Homotypic interaction of the heat-stable antigen is not responsible for its co-stimulatory activity for T cell clonal expansion

The heat-stable antigen (HSA) is an important co-stimulatory molecule on antigen-presenting cells (APC). However, the receptor on T cells that receives the co-stimulatory signal from HSA has not been identified. Because the HSA is transiently expressed on T cells after the T cell receptor/CD3 complex is engaged, and because it can bind to itself in a homotypic fashion, it has been proposed that homotypic interaction of HSA is responsible for its co-stimulatory activity. Here we test this hypothesis using mice that have a targeted mutation of the HSA gene, as well as novel transgenic mice that constitutively express HSA on T cells. We show that HSA-deficient T cells remain responsive to co-stimulation by HSA. Furthermore, constitutive expression of HSA does not enhance T cell response to co-stimulatory by HSA. Taken together, our results demonstrate that homotypic interaction of HSA is not responsible for co-stimulation mediated by HSA expressed on APC.     

A distinct role for ICOS-mediated co-stimulatory signaling in CD4+ and CD8+ T cell subsets

While the ligand of inducible co-stimulator (ICOS), B7 homologous protein, is widely expressed in somatic cells, B7-1 and B7-2 expression is mainly limited to lymphoid organs. Thus, the activation of T cells through ICOS without a CD28-mediated signal may occur in physiological situations. In order to gain a better understanding of the role of the ICOS co-stimulatory signal in immune responses, we studied the cellular response of T cells to beads coated with anti-ICOS or anti-CD28, plus sub-optimal anti-CD3 mAb. We demonstrate that while CD28 ligation induced expansion of both CD4+ and CD8+ populations, ICOS ligation only resulted in the expansion of CD8+ T cells, and induced apoptosis in the CD4+ T cell population. It was found that IL-2 is critically required for CD8+ T cell expansion triggered by ICOS ligation, whereas it had only a limited effect on the expansion of CD4+ T cells. This distinct reactivity of CD4+ and CD8+ T cell populations to exogenous IL-2 strongly correlates with the expression level of IL-2 receptor beta-chain, CD122, on T cells. Furthermore, we defined a small but distinct population of memory phenotype CD4+ T cells that constitutively express ICOS. Interestingly, while naive CD4+ T cells were unable to produce IL-2, ICOS-expressing T cells produced a substantial amount of IL-2 by stimulation with anti-ICOS/CD3 beads, suggesting that IL-2, which is indispensable for CD8+ T cell expansion, is produced by this ICOS-expressing T cell population. These results provide evidence indicating that the ICOS co-stimulatory signal plays a distinct role in the development of CD4+ and CD8+ T cell-mediated immune responses.     

A case of a novel entity: eosinophilic solid and cystic renal cell carcinoma

Eosinophilic solid and cystic renal cell carcinoma (ESC-RCC) is a relatively newly described entity characterized by specific morphological features and a consistent immunohistochemical profile. The vast majority of cases are sporadic, but tumours with identical histological appearances have been reported in patients with tuberous sclerosis complex (TSC). The distinction between a sporadic or syndrome associated ESC-RCC is not possible without, at a minimum, exploring the patient's clinical context and family history. We present a case of a young female patient who presented with bilateral renal tumours, one of which has been diagnosed as ESC-RCC, and is awaiting genetic testing to exclude underlying TSC.     

Multicentric papillary renal cell carcinoma associated with renal adenomatosis

A case of multicentric papillary renal cell carcinoma (RCC) associated with renal adenomatosis in the bilateral kidneys is reported. Bilateral multiple renal cysts in a 46-year-old man were pointed out incidentally by ultrasonography. Some of the left renal lesions were considered to be RCC, and left radical nephrectomy was performed accordingly. The left kidney was occupied by numerous solid nodules, which ranged from yellow to tan in color, and some of the large ones had foci of hemorrhage and necrosis. Microscopically, most of the tumors showed papillary RCC associated with renal adenoma, while others consisted only of adenomas. Ten months later, multiple lesions of the right kidney, which were initially considered to be multiple cysts, were found to have become enlarged and some of them were diagnosed as RCC. Thus, right radical nephrectomy was also performed, and these tumors showed the same features as the left renal tumors. The patient's familial history was not remarkable. The kidneys revealed various histological features, ranging from dysplastic to adenoma or carcinoma, including transitional or overlapping features between them. The findings suggest an adenoma-carcinoma sequence in papillary RCC. It is worth considering such entities.     

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.     

Sclerosing TSC1 mutated renal cell carcinoma: An unusual pattern mimicking MITF family translocation renal cell carcinoma

The tuberous sclerosis genes and MTOR are increasingly being found to have important roles in novel subtypes of renal cancer, particularly emerging entities eosinophilic solid and cystic renal cell carcinoma (RCC) and high‐grade oncocytic renal tumor (HOT)/RCC with eosinophilic and vacuolated cytoplasm. We report a unique renal neoplasm in a 66‐year‐old woman that initially mimicked MITF family translocation RCC due to mixed clear and eosinophilic cells, extensive stromal hyalinization, and psammoma bodies, yet which was negative for TFE3 and TFEB fluorescence in situ hybridization and a next generation sequencing (NGS) gene fusion assay. Cytoplasmic stippling triggered consideration of TSC‐associated neoplasms, and a targeted NGS assay revealed a variant in exon 21 of TSC1 resulting in c.2626G>T p.(Glu876*) truncating mutation. This report adds to the morphologic spectrum of TSC‐related renal neoplasms, including prominent stromal hyalinization as a potentially deceptive pattern. Due to the overlap in cytoplasmic stippling between eosinophilic solid and cystic RCC and HOT/RCC with eosinophilic and vacuolated cytoplasm, it is debatable which category this example would best fit. Further understanding of these entities and other renal neoplasms with alterations in the TSC genes will elucidate whether they should be considered a family of tumors.     

Cell heterogeneity in clear cell renal cell carcinoma

The aim of this study was to define the histological spectrum, frequency and significance of nonconventional tumour cells in clear cell renal cell carcinomas (CCRCC). Fifty‐one totally sampled CCRCC were studied histologically to evaluate the spectrum of cell morphology variability, its frequency and significance, and their correlation with tumour grade and stage, and other histological parameters of aggressive behaviour like necrosis. Aside from conventional clear/eosinophilic granular cells, three additional cellular types were identified and considered in this study: small clear cells, syncytial cells and rhabdoid cells. Small clear cells were detected in 11 cases (21.5%), syncytial cells in 8 (15.6%) and rhabdoid cells in 5 (9.8%). The presence of syncytial and rhabdoid cells statistically correlated with grade (p = 0.003 and p = 0.006) and stage (p = 0.049 and p = 0.05) in CCRCC. Necrosis correlated with stage (p = 0.018) and grade (p = 0.004), but not with syncytial, rhabdoid or small clear cells. The presence of syncytial and rhabdoid cells in CCRCC is a relatively frequent event that significantly correlates with high‐grade tumours and high stage status.     

Serum miR-210 as a novel biomarker for molecular diagnosis of clear cell renal cell carcinoma

Objective

Our objective was to evaluate the levels of miR-210 in tumor and serum samples of conventional renal cell cancer (cRCC) patients to explore whether circulating miR-210 in serum can be used as a biomarker for the detection of cRCC.

Methods

The paired samples from primary cRCC tumors and adjacent non-tumoral renal parenchyma were collected from 32 patients with cRCC. Serum samples were obtained from 68 patients with a cRCC before surgery, 10 samples after one week of surgery, and 42 healthy individuals were included in this study. Real-time PCR was used to measure the microRNA level. The expression of miRNAs was normalized using the dCT method. Expression levels of miR-210 were compared using the Mann–Whitney U test or Wilcoxon test. Diagnostic performance of serum miR-210 level was calculated by using the receiver operating characteristic (ROC) curve.

Results

The average miR-210 level was higher in primary cRCC tissues than in normal tissue (p = 0.004). For serum samples, the average level of miR-210 was significantly higher in cRCC patients than in controls (p < 0.001). The serum miR-210 level yielded an AUC (the areas under the ROC curve) of 0.874 with a sensitivity of 81.0% and a specificity of 79.4%. Furthermore, the average serum level of miR-210 was significantly decreased in the patients one week after the operation (p = 0.001).

Conclusion

Serum mi-210 may have a potential as a novel noninvasive biomarker for the detection of cRCC.     

Nuclear localization of Merkel cell polyomavirus large T antigen in Merkel cell carcinoma

To clarify whether mutations in the large T gene encoded by Merkel cell polyomavirus affect the expression and function of large T antigen in Merkel cell carcinoma cases, we investigated the expression of large T antigen in vitro and in vivo. Immunohistochemistry using a rabbit polyclonal antibody revealed that large T antigen was expressed in the nuclei of Merkel cell carcinoma cells with Merkel cell polyomavirus infection. Deletion mutant analyses identified an Arg-Lys-Arg-Lys sequence (amino acids 277-280) as a nuclear localization signal in large T antigen. Sequence analyses revealed that there were no mutations in the nuclear localization signal in any of the eleven Merkel cell polyomavirus strains examined. Furthermore, stop codons were not observed in the upstream of the nuclear localization signal in any of the Merkel cell carcinoma cases examined. These data suggest that the nuclear localization signal is highly conserved and functional in Merkel cell carcinoma cases.     

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。     

肾细胞癌关键基因的研究进展

肾细胞癌是一类多基因相关的肿瘤,不同组织学类型的肾癌有不同的基因改变,它们的临床特征,对治疗的反应也不尽相同。因此,对肾癌相关基因的研究不仅加深了人们对肾癌发病机制的了解,而且具有重要的临床意义。本文总结了VHL、PBRM1、MET、FH及BHD等肾癌关键基因,分析其在肾癌诊断治疗方面的价值。