ONCOLOGIA E RENE 6 novembre 2014
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1 ONCOLOGIA E RENE 6 novembre 2014 CARCINOMA DEL RENE: ASPETTI ANATOMO-PATOLOGICI Guido Martignoni Dipartimento di Patologia e Diagnostica Università di Verona
2 ISUP Consensus Conference WH 2004 on Adult Renal Tumors Vancouver, 18 march 2012 Working Group I Tumour Classification Group Chair John Srigley, Co-Chair Pete Argani, Rapporteur Ming Zhou, Other Members: John Eble, Jonathan Epstein, Ondrej Hes, Rodolfo Montironi, Satish Tickoo Working Group II Histological Prognostic Factors Group Chair Brett Delahunt, Co-chair Guido Martignoni, Rapporteur Jesse McKenney, Other Members: Ferran Algaba, John Cheville, Lars Egevad, Peter Humphrey, Cristina Magi-Galluzzi Working Group III Staging and Specimen Handling Group Chair David Grignon, Co-chair Steve Bonsib, Rapporteur Kiril Trpkov, Other Members: Mahul Amin, Athanase Billis, Antonio Lopez-Beltran, Hema Samaratunga, Pheroze Tamboli Working Group IV Biomarkers (Diagnosis, Prognosis, Prediction) Group Chair Holger Moch, Co-chair Liang Cheng, Rapporteur Steven Shen, Other Members: Victor Reuter(corresponding), Nathalie Leclerq-Roux, Maria Merino, George Netto, Puay Hoon Tan
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4 NUOVI TUMORI EPITELIALI TUBULOCYSTIC RENAL CELL CARCINOMA (RCC) ACQUIRED CYSTIC DISEASE (ACD)-ASSOCIATED RCC CLEAR CELL (TUBULO)PAPILLARY RCC MiT FAMILY TRANSLOCATION RENAL CELL CARCINOMA including t(6;11) RCC HEREDITARY LEIOMYOMATOSIS RCC SYNDROME ASSOCIATED RCC
5 ENTITA EMERGENTI / PROVVISORIE THYROID-LIKE FOLLICULAR CARCINOMA SUCCINIC DEHYDROGENASE DEFICIENCY ASSOCIATED RCC ALK TRANSLOCATION RCC
6 Tubulocystic carcinoma
7 Tubulocystic carcinoma RACEMASE CEP 7/17
8 Number of cases: 66 Mean age: 58 years (30-94) M/F: 6/1 Multifocality: 4 cases out of 20 Tumor diameter: 0,1-17 cm Grading: G3 Tubulocystic carcinoma Pathological stage: T1a (rare T1b, T2, one T3 and one T2N2) Azoulay et al. Virchows Arch 2007;451:905 Amin et al. Am J Surg Pathol.2009;33:384 Zhou et al. Am J Surg Pathol.2009;33:1840 Hora et al. World J Urol 2011;29:349.
9 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
10 Acquired Cystic Disease (ACD) AMACR
11 Should Acquired Cystic Disease (ACD)-associated RCC be Recognized as an Entity at this time? 1. Yes 80% 2. No 3. Uncertain even with personal experience/ knowledge 4. Not enough personal experience/knowledge 5% 3% 13% ISUP Consensus Conference, Vancouver 18 march 2012
12 Clear cell (tubulo)papillary RCC
13 Clear cell (tubulo)papillary RCC
14 Clear cell (tubulo)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
15 Clear cell (tubulo)papillary RCC NUMERO DI CASI: 160 (FREQUENZA: 3%) CASI IN MALATTIA RENALE TERMINALE: 63 ETÀ MEDIA: 57 anni CASI IN MALATTIA RENALE TERMINALE: 55 anni CASI NON IN MALATTIA RENALE TERMINALE: 59 anni M/F: 1.4/1 MULTIFOCALITÀ: 18 CASI DIMENSIONE MEDIA TUMORI: 2.5 cm GRADO TUTTI TUMORI G1-G2 STADIO PATOLOGICO: pt1 QUASI TUTTI TUMORI pt1a FOLLOW-UP (1-108 MESI) TUTTI CASI SENZA EVIDENZA DI RECIDIVA DI MALATTIA Tickoo 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(9): Adam et al. Histopatholgy 2011; 58(7): Park et al Kor J Surg Pathol 2012;46(6):541-7 Williamson et al. Mod Pathol Epub 2012/12/15
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18 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
19 What is required to make a diagnosis of CCPRCC/CCTPRCC? 1. Characteristic morphology only 65% 2. Morphology and immunostains 3. Morphology, immunostains and genetics 4. Uncertain even with personal experience/knowledge 5. Not enough personal experience/knowledge 18% 9% 2% 6%
20 GENE EXPRESSION PROFILE cca ccb Cluster3 Cluster3 Cluster3 Cluster3
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23 Sorbitol as a Novel Mechanism of Hypoxia-Inducible Factor (HIF) Pathway Activation in Clear Cell Papillary Renal Cell Carcinoma (CCPRCC). SK Tickoo et al. USCAP 2014 in 9/11 (82%) CCPRCCs
24 MiTF/TFE family renal translocation carcinomas t(x;1) t(x;17) t(6;11)
25 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
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27 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
28 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
29 Hereditary leiomyomatosis RCC syndrome associated RCC In 2004 WHO classification viewed as hereditary counterpart of type II PRCC; HL RCC syndrome aumosomal dominant and associated with germline mutation in the fumarate hydratase gene located at 1q42; Cutaneous and uterine leiomyomas; Prominent eosinophilic nucleulus with a clear halo, similar to the cytology of a cytomegalovirus inclusion; Frequently papillary architecture; Aggressive behaviour. Merino MJ et al Am J Surg Pathol 2007;31; 1578 Grubb RL et al J Urol 2007; 177: 2074
30 ISUP Consensus Conference WH 2004 on Adult Renal Tumors Vancouver, 18 march 2012 Working Group I Tumour Classification Group Chair John Srigley, Co-Chair Pete Argani, Rapporteur Ming Zhou, Other Members: John Eble, Jonathan Epstein, Ondrej Hes, Rodolfo Montironi, Satish Tickoo Working Group II Histological Prognostic Factors Group Chair Brett Delahunt, Co-chair Guido Martignoni, Rapporteur Jesse McKenney, Other Members: Ferran Algaba, John Cheville, Lars Egevad, Peter Humphrey, Cristina Magi-Galluzzi Working Group III Staging and Specimen Handling Group Chair David Grignon, Co-chair Steve Bonsib, Rapporteur Kiril Trpkov, Other Members: Mahul Amin, Athanase Billis, Antonio Lopez-Beltran, Hema Samaratunga, Pheroze Tamboli Working Group IV Biomarkers (Diagnosis, Prognosis, Prediction) Group Chair Holger Moch, Co-chair Liang Cheng, Rapporteur Steven Shen, Other Members: Victor Reuter(corresponding), Nathalie Leclerq-Roux, Maria Merino, George Netto, Puay Hoon Tan
31 Fuhrman Nuclear Grading Diameter Shape Nucleoli
32 Positive Responses What system do you use for grading RCC? 206* Fuhrman 96% World Health Organization 7% Broder 0.5% Japanese 2% Nucleolar 11% Other 2% Do you provide a grade for: 204* Clear cell RCC 100% Multilocular cystic RCC 67% Papillary adenoma 5% Papillary RCC 85% Chromophobe RCC 57% Oncocytoma 1% Collecting duct carcinoma 41% Renal medullary carcinoma 31% Translocation carcinoma 50% Mucinous tubular spindle cell carcinoma 37% Tubulocystic carcinoma 37% End stage renal disease associated carcinoma 52% Unclassified carcinoma 66% How do you assess Fuhrman grade? 204 Most frequent (1 0 ) pattern 2% Highest grade 83% Combined most frequent and highest grade 13% Provide % of each grade present 2% What is the minimum area of tumor assessed for grading purposes? low power field (x10 objective) 37% 1 high power field (x 40 objective) 41% 5 high power fields 10% Other 12% For Fuhrman grading do you evaluate? 205* Nucleolar prominence 99% Nuclear shape 57% Nuclear pleomorphism 79% In case of discordance, which parameter do you put most emphasis on? 205 Nucleolar prominence 68% Nuclear shape 2% Nuclear pleomorphism 28% None 2%
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34 Table 1. Ranges of Nuclear Major Axis for Cases Stratified According to Whole Case and Focal Nucleolar Grade Grade Whole case nucleolar grade Focal nucleolar grade Range Mean Range Mean M 8.04 M M 8.57 M M 8.61 M M 8.05 M M 8.91 M M 9.39 M Fuhrman Grading is not Appropriate for Chromophobe Renal Cell Carcinoma Delahunt B, Sika-Paotonu D, Bethwaite PB, McCredie MR, Martignoni G, Eble JN, Jordan TW Am J Surg Pathol 2007; 31:
35 Papillary Type 1 Papillary Type 2
36 SURVIVAL / NUCLEOLAR GRADING SURVIVAL / HISTOTYPE Am J Surg Pathol 2006;30:1091
37 ISUP Consensus Conference WH 2004 on Adult Renal Tumors Vancouver, 18 march 2012 Working Group I Tumour Classification Group Chair John Srigley, Co-Chair Pete Argani, Rapporteur Ming Zhou, Other Members: John Eble, Jonathan Epstein, Ondrej Hes, Rodolfo Montironi, Satish Tickoo Working Group II Histological Prognostic Factors Group Chair Brett Delahunt, Co-chair Guido Martignoni, Rapporteur Jesse McKenney, Other Members: Ferran Algaba, John Cheville, Lars Egevad, Peter Humphrey, Cristina Magi-Galluzzi Working Group III Staging and Specimen Handling Group Chair David Grignon, Co-chair Steve Bonsib, Rapporteur Kiril Trpkov, Other Members: Mahul Amin, Athanase Billis, Antonio Lopez-Beltran, Hema Samaratunga, Pheroze Tamboli Working Group IV Biomarkers (Diagnosis, Prognosis, Prediction) Group Chair Holger Moch, Co-chair Liang Cheng, Rapporteur Steven Shen, Other Members: Victor Reuter(corresponding), Nathalie Leclerq-Roux, Maria Merino, George Netto, Puay Hoon Tan
38 Renal sinus involvement in RCC Bonsib SM et al. Am J Surg Pathol 2000; 24:
39 Renal sinus involvement in RCC Thompson RH et al. J Urol 2005; 174:
40 ISUP Consensus Conference WH 2004 on Adult Renal Tumors Vancouver, 18 march 2012 Working Group I Tumour Classification Group Chair John Srigley, Co-Chair Pete Argani, Rapporteur Ming Zhou, Other Members: John Eble, Jonathan Epstein, Ondrej Hes, Rodolfo Montironi, Satish Tickoo Working Group II Histological Prognostic Factors Group Chair Brett Delahunt, Co-chair Guido Martignoni, Rapporteur Jesse McKenney, Other Members: Ferran Algaba, John Cheville, Lars Egevad, Peter Humphrey, Cristina Magi-Galluzzi Working Group III Staging and Specimen Handling Group Chair David Grignon, Co-chair Steve Bonsib, Rapporteur Kiril Trpkov, Other Members: Mahul Amin, Athanase Billis, Antonio Lopez-Beltran, Hema Samaratunga, Pheroze Tamboli Working Group IV Biomarkers (Diagnosis, Prognosis, Prediction) Group Chair Holger Moch, Co-chair Liang Cheng, Rapporteur Steven Shen, Other Members: Victor Reuter(corresponding), Nathalie Leclerq-Roux, Maria Merino, George Netto, Puay Hoon Tan
41 Tan et al. Am J Surg Pathol 2013;37:
42 Tan et al. Am J Surg Pathol 2013;37:
43 PAX8 Clear cell RCC Mtx Pancreas Clear cell RCC Mtx Peritoneum
44 Tan et al. Am J Surg Pathol 2013;37:
45 Chromophobe RCC Oncocytoma
46 Core biopsies nei tumori renali Volpe A. et al J Urol 2007; 178:
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48 CONCLUSIONI - Classificazione sec. ISUP - Grading sec. ISUP - TNM Immunoistochimica e FISH
49 The Verona Group 2014 The Verona Group 2000
50 Tan et al. Am J Surg Pathol 2013;37:
51 Loss of 9p 9p No Loss Loss CEP 9 LSI 9p 9q Mod Pathol. 2008;21:1-6
52 Cytogenetic profile predicts prognosis of patients with clear cell renal cell carcinoma Klatte T, Rao PN et al. J Clin Oncol 2009;10;27:746
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54 Targeted therapy - Angiogenesis 1. Rini. Clin Cancer Res 2007;13: ; 2. Faivre et al. Nat Rev Drug Disc 2007;6:734 45; 3. Homsi and Daud. Cancer Control 2007;14:285 94; 4. Andrae et al. Genes Dev 2008;22: ; 5. Kerbel. N Engl J Med 2008;358: ; 6. Sonpavde et al. Expert Opin Investig Drugs 2008;17:253 61; 7. Ma and Adjei. CA Cancer J Clin 2009;59:
55 RUOLO DEL PATOLOGO PASSATO PRESENTE FUTURO
56 STRATEGIE TERAPEUTICHE: TERAPIA CHIRURGICA TERAPIA MEDICA NEFRECTOMIA RADICALE NEFRECTOMIA PARZIALE OPEN vs LAPARO OPEN vs LAPARO ABLAZIONE CON RADIOFREQUENZA CRIOABLAZIONE WAIT AND SEE IMMUNOTERAPIA CHEMIOTERAPIA TARGETED THERAPIES SORAFENIB TEMSIROLIMUS SUNITINIB altre
57 DEFINIZIONE Hafez KS et al. J. Urol. 1999; 162:
58 376 pazienti Nefrectomia parziale Tumori ø 4 cm Jeon et al. Urology 2010; 76: 574-9
59 BIOPSIE Guida Aghi FNAB versus biopsia Sicurezza Impianti lungo il tramite Sanguinamento Accuratezza diagnostica - sensibilità Accuratezza diagnostica - specificità Falsi negativi Accuratezza nell assegnazione del grading Biopsia delle masse cistiche complesse
60 Variabili Pazienti (n=56) Età mediana (anni) 61 (51-69) Istotipo assegnato su biopsia sesso (%) Maschile Femminile 39 (69.6%) 17 (30.4%) Istotipo assegnato alla diagnosi finale su Dimensione mediana clinica (cm) pezzo operatorio 4 (3-8) Tumori benigni Cellule chiare Papillare Cromofobo Inclassificabile Totale Presentazione (%) Incidentale Sintomatica 40 (71.4%) 16 (28.6%) Tumori benigni 6 (100%) (25%) 1 (25%) 8 Trattamento chirurgico (%) Nefrectomia parziale Nefrectomia radicale 27 (48.2%) 29 (51.8%) Cellule chiare 0 34 (100%) Dimensione mediana patologica (cm) 4.5 ( ) Diagnosi finale (%) Tumore benigno Tumore maligno pt (TNM, 2002) - pt1a - pt1b - pt2 - pt3a - pt3b Coinvolgimento linfonodale (%) - pn0/pnx - pn+ Papillare (100%) 0 2 (50%) 6 8 (14.3%) 48 (85.7%) Cromofobo (75%) (46.8%) 10 (21.2%) 4 (8.5%) 5 (10.7%) 6 (12.8%) 45 (95.7%) 2 (4.3%) 56 pazienti 22 (46,8%) pt1a 45 (95,7%) pn0/pnx 43 (91,5%) pm0 Inclassificabile (25%) 1 Metastasi a distanza (%) Assenti Presenti 43 (91.5%) 4 (8.5%) Ficarra V. et al. Pathology 2011; 43:
61 Immunoistochimica Citogenetica: FISH Morfologia
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