乳头状肾细胞癌的临床病理特征及预后

目的 探讨乳头状肾细胞癌(PRCC)的临床病理特点、免疫表型和预后.方法 回顾性分析19例PRCC患者的临床和病理资料,对肿瘤组织进行免疫组化染色并鉴定其免疫表型,对患者进行随访.结果 PRCC临床上症状多不明显,常在体检时发现.光镜下PRCC组织主要由多少不等的乳头状和管状结构组成,被覆单层立方或多层柱状肿瘤细胞,乳头轴心及间质内可见泡沫细胞、砂粒体沉积,部分肿瘤细胞胞浆内可见含铁血黄索.Ⅰ型12例,Fuhrman核分级均为1～2级;Ⅱ型7例,其中5例Fuhrman核分级为3～4级.Ⅰ型和Ⅱ型PRCC不同程度地表达vimentin、EMA、CKpan、CK7、CD10和p504s,但均不表达34βE12和CK20.16例获得随访的患者中,3例分别于术后3、8和9个月死于肿瘤转移,且均为Ⅱ型PRCC;2例死于其他疾病;其余11例患者均为无瘤生存.结论 PRCC的两种亚型在形态学、免疫表型和预后上有差别,与Ⅰ型PRCC比较,Ⅱ型较Ⅰ型预后不良.PRCC细胞核分级高、出现肉瘤样成分或有透明细胞癌结构可能提示肿瘤具有侵袭性,预后不良.     

乳头状肾癌的临床病理特征及其预后因素

背景与目的：乳头状肾细胞癌相对少见,目前国内对此类肿瘤的研究较少。本研究总结乳头状肾细胞癌患者的临床病理特征,并对可能影响此类患者生存的预后因素进行探索分析。方法：回顾分析64例乳头状肾细胞癌患者的临床、病理及随访资料。研究终点为总生存期,生存分析数据采用Kaplan-Meier法进行计算,并用Log-rank法对生存率进行比较,进一步对有意义的因素行COX模型多因素回归分析。结果：乳头状肾细胞癌占同期肾癌的6.04%,中位年龄为55岁(22~78岁),54.7%的患者为无症状性肾癌。Ⅰ型肿瘤22例(34.4%),Ⅱ型肿瘤42例(65.6%),组织学亚型与肿瘤的TNM分期、Fuhrman分级和手术方式显著相关。中位随访时间为46.0个月(19~133个月),共14例(21.9%)患者死亡,其中Ⅰ型1例(4.5%),Ⅱ型13例(31.0%,P=0.018),总生存率分别为85.7%和55.8%。单因素分析显示,伴有临床症状、Ⅱ型乳头状肾细胞癌、Fuhrman Ⅲ~Ⅳ级、淋巴结受累、远处转移和肾周脂肪侵犯是此类患者预后的影响因素,多因素分析显示,仅远处转移是影响总生存期的独立因子,差异有统计学意义(HR=14.78,P=0.004)。结论：与国外数据相比,我国乳头状肾细胞癌占肾癌的比重低,Ⅱ型肿瘤相对较常见。确诊时发生转移是影响此类患者总生存期的重要因素。     

乳头状肾细胞癌的临床治疗分析——附23例报告

目的总结分析乳头状肾细胞癌的临床特点,提高其治疗水平。方法回顾性分析1980～2000年收治的23例乳头状肾细胞癌患者的临床资料。男14例,女9例。中位年龄48岁（24～71岁）。左侧11例,右侧12例。在19例初治的患者中,临床表现血尿8例（42．1％）,腰痛7例（36．8％）,无症状者4例（21．1％）;肾脏肿瘤中位最大径5．5cm（2．5～10．0cm）。另4例为外院术后出现复发和转移。结果乳头状肾细胞癌占同期收治肾癌的2．4％（23／975）。失随访4例。术后总5年生存率69．6％。其中初治19例,5年生存率为84．2％。14例早期局限性癌（T1a～T2N0M0）患者5年生存率100％,但2例分别于术后7年6个月和10年出现转移,其中1例双肺转移患者行肺转移瘤切除和生物化疗后已生存9年且健在,1例失访。3例局部淋巴结转移和2例远处转移的患者中,1例术后2年6个月出现肺转移瘤和切口转移手术联合生物化疗后生存3年,1例同期肺转移瘤患者行肺转移瘤切除和放疗后生存6年,而余3例中,2例失访,1例生存6个月。而外院初治出现复发的4例中,2例患者再次行复发肿瘤切除,分别生存1年和2年6个月,另2例转移患者中,1例生存9个月,1例失访。结论乳头状肾细胞癌在国内少见。早期局限性乳头状肾细胞癌术后预后良好。对于复发或转移的乳头状肾细胞癌患者,手术切除转移瘤或复发瘤可提高生存期。     

Chemotherapy for non-clear-cell renal cell carcinoma

Clear-cell carcinoma is the most common histopathologic subtype of kidney tumors. Consequently, clinical trials for advanced-stage kidney cancer have focused on patients with clear-cell carcinoma and not on the less common subtypes, including papillary, chromophobe, collectingduct carcinoma, and sarcomatoid-variant tumors. Whereas immunotherapy has constituted the standard treatment for patients with clear-cell renal cell carcinoma (RCC), it does not appear to have activity in the management of patients with other histologic subtypes. Novel therapies, including those targeting the vascular endothelial growth factor pathway, have recently demonstrated significant activity in clear-cell RCC. Historically, chemotherapy has shown limited activity in advanced-stage RCC; however, clinical trials to date have failed to individualize treatment based on histologic subtype. In this article, we will review the literature and present our experience with the use of chemotherapy in patients with non-clear-cell kidney cancer by histologic subtype.     

Brain metastasis of a papillary renal cell carcinoma, identified as type 2

Papillary renal cell carcinomas (PRCCs) tend to metastasize to lymph nodes, while metastasis to the brain is extremely rare. We report the case of a man who had a brain metastasis of PRCC type 2. He was brought to our hospital due to the sudden onset of convulsions. Diagnostic imaging studies showed a metastatic brain tumor in the left parietal lobe, and a primary renal tumor in the right kidney, with paraaortal lymph node metastases. An excision of brain tumor was performed. The brain tumor had a papillary structure with eosinophilic cytoplasm. Five weeks later nephrectomy was carried out. Histological analysis of the nephrectomy specimen revealed the same papillary structure, which was compatible with PRCC type 2.     

MicroRNAs as prognostic molecular signatures in renal cell carcinoma: a systematic review and meta-analysis

This is a systematic review of studies investigating the prognostic value of different microRNAs (miRs) in renal cell carcinoma (RCC). Twenty-seven relevant studies were identified, with a total of 2578 subjects. We found that elevated expression of miR-21, miR-1260b, miR-210, miR-100, miR-125b, miR-221, miR-630, and miR-497 was associated with a poor prognosis in RCC patients. Conversely, decreased expression of miR-106b, miR-99a, miR-1826, miR-215, miR-217, miR-187, miR-129–3p, miR-23b, miR-27b, and miR-126 was associated with a worse prognosis. We performed meta-analyses on studies to address the prognostic value of miR-21, miR-126, miR-210, and miR-221. This revealed that elevated miR-21 expression was associated with shorter overall survival (OS; hazard ratio [HR], 2.29; 95% confidence interval [CI], 1.28–4.08), cancer specific survival (CSS; HR, 4.16; 95% CI, 2.49–6.95), and disease free survival (DFS; HR, 2.15; 95% CI, 1.16–3.98). The decreased expression of miR-126 was associated with shorter CSS (HR, 0.35; 95% CI, 0.15–0.85), OS (HR, 0.45; 95% CI, 0.30–0.69), and DFS (HR 0.30; 95% CI, 0.18–0.50). Our comprehensive systematic review reveals that miRs, especially miR-21 and miR-126, could be promising prognostic markers and useful therapeutic targets in RCC.     

MicroRNA profiles classify papillary renal cell carcinoma subtypes

Background:

Besides the conventional clear-cell renal cell carcinoma (ccRCC), papillary RCC (pRCC) is the second most common renal malignancy. Papillary RCCs can further be subdivided into two distinct subtypes. Although a clinical relevance of pRCC subtyping has been shown, little is known about the molecular characteristics of both pRCC subtypes.

Methods:

We performed microarray-based microRNA (miRNA) expression profiling of primary ccRCC and pRCC cases. A subset of miRNAs was identified and used to establish a classification model for ccRCC, pRCC types 1 and 2 and normal tissue. Furthermore, we performed gene set enrichment analysis with the predicted miRNA target genes.

Results:

Only five miRNAs (miR-145, -200c, -210, -502-3p and let-7c) were sufficient to identify the samples with high accuracy. In a collection of 111 tissue samples, 73.9% were classified correctly. An enrichment of miRNA target genes in the family of multidrug-resistance proteins was noted in all tumours. Several components of the Jak-STAT signalling pathway might be targets for miRNAs that define pRCC tumour subtypes.

Conclusion:

MicroRNAs are able to accurately classify RCC samples. Deregulated miRNAs might contribute to the high chemotherapy resistance of RCC. Furthermore, our results indicate that pRCC type 2 tumours could be dependent on oncogenic MYC signalling.     

中性粒、淋巴细胞及两者比值对肾癌的预后意义

目的:探讨术前外周血中性粒细胞计数、淋巴细胞计数及两者比值对肾透明细胞癌(CCRCC)患者预后的意义。方法:回顾性分析初诊并术后病理证实的296例CCRCC患者的临床资料及随访情况,应用Cox回归分析的最小P值法获得三因素在计算总生存率时的最佳临界值,并以此为界值将患者分为低、高两组,分别应用Kaplan-Meier、Log-rank法和Cox回归模型进行单因素和多因素分析。结果:仅中性粒细胞最佳临界值(3.48×109/L即中位数,P=0.029)有统计学意义。低中性粒细胞组1年、3年、5年的总生存率(OS)和无进展生存率(PFS)分别为100%、100%、97%和99%、99%、92%,高中性粒细胞组1年、3年、5年的OS和PFS分别为98%、96%、94%和97%、93%、81%,两组OS(P=0.040)和PFS(P=0.021)比较有统计学意义。单因素分析显示,发病方式、中性粒细胞计数、肿瘤坏死情况、病理分级、病理T分期、肿瘤大小、病理TNM分期是以OS为终点事件的预后因素。同时,中性粒细胞计数、肿瘤大小、病理TNM分期也是以PFS为终点事件的预后因素。多因素分析显示,病理T分期(P=0.036)和TNM分期(P=0.011)是以PFS为终点事件的独立预后因素,中性粒细胞计数分别是以OS(P=0.029)和PFS(P=0.017)为终点事件的独立预后因素。结论:术前外周血中性粒细胞计数较高是CCRCC预后不良的独立预后因素。     

肾细胞癌的相关标志物

肾细胞癌是成年人肾脏最常见的恶性肿瘤,其自然过程极难预料,仅依靠分期和分级等尚不能提供足够的预后信息.寻找适合的肿瘤标志物有助于该病的诊断和监测,提供更有效的预后信息,确定发生复发和转移的风险,甚至可以作为肿瘤靶向治疗的标靶,并有助于深入了解肾细胞癌的疾病发展过程和揭示与之有关的分子生物学信息.本文回顾分析了近年来RCC相关性肿瘤标志物的最新研究进展情况.     

肾嫌色细胞癌的诊断和治疗

目的：探讨肾嫌色细胞癌（renal chromophobe cell carcinoma,RCCC）的临床特征、病理学特点、诊断、治疗方法和预后。方法：回顾性分析2010年2月至2015年4月期间经病理检查证实的11例 RCCC 患者的临床资料,结合相关文献复习并进行讨论。结果：11例患者中7例男性,4例女性,年龄40～71岁,平均59岁。肿物直径3．5～14．5cm。病变位于右侧者6例,左侧5例。术前无症状者6例,单纯性腰背部疼痛不适5例。11例患者均经 CT 检查确诊,均行手术治疗。手术过程顺利,术后均有病理证实为肾嫌色细胞癌。出院后随访3～36个月,无肿瘤复发和转移。结论：RCCC 是一种低度恶性,少见的肾脏肿瘤。手术治疗是首选方法,预后较好。     

Cabozantinib inhibits tumor growth and metastasis of a patient-derived xenograft model of papillary renal cell carcinoma with MET mutation

MET plays an important role in the development and progression of papillary renal cell carcinoma (pRCC). Evaluation of efficacy of MET inhibitors against pRCC has been hampered by limited preclinical models depicting MET abnormalities. We established a new patient-derived xenograft (PDX) model of pRCC carrying an activating mutation of MET and tested the ability of cabozantinib, an inhibitor of receptor tyrosine kinases including MET, to inhibit tumor growth and metastasis. Precision-cut, thin tissue slices from a pRCC specimen obtained by nephrectomy were implanted under the renal capsule of RAG2^?/?γC^?/? mice to establish first generation TSG-RCC-030. Histologic and genetic fidelity and metastatic potential of this model were characterized by immunohistochemistry, direct DNA sequencing and quantitative polymerase chain reaction (qPCR). The effect of cabozantinib on tumor growth and metastasis was evaluated. Whether measurements of circulating tumor DNA (ctDNA) by allele-specific qPCR could be used as a biomarker of tumor growth and response to therapy was determined. Subrenal and subcutaneous tumor grafts showed high take rates and metastasized to the lung. Both primary tumors and metastases expressed typical markers of pRCC and carried the same activating MET mutation as the parental tumor. Cabozantinib treatment caused striking tumor regression and inhibited lung metastasis in TSG-RCC-030. Plasma ctDNA levels correlated with tumor volume in control mice and changed in response to cabozantinib treatment. TSG-RCC-030 provides a realistic preclinical model to better understand the development and progression of pRCC with MET mutation and accelerate the development of new therapies for pRCC.     

Immune infiltration in renal cell carcinoma

Immune infiltration of tumors is closely associated with clinical outcome in renal cell carcinoma (RCC). Tumor‐infiltrating immune cells (TIICs) regulate cancer progression and are appealing therapeutic targets. The purpose of this study was to determine the composition of TIICs in RCC and further reveal the independent prognostic values of TIICs. CIBERSORT, an established algorithm, was applied to estimate the proportions of 22 immune cell types based on gene expression profiles of 891 tumors. Cox regression was used to evaluate the association of TIICs and immune checkpoint modulators with overall survival (OS). We found that CD8+ T cells were associated with prolonged OS (hazard ratio [HR] = 0.09, 95% confidence interval [CI].01‐.53; P = 0.03) in chromophobe carcinoma (KICH). A higher proportion of regulatory T cells was associated with a worse outcome (HR = 1.59, 95% CI 1.23‐.06; P < 0.01) in renal clear cell carcinoma (KIRC). In renal papillary cell carcinoma (KIRP), M1 macrophages were associated with a favorable outcome (HR = .43, 95% CI .25‐.72; P < 0.01), while M2 macrophages indicated a worse outcome (HR = 2.55, 95% CI 1.45‐4.47; P < 0.01). Moreover, the immunomodulator molecules CTLA4 and LAG3 were associated with a poor prognosis in KIRC, and IDO1 and PD‐L2 were associated with a poor prognosis in KIRP. This study indicates TIICs are important determinants of prognosis in RCC meanwhile reveals potential targets and biomarkers for immunotherapy development.     

Low CAIX expression and absence of VHL gene mutation are associated with tumor aggressiveness and poor survival of clear cell renal cell carcinoma

We attempted to describe, in a series of clear cell renal cell carcinoma (RCC), the relationship between CAIX expression, VHL gene mutations, tumor characteristics and outcome. Radical nephrectomy was performed in 100 patients. Genomic DNA was extracted from frozen tumor samples. Four amplimers covering the whole coding sequence of the VHL gene were synthesized by PCR and sequenced. The monoclonal antibody M75 was used to evaluate CAIX protein expression immunohistochemically. VHL mutations were identified in 58 patients (58%) and high CAIX expression (>85%) was observed in 78 (78%). Tumors with VHL mutation showed higher CAIX expression than those without (p = 0.02). Low CAIX expression and absence of VHL mutation were associated with a more advanced tumors e.g., higher T stages and presence of metastases. VHL mutation and high CAIX expression predicted longer progression-free survival (p = 0.037) and disease-specific survival (p = 0.001), respectively. In combination, they defined three prognostic groups (p = 0.002): (i) good prognosis, defined as VHL mutation and high CAIX (2-year survival: 86%), (ii) intermediate prognosis with either VHL mutation or high CAIX (69%), and (iii) poor prognosis with no VHL mutation and low CAIX (45%, median survival 18 months). CAIX expression, but not VHL mutational status, was an independent prognostic factor in multivariate analysis. Taken together, CAIX expression and VHL mutational status are able to stratify patients with clear cell RCC into distinct groups with regards to clinicopathological variables and prognosis, with low CAIX expression and absence of VHL mutation being associated with a poor clinicopathological phenotype and diminished survival.     

多房囊性肾细胞癌的诊断与治疗简

目的：探讨多房囊性肾细胞癌（MCRCC）的临床特点、治疗方法和预后,以提高术前诊断及选择合适的治疗方法。方法：回顾性分析1996年4月-2010年10月间23例MCRCC患者的临床资料,分析其临床、病理、治疗和预后的特点。结果：术前B超诊断为MCRCC15例,CT诊断为MCRCC19例。所有患者均接受手术治疗,术后效果良好。术后病理均为透明细胞癌。17例术后随访平均29个月（12—73个月）,无瘤存活13例。结论：MCRCC无特殊临床表现,主要依靠影像学检查诊断,术中须行病理检查,手术治疗效果满意,预后佳。     

透明细胞乳头状肾细胞癌临床病理特征分析

目的:探讨透明细胞乳头状肾细胞癌（CCPRCC）的临床及病理学特征。方法:回顾性分析6例CCPRCC的临床特征、组织学特点及免疫表型,并复习相关文献。结果:6例肿瘤均位于肾皮质内,肿瘤边界清晰,有纤维性包膜,切面灰红或灰黄色,部分呈囊性改变。镜下肿瘤呈乳头状、管状、囊性及实性混合性生长,胞浆透明,细胞核远离基底膜,世界卫生组织（World Health Organization,WHO）/国际泌尿病理协会（International Society of Urological Pathology,ISUP)分级为1级或2级。免疫表型:6例肿瘤组织均表达CK7、PAX-8和34βE12,CAIX呈“杯状”或完全膜阳性表达。1例CD10部分阳性,其余5例CD10阴性。所有病例AMACR和TFE3均为阴性。结论:透明细胞乳头状肾细胞癌是一种少见的肾肿瘤,呈惰性生物学行为。形态上应与具有透明细胞和乳头状结构的肾细胞癌鉴别,可借助免疫组织化学和分子遗传学检测予以鉴别。     

血清IL-22在肾透明细胞癌患者预后分析中的应用价值

目的:研究IL-22在肾透明细胞癌（clear cell renal cell carcinoma,ccRCC）患者血清中的表达情况、临床意义及其在患者预后分析中的应用价值。方法:收集168例ccRCC患者的血清,同时以30例健康志愿者血清作为对照。采用ELISA法检测两组对象血清IL-22的表达水平。生存分析探讨IL-22表达水平与患者预后情况的关系。Cox比例风险模型分析影响患者生存时间的危险因素。结果:ccRCC患者血清中的IL-22水平明显高于健康志愿者。对ccRCC患者随访5~63个月,平均（45±12.4）个月,IL-22高水平组的无进展生存率及总体生存率明显低于低水平组。多因素分析结果表明,血清IL-22表达水平、肿瘤直径、肿瘤分化程度及肿瘤TNM分期是影响ccRCC患者生存期的独立危险因素。结论:ccRCC患者血清IL-22表达水平偏高,且IL-22高水平表达患者预后较差。血清IL-22表达水平在ccRCC患者的预后判断中具有较好的应用价值。     

透明细胞乳头状肾细胞癌7例报告并文献复习

背景与目的：透明细胞乳头状肾细胞癌是最近发现的一种少见的肾脏上皮源性恶性肿瘤,其生物学行为惰性,预后较好,该研究旨在分析透明细胞乳头状肾细胞癌的临床及病理学特点,与其他亚型鉴别,以免过度治疗。方法：收集7例透明细胞乳头状肾细胞癌病例,应用组织病理学、免疫组织化学法并结合相关文献分析其镜下及临床特点。结果：7例患者肿块均位于肾内,切面灰红或灰黄色,实性或囊实性,镜下肿瘤组织呈腺管状、微囊状或乳头状结构,肿瘤以一种结构为主或多种结构混合存在。细胞质透明,细胞核圆形或卵圆形,世界卫生组织（World Health Organization,WHO）/国际泌尿病理协会（International Society of Urological Pathology,ISUP）细胞核分级为1或2级。免疫表型：7例均表达CK7、CK8、vimentin、PAX-8、CA9和CK34βE12,Ki-67增殖指数为5%~10%,7例均不表达CD117、TFE3和CD10。对本组7例患者随访2个月至4年,均无复发及转移。结论：透明细胞乳头状肾细胞癌是一种少见的低度恶性肿瘤,形态学上与多种具有透明细胞和（或）乳头状细胞的肾癌有重叠,需要借助免疫组织化学进行鉴别。     

Pericyte coverage of differentiated vessels inside tumor vasculature is an independent unfavorable prognostic factor for patients with clear cell renal cell carcinoma

BACKGROUND.

The objective of this study was to evaluate the effect of pericyte coverage (PC) of differentiated tumor microvessels on the prognosis of patients with clear cell renal cell carcinoma (CCRCC).

METHODS.

Samples from 2 cohorts of patients with CCRCC (101 Asian patients and 524 US patients) were prepared using 2 different histologic approaches: routine sectioning versus tissue microarray. Then, the samples were immunohistochemically doubled‐stained for a pericyte marker (alpha smooth muscle actin [α‐SMA]) and a differentiated vessel marker (cluster of differentiation 34 [CD34]), followed by multispectral image capturing and computerized image analyses to quantify the microvessel density (MVD) and the PC of differentiated vessels. The correlations of PC and the MVD:PC ratio with clinicopathologic characteristics were analyzed.

RESULTS.

There was an inverse correlation between differentiated MVD and PC. Higher PC correlated with more aggressive clinicopathologic characteristics of CCRCC in both cohorts, including more advanced T‐classification, higher pathologic grades, and the occurrence of tumor necrosis. The MVD:PC ratio was an independent favorable prognostic factor for overall and recurrence‐free survival in the Asian cohort and for recurrence‐free survival in the US cohort. PC also was an independent prognostic factor, with higher PC predicting a poorer outcome. The combination of PC and MVD was better at distinguishing the outcome of patients with CCRCC. PC combined with differentiated MVD or with the MVD:PC ratio provided additional, independent prognostic information to the Leibovich risk model, and that information was used to generate improved risk models.

CONCLUSIONS.

The authors consistently observed that higher PC was correlated with more aggressive clinicopathologic characteristics. PC was an independent unfavorable prognostic factor. The authors concluded that pericytes should be considered for therapeutic targeting. Cancer 2013. © 2012 American Cancer Society.