Pediatric renal cell carcinoma associated with Xp11.2 translocation/TFE3 gene fusion

Renal cell carcinoma (RCC) in children and young adults is rare and pathologically problematic. RCC can be either hereditary or sporadic and has a guarded prognosis because appropriate management has not been established. A case of RCC in an 11-year-old is reported. The clinical presentation was a right abdominal mass, hematuria, urinary tract infection, and wasting. Radio-logically, the mass was found within the right kidney with calcification and paraaortic lymphadenopathy. The postsurgical diagnosis was Wilms' tumor stage T4N2M0. On gross inspection, the tumor was ill defined, extending across Gerota's fascia and into the ureter lumina. Microscopically, the tumor consisted of malignant epithelial cells with clear and eosinophilic cytoplasm in nested, papillary, and alveolar configuration. Hyaline nodules, psammoma bodies, vascular invasion, capsular invasion, and extension into the ureter were also found. Immunohistochemically, the cells showed strong nuclear immunoreactivity for TFE3. We concluded that this case was an RCC associated with Xp11.2 translocation/TFE3 fusion, Fuhrman grade 3, stage IV.     

A novel RBMX‐TFE3 gene fusion in a highly aggressive pediatric renal perivascular epithelioid cell tumor

We report an Xp11 translocation perivascular epithelioid cell tumor (PEComa) with a novel RBMX‐TFE3 gene fusion, resulting from a paracentric X chromosome inversion, inv(X)(p11;q26). The neoplasm occurred in an otherwise healthy 12‐year‐old boy who presented with a large left renal mass with extension into the inferior vena cava. The patient was found to have multiple pulmonary metastases at diagnosis and died of disease 3 months later. The morphology (epithelioid clear cells with alveolar and nested architecture) and immunophenotype (TFE3 and HMB45 strongly positive; actin, desmin, and PAX8 negative) was typical of an Xp11 translocation PEComa; however, TFE3 rearrangement was initially not detected by routine TFE3 break‐apart fluorescence in situ hybridization (FISH). Further RNA sequencing revealed a novel RBMX‐TFE3 gene fusion, which was subsequently confirmed by fusion assay FISH, using custom design RBMX and TFE3 come‐together probes. This report describes a novel TFE3 gene fusion partner, RBMX, in a pediatric renal PEComa patient associated with a fulminant clinical course. As documented in other intrachromosomal Xp11.2 inversions, such as fusions with NONO, RBM10, or GRIPAP1 genes, the TFE3 break‐apart might be below the FISH resolution, resulting in a false negative result.     

Malignant perivascular epithelioid cell tumor (PEComa) of cervix with TFE3 gene rearrangement: a case report

In this study, we reported the first PEComa arising within the cervix with TFE3 gene rearrangement and aggressive biological behavior. Morphologically, the tumor showed infiltrative growth into the surrounding parenchyma. The majority of tumor cells were arrayed in sheets, alveolar structures, or nests separated by delicate fibrovascular septa. There was marked intratumoral hemorrhage, necrosis, and stromal calcifications. The tumor cells had abundant clear cytoplasm, focally containing finely granular dark brown pigment, morphologically considered to be melanin. Immunohistochemically, the tumor cells demonstrated moderately (2+) or strongly (3+) positive staining for TFE3, HMB45, and Melan A but negative for CKpan, SMA, S100, PAX8, and PAX2. The presence of Ki-67 protein demonstrated a moderate proliferation rate, with a few Ki-67-positive nuclei. Using a recently developed TFE3 split FISH assay, the presence of TFE3 rearrangement was demonstrated. All these clinicopathologic features are suggestive of TFE3-rearranged PEComas of the cervix. Our results both expand the known characteristics of primary cervix PEComas and add to the data regarding TFE3 rearrangement-associated PEComas.     

Fine‐needle aspiration findings of Xp11 translocation renal cell carcinoma metastatic to a hilar lymph node

Xp11 translocation renal cell carcinoma (RCC) is a specific type of renal cell carcinoma recently placed under the “MiT family translocation RCC” at the last 2013 ISUP Vancouver classification of renal neoplasia. This tumor contains variable proportions of clear cells and could easily mimic papillary RCC, clear cell type, and clear cell papillary RCC. Given the small number of published cytologic findings of this tumor, it could easily present as a diagnostic pitfall. We describe a case of a 23‐year‐old man with a history of prior nephrectomy who presented with multiple mediastinal lymphadenopathies on imaging surveillance follow‐up. Fine‐needle aspiration of the lymph node showed tumor cells with voluminous clear to eosinophilic cytoplasm, well‐defined cell borders and hyperchromatic nuclei arranged in papillary architecture. Review of the prior nephrectomy specimen showed papillary cores surrounded by cells with voluminous clear to finely granular eosinophilic cytoplasm and distinct cell borders. Immunohistochemical stains performed on the nephrectomy specimen showed tumor positivity for CD10, E‐cadherin, a‐methylacyl coenzyme A racemase, and TFE3 supporting the diagnosis of Xp11 translocation renal cell carcinoma. Although this tumor was initially described predominantly in children, it could also occur in adults, as seen in this case. Familiarity with the cytologic findings of this tumor, use of immunohistochemical stains, or cytogenetic test to determine the type of gene fusion will be extremely useful in arriving at the correct diagnosis. Diagn. Cytopathol. 2017;45:456–462. © 2017 Wiley Periodicals, Inc.     

Altered expression of key cell cycle regulators in renal cell carcinoma associated with Xp11.2 translocation

Renal cell carcinoma (RCC) is a rare tumor in the pediatric population. Recently, a phenotypically and genetically distinct kidney carcinoma, mainly prevalent in children and associated with an Xp11.2 translocation or TFE3 gene fusion, has been described. It has been advanced that in this subtype of RCC, there is an accumulation of cyclin D1, cyclin D3, and p21 ^(wafl/cip1). The aim of the present study was to figure out in two pediatric RCC recently diagnosed in our department (one clear cell-type RCC and one TFE3-positive RCC) whether those features are indeed specific of the latter tumor or occur in pediatric RCC irrespective of the tumor type. The following immunostains were performed in both cases: Ki67, p16^ink4a, p21 ^(wafl/cip1), p27^kip1, p53, p63, mdm2, cyclin D1, cyclin D3, TFE3, CD10, vimentin, E-cadherin, and RCC-antigen. We observed in the TFE3-positive carcinoma an intense immunoreaction for p21 ^(wafl/cip1), cyclin D1, and cyclin D3, without expression for p53, p16, p27^kip1, and mdm2, whereas the immunoexpression profile observed in the classic RCC was similar to that of clear cell, adult-type RCC.     

Fine-needle aspiration of a Xp11.2 translocation/TFE3 fusion renal cell carcinoma metastatic to the lung: report of a case and review of the literature

A 57-yr-old woman presented to the National Cancer Institute (NCI) with a history of nephrectomy for a clear cell renal cell carcinoma (RCC), Fuhrman grade 3 of 4 diagnosed 1 yr prior to admission to the NCI. A CT scan done upon admission revealed multiple bilateral lung masses. A CT-guided fine-needle aspiration (FNA) of one of the lung masses revealed a cellular specimen composed primarily of follicular structures surrounding dense hyalinized central cores. The cells in the follicular structures displayed bland nuclei and had granular to vacuolated cytoplasm. Papillary structures were also appreciated. Immunocytochemical studies showed tumor cells that were strongly vimentin and TFE3 positive. Focal staining for AE1/AE3 and CD10 was observed, as was negative staining for EMA. A surgical biopsy specimen reflected the FNA findings and demonstrated a similar immunoprofile. These findings correspond to the recently described Xp11.2 translocation/TFE3 fusion renal cell carcinoma. To our knowledge, this is the first report describing the cytologic features of an Xp11.2 translocation/TFE3 fusion RCC.     

Recent classification of renal epithelial tumors

The recent classification of renal tumors is based on genetic evidence as well as on histologic features. Malignant tumor includes clear cell renal carcinoma (RCC), multilocular cystic RCC, papillary RCC, chromophobe RCC, carcinoma of the collecting duct of Bellini, renal carcinoma associated with Xp11.2 translocations/TFE3 gene fusions and mucinous tubular and spindle cell carcinoma. Benign tumor is subdivided into papillary adenoma, renal oncocytoma and metanephric adenoma. Recently, new disease entities such as acquired cystic disease-associated RCC, clear cell papillary RCC and renal carcinoma with t(6;11)(p21:q12) have been discovered. In this article, we briefly review and introduce the clinical, morphological and genetic features of these tumor entities.     

Renal cancer associated with Xp11.2 translocation/TFE3 gene fusion: Clinicopathological analysis of 13 cases

ObjectiveTo explore the clinicopathological characteristics, immunohistochemical phenotype, diagnosis and differential diagnosis of renal cell carcinoma associated with Xp11.2 translocation/TFE3 gene fusion.MethodsThe clinical history, pathological morphology, immunohistochemical phenotype and related molecular test results of 13 cases of Xp11.2 translocation/TFE3 gene fusion-related renal cell carcinoma were retrospectively analyzed, and the relevant literature was reviewed.ResultsOf the 13 patients, 5 were males and 8 were females. The age of onset ranges from 8 to 73 years old, most of which were middle-aged and elderly patients. Among them, there were 3 cases of left kidney tumor and 10 cases of right kidney tumor. In the treatment method, 2 of the 13 patients underwent partial nephrectomy, and 11 underwent radical nephrectomy. Histopathological morphology showed papillary, nested, tubular and acinar structures. The cytoplasm was transparent or eosinophilic, and the interstitial fibrosis was accompanied by chronic inflammatory cell infiltration, hemosiderin deposition and foam cell aggregation. The immunohistochemical analysis of 13 patient specimens all expressed TFE3 antibody, and the expression intensity was strongly positive; gene FISH detection technology revealed the breakage and rearrangement of TFE3 gene in 12 assessable cases. One of thirteen patients had a metastasis at follow-up from 3 to 69 months.ConclusionsThis type of kidney cancer was a rare subtype. Because of its complex and changeable shape, it has a high degree of overlap with other kidney cancer subtypes, and the missed diagnosis rate and misdiagnosis rate are extremely high. The diagnosis is mainly based on pathomorphology and immunohistochemistry, TFE3 positive expression and TFE3 gene destruction and rearrangement.     

Xp11.2 translocation renal cell carcinoma with very aggressive course in five adults

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).     

Recent advances of immunohistochemistry for diagnosis of renal tumors

The recent classification of renal tumors has been proposed according to genetic characteristics as well as morphological difference. In this review, we summarize the immunohistochemical characteristics of each entity of renal tumors. Regarding translocation renal cell carcinoma (RCC), TFE3, TFEB and ALK protein expression is crucial in establishing the diagnosis of Xp11.2 RCC, renal carcinoma with t(6;11)(p21;q12), and renal carcinoma with ALK rearrangement, respectively. In dialysis‐related RCC, neoplastic cells of acquired cystic disease‐associated RCC are positive for alpha‐methylacyl‐CoA racemase (AMACR), but negative for cytokeratin (CK) 7, whereas clear cell papillary RCC shows the inverse pattern. The diffuse positivity for carbonic anhydrase 9 (CA9) is diagnostic for clear cell RCC. Co‐expression of CK7 and CA9 is characteristic of multilocular cystic RCC. CK7 and AMACR are excellent markers for papillary RCC and mucinous tubular and spindle cell carcinoma. CD82 and epithelial‐related antigen (MOC31) may be helpful in the distinction between chromophobe RCC and renal oncocytoma. WT1 and CD57 highlights the diagnosis of metanephric adenoma. The combined panel of PAX2 and PAX8 may be useful in the diagnosis of metastatic RCC.