Case 1 -

Xp11.2 Translocation Renal Cell Carcinoma Guliz Barkan Loyola University Medical Center Maywood, IL

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Clinical History An 82-year-old man presented with severe dyspnea on exertion and severe pain between his scapulae. He had a significant past medical history of adenocarcinoma of the colon, and a recent history of prostatic carcinoma with a TRUS prostatic biopsy revealing prostatic adenocarcinoma, Gleason score 4+4=8. In an effort to evaluate the dyspnea, a chest X-ray was taken, followed by CT of the abdomen, thorax, and pelvis. Imaging showed enlarged mediastinal, retroperitoneal, and retrocrural lymph nodes, numerous lung nodules < 5 mm, bilateral pleural effusions, ascitis and a heterogenous 6.0 x 6.1 x 5.3 cm. mass occupying most of the right kidney. An FNA of the renal mass was performed. Case 1 - Slide 1 Click to view with ImageScope Click to view with a Web-Based Viewer Case 1 - Slide 2 Click to view with ImageScope Click to view with a Web-Based Viewer Case 1 - Figure 1 Pap 10x Case 1 - Figure 2 Pap 40x Case 1 - Figure 3 Pap 60x Case 1 - Figure 4 DiffQuik 40x Case 1 - Figure 5 Pap 40x Case 1 - Figure 6 Cell Block 20x Diagnosis: Xp11.2 Translocation Renal Cell Carcinoma Cytologic Diagnosis: Renal cell carcinoma associated with Xp11.2 Translocation Histologic Diagnosis: There is no corresponding histologic diagnosis for the renal mass. The patient passed away before a definitive procedure could be undertaken, and an autopsy was denied. Final diagnosis was confirmed by strong (nuclear) immunohistochemical positivity for TFE 3 on the cell block section. Cytologic Findings: The smears are highly cellular showing large three dimensional clusters, papillary structures, and cells associated with extracellular matrix-like material. The cells have a finely vacuolated cytoplasm, low N: C ratio, and prominent nucleoli. Some cells have intracytoplasmic hemosiderin pigment. There is occasional nuclear hyperchromasia and pleomorphism, and there are rare mitotic figures. The differential diagnosis (based on morphology alone) includes renal cell carcinoma, clear cell type and papillary type. In cases in which tumor cells have a clear vacuolated cytoplasm and widespread papillary structures the differential diagnosis of translocation type renal cell carcinoma should be considered and an immunohistochemical stain for TFE 3 should be performed to rule in/out this diagnosis. The table shows immunohistochemical differentiation between renal cell carcinoma clear cell type, papillary type and translocation type.   CD 10 RCC ma Vimentin AE1/AE3 CK 7 AMACR TFE 3 Clear cell carcinoma + + + + - - - Papillary carcinoma + + + + + + - Translocation type carcinoma + + +/- +/- - - + Discussion: Translocation (Xp11.2) renal cell carcinomas are relatively rare tumors and have predominantly been diagnosed in children. It is estimated that approximately one third of pediatric renal cell carcinomas are TFE3-related translocation carcinomas. Unlike in children, although clear cell carcinomas make up 70% of renal cell carcinomas in adults and 53% in young adults, the exact incidence of TFE3 translocation carcinomas in these age groups is not known. Although in the pediatric age group most tumors present at an advanced stage, the clinical course is thought to be indolent. However, recent studies have shown that the tumor follows a very aggressive clinical course in young adults. The Xp11.2 translocation carcinomas are characterized by various chromosomal translocations, all of which may involve a breakpoint at Xp11.2, and all of which result in fusion involving the TFE3 transcription factor gene that maps to this locus. Five distinct gene fusions involving TFE3 have been characterized and include the following: ASPL-TFE3 t(X;17)(p11.2;q25) PRCC-TFE3 t(X;1)(p11.2;q21) PSF-TFE3 t(X;1)(p11.2;p34) NoNo-TFE3 inv(X)(p11;q12) CLTC-TFE3 t(X;17)(p11.2;q23) Of note, the ASPL-TFE3 fusion renal cell carcinoma has identical breakpoints to alveolar soft part sarcoma, a rare pediatric soft tissue neoplasm of uncertain histogenesis. The gross appearance of these tumors can closely resemble conventional clear cell carcinoma; they usually are tan-yellow with areas of hemorrhage and necrosis. Cytologically tumor cells are arranged in papillary formations and nests. The cells have well defined cell borders and predominantly clear, and occasionally granular, eosinophilic cytoplasm. Especially in the tumors with ASPL-TFE3 gene fusions (voluminous cell variant) microscopically cells with voluminous clear to eosinophilic cytoplasm; vesicular nuclear chromatin, and prominent nucleoli are seen. Psammoma bodies are also frequently observed. Strong nuclear immunoreactivity for TFE3 proves to be highly sensitive and specific for tumors with TFE3 fusion proteins. These tumors usually underexpress epithelial markers (EMA and cytokeratin) and vimentin whereas they show strong CD10 positivity, as seen in our case. The optimal therapy for Xp11 translocation carcinomas remains to be determined. Given that immunotherapy has been the standard treatment for patients with advanced stage renal cell carcinomas, some patients with Xp11 translocation carcinoma have also received this therapy without associated significant response. Additional gene expression profiling studies have suggested a novel therapeutic target in Xp11 translocation carcinomas. In vitro studies have demonstrated that ASPL-TFE3 fusion protein common to ASPS and Xp11 translocation carcinomas transactivate the MET promoter, increasing MET mRNA expression. High levels of MET protein have also been shown by Immunohistochemistry and Western Blotting. In addition, the ASPL-TFE3 cell lines have shown diminished growth in response to either a selective inhibitor of MET tyrosine kinase or RNA interference mediated knockdown of MET. Therefore MET tyrosine kinase inhibitors could be potentially used as a targeted therapy modality to treat these translocation carcinomas. References: Argani P, Olgac S, Tickoo S, Ladanyi M et al. Xp11 Translocation Renal Cell Carcinoma in Adults: Expanded Clinical, Pathologic and Genetic Spectrum. Am J Surg Pathol. 2007;31(8):1149-1160. Mansouri D, Dimet S, Vielh P et al. Diagn Cytopathol.2006;34(11);757-760. Meyer P, Picken M et al. Xp11.2 Translocation renal cell carcinoma with very aggressive course in five adults. Am J Clin Pathol 2007;128:70-79. Argani et al. Translocation carcinomas of the kidney. Clin Lab Med 2005;25:363-378.