) - deficient RCC Mostly low stage, low grade May behave aggressively: - high nuclear grade - tumor necrosis - sarcomatoid differentiation 11% metastatic rate at longterm F-U Genetic evaluation of 1 st - degree relatives may be considered Gill et al. AJSP 2014
54 A distinctive low-grade oncocytic FH-deficient RCC, morphologically reminiscent of SDH-deficient RCC (Smith SC et al. Histopathology 2017; Li Y et al. Histopathology Novel form of FH deficient RCC with low grade oncocytic morphology, in 4 males (aged years) Solid, nested and focally tubular architecture; uniform polygonal cells; flocculent, vacuolated eosinophilic cytoplasm, scattered inclusions, fine chromatin, inconspicuous nucleoli FH deficient with retained SDHB expression
55 Low-grade oncocytic FH-deficient RCC 55
56 Low-grade oncocytic FH-deficient RCC 56
57 Emerging/provisional renal cell carcinomas WHO 2016
58 Renal cell carcinoma associated with prominent angio(leiomyomatous) stroma Renal angiomyoadenomatous tumour (RAT) Some are variants of CCRCC or CCPRCC Sporadic or associated with tuberous sclerosis Branching tubules and papillae lined by clear/granular cells surrounded by abundant vascular and smooth muscle stroma CK7 +, CD10 + AMACR No 3p deletion; no trisomy 7 or 17 Michal et al. Ann Diagn Pathol 2000
59 ALK translocation renal cell carcinoma Chromosomal rearrangements involving anaplastic lymphoma kinase gene (ALK) at 2p23 result in fusion with various partner genes
60 ALK translocation renal tumors VCL-ALK VCL-ALK VCL-ALK TPM3-ALK; ELM4-ALK ALK rearrang. STRN-ALK Age (yrs) , 53 61, 59 33, 38 Sex M M M F, F M, M F, M Ethnicity African- American African- American African- American Japanese - Japanese Sickle cell Yes Yes Yes No No No Follow-up 9 mo, alive 21 mo, alive 19 mo, alive 2 y alive, 3 y alive Dead, 4 y; 1.4 y 9 y, 15 y nodal recurrence; 27 y alive; 3 mo alive w distant mets Size ; 2.5, ; 5.0 <4.0; 4.5 Location Medulla Medulla Pelvis Cortex - Medulla to cortex Pattern Author Diffuse sheet-like, polygonal cells Debelenko et al Solid, spindleshaped cells Marino- Enriquez et al Sheets of spindledpolygonal cells Smith et al Papillary, tubular and cribriform; eosinoph, clear cell Sugawara et al Papillary, cleareosinophilic cytoplasm Sukov et al Papillary, cribriform, solid; eosinophilic cytoplasm; signetring cell, rhabdoid Kusano et al. 2016
61 ALK rearrangement in sickle cell trait-associated RCC 3 RCC harboring a t(2;10)(p23;q22) translocation resulting in fusion of vinculin (VCL) and ALK Patients age: 6, 6 and 16 yrs VCL-ALK RCCs have distinctive morphology: polygonal to spindle cells with abundant eosinophilic cytoplasm and frequent intracytoplasmic lumina Marino-Enriquez et al. Genes Chromosomes Cancer 2011; Debelenko et al. Mod Pathol 2011; Smith et al. AJSP 2014
62 TPM3-ALK and EML4-ALK fusion in RCC Micropapillary Papillary with mucin production Rhabdoid Sugawara et al. Cancer 2012 Courtesy of Kengo Takeuchi, Tokyo and Naoto Kuroda, Kochi
63 ALK- rearrangement and copy number gain in adult renal tumors ALK rearrangements (<1%) ALK rearrangement was associated with poor outcome ALK copy number gain (10%) In CCRCC, ALK copy number gain was associated with tumor size, nuclear grade, and worse 10-yr cancer-specific survival Any benefit from ALK inhibitor (crizotinib) treatment??? Sukov et al. Mod Pathol 2012
64 Eosinophilic, solid, and cystic (ESC) - RCC Sporadic and in patients with tuberous sclerosis (TS) Sporadic tumors all in Solid and macrocystic or only solid appearance Microscopically: - Cysts lined by cells with pronounced hobnail arrangement - Cells with voluminous eosinophilic cytoplasm, prominent granular cytoplasmic stippling - Round to oval nuclei with prominent nucleoli Indolent behavior: 13/14 patients without disease progression after 2 to 138 months (mean 53) Trpkov at al. AJSP 2016
65 Eosinophilic, Solid, and Cystic Renal Cell Carcinoma 65
66 Eosinophilic, Solid, and Cystic Renal Cell Carcinoma 66
67 Eosinophilic, Solid, and Cystic Renal Cell Carcinoma pronounced hobnail arrangement 67
68 Eosinophilic, Solid, and Cystic Renal Cell Carcinoma cytoplasmic stippling 68
69 Eosinophilic, Solid, and Cystic Renal Cell Carcinoma 69
70 Eosinophilic, solid, and cystic (ESC) - RCC: IHC and differential diagnosis PAX-8 CAIX CD10 CK20 CK7 AMACR CD117 ACD-RCC patchy - Oncocytoma HLRCC SDH-deficient RCC ACD-associated RCC
71 Eosinophilic solid and cystic renal cell carcinomas have metastatic potential Li Y et al. Histopathology 2018; McKenney J et al. Histopathology y/o female with multifocal ESC RCC with liver and lung metastases 69 y/o female with 15 cm ESC RCC with hilar lymph node metastasis (see pic) 4/10 ESC were multifocal (one bilateral) 4/10 ESC occurred in males
72 Take Home Message Renal tumors are not a single histologic, clinical or molecular entity Current classification integrates genetic based information with conventional histology and IHC Discovery of genetic markers will enable more precise categorization of RCCs possibly leading to better risk stratification and more appropriate therapies
73 THANK YOU!
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