Case 2 -

Renal Cell Carcinoma Associated with Xp11/TFE3 Translocation Jesse K. McKenney Stanford University Medical Center Palo Alto, CA

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Clinical History: A 32 year old woman presented with abdominal pain. Imaging studies revealed lymphadenopathy in the retroperitoneum and mediastinum and a calcified renal "cyst". A core biopsy of the retroperitoneal adenopathy was performed as well as a subsequent partial nephrectomy. Case 2 - Slide 1 Click to view with ImageScope Click to view with a Web-Based Viewer Case 2 - Figure 1 Needle core biopsy of retroperitoneal lymph node. Neoplasm with nested architecture and eosinophilic granular cytoplasm Case 2 - Figure 2 Needle core biopsy of retroperitoneal lymph node. Associated psammomatous calcifications. Case 2 - Figure 3 Partial nephrectomy. Gross photograph of ossified renal mass. Case 2 - Figure 4 Partial nephrectomy. Over 95% of the tumor was ossified with no viable neoplastic cells. Case 2 - Figure 5 Partial nephrectomy. Low power: Small islands of neoplastic cells within the ossified mass. Case 2 - Figure 6 Partial nephrectomy. Intermediate power: Small islands of neoplastic cells with nested architecture and eosinophilic granular cytoplasm, identical to original lymph node metastases. Case 2 - Figure 7 Partial nephrectomy. High power: Neoplastic cells with prominent nested architecture and eosinophilic granular cytoplasm. Diagnosis: Renal cell carcinoma associated with Xp11/TFE3 translocation Discussion: Case work-up: This patient presented with widely metastatic disease of unknown primary site. She had a remote history of a simple renal cyst, which was aspirated approximately 7 years prior, and the concomitant renal lesion was radiographically thought to represent a residual calcified cyst unrelated to her disseminated disease. The differential diagnosis included mainly alveolar soft part sarcoma, Xp11/TFE3 renal cell carcinoma, and clear cell renal cell carcinoma with granular features. Immunohistochemically, the tumor expressed strong and diffuse nuclear TFE3, excluding the latter. The presence of associated calcifications, the nodal metastatic pattern, and the ossified renal mass were thought to support a diagnosis of Xp11/TFE3 renal cell carcinoma. The partial nephrectomy specimen confirmed the presence of a morphologically similar renal neoplasm, confirming the diagnosis. (Note: This degree of calcification/ossification was recently described by Argani et al. in their study of adult Xp11 RCCs). History of Xp11/TFE3 renal cell carcinoma: Renal cell carcinoma classification reached its modern state with the publication of the internationally accepted Heidelberg system in 1997. This system offered a more precise classification by establishing morphologic criteria to reflect the known distinctive genetic subtypes of RCC: clear cell, papillary, chromophobe, and collecting duct/medullary. Tumors that did not fit these diagnostic categories were diagnosed as unclassified. A major advance in this consensus classification system was the concept that the "granular" subtype was not an acceptable diagnostic category because it represented a heterogeneous group of different tumors, and not a distinct entity. Since 1997, other novel renal cell carcinoma subtypes have been added including, among others, multilocular cystic carcinoma, mucinous tubular and spindle cell carcinoma, tubulocystic carcinoma, Xp11/TFE3 carcinoma, and t(6;11) carcinoma. Our current knowledge of translocation associated renal cell carcinomas has evolved slowly from cytogenetic case reports and series of RCC in children and adolescents. Many tumors were initially described as papillary RCC variants bearing novel translocations involving the X chromosome. The first series of these Xp11 carcinomas was likely described in 1968 as "tubulopapillary carcinoma of the kidney in children", well before the translocation was known. In 1996, two groups reported that the X;1 translocation fused PRCC to a transcription factor named TFE3. In 1999, Renshaw et al. published a series of RCC in children and young adults and described 4 cases of "voluminous type", which they suggested represented a unique subset of pediatric RCC possibly related to alterations of the X chromosome and TFE3. The first formal series of Xp11/TFE3 RCC with molecular confirmation were published by Argani et al. in 2001 (ASPL-TFE3 fusion) and 2002 (PRCC-TFE3 fusion). Since that time, additional series have been reported, including cases in adults, an expanded morphologic spectrum, and additional translocation partners. The Xp11/TFE3 subtype was formally accepted as entity by the WHO in 2004. Clinical spectrum: Although the Xp11/TFE3 associated renal cell carcinomas were described in children and young adults, they are now also reported in older adults. While they represent a large percentage of RCC in younger patients, they are thought to be much rarer in adults where clear cell carcinoma is most common. However, it is likely that the Xp11/TFE3 carcinomas are under recognized in adults because of their morphologic overlap with more common subtypes (clear cell and papillary) and because cytogenetics is not routinely performed for all adult renal tumors as is routine in children. Because RCC in the adult population is far more common than pediatric RCC (approximately 25,000 adult RCC versus 25 pediatric RCC per year), adult Xp11/TFE3 carcinomas may possibly outnumber pediatric cases. asdf Morphologic spectrum: Xp11/TFE3 RCC is classically characterized by neoplastic cells with voluminous clear to granular eosinophilic cytoplasm and a papillary to nested architecture. Associated psammomatous calcifications are fairly common. The morphologic spectrum is broad, however, and includes dense tumor calcification/ossification, tumor giant cells, a biphasic pattern mimicking t(6;11) RCC, and neoplastic spindled cells. Studies have also reported cystic change. asdf Immunophenotype: Xp11/TFE3 RCC has an immunophenotype distinct from other RCC subtypes. Expression of epithelial markers in the translocation carcinoma is typically absent to focal. Antibody Xp11/TFE3 Clear cell Papillary CK AE1/3 -/ focal + + + CK7 - / focal + - (+ in cystic areas) + EMA -/ focal + + + CD10 + + + RCC + + + Vimentin -/+ + + Racemase + - + CA IX -/+ (40%) + +/- PAX-2 - in one series + + MelanA -/ rare + cases - - HMB-45 -/ rare + cases - - TFE3 + - - Translocations: A number of translocation partners have been described in the Xp11/TFE3 subtype of RCC, including: PRCC (1q21) ASPL (17q25) PSF (1p34) NonO/p54nrb (inv-Xq12) CLTC (17q23) ? (3q23) Differential diagnosis: Because of the nested morphology and granular cytoplasm, alveolar soft part sarcoma may enter the differential diagnosis, especially if a renal mass has not been identified. The presence of psammomatous calcifications, areas with distinct papillary architecture, and cytokeratin expression (although only present in a small subset of Xp11/TFE3 RCC) may be helpful in recognizing Xp11/TFE3 RCC. Alveolar soft part sarcoma contains intracytoplasmic crystals that are highlighted by PAS, which are absent in Xp11/TFE3 RCC. Strong nuclear TFE3 immunoreactivity would be seen in both tumors and is not discriminatory. Other immunohistochemical markers of RCC, as listed in the table above, may also be useful. By molecular analysis, the non-ASPL subtypes of Xp11/TFE3 RCC would be readily distinguishable from alveolar soft part sarcoma because of a distinct fusion partner. In RCCs with an ASPL fusion partner, the distinction is more complicated because the translocation breakpoints are cytogenetically identical to alveolar soft part sarcoma. However, the RCC translocations are balanced, in contrast to those of alveolar soft part sarcoma, which are typically unbalanced. Paraganglioma and granular cell tumor may also be considered. Paraganglioma should express endocrine markers such as synaptophysin and chromogranin, while granular cell tumor shows diffuse reactivity to S-100 protein; these markers are negative in Xp11/TFE3 RCC. Both paraganglioma and granular cell tumor are TFE3 negative by immunohistochemistry. For clinically apparent primary renal neoplasms, the differential diagnosis would include mainly t(6;11) RCC, clear cell RCC, chromophobe CC, post-neuroblastoma RCC, and papillary RCC. All of these neoplasms may be morphologically indistinguishable from Xp11/TFE3 RCC; however, by definition, they all lack a TFE3 rearrangement. Clinical outcome: Our knowledge of prognostic factors and clinical behavior in Xp11/TFE3 RCC is somewhat limited. Some studies suggest that, in children, these carcinomas may be indolent even in the presence of lymph node metastases. There are, however, reports of cases with aggressive behavior in children. In adults, Xp11/TFE3 may be an aggressive carcinoma subtype. Treatment: The treatment of metastatic RCC has undergone significant changes in the last few years given the emergence of targeted therapies inhibiting VEGF, multiple tyrosine kinases, and mTOR. There is very little data on specific treatment options for Xp11/TFE3 RCC because of its rarity and its relatively recent description. However, a recent study has shown that TFE3 fusions activate MET signaling and suggests the possibility of MET inhibition as a potential therapeutic modality. References: Wetyerman MAJ, Wilbrink M, and van Kessel AG. Fusion of the transcription factor TFE3 gene to a novel gene, PRCC, in t(X;1)(p11;q21)-positve papillary renal cell carcinomas. Proc Natl Acad Sci USA 1996;93:15294-15298. Sidhar SK, Clark J, Gill S, Hamoudi R, Crew AJ, Gwilliam R, Ross M, Linehan WM, Birdsall S, Shipley J, Cooper CS. 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. Hum Molecular Genetics 1996;5(9):1333-1338. Imbert MC, Gerard-Marchant R, Schwesguth O, et al. Tubulopapillary carcinoma of the kidney in children: apropos of 9 observations. Ann Pediatr 1968;15:1094-104. Renshaw AA, Granter SR, Fletcher JA, Kozakewich HP, Corless CL, Perez-Atayde AR. Renal cell carcinomas in children and young adults. Increased incidence of papillary architecture and unique subtypes. Am J Surg Pathol 1999;23(7):795-802. Argani P, Antonescu CR, Illei PB, Lui MY, Timmons CF, Newbury R, Reuter VE, Garvin AJ, Perez-Atayde AR, Fletcher JA, Beckwith JB, Bridge JA, Ladanyi M. Primary renal neoplasms with ASPL-TFE3 gene fusion of alveolar soft part sarcoma. A distinctive tumor entity previously included among renal cell carcinomas of children and adolescents. Am J Pathol 2001;159(1):179-192. Argani P, Antonescu CR, Couturier J, Fournet J-C, Sciot R, Debiec-Rychter M, Hutchinson B, Reuter VE, Boccon-Gibod L, Timmons CF, Hafez N, Ladanyi M. PRCC-TFE3 renal carcinomas. Morphologic, immunohistochemical, ultrastructural , and molecular analysis of an entity associated with the t(X;1)(p11.2;q21). Am J Surg Pathol 2002;26(12):1553-1566. Argani P, Lal P, Hutchinson B, Lui MY, Ladanyi M. Aberrant nuclear immunoreactivity for TFE3 in neoplasms with TFE3 gene fusions. A sensitive and specific immunohistochemical assay. Am J Surg Pathol 2003;27(6):750-761. Eble JN, Sauter G, Epstein JI, et al. Pathology and Genetics of Tumours of the Urinary System and Male Genital Organs. Lyon, France: IARC; 2004. World Health Organization Classification of Tumours. Argani P, Olgac S, Tickoo SK, Goldfischer M, Moch H, Chan DY, Eble JN, Bonsib SM, Jimeno M, Lloreta J, Billis A, Hicks J, De Marzo AM, Reuter VE, Ladanyi M. Xp11 translocation renal cell carcinoma in adults: expanded clinical, pathologic, and genetic spectrum. Am J Surg Pathol 2007;31(8):1149-1160. Geller JI, Argani P, Adeniran A, Hampton E, De Marzo A, Hicks J, Collins MH. Translocation renal cell carcinoma. Lack of negative impact due to lymph node spread. Cancer 2008;112(7):1607-1616. Wu A, Kunju LP, Cheng L, Shah RB. Renal cell carcinoma in children and young adults: analysis of clinicopathological, immunohistochemical, and molecular characteristics with an emphasis on the spectrum of Xp11.2 translocation associated and unusual clear cell types. Histopathol 2008;53(5):533-544. Meyer PN, Clark JI, Flanigan RC, Picken MM. Xp11.2 translocation renal cell carcinoma with very aggressive course in 5 adults. Am J Clin Pathol 2007;128:70-79. Tsuda M, Davis IJ, Argani P, Shukla N, McGill GG, Nagai M, Saito T, Lae M, Fisher DE, Ladanyi M. TFE3 fusions activate MET signaling by transcriptional up-regulation, defining another class of tumors as candidates for therapeutic MET inhibition. Cancer Res 2007;67(3):919-929.