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.     

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.     

Characterization of a familial RCC-associated t(2;3)(q33;q21) chromosome translocation

A Polish family was identified in which multifocal clear cell renal carcinoma segregated with a balanced constitutional chromosome translocation, t(2;3)(q33;q21), similar to the renal cell cancer-associated t(2;3)(q35;q21) reported in a Dutch family. Bacterial artificial chromosome (BAC) contigs encompassing the 2q and 3q breakpoints were constructed and BACs crossing the breakpoints were partially sequenced. All known regional markers, genes, and expressed sequence tags (ESTs) were mapped relative to the contigs, as well as to the breakpoint sequences. Two single ESTs mapped within the 2q breakpoint BAC, whereas the repeat-rich 3q breakpoint region was gene poor. Physical mapping suggested that the 3q break was in 3q13, possibly near the border with 3q21. Physical mapping illustrated that the 2q break was closely telomeric to the 2q31 FRA2G site, consistent with the G-band assignment. Characterization of full-length cDNAs for the ESTs near the 2q break will determine if a gene(s) is altered by this familial translocation. Received: June 8, 2001 / Accepted: August 27, 2001     

Clear cell renal cell carcinoma with wild‐type von Hippel‐Lindau gene: a non‐existent or new tumour entity?

The current World Health Organisation (WHO) classification of renal tumours is based on characteristic histological features or specific molecular alterations. von Hippel‐Lindau (VHL) alteration is the hallmark of clear cell renal cell carcinoma (RCC). After identification of the MiT translocation family of tumours, clear cell papillary renal cancer and others, the group of ccRCC with wild‐type VHL is small. TCEB1 mutation combined with chromosome 8q loss is an emerging tumour entity with wild‐type VHL. Inactivation of TCEB1 increases HIF stabilisation via the same mechanism as VHL inactivation. Importantly, recent molecular analyses suggest the existence of another ‘VHL wild‐type’ evolutionary subtype of clear cell RCC in addition to TCEB1 mutated RCC and clear cell papillary renal cancer. These tumours are characterised by an aggressive behaviour, high tumour cell proliferation rate, elevated chromosomal instability and frequent presence of sarcomatoid differentiation. Future clinicopathological studies will have to provide data to determine whether TCEB1 tumours and clear cell RCC with wild‐type VHL are separate tumour entities or represent variants of a clear cell RCC tumour family.     

miR-210对肾透明细胞癌血管生成的影响

目的探讨miR-210对肾透明细胞癌血管生成的影响。方法检测40例肾透明细胞癌组织标本中miR-210的表达,并分析其与相应癌组织中微血管密度(MVD)的关系。通过miR-210反义寡核苷酸(miR-210-ASO)技术抑制肾透明细胞癌细胞系786-O细胞中miR-210表达,RT-q PCR检测转染效果。三维培养实验观察对照组、阴性对照组和miR-210-ASO组肿瘤细胞上清液对人脐静脉内皮细胞(HUVEC)管腔形成数量的影响。建立裸鼠移植瘤模型,应用endomucin免疫荧光染色于激光共聚焦显微镜下观察抑制miR-210对移植瘤生长,血管形成和VEGF表达的影响。结果肾透明细胞癌组织标本中miR-210的表达与微血管密度呈正相关(P0.05),经miR-210-ASO转染的786-O细胞其miR-210表达明显下降(P0.05)。miR-210-ASO组细胞上清液培养的HUVEC细胞管腔形成数量显著少于对照组和阴性对照组(P0.05)。miR-210-ASO组细胞形成的移植瘤体积小于对照组,且微血管数量和VEGF的表达量显著少于对照组(P0.05)。结论抑制miR-210可降低肾透明细胞癌中血管生成数量。     

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.     

Oncocytic renal cell carcinoma having papillotubular growth: rare morphological variant of papillary renal cell carcinoma

Herein is described a unique renal cell tumor with previously unreported morphological and immunohistochemical features. The patient was a 78-year-old Japanese man. A huge left renal tumor was found on ultrasound during evaluation of left abdominal distention. The tumor was macroscopically characterized by a non-infiltrative border, pale yellow to grayish color, foci of hemorrhage and partial edematous change. Histologically the tumor had an extensive small tubular growth pattern often with papillary fronds mainly composed of oncocytic cells with deeply eosinophilic granular cytoplasm. Clear vacuolated cells were scattered among the oncocytic cells. The present case had an unusual immunohistochemical profile for all known types of renal cell tumors, but both the oncocytic cells and the clear vacuolated cells were strongly immunoreactive for α-methylacyl-coenzyme A racemase. It is concluded that the tumor may be a candidate for a rare variant of papillary renal cell carcinoma. Further cases having similar features are awaited for a definitive classification of this tumor as a previously undescribed tumor type.     

Renal Cell Carcinoma Metastatic to the Thyroid Gland: A Comparative Molecular Study Between the Primary and the Metastatic Tumor

A case of renal cell carcinoma metastatic to the thyroid gland is presented. The thyroid tumor showed typical features: clear cells arranged in nets with a prominent sinusoidal vascular pattern. The histologic appearance was identical to the renal tumor removed 6 yr before. A comparative molecular study between the primary and the metastatic tumor showed a common profile with a loss of heterozygosity at identical loci on chromosome 3, which provided further support to the metastatic nature of the thyroid tumor. However, the frequent existence of allele losses on chromosome 3p in both renal cell carcinomas and primary thyroid follicular carcinomas rest some force from such a molecular approach to the differential diagnosis of thyroid tumors that contain a predominant population of clear cells.     

Decreased expression of mucin 18 is associated with unfavorable postoperative prognosis in patients with clear cell renal cell carcinoma

Background: MUC18 is correlated with tumor progression and metastasis in types of malignancy. But the role of MUC18 in clear cell renal cell carcinoma remains unclear. In this study, we aimed to investigate the expression of MUC18 and its correlation with clinical outcomes in clear cell renal cell carcinoma. Patients and Methods: Immunohistochemical staining was performed in samples from 288 patients with clear cell renal cell carcinoma. We used Kaplan-Meier method and Cox proportional hazard models to value the association between MUC18 expression and clinical outcome. Nomogram was constructed to predict overall survival at 5 and 8 years after nephrectomy. Results: MUC18 expression was significantly decreased in tumor compared to non-tumor tissue (P<0.001). Lower MUC18 expression in tumor predicted a shorter survival time (P=0.007). By multivariate cox analysis, MUC18 was defined as an independent prognostic factor (P=0.006). The nomogram performed better in predicting 5- and 8-year overall survival than the TNM stage alone in clear cell renal cell carcinoma. Conclusion: MUC18 is an independent prognostic factor for clear cell renal cell carcinoma and could be incorporated with the other parameters to predict 5- and 8-year overall survival for clear cell renal cell carcinoma patients.     

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.     

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.     

超声造影与增强CT对小肾癌诊断价值及不同病理类型超声造影表现的研究

目的 通过对比超声造影与增强CT在小肾癌中的诊断准确率及不同病理类型超声造影的表现,探讨超声对小肾癌及不同病理类型的诊断价值,提高小肾癌的诊断水平。方法 回顾性分析2010年6月~2017年12月我院收治的60例直径小于4 cm肾占位性病变患者的超声造影和增强CT检查资料,并根据病理检查结果进行对比研究,比较两种检查方法对小肾癌的诊断准确率、灵敏度、阳性预测值和阴性预测值,同时对比不同病理类型的小肾癌在超声造影下的灌注特点。结果 超声造影诊断准确率为96.67%,高于增强CT的95.00%,差异无统计学意义（P＞0.05）。肾透明细胞癌主要以快进快退为主（42.86%）,其次为快进慢退（36.73%）、等进等退（8.16%）和其他（8.16%）、慢进慢退（4.08%）;乳头状肾细胞癌主要以慢进慢退（57.14%）,其次为快进快退为主（42.86%）;嫌色细胞癌均为快进快退（100.00%）;错构瘤为慢进慢退（100.00%）;嗜酸性粒细胞瘤为快进慢退（100.00%）。结论 肾癌的病理类型以透明细胞癌为主,透明细胞癌的超声造影表现主要以快进快退为主,乳头状肾细胞癌以慢进慢退为主,嫌色细胞癌以快进快退为主。通过超声造影提示基本可以评估小肾癌的病理类型,超声造影、增强CT对小肾癌的诊断都具有较高的价值,但增强CT可以为小肾癌精确定位诊断提供重要参考。若两者联合使用,有助于提高诊断准确率,为临床的诊断及临床手术方案的拟定提供更大的帮助。     

Conventional renal cancer in a patient with fumarate hydratase mutation

Hereditary leiomyomatosis and renal cell cancer (HLRCC) is a tumor predisposition syndrome caused by mutations in the fumarate hydratase (FH) gene. HLRCC is characterized by uterine and cutaneous leiomyomas, renal cell cancer, and uterine leiomyosarcoma. Typically, renal cell cancers in HLRCC are unilateral and display a papillary type 2 or ductal histology. We describe here a 23-year-old patient carrying a novel FH mutation (N330S) with a bilateral renal cell center. Carcinoma of the right kidney showed papillary structure, but the left tumor was diagnosed as a conventional (clear cell) renal carcinoma, a type not previously described in HLRCC. The clear cell renal carcinoma also displayed loss of the normal FH allele and the FH immunostaining. Our finding extends the number of cases in which HLRCC can be suspected, and the FH immunohistochemistry may serve as a useful tool to screen for HLRCC in young individuals with clear cell renal carcinoma.     

The evolution of collagen expression in sarcomatoid renal cell carcinoma

The development of a sarcomatoid morphotype is recognized as an extreme form of dedifferentiation in renal cell carcinoma and is associated with a poor prognosis. Although sarcomatoid renal cell carcinoma shows pronounced spindle cell morphology, clear cell renal cell carcinoma may show early spindle cell change with cellular elongation, and the prognostic significance of this is debated. To determine the relationship between sarcomatoid renal cell carcinoma and clear cell renal cell carcinoma showing early spindle cell change, we have investigated collagen expression using immunohistochemistry in these 2 tumor types. Both sarcomatoid renal cell carcinoma and early spindle cell change tumors showed pericellular interstitial expression of collagen types I and III, whereas sarcomatoid renal cell carcinoma also showed cytoplasmic expression of these collagen types. Expression of these collagen types in typical clear cell renal cell carcinoma was, in occasional cases, limited to faint and patchy staining in a pericellular interstitial distribution. Tumor cells did not stain for collagen type IV in sarcomatoid renal cell carcinoma, early spindle cell change, or typical clear cell renal cell carcinoma. In sarcomatoid renal cell carcinoma, there was diffuse pericellular expression of collagen type V and patchy pericellular expression of collagen type VI, whereas early spindle cell change tumors showed patchy pericellular staining with antibodies to collagen type V. Collagen type VI expression in early spindle cell change was largely confined to the vascular adventitia and areas of scarring, although very occasional foci of faint interstitial staining were also seen. In typical clear cell renal cell carcinoma, staining of collagen types V and VI was limited to the vascular adventitia and foci of desmoplasia, whereas no staining of tumor cell cytoplasm were seen. This study has shown that collagen expression of sarcomatoid renal cell carcinoma differs from that of early spindle cell change and provides validating evidence that these 2 morphotypes should not be considered together for classification purposes.     

Expression of EphA2 protein is positively associated with age,tumor size and Fuhrman nuclear grade in clear cell renal cell carcinomas

The receptor tyrosine kinase of EphA2 has been shown frequently overexpressed in various types of human carcinomas, which implicated that it plays important roles in carcinogenesis. Although EphA2 protein expression has been investigated in many types of human carcinomas, the relationship between the expression of EphA2 protein in clear cell renal cell carcinoma was not well documented. In the present study, using specific anit-EphA2 polyclonal antibody and immunohistochemistry, we evaluated EphA2 protein expression levels in clear cell RCC specimens surgically resected from 90 patients. Our results shows that EphA2 protein was positively expressed in all normal renal tubes of 90 samples (100%, 3+), which was expressed at low levels in renal cortex but high levels in the collecting ducts of the renal medulla and papilla. EphA2 was negatively or weakly expressed in 30 out of 90 samples (33.3%, 0/1+), moderately expressed in 24 samples (26.7%, 2+) and strongly expressed in 36 samples (40%, 3+). Expression of EphA2 was positively associated with age (P=0.029), tumor diameters (P<0.001) and Fuhrman nuclear grade (P<0.001). Our results indicate that EphA2 variably expressed in clear cell renal cell carcinomas. High expression of EphA2 was more often found in big size and high nuclear grade tumors, which indicated EphA2 protein may be used as a new marker for the prognosis of clear cell renal cell carcinoma.     

Metastasis of breast cancer to renal cancer: report of a rare case

Tumor-to-tumor metastasis (TTM) is a rare phenomenon. We present a case of an invasive ductal carcinoma (IDC) of the breast metastasizing to a clear cell renal cell carcinoma (RCC). Breast cancer (BC) metastasis to the RCC is rarely reported, especially in resected kidney tumor. In several cases reported, IDC was the exclusively histologic type of BC metastasized to RCC. It seems that the different molecular type of IDC doesn’t affect the metastatic tendencies to RCC. TTM was an indicator of diffuse disease. For any patient with a history of breast cancer, especially with multi-organs metastasis, resection of kidney tumor should be carefully considered.     

Sarcomatoid Renal Cell Carcinoma Metastatic to the Heart: Report of a Case

An unusual case of metastatic sarcomatoid renal cell carcinoma is presented. Fifteen months after nephrectomy for a typical clear cell carcinoma, a 63-year-old man presented with bilateral pleural effusions, cardiomegaly, and tamponade. A pericardial biopsy showed an anaplastic spindle cell tumor that was strongly keratin positive and showed desmosomes ultrastructurally. The patient died shortly thereafter, and the autopsy revealed massive tumor infiltration of the heart, pulmonary and adrenal metastases, and tumor nodules at the incision site of his nephrectomy. The differential diagnosis of sarcomatoid renal cell carcinoma is discussed.     

Sarcomatoid Renal Cell Carcinoma Metastatic to the Heart: Report of a Case

An unusual case of metastatic sarcomatoid renal cell carcinoma is presented. Fifteen months after nephrectomy for a typical clear cell carcinoma, a 63-year-old man presented with bilateral pleural effusions, cardiomegaly, and tamponade. A pericardial biopsy showed an anaplastic spindle cell tumor that was strongly keratin positive and showed desmosomes ultrastructurally. The patient died shortly thereafter, and the autopsy revealed massive tumor infiltration of the heart, pulmonary and adrenal metastases, and tumor nodules at the incision site of his nephrectomy. The differential diagnosis of sarcomatoid renal cell carcinoma is discussed.     

Association of a novel constitutional translocation t(1q;3q) with familial renal cell carcinoma

Four cases of late onset clear cell renal cell carcinoma (RCC), a case of gastric cancer, and a case of exocrine pancreatic cancer were identified in a Japanese family. In order to elucidate the underlying mechanism for tumorigenesis in this family, extensive genetic studies were performed including routine and spectral karyotyping (SKY), fluorescence in situ hybridisation (FISH), comparative genomic hybridisation (CGH), loss of heterozygosity studies (LOH), and VHL mutation analysis. A germline translocation t(1;3)(q32-q41;q13-q21) was identified by karyotyping in five members of the family including all three RCC cases tested. The translocation was refined to t(1;3)(q32;q13.3) by FISH analysis using locus specific genomic clones, and the two breakpoints were mapped to a 5 cM region in 3q13.3 and a 3.6 cM region in 1q32. Both CGH and allelotyping using microsatellite markers showed loss of the derivative chromosome 3 carrying a 1q segment in the three familial RCCs analysed. Additional chromosomal imbalances were identified by CGH, including amplifications of chromosomes 5 and 7 and loss of 8p and 9. No germline VHL mutation was found but two different somatic mutations, a splice (IVS1-2A>C) and a frameshift (726delG), were identified in two RCCs from the same patient confirming their distinct origin.Taken together, these results firmly support a three step model for tumorigenesis in this family. A constitutional translocation t(1q;3q) increased the susceptibility to loss of the derivative chromosome 3 which is then followed by somatic mutations of the RCC related tumour suppressor gene VHL located in the remaining copy of chromosome 3.


Keywords: familial renal cell carcinoma; translocation; von Hippel-Lindau disease; loss of heterozygosity