Classificazione anatomo-patologica nei RCC Matteo Brunelli. Department of Pathology and Diagnostic, University di Verona, Italy

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1 Classificazione anatomo-patologica nei RCC Matteo Brunelli Department of Pathology and Diagnostic, University di Verona, Italy

2 WHO 2004 AFIP 2004 =

3 ISUP Vancouver Classification 2013

4 5 newentities 3 emerging

5 WHO % 15% 5% 5%

6 GENETIC HISTOTYPES Clear cell CD10 3/3p Papillary CK Chromophobe PV 6 Oncocytoma S100A1 6-17

7 HISTOTYPES New renal histotypes: CLEAR CELL PAPILLARY RCC TUBULOCYSTIC CARCINOMA ACQUIRED CYSTIC DISEASE (ACD)-ASSOCIATED RCC TANSLOCATION RENAL CELL CARCINOMAs THYROID-LIKE FOLLICULAR CARCINOMA Hybrid oncocytic chromophobic tumor

8 Clear cell papillary RCC CEP3 / 3p CEP7 / CEP17 FISH ICH 7 17 Y 3p CD10 AMACR CK7 normal neg neg + CK7 Gobbo et al. Am J Surg Pathol.2008;32:1239

9 Clear cell papillary RCC CGH MS MLPA Chromosome 3 Methylation status VHL ( ) VHL ( ) Copy number VHL ( ) VHL ( )

10 GENE EXPRESSION PROFILE cca ccb Cluster3 Cluster3 Cluster3 Cluster3

11 Clear cell papillary RCC CGH CK7 34βE12 Chromosome 3 CD10

12 Should Clear Cell Papillary Renal Cell Carcinoma be Recognized as an Entity at this time? 1. Yes 85% 2. No 3. Uncertain even with personal experience/ knowledge 4. Not enough personal experience/knowledge 10% 2% 3% ISUP Consensus Conference, Vancouver 18 march 2012

13 Clear cell papillary RCC NUMBER OF CASES: 82 (FREQUENCY: 0.8%, 23/3000) CASES IN END STAGE RENAL DISEASE: 51 CASES NOT IN END STAGE RENAL DISEASE: 31 MEAN AGE: 56 CASES IN END STAGE RENAL DISEASE: 55 CASES NOT IN END STAGE RENAL DISEASE: 59 M/F: 1,5/1 MULTIFOCALITY: 9 CASES 5 CASES IN END STAGE RENAL DISEASE TUMOR DIMENSION: 3 cm CASES IN END STAGE RENAL DISEASE: 2,5 cm CASES NOT IN END STAGE RENAL DISEASE: 3,4 cm GRADING ALL TUMORS G1-G2 PATHOLOGIC STAGE: pt1 ALL TUMORS pt1a EXCEPT 3 CASES pt1b FOLLOW-UP (1-85 month) ALL CASES WITHOUT EVIDENCE OF RECURRENCES Tikoo et al. Am J Surg Pathol.2006;30:141 Gobbo et al. Am J Surg Pathol.2008;32:1239 Nouh et al. BJUI 2009;105: 620 Aydin et al Am J Surg Pathol 2010;34:1608 Rohan et al. Mod Pathol 2011;24:1207 Adam et al. Histopathology 2011; 58: 1064

14 WHO 200 Clear cell papillary renal cell carcinoma / tumor

15

16

17 CEP3 / 3p

18 RCC with prominent leiomyomatous proliferation CGH MS MLPA Methylation status Copy number VHL ( ) VHL ( ) VHL ( ) VHL ( ) 6 NA 0.33 NA Chromosome 3 SEQUENCING ANALYSIS 6 Exon1 Exon 2 Exon 3

19 Renal angiomyoadenomatous tumor (RAT) CD10 CK7 VHL -- / + ++ WT Sm Act Michal et al. Virchows Arch, 2011, 754:89-99

20 Do you think Clear Cell Papillary Renal Cell Carcinoma and RAT are related? 1. They are probably the same entity 2. They are probably different entities 3. Uncertain even with personal experience/knowledge 4. Not enough personal experience/knowledge 52% 32% 8% 8% ISUP Consensus Conference, Vancouver 18 march 2012

21 NEW HISTOTYPES

22 UNUSUAL HISTOTYPES New renal histotypes: CLEAR CELL PAPILLARY RCC TUBULOCYSTIC CARCINOMA ACQUIRED CYSTIC DISEASE (ACD)-ASSOCIATED RCC TANSLOCATION RENAL CELL CARCINOMAs THYROID-LIKE FOLLICULAR CARCINOMA

23 2012

24 MiTF/TFE family renal translocation carcinomas t(x;1) t(x;17) t(6;11)

25 MiTF/TFE family renal translocation carcinomas Fusion ASPL-TFE3 PRCC-TFE3 PSF-TFE3 NonO-TFE3 CLTC-TFE3?-TFE3 Alpha-TFEB Translocation 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(6;11)(p21;q12)

26 WHO 200 MITF/TFE family renal translocation carcinomas Clear cell papillary renal cell carcinoma / tumor

27 Translocation carcinomas Xp11.2 TFE3 T(6;11) TFEB OVEREXPRESSION TFE3 immunohistochemical detection TFEB Pecciarini L, Cangi MG, Lo Cunsolo C, Macri' E, Dal Cin E, Martignoni G, Doglioni C. Characterization of t(6;11)(p21;q12) in a renalcell carcinoma of an adult patient. Genes Chromosomes Cancer. 2007;46:419

28 TFE3 and TFEB IHC can sometimes be problematic 1. nonstandardized or excessive/inadequate fixation may result in false negative results 1 2. weak staining is difficult to interpret; a recent study 2 has suggested that such cases do not show TFE3 fusions, supporting the original scoring system proposed by Argani et al 1 which classifies weak staining as a negative result 3. oversensitive antigen retrieval techniques can result in detection of native TFE3, which is ubiquitously expressed 4. lot-to-lot differences in the antibody are another potential source of variability 1 Argani P, Lal P, Hutchinson B, et al. Am J Surg Pathol Zhong et al. Abstract n USCAP 2009

29 Cathepsin K immunoreactivity distinguishes MiTF/TFE family renal translocation carcinomas from other renal carcinomas Case # Genetic Cathepsin K 1 t(x;1)(p11;q21) 90% 2 t(x;1)(p11;q21) 100% 3 t(x;1)(p11;q21) 80% 4 t(x;1)(p11;q21) 90% 5 t(x;1)(p11;q21) 70% 6 t(x;1)(p11;p34) Neg 7 t(x;1)(p11;p34) 80% 8 t(x;1)(p11;p34) Neg 9 t(x;17)(p11;q25) Neg 10 t(x;3)(p11;q23) Neg 11 t(6;11)(p21;q12) 100% 12 t(6;11)(p21;q12) 90% 13 t(6;11)(p21;q12) 80% 14 t(6;11)(p21;q12) 100% 15 t(6;11)(p21;q12) 100% 16 t(6;11)(p21;q12) 90% 17 t(6;11)(p21;q12) 90% Martignoni G, Pea M, Gobbo S, Brunelli M, Bonetti F, Segala D, Pan CC, Netto G, Doglioni C, Hes O, Argani P, Chilosi M Modern Pathology 2009

30

31 FISH and TFE3 Xp11 Xp11 Translocation Renal Cell Carcinoma TFE3 (Xp11) break apart, Kreatech Diagnostics

32 Translocation RCC Xp11

33

34 Translocation RCC t(6;11) Ck AE1-3 HMB45 Argani et al. Am J Pathol 2001;158:2089

35 When should TFE3 and TFEB analysis (IHC and/or FISH) be requested to identify translocation RCC cases? 1. When RCC is diagnosed in a patient under 30 years of age 80% 2. When the morphology is suggestive of translocation RCC in a patient older than 30 year of age 3. Both A and B 4. I do not request for TFE3 or TFEB immunostaining 3% 12% 6% ISUP Consensus Conference, Vancouver 18 march 2012

36 Should t(6;11) RCC be Recognized as an Entity at this time? 1. Yes, include it with Xp11 RCC under MiT Family Translocation RCC 69% 2. Yes, make it its own category 3. No 4. Uncertain even with personal experience/knowledge 5. Not enough personal experience/knowledge 17% 2% 2% 10% ISUP Consensus Conference, Vancouver 18 march 2012

37 Tubulocystic carcinoma

38 Tubulocystic carcinoma RACEMASE CEP 7/17

39 Should Tubulocystic-RCC be recognized as an entity at this time? 1. Yes 73% 2. No 3. Uncertain even with personal experience/ knowledge 4. Not enough personal experience/knowledge 5% 7% 14% ISUP Consensus Conference, Vancouver 18 march 2012

40 Differentialdiagnosis Clear cell RCC Papillary RCC Pseudopapillary architecture Clear cytoplasm

41 Cellule Chiare Papillare Cromofobo Oncocitoma CD10 racemasi PV S100A1 PV Ck7 S100A1 Ck7 Martignoni G et al. Role of molecular markers in the diagnosis and prognosis of renal cell carcinoma. Anal Quant Cytol Histol; in press

42 GENETIC HISTOTYPES Carcinoma cromofobo (variante eosinofila) Oncocitoma CEP cromosoma 6 Brunelli M. Mod Pathol 2005;18:161-9.

43 Markers diagnostici, prognostici e predittivi di risposta terapueutica

44 METHODS ph mtor ccrcc

45 METHODS mtor Rene normale (green) ccrcc (green)

46 SENSIBILITY AND SPECIFICITY

47 Clear cell renal cell carcinoma 3p deletion VHL deletion

48

49 Biological reasons Siebert et al. J Urol 1998;160:534

50 ALK renalcellcarcinoma

51 Conclusions New entities ISUP Vancouver Classification Rare entities: ALK renal cell carcinoma Immunohistochemistryand molecularanalysis: differential diagnosis Classificazione molecolare: triple negative clear cell renalcellcarcinoma (VHL, 3p, methylation), carcinomi mtor positivi

52 Conclusions

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