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M. Brunelli & G. Martignoni MDDipartimento di Patologia e Diagnostica
Università di Verona
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=
WHO 2004 AFIP 2004
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Cellule Chiare
CD10 3/3p
Papillare
CK7 7-17
Cromofobo
PV 6
Oncocitoma
S100A1 6-17
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WH 2004WHO 2004
≈70%
≈15%≈5%
≈5%
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Komai Y et al. Clin Cancer Res. 2009
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Traslocazione
Xp11Traslocazione
Xp11
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Tomlinson et al. Cancer Genet Cytogenet. 1991
CARCINOMI CON TRASLOCAZIONE DI Xp11
Cytogenetics of a renal cell carcinoma in a 17-month-old child.
Evidence for Xp11.2 as a recurring breakpoint.
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Sidhar et al. Hum Mol Genet. 1996
TFE3
Cromosoma Xp11.2PRCC
Cromosoma 1q21.2
PRCC-TFE3
mRNA
PRCC-TFE3
Proteina chimerica
The t(X;1)(p11.2;q21.2) translocation in papillary renal cell carcinoma fuses a novel gene PRCC to the
TFE3 transcription factor gene.
Gene di fusione DNA
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t(X;17)(p11.2;q25)
t(X;1)(p11.2;p34)
inv(X)(p11;q12)
ASPL
TFE3
PSF
NonO
TFE3
TFE3
PRCC
TFE3
t(X;1)(p11.2;q21)
DNA RNA Proteina
PRCC-TFE3
PSF-TFE3
ASPL-TFE3
NonO-TFE3
CARCINOMI CON TRASLOCAZIONE DI Xp11
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Argani et al. Am J Pathol 2001;158:2089
HMB45Ck AE1-3
Traslocazione
t(6;11)Traslocazione
t(6;11)
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TFEB
Cromosoma 6p21Alpha
Cromosoma 11q13
TFEB
Proteina nativa
Gene di fusione DNA
Alpha-TFEB
mRNA
Kuiper et al. Hum Mol Genet 2003;12:1661
GENI COINVOLTI NELLA TRASLOCAZIONE t(6;11)
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Aberrant nuclear immunoreactivity for TFE3 in neoplasms with TFE3 gene fusions: a sensitive and specific immunohistochemical assay
Argani et al. Am J Surg Pathol 2003
Renal carcinomas with the t(6;11)(p21;q12): clinicopathologic features and demonstration of the specific alpha-TFEB gene fusion by immunohistochemistry, RT-PCR, and DNA PCR
Argani et al. Am J Surg Pathol 2005
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Immunoistochimica per TFE3 e TFEB
PUO’ DARE PROBLEMI
Argani P, Lal P, Hutchinson B , et al. Am J Surg Pathol 2003Zhong et al. Abstract n. 924- USCAP 2009
la fissazione del materiale non standardizzata falsi negativifalsi negativi
L’immunoreattività cosiddetta debole difficile da
interpretaredifficile da
interpretare
Tecniche di rilevazione antigenica troppo sensibili falsi positivifalsi positivi
Le differenze di questi anticorpi osservate tra diversi lotti mancata
riproducibilitàmancata
riproducibilità
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Kuiper et al. Nucleic Acids Res 2004;32:2315
Funzionano formando omo- ed etero-dimeri
Dai loro relativi livelli dipende l’espressione genica dei loro geni bersaglio
Regolano l’espressione di geni tessuto specifici
Sono espressi costitutivamentein molti organi e tessuti umani
TFECMiTF TFEBTFE3
MiTF/TFE Family
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catepsina k
Linking osteopetrosis and pycnodysostosis:
regulation of cathepsin K expression by the microphthalmia transcription factor family
MiTF
MiTF GFP mutMiTF
MiTF
vector
Motyckova G et al. 2001
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Caso # Genetica Catepsina 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%
Cathepsin K immunoreactivitydistinguishes MiTF/TFE family renal translocation carcinomas
from other renal carcinomas
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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WH 2004WHO 2004
MITF/TFE family renal translocation carcinomas
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Cellule chiare RCC
Architettura pseudopapillare
Papillare RCC
Citoplasma chiaro
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Martignoni G et al. Anal Quant Cytol Histol; 2007
Papillare RCC
Cellule chiare RCC
CD10
AMACR CK7
CK7
7/17
3p
Gobbo S et al. Am J Surg Pathol; 2008;32:1780-6
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Am J Surg Pathol 2006
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AMACRCK7
Clear-cell papillary RCC of the end-stage kidneys
Tickoo et al. Am J Surg Pathol. 2006
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CK7
CEP3 / 3p CEP7 / CEP17
CK7AMACRCD103pY177
ICHFISH
+negnegnormale
Clear-cell papillary RCC: FISH
Gobbo et al. Am J Surg Pathol.2008;32:1239
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Clear-cell papillary RCC
NUMERO CASI (18)CASI IN END STAGE RENAL DISEASE: 14CASI NON IN END STAGE DISEASE: 4
ETÀ MEDIA (57 anni)CASI IN END STAGE RENAL DISEASE: 55 anniCASI NON IN END STAGE DISEASE: 60 anni
RAPPORTO M/F: 1/1
MULTIFOCALITÀ (3)3 CASI IN END STAGE RENAL DISEASE
DIMENSIONE TUMORE (3 cm)CASI IN END STAGE RENAL DISEASE: 2,5 cmCASI NON IN END STADE DISEASE: 3,4 cm
GRADINGTUTTI G1-G2
STADIO PATOLOGICO (pT1)TUTTI pT1a FUORCHÉ UN pT1b
Tikoo et al. Am J Surg Pathol.2006;30:141Gobbo et al. Am J Surg Pathol.2008;32:1239Nouh et al. BJUI 2009;105: 620
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WH 2004WHO 2004
Clear cell papillary renal cell carcinoma / tumor
MITF/TFE family renal translocation carcinomas
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Tubulocystic carcinoma
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Tubulocystic carcinoma
RACEMASE CEP 7/17
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Tubulocystic carcinomaNUMERO CASI: 62
ETÀ MEDIA: 58 anni (30-94)
RAPPORTO M/F: 6/1
MULTIFOCALITÀ: RIPORTATA IN 4 CASI SU 20
DIMENSIONE TUMORE: 0,1-17 cm
GRADING: G3
STADIO PATOLOGICO: PREVALENTEMENTE T1a (ALCUNI T1b, T2 E UN T2N2)
Azoulay et al. Virchows Arch 2007;451:905Amin et al. Am J Surg Pathol.2009;33:384Zhou et al. Am J Surg Pathol.2009;33:1840
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WH 2004WHO 2004
Clear cell papillary renal cell carcinoma / tumor
Tubulocystic carcinoma
MITF/TFE family renal translocation carcinomas
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Conclusioni
• Classificazione condivisa
• Istotipi genetici
• Diagnosi morfo-molecolare
• WHO 20.. :
Clear cell papillary renal cell carcinoma / tumor
Tubulocystic carcinoma
MITF/TFE family renal translocation carcinomas