Clinical heterogeneity of Xp11 translocation renal cell carcinoma: impact of fusion subtype, age, and stage

Abstract

Xp11 translocation renal cell carcinomas harbor chromosome translocations involving the Xp11 breakpoint, resulting in gene fusions involving the TFE3 gene. The most common subtypes are the ASPSCR1-TFE3 renal cell carcinomas resulting from t(X;17)(p11;q25) translocation, and the PRCC-TFE3 renal cell carcinomas, resulting from t(X;1)(p11;q21) translocation. A formal clinical comparison of these two subtypes of Xp11 translocation renal cell carcinomas has not been performed. We report one new genetically confirmed Xp11 translocation renal cell carcinoma of each type. We also reviewed the literature for all published cases of ASPSCR1-TFE3 and PRCC-TFE3 renal cell carcinomas and contacted all corresponding authors to obtain or update the published follow-up information. Study of two new, unpublished cases, and review of the literature revealed that 8/8 patients who presented with distant metastasis had ASPSCR1-TFE3 renal cell carcinomas, and all but one of these patients either died of disease or had progressive disease. Regional lymph nodes were involved by metastasis in 24 of the 32 ASPSCR1-TFE3 cases in which nodes were resected, compared with 5 of 14 PRCC-TFE3 cases (P ¼ 0.02).; however, 11 of 13 evaluable patients with ASPSCR1-TFE3 renal cell carcinomas who presented with N1M0 disease remained disease free. Two PRCC-TFE3 renal cell carcinomas recurred late (at 20 and 30 years, respectively). In multivariate analysis, only older age or advanced stage at presentation (not fusion subtype) predicted death. In conclusion, ASPSCR1-TFE3 renal cell carcinomas are more likely to present at advanced stage (particularly node-positive disease) than are PRCC-TFE3 renal cell carcinomas. Although systemic metastases portend a grim prognosis, regional lymph node involvement does not, at least in short-term follow-up. The tendency for PRCC-TFE3 renal cell carcinomas to recur late warrants long-term follow-up. Modern Pathology (2014) 27, 875-886; doi:10.1038/modpathol.2013; published online 6 December 2013Keywords: ASPSCR1; PRCC; renal cell carcinoma; Xp11 translocation carcinoma Xp11 translocation renal cell carcinomas are characterized by chromosome translocations involving the Xp11 breakpoint, resulting in gene fusions involving the TFE3 transcription factor gene, which maps to this locus. 1,2 The most common subtypes of Xp11 translocation renal cell carcinomas are the ASPSCR1-TFE3 (also known as ASPL-TFE3) renal cell carcinomas resulting from a t(X;17)(p11;q25) translocation, 3 and the PRCC-TFE3 renal cell carcinomas, resulting from a t(X;1)(p11;q21) translocation. 4 As most cytogenetically or molecularly confirmed cases have been described in case reports or small series, a formal clinical comparison of these two subtypes of Xp11 translocation RCC has not been performed.We report two new genetically confirmed Xp11 translocation renal cell carcinomas, one with an ASPSCR1-TFE3 gene fusion and the other with a PRCC-TFE3 gene fusion. We review the literature for all published cases of ASPSCR1-TFE3 renal cell carcinomas (41 cases...

MiT Family Translocation-Associated Renal Cell Carcinoma: A Contemporary Update With Emphasis on Morphologic, Immunophenotypic, and Molecular Mimics

“…12,13 In adults, the prognosis for Xp11 t-RCC is similar to that for clear cell RCC 14 ; however, children with Xp11 t-RCC may have a more favorable outcome. 15 The gross features of Xp11 t-RCC are similar to those of clear cell RCC; Xp11 t-RCCs are typically solid, tan-gray tumors with necrosis, hemorrhage, and occasional papillary formations. Microscopically, these tumors are often composed of large, epithelioid cells with abundant clear to eosinophilic/granular cytoplasm arranged in branching, papillary structures with delicate fibrovascular cores and/or a nested architecture; the nuclei are generally high grade and enlarged with variable nuclear membrane irregularity and nucleolar prominence ( Figure 1, A through D).…”

Treating renal cell carcinoma in young adults: challenges and solutions

“…1 In the review by Ellis et al, 20 one patient with the ASPL subtype had a complete response to sorafenib, and in another study, one patient with the PRCC had a complete response to sunitinib. 23,24 While the use of TKIs shows some promise, many other patients have failed to respond to TKIs.…”

“…They can be reliably differentiated by their variable expression of cathepsin-K; PRCC is usually positive, while ASPL always stains negative. 20 A retrospective review by Ellis et al 20 yielded the following key points: • ASPL tended to present at a more advanced stage and was more likely to present as N1 or M1.…”

Biomarker, Molecular, and Technologic Advances in Urologic Pathology, Oncology, and Imaging

“…In contrast, PRCC-TFE3 RCCSs tend to have less-abundant cytoplasm with fewer psammomatous calcifications and more compact and nested growth patterns. 3,9 The most common morphologic mimicker of Xp11 RCC is clear cell RCC with focal papillary or pseudopapillary features, 7 in which the carbonic anhydrase IX (CAIX) immunohistochemical (IHC) stain is helpful in the differential diagnosis because it demonstrates diffuse, membranous staining in clear cell RCC. 10 Papillary RCC with clear cell features can be differentiated from Xp11 RCC by its diffuse labeling with cytokeratin 7 and because clear cell areas in a true papillary RCC tend to be focal and associated with degenerative changes.…”

“…Overall, survival is similar to that seen in patients with clear cell RCC, and among patients with PRCC-TFE3 RCC and ASPSCR1-TFE3 RCC, only advanced stage and older age at diagnosis independently predicted death in a multivariate analysis of the 2 tumors. 9 In summary, Xp11 RCC should be considered when assessing any RCC, in both children and adults, that has clear cell and papillary morphology and IHC features that are difficult to classify. Cytogenetic studies with fluorescence in situ hybridization can provide a definitive diagnosis, and TFE3 IHC in combination with cathepsin K IHC can aid in identifying lesions that should be triaged for cytogenetic testing.…”