P70S6K在Xp11.2易位/TFE3基因融合相关性肾癌中的表达及临床意义

目的检测P70S6K在Xp11.2易位/TFE3基因融合相关性肾癌(renal cell carcinoma associated with Xp11.2 translocation/TFE3 gene fusion,TFE3 RCC)中的表达,探讨其在TFE3 RCC发生、发展中的作用及临床意义。方法采用免疫组化法检测23例确诊的TFE3 RCC、14例肾透明细胞癌(clear cell RCC,CCRCC)和6例乳头状肾细胞癌(papillary RCC,PRCC)组织中P70S6K的表达,观察其表达与三种RCC的关系,同时观察P70S6K表达与TFE3 RCC发生、发展和相关临床病理参数的关系。结果 P70S6K在TFE3 RCC组织中的表达(91.3%)明显高于其在CCRCC组织(64.2%)和PRCC组织中的表达(66.6%),差异有显著性(P0.05)。P70S6K在TFE3 RCC组织中阳性表达水平的H-score评分值(88.2±9.8)亦显著高于其在CCRCC组织(54.4±7.6)和PRCC组织(43.7±6.2)中阳性表达水平的H-score评分值,差异具有显著性(P0.05)。P70S6K表达与TFE3 RCC患者年龄、有无淋巴结转移和脉管瘤栓有关,与患者性别、肿瘤直径等临床病理参数无关。结论与CCRCC和PRCC组织相比,TFE3 RCC组织中P70S6K表达显著增高,有助于TFE3 RCC的鉴别诊断。P70S6K在TFE3 RCC组织中高表达,同时提示mTOR信号通道在TFE3 RCC的发生、发展中可能起重要作用。为TFE3 RCC的靶向治疗寻找潜在药物靶点提供一定的理论基础。     

Xp11.2易位/TFE3基因融合相关性肾癌的临床病理学特点

目的 探讨Xp11.2易位/TFE3基因融合相关性肾癌的临床病理学特点.方法 对4例Xp11.2易位/TFE3基因融合相关性肾癌进行临床资料分析、组织学观察和免疫组化研究,并复习相关文献.结果 4例患者年龄自6～20岁,均具有腰痛的症状和较高的临床分期.肿瘤最大径2.5～10 cm,切面灰黄间灰红色.组织学上,肿瘤显示乳头状和腺泡状2种生长方式, 间质可见钙化.肿瘤细胞界限清楚,胞质淡红染至透亮,染色质呈泡状,核仁易见.4例肿瘤均弥漫高表达TFE3和CD10,不同程度表达CK、EMA和vimentin.结论 Xp11.2易位/TFE3基因融合相关性肾癌是最近被定义的一种罕见肿瘤,好发于年轻患者,预后较差.其诊断主要依靠特征性的组织病理学改变和免疫标记TFE3阳性.     

Cyto‐histological correlation of Xp11.2 translocation/TFE3 gene fusion associated renal cell carcinoma: Report of a case with review of literature

The MiT family translocation renal cell carcinomas (RCCs) are relatively rare in comparison to the conventional RCC. The cytologic features overlap with conventional clear cell RCC and papillary RCCs, thereby making the diagnosis extremely challenging. Here, we describe a case of TFE3 translocation associated RCC in a 58‐year‐old patient, with emphasis on cytomorphologic features and clues toward this diagnostic entity. Correlating the cytohistologic findings and review of touch imprints revealed that presence of hyaline nodules resembling leisegang rings and psammoma bodies in cytologic smears from kidney tumors serve as an important clue in raising a suspicion for the diagnosis of MiT family translocation RCCs.     

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.     

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.     

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.     

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.     

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 subtypes

Aims: Recent studies suggest that paediatric renal cell carcinoma (RCC) may represent a distinct group of tumours; however, its biological behaviour and classification remain poorly understood. The aim was to analyse 13 RCCs from patients ≤23 years of age to determine their clinicopathological, immunohistochemical and molecular characteristics. Methods and results: The histological spectrum included: Xp11.2 translocation‐associated (6/13 patients, 46%), clear cell (5/13 patients, 38%), papillary (1/13 patients) and unclassified (1/13 patients) types. The Xp11.2 translocation‐associated RCCs had a wide morphological spectrum, with high nuclear grade cells with abundant cytoplasm ranging from clear to granular and architecture ranging from solid to papillary. These tumours lacked cytokeratin expression and were confirmed by nuclear reactivity for TFE3 protein. Most of these translocation‐associated tumours presented at high stage and had an unfavourable outcome. Three clear cell RCCs had unusual features that have not been previously characterized, including solid and cystic architecture, cells with abundant eosinophilic cytoplasm yet low nuclear grade and focal cytoplasmic inclusions, resembling oncocytoma. Deletion of subtelomeric 3p25 was observed in two of these RCCs. Conclusions: Xp11.2 translocation‐associated RCC represents a predominant and aggressive subtype in the paediatric age group. Increased awareness of this subtype is important due to its heterogeneous morphology.     

儿童肾细胞癌3例临床病理分析

目的：探讨儿童肾细胞癌(renal cell carcinoma,RCC)的临床病理特征、分类、诊断与鉴别诊断。方法：收集2003年~至今湖南省儿童医院3例儿童RCC病例,其中男性2例,女性1例,年龄5.5~9岁。进行光镜及免疫组化检测重新分类。结果：1例镜下以乳头状结构排列胞浆透亮的癌细胞为主,乳头间可见纤维、血管及炎细胞浸润,伴有较多钙化小体结构;其余2例镜下均以实性巢索状、腺管状排布的嗜酸性颗粒癌细胞为主,灶性区域有少量透明癌细胞排列成不典型乳头状结构,未见钙化小体;免疫组化结果：其中1例表达TFE3、Vimentin、CK-pan和CEA;第2例表达Vimentin、CK-pan、CEA及p53;第3例表达Vimentin、CK-pan、CEA、NSE、CgA、Syn及Ki-67。结论：儿童RCC较少见,HE形态下以乳头状结构排列的透明癌细胞类型需结合TFE3免疫组织化学或基因检测等手段明确诊断。术前采用静脉化疗能提高肿瘤完整切术率。儿童RCC整体预后与成人相比较好,但Xp11.2易位/TFE3基因融合相关性肾癌(Xp11 RCC)预后较透明细胞性肾细胞癌(clear cell renal cell carcinoma,CCRCC)差,由于其在儿童期多表现为惰性进展,需长期的随访观察。     

Overexpression of cyclin D1, D3, and p21 in an infantile renal carcinoma with Xp11.2 TFE3-gene fusion

Renal carcinomas harboring the TFE-3 translocation are rare and occur predominately in children and adolescents. Here, we report a case of infantile renal carcinoma with TFE3 translocation and show that the cell cycle is deregulated in this type of carcinoma. It is characterized by nuclear accumulation of cyclin D1 and D3 in combination with high levels of cyclin-dependent kinase inhibitor p21Cip1/Waf1 but without accumulation of p53, p16INK4a, or mdm2. The combined overexpression of p21, cyclin D1, and cyclin D3 was found exclusively in this type but not in other, more common types of renal carcinoma/oncocytoma (n=27). These results further underscore that renal carcinomas with Xp11. 2 translocations/TFE3-gene fusion represent a special type of renal neoplasm showing deregulation of specific cell cycle components. The analysis of further cases has to prove whether the derangement of the cell cycle is uniform and correlates with the specific type of molecular genetic derangement.