[885] Differential Expression of Cathepsin-K in Neoplasms Harboring TFE3 Gene Fusions.

Guido Martignoni, Stefano Gobbo, Philippe Camparo, Matteo Brunelli, Enrico Munari, Diego Segala, Maurizio Pea, Franco Bonetti, Marc Ladanyi, George J Netto, Marco Chilosi, Pedram Argani. University of Verona, Italy; Van Andel Research Institute, Paris, France; Hospital Orlandi, Bussolengo, Italy; Memorial Sloan-Kettering Cancer Center, New York; Johns Hopkins Hospital, Baltimore

Background: Cathepsin-K is a papain-like cysteine protease whose expression is driven by microphthalmia transcription factor (MiTF) in osteoclasts. TFE3 and TFEB are related members of the same transcription factor subfamily as MiTF, and all 3 have overlapping transcriptional targets. We have previously shown that all t(6;11) renal cell carcinomas (RCC), which are known to harbor an Alpha-TFEB gene fusion, as well as a subset of the Xp11 translocation RCC, which harbor various TFE3 gene fusions, express cathepsin-K, while no other common RCC subtype does (Mod Pathol 2009; 22:1106-1022). We have hypothesized that aberrant overexpression of TFEB or certain TFE3 fusion proteins essentially function like MiTF in these RCC, and thus activate cathepsin-K expression. However, the expression of cathepsin-K in specific subtypes of Xp11 translocation RCC, as well as alveolar soft part sarcoma (ASPS) which harbors the same ASPL-TFE3 gene fusion as some Xp11 translocation RCC, has not been specifically addressed.
Design: We performed immunohistochemistry for cathepsin-K on the following neoplasms: 11 genetically confirms t(X;1)(p11;q21) RCC, which harbor PRCC-TFE3 gene fusion; 8 genetically confirmed t(X;17)(p11;q25) RCC, which harbor the ASPL-TFE3 gene fusion; and 7 ASPS, all of which harbor the ASPL-TFE3 gene fusion. The percentage and intensity of neoplastic cells labeling was assessed.
Results: All 7 ASPS strongly expressed cathepsin-K in a mean of 85% of neoplastic cells (range 70-100%). In contrast, all 8 ASPL-TFE3 RCC were completely negative for cathepsin-K. However, 11 of 13 PRCC-TFE3 RCC expressed cathepsin-K in a mean of 80% of neoplastic cells (range 30-90%).
Conclusions: Diffuse expression of cathepsin-K distinguishes from ASPS from ASPL-TFE3 RCC, which harbor the same gene fusion. The latter can be useful diagnostically, especially when ASPS presents in an unusual site (such as bone) or with clear cell morphology which raises the differential diagnosis of metastatic ASPL-TFE3 RCC. The difference in expression of cathepsin-K between the PRCC-TFE3 RCC and ASPL-TFE3 RCC together with the recently observed clinical differences between these subtypes of Xp11 translocation RCC, suggests the possibility of subtle functional differences between these two related fusion proteins.
Category: Genitourinary (including renal tumors)

Tuesday, March 1, 2011 1:30 PM

Platform Session: Section A, Tuesday Afternoon


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