TFE3-renal carcinoma in an adult patient: a case with strong expression of phosphorylated hepatocyte growth factor (HGFR)/Met

TFE3-renal carcinoma is rare in adults. Patients with this disease often have a poor prognosis, because it has reached an advanced stage at presentation, and there is lack of an effective therapy. The exact mechanism of its malignant behavior is still unclear. In recent years, a significant relationship between TFE3 fusion protein and hepatocyte growth factor receptor (HGFR)/Met tyrosine kinase activity was reported in several malignancies. We previously reported that phosphorylation of HGFR/Met was associated with malignant aggressiveness and survival in patients with conventional RCC. Here, using immunohistochemical techniques, we examined two types of phosphorylated HGFR/Met (pY1234/1235 and pY1349) in a specimen of a 29-year-old man with TFE3-renal carcinoma. Strong expression of both proteins was detected in carcinoma cells, but not in normal kidney tissues. In addition, they were expressed more strongly in TFE3-renal carcinoma than in conventional RCC. Although tumor was diagnosed at T1N0M0 and the patient received radical nephrectomy, the tumor metastasized to multiple organs, and he died 2 years after surgery. We speculate that upregulated phosphorylation of HGFR/Met could be partly associated with the malignant aggressiveness and poor survival of this patient.     

A renal cell carcinoma with EWSR1‐TFE3 fusion gene

Both EWSR1 and TFE3 are well‐known oncogenes. EWSR1 encodes an RNA‐binding protein involved in multiple soft tissue tumors, including Ewing's sarcoma/peripheral neuroectodermal tumor, desmoplastic small round cell tumor, soft tissue clear cell sarcoma (malignant melanoma of soft parts), extraskeletal myxoid chondrosarcoma, and myxoid liposarcomas. TFE3 regulates both Golgi and lysosomal homeostasis and is rearranged in renal cell carcinoma (RCC), alveolar soft part sarcoma, epithelioid hemangioendothelioma, and perivascular epitheloid cell tumors (PEComas). In this report, we found a rare case of RCC with a fusion between 5′ EWSR1 and 3′ TFE3. The fusion product retained most functional motifs of TFE3. The oncogenic mechanism likely involves TFE3 overexpression through its juxtaposition with the regulatory elements of EWSR1 and its translocation to the nucleus, resulting in the deregulation of Golgi and lysosomal homeostasis. This is a second case of RCC containing EWSR1‐TFE3 fusion.     

Xp11.2 translocation renal neoplasm with features of TFE3 rearrangement associated renal cell carcinoma and Xp11 translocation renal mesenchymal tumor with melanocytic differentiation harboring NONO-TFE3 fusion gene

Xp11.2 translocation/TFE3 rearrangement-associated renal cell carcinoma (RCC) and Xp11 translocation renal mesenchymal tumor are distinct tumor entity. To broaden the spectrum of Xp11 neoplasms, we investigated a novel tumor exhibiting morphologies overlapping Xp11.2 translocation/TFE3 rearrangement-associated RCC and the mesenchymal counterpart with melanocytic differentiation by immunohistochemistry, fluorescence in situ hybridization (FISH) and RNA sequencing, as well as literature review. Histologically, the tumor was composed of three different types of tumor cells, including a large proportion of clear cells, small round cells, and a few spindle cells, presenting a relatively clear border in the majority area. The nuclei of all tumor cells showed extensively and strong positive expressions of TFE3. Whereas, the clear cells positively expressed the RCC-related markers including PAX8, RCC marker and CD10, and negatively expressed HMB45; On the contrary, the small round cells and spindle cells positively expressed melanocytic marker HMB45, and negatively expressed PAX8, RCC marker and CD10. The ki67 index was higher in the small round cells and spindle cells than that in the clear cells. FISH revealed the rearrangement of TFE3 gene in all the three types of cells. The NONO-TFE3 fusion gene was detected in all tumor cells by RNA sequencing. This unique Xp11 translocation-associated neoplasm might represent a distinct entity overlapping Xp11 translocation RCC and the mesenchymal counterpart with melanocytic differentiation, broadening the spectrum of Xp11 neoplasms. The patient died of tumor recurrence and lung metastasis after seven months after the surgery suggesting those tumors have an unfavorable prognosis.     

Cytogenomics and gene expression in a case of metachronous bilateral renal cell carcinomas with drop metastasis: Resolving a diagnostic dilemma with molecular technologies

Metachronous bilateral renal cell carcinomas (RCCs) are rare but well known. We present a case of metachronous bilateral RCCs with a ureter orifice metastasis, for which the pathological diagnosis was confirmed with single nucleotide polymorphism microarray (SNP‐M) and gene expression assay (GEA). A 53‐year‐old man presented with a right ureteral obstruction. A cystoscopy showed a large pedunculated tumor emanating from the right ureteral orifice, consistent with a drop metastasis, which was biopsied. He had a history of a clear cell RCC (ccRCC) 1.5 years prior and a right renal pelvic mass found 8 months later. Histologically, the biopsied right ureteral tumor demonstrated sheets of poorly differentiated cancer cells composed of a mixture of spindled and focal clear cell components. The main differential diagnosis was metastatic RCC versus urothelial carcinoma, but the immunohistochemical profile was not contributory. SNP‐M revealed a genomic profile consistent with a metastatic ccRCC with loss of chromosome 3p. GEA showed a gene expression pattern consistent with kidney origin. The cytogenomic array also identified chromosome copy number patterns that were shared between both kidney tumors. This finding suggests that both tumors had a common origin, and thus, the metachronous ccRCC in the contralateral kidney represents a metastasis.     

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.     

Clear cell papillary renal cell carcinoma: a review

The disease concept of clear cell (tubulo) papillary renal cell carcinoma (CCP-RCC) as a distinct subtype of renal cell carcinoma has been recently established. First described in the setting of end stage renal disease, this tumor type is more frequently recognized and encountered in a sporadic setting. In this article, we provide an overview of the recent understanding of this tumor. Macroscopically, tumors are well circumscribed with well-developed tumor capsule. Histologically, the tumor cells are cuboidal to low columnar cell with clear cytoplasm and papillary and tubulo-papillary configuration. Immunohistochemically, tumor cells generally show diffuse expression for cytokeratin 7, CA9 (cup-shaped pattern), HIF-1, GLUT-1 and high molecular weight cytokeratin, but negative for AMACR, RCC Ma and TFE3. CD10 is negative or focally positive in most tumors. Genetically, this tumor has no characteristics of clear cell RCC or papillary RCC. Prognostically, patients with CCP-RCC behave in an indolent fashion in all previously reported cases. In conclusion, although this tumor has been integrated into recent International Society of Urologic Pathology Classification of renal neoplasia, both aspects of disease concept and clinical behavior are yet to be fully elucidated. Further publications of large cohorts of patients will truly help understand the biologic potential and the molecular underpinnings of this tumor type.     

Small cell carcinoma of the ureter with squamous cell and transitional cell carcinomatous components associated with ureteral stone.

We report a case of primary small cell carcinoma of the ureter with squamous cell and transitional cell carcinomatous components associated with ureteral stone, which is unique in that the patient has remained free of tumor recurrence for 36 months after the surgery without adjuvant chemotherapy or radiotherapy. A 60-yr-old man presented himself with a right flank pain. Computed tomography revealed an ill-defined mass and a stone in the lower one third of the right ureter, and hydronephroureterosis above the stone-impacted site. The patient underwent right nephroureterectomy and stone removal. Upon gross examination, a 3.8 x 1.8 x 1.2 cm white and partly yellow mass was noted in the anterior part of the ureter, resulting in indentation of the ureteral lumen on the posterior side. Light microscopic examination revealed that the mass was mainly composed of small cell carcinoma, and partly squamous cell and transitional cell carcinomatous components. The overlying ureteral mucosa and renal pelvis also contained multifocal dysplastic transitional epithelium and transitional cell carcinoma in situ. There was no vascular invasion, and the surgical margins were free of tumor. The small cell carcinomatous component was positive for chromogranin, neuron specific enolase, synaptophysin, and pancytokeratin but negative for high molecular-weight cytokeratin (K-903) by immunohistochemistry.     

伴有TFE3扩增的肾脏上皮样血管平滑肌脂肪瘤

目的探讨伴有TFE3扩增的肾脏上皮样血管平滑肌脂肪瘤(epithelioid angiomyolipoma,EAML)的病理学特征、鉴别诊断及生物学行为。方法对1例伴有TFE3扩增的肾脏EAML进行组织形态学观察、免疫组化染色及荧光原位杂交(fluores-cence in situ hybridization,FISH)检测,追踪随访患者预后,并复习相关文献。结果该例EAML呈片状弥漫分布,瘤细胞呈上皮样改变,细胞形态异型性较大,核分裂象易见。肿瘤侵犯包膜。瘤细胞表达SMA、TFE3、cathepsin K,TFE3基因出现多倍体扩增,未见易位发生。患者第一次手术3个月后肿瘤复发,术后半年腹腔肿瘤广泛侵犯、肺部见转移。结论伴有TFE3扩增的EAML组织学形态及生长方式更具恶性特征,预后更差,与经典型EAML有所不同,需与其他形态学相似的肿瘤相鉴别。     

Xp11 translocation carcinoma of the kidney presenting with multilocular cystic renal cell carcinoma-like features

Reported is the case of a 17-year-old girl with a multicystic tumor in the middle of the right kidney. Partial nephrectomy revealed an epithelial neoplasm with multilocular cystic renal cell carcinoma pattern. The cells exhibited strong nuclear reactivity for TFE3 protein and supported the diagnosis of Xp11 translocation carcinoma of the kidney. A similar case has not been found in the literature. The example emphasizes the high index of suspicion needed for an accurate diagnosis of renal carcinomas.     

The relationships among tumor-infiltrating lymphocytes, histopathologic findings, and long-term clinical follow-up in renal cell carcinoma.

The relative abundance of tumor-infiltrating mononuclear cells (TIM) was retrospectively evaluated by immunohistology in nephrectomy specimens from 24 cases of human renal cell carcinoma (RCC). The extent of T-lymphocyte (T-cell) and B-lymphocyte (B-cell) infiltration of the tumors was graded semiquantitatively (0 to 4) in each case. Results of this analysis were correlated with clinical evidence of recurrent RCC, histologic evidence of venous invasion, tumor necrosis, and histologic cell type. Clinical follow-up demonstrated the presence of recurrent tumors in four of the 24 cases (17%), and these cases correlated with higher stage and pathologic grade tumors, as well as significantly increased TIM. Venous invasional and tumor necrosis correlated directly with tumor size, pathologic grade, and extent of TIM. Venous invasion was also associated with advanced stage. The group of cases with mixed or granular histologic cell type was associated with advanced stage, high pathologic grade, and increased T-cell infiltration compared to the clear-cell group of tumors. Overall, the pathologic grade demonstrated the highest correlation coefficients with clinical and TNM stage, but also correlated directly with the extent of T-cell infiltration of the tumor. These results confirm previous findings demonstrating a correlation in RCC between increased T-cell infiltration and both high clinical stage and pathologic grade. In addition, increased T-cell infiltration was found to correlate with tumor recurrence, indicating that such infiltration, along with high pathologic grade, is another indicator of poor prognosis in RCC.     

Significance of lymphatic invasion and proliferation on regional lymph node metastasis in renal cell carcinoma

We studied the associations of lymphatic invasion and lymphatic vessel density around tumors with lymph node (LN) status in renal cell carcinoma (RCC) by immunohistochemical analysis using D2-40 antibody as a lymphatic marker. Surgically removed specimens from 76 cases with RCC, including 16 cases with LN metastasis, were used. Lymphatic vessel density around the tumor increased compared with normal kidneys but was not significant by LN status. Tumor size, tumor cell types, patterns of tumor growth, nuclear grade of tumor cells, venous invasion, lymphatic invasion, and primary tumor stage were predictive factors for LN metastasis. Based on multivariate regression analysis, only lymphatic invasion was an independent risk factor for LN metastasis. The immunohistochemical detection of lymphatics was useful for identifying the lymphatic invasion of RCC, and the presence of lymphatic invasion around RCC was an independent predictive factor for LN metastasis.     

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.     

Mucinous tubular and spindle cell carcinoma of the kidney with prominent papillary component,a non-classic morphologic variant. A histologic,immunohistochemical, electron microscopic and fluorescence in situ hybridization study

Mucinous tubular and spindle cell carcinoma (MTSCC) is a rare type of kidney tumor with relatively indolent behavior. Non-classic morphological variants have not been well studied and rarely been reported. We report a challenging case MTSCC with a peculiar morphology in a 42-year-old man, arising in a background of end-stage renal disease (ESRD). Predominant areas with extensive papillary architecture, psammoma bodies and stromal macrophageal aggregates, reminiscent of a papillary renal cell carcinoma (papillary RCC), were intermixed with foci that transitioned into a MTSCC-like morphology exhibiting elongated tubules and a low grade spindle cell component in a background of mucinous stroma. Immunohistochemistry demonstrated diffuse positivity for P504s/AMACR and vimentin in tumor cells. Focal positivity for RCC, CD10 and CK7 was also noted. Kidney-specific cadherin, cytokeratin 34betaE12 and TFE3 stains were negative in the tumor. The major differential diagnostic considerations were papillary RCC, clear cell papillary RCC, and Xp11.2 translocation carcinoma. Negative FISH studies for trisomy 7 and 17 in both papillary and spindled components supported the diagnosis of MTSCC. The ultrastructural profile was not entirely indicative of the cellular origin of the tumor. Cytogenetic analysis should be performed in atypical cases of MTSCC for precise diagnosis.