MiT家族异位肾细胞癌18例临床病理特征及VHL基因分析

目的探讨MiT家族异位肾细胞癌(MiT family translocation renal cell carcinoma, MiTF RCC)的临床病理学特征及VHL基因分析。方法回顾性分析18例MiTF RCC的临床病理学特征,并复习相关文献;采用FISH技术检测VHL基因。结果 18例MiTF RCC包括16例TFE3异位肾细胞癌(TFE3 translocation renal cell carcinoma, TFE3t RCC)和2例TFEB异位肾细胞癌(TFEB translocation renal cell carcinoma, TFEBt RCC),患者年龄14～60岁,平均36岁,10例因腰部不适或无痛肉眼血尿入院。眼观:MiTF RCC切面灰黄色。镜检:肿瘤可见部分纤维包膜,4例包膜钙化,由上皮样透明细胞、嗜酸细胞构成的乳头状、巢状及腺泡状结构。TFE3t RCC可见砂砾体,TFEBt RCC未见双相形态中的小细胞。免疫表型:18例中15例上皮标记阳性,15例CD10阳性,10例vimentin阳性,8例CK7阳性。18例TFE3均阳性。12例中5例HMB-45或者Melan A阳性。4例中1例PD-L1弥漫强阳性。16例VHL基因中1例3倍体。患者均接受手术切除,术后随访14例,随访13～44个月,平均30个月,均生存。结论 MiTF RCC是较为少见的RCC,确诊依赖分子检测,目前以手术切除为主,预后尚未明确。     

肾黏液样小管状和梭形细胞癌伴Xp11.2易位/TFE3基因融合相关性肾癌1例并文献复习

目的探讨肾黏液样小管状和梭形细胞癌(mucinous tubular and spindle cell carcinoma,MTSCC)伴Xp11.2易位/TFE3基因融合相关性肾癌(renal carcinomas associated with Xp11.2 translocations/TFE3 gene fusions,Xp11.2 RCC)的临床病理学特征、诊断及鉴别诊断。方法回顾性分析1例MTSCC伴Xp11.2 RCC的影像学、组织学及免疫表型特点,并复习相关文献。结果患者女性,60岁,增强CT检查示左肾中极见一直径约2.3 cm的圆形低密度区,界淸。镜下见肿瘤呈浸润性生长,由两种不同的形态组成:梭形细胞区和乳头状区。梭形细胞区肿瘤细胞梭形,胞质红染,可见紧密排列的小管结构;乳头状区肿瘤细胞乳头状排列,可见大量透明细胞及砂粒体。免疫表型:两种区域肿瘤细胞均表达vimentin、CK7、CK19、RCC、CD10,乳头状区肿瘤细胞表达TFE3。结论 MTSCC及Xp11.2 RCC均是临床少见的肿瘤,两种肿瘤组成的混合型肾细胞癌罕见。诊断依据组织学形态及免疫表型。     

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。     

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.     

儿童肾透明细胞癌的病理及其癌细胞DNA定量分析

目的：探讨儿童肾透明细胞癌病理形态特点及癌细胞DNA含量和倍体的关系。方法：对4例儿童肾透明细胞癌组织进行病理形态观察,并用图象分析仪对癌细胞DNA进行定量分析。结果：4例癌细胞胞质透明呈透明细胞且有乳头状结构,其中2例乳头状结构超过50％,3例均见钙化小体及明显出血坏死,DNA检测,DNA平均指数1．31,呈2倍体型,高2倍体型或亚4倍体型,结论：儿童肾透明细胞癌病理形态特点为癌细胞胞质透明,以乳头状结构为主,可见钙化小体,常伴出血,坏死,癌周肾小球,肾小管基本正常为特征,癌细胞DNA呈2倍体或高2倍体型或亚4倍体型。     

Xp11.2易位/TFE3基因融合相关性肾癌的病理特征与临床分析

目的探讨Xp11．2易位／TFE3基因融合相关性肾癌的临床病理特征、免疫表型、鉴别诊断及预后。方法对11例Xp11．2易位／TFE3基因融合相关性肾癌进行光镜观察和免疫组织化学研究及随访10～112个月,并复习相关文献。结果11例肿瘤中女性7例,男性4例。年龄8～26岁,平均16、3岁。肿块直径2．5～6．0cm。光镜下癌组织呈两种结构,一种为腺管状、乳头状、巢状分布。细胞界限清楚,有大量透明或嗜酸性胞质。泡状染色质、核仁明显,沙砾体多见。另一种结构更加紧密,多见实性巢状结构,癌细胞缺乏大量的胞质,核仁不明显,沙砾体少见。免疫表型：本组11例均TFE3、CD10、a-甲酰基-CoA消旋酶（P504s）弥漫表达,细胞广谱角蛋白（CK—pan）、上皮细胞膜抗原（EMA）、波形蛋白仅部分病例表达,所有病例CK7、肾脏特异性钙黏蛋白（Ksp—cadherin）、CD117阴性表达。结论Xp11．2易位／TFE3基因融合相关性肾癌是一种少见肿瘤,诊断主要依据患者的年龄。病理学形态和免疫组织化学TFE3阳性。     

成人肾细胞癌中TFE3重排:大系列连续治疗且有预后的病例的临床及病理特征分析

染色体Xp11.2易位性肾细胞癌(RCC)是最新认识的一种RCC亚型,分子遗传学上表现为TFE3基因重排。RCC中TFE3基因重排最初报道于儿童,随后显示其占儿童肾肿瘤的一部分,这部分病例虽仅有短期随访,但研究发现伴有该基因重排的RCC预后较好。随着研究不断深入,成人     

肾细胞癌中c-kit蛋白表达和DNA倍体分析的临床病理学意义

目的 探讨肾细胞癌（renal cell carcinoma,RCC）各组织学类型中c-kit蛋白表达和DNA倍体分析的临床病理学意义。方法 选取32例透明细胞肾细胞癌、26例乳头状肾细胞癌、20例嫌色细胞肾细胞癌和10例癌旁正常肾组织共88例蜡块组织标本作为实验对象。并应用免疫组化染色方法检测c-kit蛋白的表达,用流式细胞仪技术进行DNA倍体分析。结果 在透明细胞肾细胞癌中c-kit呈阴性,26例乳头状肾细胞癌和20例嫌色细胞肾细胞癌标本均呈c-kit强阳性表达;在乳头状肾细胞癌中,c-kit阳性信号主要存在于胞质;而在嫌色细胞肾细胞细胞癌中,c-kit阳性信号主要表达在细胞膜上;在癌旁正常肾组织中可见肾小管上皮细胞的阳性表达信号。c-kit蛋白表达与肾细胞癌的分级和分期无相关性。另外,DNA异倍体分析结果表明,43.8%的透明细胞肾细胞癌、46.2%的乳头状肾细胞癌和30.0%的嫌色细胞肾细胞癌存在DNA异倍体现象;而正常肾组织均为DNA二倍体。结论 c-kit蛋白表达检测可以作为肾细胞癌诊断和组织学分型的重要指标,同时,DNA倍体分析在肾细胞癌的诊断和预后判定中也有重要的辅助意义。     

具有透明细胞乳头状肾细胞癌形态特征的透明细胞性肾细胞癌的临床病理特征

目的探讨具有透明细胞乳头状肾细胞癌形态特征的透明细胞性肾细胞癌(clear cell papillary renal cell carcinoma-like clear cell renal carcinoma, CCPRCC-like CCRCC)的临床和病理特征, 旨在提高对该类肿瘤的认识。方法回顾性分析浙江大学医学院附属第一医院诊断的3例CCPRCC-like CCRCC的临床资料、组织学形态及免疫表型, 随访患者预后并复习相关文献。结果男性2例, 女性1例, 平均年龄43岁。肿块最大径9 cm。镜下观察3例病例均包含透明细胞乳头状肾细胞癌样(CCPRCC-like)及透明细胞性肾细胞癌样(CCRCC-like)两种区域, 前者在整个瘤体所占比例为20%～90%。CCPRCC-like区域含有囊、乳头、腺管状结构。细胞核远离基底膜, 细胞核WHO/国际泌尿病理协会(ISUP)分级1级。在CCPRCC-like区域, 细胞角蛋白(CK)7表达范围10%～80%, 中等及以上强度表达。CD10表达均为100%, 主要为顶端胞膜表达。在CCRCC-like区域, 1例CK7阴性, 其余...     

Renal cell carcinoma classification: what matters?

Renal cell carcinoma classification may seem to be increasing dramatically in complexity over the last 10 years. Although integration of morphology, immunohistochemistry, and molecular features continues to refine different tumor types and dissect subgroups from long-established categories of renal cancer, only a select subset of these distinctions are of highest importance for clinical management. In the metastatic setting, distinction of clear cell from non-clear cell renal cancer is important, as there are different treatment pathways for these two groups. Another select handful of tumor types are highly aggressive (sarcomatoid, medullary, collecting duct, and fumarate hydratase-deficient carcinomas), which may necessitate different therapy from other non-clear cell carcinomas. A few tumor types are highly favorable, especially chromophobe carcinoma and clear cell papillary carcinoma (which is likely to be reclassified as a “tumor” rather than carcinoma soon). Still other tumor histologies often imply a hereditary syndrome solely based on their diagnosis, particularly succinate dehydrogenase-deficient and fumarate hydratase-deficient cancers. Although several eosinophilic tumor types with subtly different features have been recently recognized, it is not clear at present that discriminating them from chromophobe carcinoma is critical, as behavior appears to be largely favorable. Therefore, although some aspects of surgical pathology rely heavily on molecular diagnostics, histologic pattern and select immunohistochemical markers can resolve the differential diagnosis in most renal neoplasms, without need for complex molecular analysis.     

Sarcomatoid conversion of clear cell renal cell carcinoma in relation to epithelial-to-mesenchymal transition

Approximately 8% of clear cell renal cell carcinoma cases contain regions of radically different morphology, demonstrating a mesenchymal appearance histologically resembling sarcomas. These biphasic neoplasms are called sarcomatoid clear cell renal cell carcinoma. Patients diagnosed with sarcomatoid clear cell renal cell carcinoma face a considerably worse prognosis due to an increased propensity for metastasis. In the present study we investigate whether the sarcomatoid conversion of clear cell renal cell carcinoma could be interpreted as linked to the process of epithelial-mesenchymal transition. Using 6 biphasic clear cell renal cell carcinoma cases we show that sarcomatoid clear cell renal cell carcinoma shares characteristic markers associated with loss of von Hippel-Lindau tumor suppressor with conventional clear cell renal cell carcinoma and also exhibits a markedly higher proliferative index. Furthermore the sarcomatoid elements demonstrate an enhanced expression of epithelial-mesenchymal transition related mesenchymal markers as compared with the clear cell renal cell carcinoma counterparts. We further selected a representative case, clinically demonstrating direct overgrowth of the sarcomatoid component into the liver and colon, for extended immunohistochemical characterization, resulting in a further set of positive and negative epithelial-mesenchymal transition markers as well as pronounced transforming growth factor β positivity, indicating that sarcomatoid clear cell renal cell carcinoma may be associated to epithelial-mesenchymal transition. Transforming growth factor β1 exposure of in vitro cultured primary clear cell renal cell carcinoma cells resulted in cells adopting a mesenchymal morphology similar to sarcomatoid clear cell renal cell carcinoma. Corresponding changes in RNA levels for key epithelial-mesenchymal transition markers were also seen. We therefore suggest that sarcomatoid clear cell renal cell carcinoma morphologically and immunohistochemically may represent a completed epithelial-mesenchymal transition and that transforming growth factor β1 could be an important driving force during the sarcomatoid transdifferentiation of clear cell renal cell carcinoma.     

Osteopontin is differentially expressed in renal cell tumors

ABSTRACT

Osteopontin (OPN) has been shown to play a significant role in regulating the aggressiveness of cancer cells and promote tumor growth. Evaluation of this phosphorylated extracellular glycoprotein expression may help estimate its use as a potential prognostic marker in tumorigenesis of different renal tumors. The objective of the present study was to characterize for the first time the expression pattern of OPN in primary renal tumors and correlate its association to tumor progression and survival. A total of 68 primary renal tumors (clear cell renal cell carcinoma, oncocytoma, renal cell carcinoma, invasive urothelial carcinoma, papillary renal cell carcinoma, chromophobe renal cell carcinoma, papillary urothelial carcinoma) were analyzed by immunohistochemical staining and Western blot methods. Expression of OPN in relation to grading, histologic type of tumor, and survival was statistically assessed. Study data demonstrated that OPN is differentially expressed in various renal tumor cells types. It was shown that OPN is predominantly expressed at the protein level in clear cell renal cell carcinoma when compared to other types of renal tumors. In conclusion, osteopontin may be involved in the pathogenesis of renal tumors. However, the role of OPN expression in predicting the biological response requires further evaluation.     

Ultrastructural Evaluation of Renal Cell Oncocytomas

The utility of ultrastructural evaluation of eosinophilic renal cell neoplasms is illustrated by two case studies. The differential diagnosis between granular renal cell carcinoma and renal cell oncocytoma may be difficult. Ultrastructural demonstration of the presence of abundant mitochondria is useful in the definitive diagnosis of fine-needle aspiration specimens, those neoplasms with nuclear pleomorphism, or in patients requiring renal parenchymal sparing surgery.     

Ultrastructural Evaluation of Renal Cell Oncocytomas

The utility of ultrastructural evaluation of eosinophilic renal cell neoplasms is illustrated by two case studies. The differential diagnosis between granular renal cell carcinoma and renal cell oncocytoma may be difficult. Ultrastructural demonstration of the presence of abundant mitochondria is useful in the definitive diagnosis of fine-needle aspiration specimens, those neoplasms with nuclear pleomorphism, or in patients requiring renal parenchymal sparing surgery.     

The expanding role of renal mass biopsy

Usage of renal mass biopsy has increased in recent years, ranging from selected clinical scenarios to routine implementation in some institutions. Major tasks for the field of diagnostic histopathology include discriminating primary renal cell cancers from other tumors, especially metastases, hematolymphoid tumors, and urothelial carcinoma. Within primary renal cell neoplasms, relevant distinctions include recognizing clear cell papillary renal cell carcinoma, which despite its resemblance to clear cell cancer is nonaggressive, as well as discriminating oncocytoma from chromophobe carcinoma. Helpful immunohistochemical markers include PAX8 for verification of primary renal cell lineage and carbonic anhydrase IX for support of clear cell subtype. Cytokeratin 7 is generally considered the best marker for discriminating oncocytoma from chromophobe renal cell carcinoma, showing only rare positive cells in oncocytoma and greater staining in chromophobe carcinoma. For metastatic tumors, attempting to discriminate clear cell from non-clear cell types may be important for treatment selection.     

Expression of S-100 protein in renal cell neoplasms

Polyclonal antibody to S-100 protein has been routinely applied for initial screening of various types of tumors, including, melanocytic tumors and neurogenic tumors. S-100 protein has been shown to have a broad distribution in human tissues, including renal tubules. The potential utility of S-100 protein in renal cell neoplasms has not been extensively investigated. Using an EnVision-Horseradish Peroxidase (HRP; Dako, Carpinteria, Calif) kit, we evaluated the diagnostic value of S-100 protein on tissue microarray sections from 175 cases of renal epithelial neoplasm (145 primary renal neoplasms and 30 metastatic renal cell carcinomas) and 24 non-neoplastic renal tissues. Immunohistochemical stains for pancytokeratin, HMB-45, and Mart-1 were also performed. Western blot using the same antibody (anti-S-100 protein) was performed on 10 cases of renal cell neoplasm. The results demonstrated that nuclear and cytoplasmic staining pattern for S-100 protein was observed in 56 (69%) of 81 conventional (clear cell) renal cell carcinomas (RCCs), 10 (30%) of 33 papillary RCCs, 1 (6%) of 16 ChRCCs, and 13 (87%) of 15 oncocytomas. Among the 81 cases of CRCC, positivity for S-100 protein was seen in 41 (71%) of 58 and 15 (65%) of 23 cases with Furhman nuclear grade I/II and III/IV, respectively. Focal immunostaining was present in 22 (92%) of 24 normal renal tubules. Similar staining pattern was observed in 21 (70%) of 30 metastatic RCCs. Western blotting demonstrated the S-100 protein expression in both renal cell neoplasm and normal renal tissue. Overexpression of S-100 in oncocytomas compared with ChRCCs was confirmed by the data of Western blot and cDNA microarray analysis. Importantly, 14.8% (12/81) of clear cell RCC and 13.3% (4/30) of metastatic RCC revealed an immunostaining profile of pancytokeratin (-)/S-100 protein (+). These data indicate that caution should be taken in interpreting an unknown primary with S-100 positivity and cytokeratin negativity. In addition, it suggests that S-100 has a diagnostic value in differentiating oncocytoma from ChRCC.     

Histopathologic approaches to the infiltrative renal mass

Most renal masses are round or oval, well-circumscribed, and demonstrate a well-defined interface from the normal renal parenchyma. However, a small subset of renal tumors exhibits an infiltrative pattern, with a poorly-defined interface with the renal parenchyma and entrapment of normal structures. These infiltrative renal malignancies generally show more aggressive clinical course and are associated with a poorer prognosis compared to the more typical renal neoplasms. Main differential diagnoses for a renal mass with infiltrative histology would include urothelial carcinoma, fumarate hydratase (FH)-deficient renal cell carcinoma (RCC), medullary RCC, metastatic cancer from another organ, and rare patterns of clear cell or papillary RCC. Non-epithelial processes may include lymphoma and various infectious, inflammatory, immune-mediated, and vascular mimics. Collecting duct carcinoma is extremely rare in modern practice and is essentially a diagnosis of exclusion once the previous considerations are thoroughly argued against. The aim of this review is to familiarize pathologists with the spectrum of entities that can present as infiltrative masses in the kidney, and to highlight the most relevant immunohistochemical or other tools to facilitate accurate diagnoses and appropriate patient management.