Diagnosis of Xp11 translocation renal cell carcinomas in adult patients under 50 years: Interest and pitfalls of automated immunohistochemical detection of TFE3 protein

Renal cell carcinomas associated with Xp11.2 translocations form a new and little known entity of the WHO 2004 classification. An immunohistochemical (IHC) test aiming at demonstrating the nuclear expression of the protein TFE3, product of a gene frequently involved in translocation, has been proposed as a diagnostic tool. The aims of this work were to define our evaluation criteria of the immunohistochemical test with the antibody anti-TFE3 and to describe new cases of renal cell carcinomas with TFE3 translocations.     

Nierenzellkarzinome bei jungen Patienten

Renal cell carcinoma in children and adolescents is rare and comprises only about 1% of renal tumors in this age group. Since the last WHO classification in 1997, new entities of renal tumors in young patients have been described and have been included into the new 2004 WHO renal cell carcinoma classification. Renal cell carcinoma associated with neuroblastoma comprises 2.5% of renal cell carcinoma in young patients. It occurs several years after neuroblastoma. A large proportion of these tumors show allelic imbalance of chromosomes 20q13, 2p31-32.2, 13q22 and 14q31. TFE3-translocation carcinomas correspond to approximately 20% of renal cell carcinomas in the pediatric and adolescent age group. Both translocations t(X;17)(p11.2;q25) and t(X;1)(p11.2;q21.2) result in immunohistochemically detectable TFE3 protein overexpression. By conventional morphology, TFE3-translocation carcinomas typically show prominent "voluminous" clear cytoplasm and partially papillary architecture. Even according to the revised 2004 WHO classification, in children and adolescents, far more renal cell carcinomas than in the adult age group are currently not classifiable but constitute a phenotypically heterogeneous group with ample potential for future renal cell carcinoma subtypes.     

青少年肾细胞癌的临床病理及分子遗传学研究

目的 探讨青少年肾细胞癌的临床病理特征、遗传学改变、鉴别诊断及预后.方法 对46例青少年肾细胞癌进行光镜观察及免疫组织化学染色,随访并复习相关文献.对46例肿瘤进行von Hippel-Lindau(VHL)基因区域杂合性缺失(LOH)及VHL基因突变筛查.结果 共诊断19例Xp11.2易位/TFE3基因融合相关性肾癌(Xp11 RCC)、9例透明细胞癌、17例乳头状肾细胞癌(PRCC)和1例不能分类肾细胞癌.19例Xp11 RCC均TFE3阳性,而TFEB阴性.8例肿瘤具有巢状和乳头状结构形态类似t(X;17)ASPL-TFE3型肾癌,6例肿瘤组织学类似t(X;1)PRCC-TFE3型肾癌,4例肿瘤形态像透明细胞癌,1例肿瘤组织学形态文献中未被检索到,表现为细胞核呈毛玻璃样,核仁不明显,可见核沟,肿瘤间质见大量黏液.LOH及VHL突变检测结果显示,仅1例透明细胞癌和1例2型PRCC存在LOH,并且该2型PRCC的VHL基因的一个剪切位点存在胚系突变,553+5 G→C.其余45例均未检测出VHL突变.统计学分析表明TFE3阳性肾细胞癌比TFE3阴性肾细胞癌更倾向于高病理分期(pT3/pT4),并且预后较差(P=0.035).结论 青少年肾细胞癌表现出不同的组织学形态以及分子遗传学背景.其中Xp11 RCC为最常见的肾癌亚型.TFE3阳性肾细胞癌的预后要差于TFE3阴性肾细胞癌.     

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.     

An adult case of melanotic Xp11 translocation renal cancers: distinct entity or sub-entity?

Melanotic Xp11 translocation renal cancer is a recently recognized aggressive epithelioid neoplasm with features overlapping between PEComa, carcinoma, and melanoma, in which TFE3 gene fusions coexist with melanin synthesis. These findings support the idea that melanotic Xp11 translocation renal cancer is a distinct variant of the MiT/TFE3 family neoplasms. The authors describe a pigmented renal tumor occurring in a 30-year-old woman with distinct morphology and immunohistochemical characteristics as Xp11 translocation renal cancer.     

Pediatric renal cell carcinoma: clinical, pathologic, and molecular abnormalities associated with the members of the mit transcription factor family

We describe the clinical features, outcome, pathology, cytogenetics, and molecular aspects of 13 pediatric papillary renal cell carcinomas during a 19-year period. Seven cases (54%) had translocations involving Xp11.2 (TFE3). They were identified by cytogenetic, molecular, and/or immunohistochemical analyses. All Xp11.2+ translocations were TFE3+ by immunostaining. Cytogenetic and/or polymerase chain reaction analyses identified 3 cases with t(X17) and 1 case with t(1;17), and all had additional translocations. Histologic features in common in TFE3+ tumors also were present in some TFE3- tumors. One TFE3- tumor had complex cytogenetic abnormalities, 55XY,+2,del(3)(p14),+7,+8,+12,+13,+16,+17,+20[11 ], and 2 cases had normal karyotypes. None had t(6;11)/TFEB+ immunostaining. Five cases had focal, weak MITF tumor immunostaining. The key clinical findings were as follows: (1) The presence of an Xp11.2 (TFE3) translocation frequently is associated with advanced stage at initial examination. (2) All patients who underwent complete, partial nephrectomy with clear margins (adequate only for stage 1) and resection of metastases were alive and relapse-free at last follow-up. (3) The mean +/- SD event-free survival and overall survival rates at 5 years were both 92% +/- 7.4%. (4) One patients with a TFE3+ and MITF+ tumor and 66-87,XXY,der(1)t(1;8)del(4)(q?) der(11)t(11;15)der17t(X;17 abnormalities died 9 months after diagnosis.     

Subtypes of renal cell carcinoma with defined genomic alterations: diagnostic and prognostic significance

The World Health Organization (WHO) 2016 classification of renal neoplasia defines renal cell carcinomas (RCCs) with genomic alterations: (1) succinate dehydrogenase deficient (SDH) RCC, (2) hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome-associated RCC and (3) the MiT family translocation carcinoma (Xp11 translocation carcinoma and t(6;11) carcinoma). Genomic alterations also define two syndromes associated with RCC that have a varied histology; tuberous sclerosis complex and Birt-Hogg-Dube. This review will examine the WHO entities and the two aforementioned syndromes, and discuss a genomic alteration (TCEB1 mutation) that appears to define a subset of clear cell RCCs that histomorphologically overlap with clear cell tubulopapillary RCC. The focus will be on diagnostic considerations from the pathologic perspective, and include discussion of clinical features, prevalence, prognosis, common and uncommon immunohistochemistical stains and molecular testing.     

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.     

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.     

肾细胞癌的临床病理与免疫表型研究

目的 研究肾细胞癌的临床病理特征、预后及免疫表型特点.方法 复习114例肾细胞癌的临床病理资料、HE切片,按2004年WHO肾肿瘤分类标准重新分类、随访并进行免疫组织化学染色.结果 114例.肾细胞癌包括5个类型,肾透明细胞癌77例(67.5%)、乳头状肾癌11例(9.6%)、肾嫌色细胞癌14例(12.3%)、Xp11.2易位_/TFE3基因融合相关性肾癌10例(8.8%)、未能分类肾肿瘤2例(1.8%).免疫组织化学结果,肾透明细胞癌主要表达CK(93.5%,72/77)、CD10(93.5%,72/77)、波形蛋白(75.3%,58/77),乳头状肾癌主要表达α-甲酰基辅酶A消旋酶(AMACR,11/11),肾嫌色细胞癌主要表达CD117(11/14),Xp11.2易位/TFE3基因融合相关性肾癌TFE3、AMACR、CD10和CK的阳性率分别为10/10、10/10、9/10和7/10.结论 肾癌是一组形态学上各有特征的异质性肿瘤,在形态学基础上,CD10、波形蛋白、CD117、AMACR、CK7、TFE3有助于亚型的诊断.