Xp11.2 Translocation Renal Cell Carcinoma With Very Aggressive Course in Five Adults

Abstract and Introduction

Abstract

Renal cell carcinomas associated with Xp11.2 translocations (TFE3 gene fusions) are rare tumors predominantly reported in children. We studied 5 cases of translocation carcinoma in adult patients, 18 years or older (mean age, 32.6 years). Tumors were examined histologically, immunohistochemically, and electron microscopically and correlated with the clinical picture. Most tumors showed solid sheets of clear to eosinophilic cells with rich vasculature and foci of papillary or pseudopapillary architecture. All cases showed strong nuclear positivity for TFE3. Vimentin and CD10 were positive in the cytoplasm. A panel of cytokeratin antibodies, smooth muscle actin, CD45, HMB45, and calretinin were negative. Patients had nonspecific initial complaints and were diagnosed with advanced disease, most with distant metastases. Various treatments met with minimal success. Unlike pediatric patients, the adult patients followed a rapidly terminal course, with a mean survival of 18 months after diagnosis (range, 10-24 months).

Introduction

Based on the cytoplasmic appearance of tumor cells in H&E-stained sections, renal cell carcinomas (RCCs) originally were categorized as 1 of 3 entities: clear cell carcinoma, granular cell carcinoma, or mixed clear and granular cell carcinoma. With the increased use of new methods for examining tumors, the classification of RCCs has expanded and evolved^[1,2] and currently includes clear cell (conventional), papillary, chromophobe, collecting duct, and the recently recognized mucinous tubular and spindle cell carcinoma. A number of new entities with characteristically eosinophilic cytoplasm have emerged from the granular cell category, including chromophobe carcinoma, oncocytoma, and epithelioid angiomyolipoma.

Despite these changes in classification, 75% of epithelial renal tumors are still diagnosed as clear cell (conventional) carcinoma. The likely explanation for this high rate of diagnosis is that RCC, clear cell type, is heterogeneous and contains several entities that are not discernible with currently applied methods. In support of this explanation, translocations involving the Xp11.2 locus were recently detected in a number of RCCs previously classified as clear cell type.^[1-3]

Translocations involving Xp11.2 have been demonstrated in alveolar soft part sarcoma.^[3,4] The gene of interest, located at Xp11.2, is TFE3, a member of the microphthalmia transcription factor (MiTF) family.^[5] Members of this family of proteins code for basic-helix-loop-helix leucine-zipper transcription factors that bind DNA as homodimers or heterodimers.^[5,6] Other members of this family include TFEB and TFEC, at least one of which (TFEB) is also involved in other recently recognized RCCs.^[7]

In RCCs, fusion of TFE3 with several different genes can occur, depending on the exact translocation. Currently, 4 distinct recipient genes have been identified: PRCC (1q21), ASPL (17q25), PSF (1p34), and NonO (Xq12).^[4,8-10]

RCCs associated with Xp11.2 translocations are rare and predominantly reported in children.^[1] RCCs resulting from these translocations typically have papillary architecture and are composed of cells with voluminous clear or eosinophilic cytoplasm. Although little is known of the clinical course of these tumors, they are believed to be indolent, even when diagnosed at advanced stages.^[1]

We summarize the histologic and clinical findings in 5 adult cases of translocation RCC with immunohistochemical evidence of TFE3 overexpression. All patients had nonspecific disease manifestations followed by a rapidly terminal disease course.