Inherited forms of renal cell carcinoma.

It is estimated that up to 2% of renal cell cancer (RCC) clusters in families. Several forms of hereditary RCC have been characterized with specific clinical, histopathological, and genetic features. The most common of these is von Hippel-Lindau (VHL) disease caused by mutations in the VHL gene and predisposing to clear cell RCC. Predisposition to papillary RCC is present in hereditary leiomyomatosis and renal cell cancer (HLRCC) and hereditary papillary renal cell carcinoma (HPRC). Identification of the genetic defects causing these diseases has enlightened the molecular pathogenesis of RCC, and moreover, provided means to improve patient management. Genetic testing enables early diagnosis of the disease, after which individuals at-risk can be guided to regular surveillance. Screening facilitates detection of presymptomatic early tumors broadening treatment options and potentially improving prognosis. Thus, identification of individuals with inherited cancer susceptibility is important as special management of these patients improves disease outcome. The purpose of this review is to provide clues for identification and management of hereditary renal cancer patients in clinical practice.     

Inzidenz und Langzeitprognose des papill?ren Nierenzellkarzinoms

Objectives

Papillary renal cell carcinoma (pRCC) represents the largest subgroup of non-clear-cell kidney cancer. In this retrospective multicenter study, we assessed tumor characteristics and long-term prognosis of patients with pRCC in comparison with conventional clear-cell cancer (ccRCC).

Methods

We evaluated 2,804 patients who had undergone renal surgery for pRCC or ccRCC between 1990 and 2006. The mean follow-up was 65 months.

Results

Both pRCC and ccRCC groups were comparable concerning age, tumor grade and the incidence of regional lymph node metastasis at diagnosis. The percentage of male patients was higher in pRCC than in ccRCC (76.0% vs. 63.6%), pRCC patients suffered less often from advanced tumors (22.3% vs. 38.1%), visceral metastasis at diagnosis (8.1% vs. 14.5%) and died less frequently due to RCC progression (16.3% vs. 29.6%). Applying multivariable analyses pRCC was found to be an independent predictor of a favorable clinical course for patients with organ-confined RCC. In contrast in advanced disease papillary histology was significantly associated with a poor prognosis and early tumour-related death.

Conclusions

pRCC seem to be stratified into two different prognostic groups. Localized pRCC has a significantly better prognosis than ccRCC. In contrast, advanced pRCC is characterized by a worse clinical outcome. Whether these two different pRCC cohorts are consistent with the recently defined types 1 and 2 pRCC subtypes or are characterized by other typical genetic alterations, which would lead to a novel pRCC subclassification is currently under investigation within the German Renal Cancer Network.     

Risk of Renal Cell Carcinoma Among Kidney Transplant Recipients in the United States

Renal cell carcinoma (RCC) is a common malignancy following kidney transplantation. We describe RCC risk and examine RCC risk factors among US kidney recipients (1987–2010). The Transplant Cancer Match Study links the US transplant registry with 15 cancer registries. Standardized incidence ratios (SIRs) were used to compare RCC risk (overall and for clear cell [ccRCC] and papillary subtypes) to the general population. Associations with risk factors were assessed using Cox models. We identified 683 RCCs among 116 208 kidney recipients. RCC risk was substantially elevated compared with the general population (SIR 5.68, 95% confidence interval 5.27–6.13), especially for papillary RCC (SIR 13.3 versus 3.98 for ccRCC). Among kidney recipients, RCC risk was significantly elevated for blacks compared to whites (hazard ratio [HR] 1.50) and lower in females than males (HR 0.56). RCC risk increased with prolonged dialysis preceding transplantation (p‐trend < 0.0001). Risk was variably associated for RCC subtypes with some medical conditions that were indications for transplantation: ccRCC risk was reduced with polycystic kidney disease (HR 0.54), and papillary RCC was increased with hypertensive nephrosclerosis (HR 2.02) and vascular diseases (HR 1.86). In conclusion, kidney recipients experience substantially elevated risk of RCC, especially for papillary RCC, and multiple factors contribute to these cancers.     

Epidemiology,Aetiology, and Pathogenesis of Renal Cell Carcinoma

Significant advances in molecular medicine have made renal cell carcinoma (RCC) the prototype solid organ malignancy for targeted medical cancer treatment. Theseis new options have made it possible to prolong the life of patients with metastatic disease. However, we are far away from thoroughly understanding the molecular processes of RCC development let alone from being able to cure advanced renal cancer. RCC is the most common renal neoplasia and it remains a very aggressive and often fatal disease.There are several known histologic subtypes of this heterogeneous tumor entity with associated distinct molecular alterations and different clinical outcomes [1], [2], [3], [4]. The clear cell renal cell carcinoma (ccRCC) is the most common and apparently most aggressive RCC subtype with the highest rates of local invasion, metastasis and mortality. It constitutes 70–80% of all renal cancers [1], [5]. It is estimated that more than 30% of patients with RCC have metastatic disease at the time of diagnosis and 30% of organ-confined RCCs will develop metastatic disease after local treatment [6]. Thus, RCC remains a very major challenge.     

Treatment Approaches in Renal Cell Carcinoma: Past,Present, and Future Perspectives

Treatment of localised renal cell carcinoma (RCC) is well established, and surgical resection is curative for most patients. However, for patients with either metastatic disease or whose local disease subsequently metastasises, treatment options have until recently been limited to cytokine therapy or chemotherapy, both of which are ineffective in the majority. As a result, prognosis has been poor for patients with metastatic RCC (mRCC). A better understanding of the pathogenesis of RCC has led to the development and application of therapies targeted at key molecules involved in angiogenesis, which is an integral part of tumour growth and invasion. Research has shown that mutations in the von Hippel-Lindau (VHL) tumour suppressor gene lead to increased expression of vascular endothelial growth factor (VEGF), an angiogenic factor that is frequently over-expressed in clear-cell RCC, and which is believed to contribute to the hypervascularity of RCC. Therefore, novel therapeutics have been developed that target proteins in the VHL–VEGF pathway, with the aim of inhibiting angiogenesis. These agents include sunitinib, sorafenib, temsirolimus, and bevacizumab, all of which improve clinical outcomes compared with immunotherapy or placebo. Although patients with mRCC are now offered a better prognosis, several questions remain: how do we optimise clinical use of these novel agents, how do we identify patients most likely to benefit from targeted therapies, and can combination therapies further improve outcomes? This article reviews the past and present treatment for mRCC and considers the future challenges.     

Das Nierenzellkarzinom

Approximately 85% of all malignant tumors of the kidney are renal cell carcinomas (RCC). Sonography is the leading examination for early detection of kidney tumors. The treatment of RCC has been enriched in recent years by new therapeutic options for localized and metastatic cancer. The classification of RCC is based on TNM and UICC criteria. The so-called Motzer criteria are being increasingly employed to assess prognosis and monitor therapy and as the basis for reaching decisions on choosing the type of systemic treatment.     

The Clinicopathologic and Molecular Landscape of Clear Cell Papillary Renal Cell Carcinoma: Implications in Diagnosis and Management

BackgroundClear cell papillary renal cell carcinoma (CCPRCC) is a recently described tumor entity. Several questions remain about its epidemiology, molecular features, and clinical behavior.ObjectiveTo comprehensively evaluate clinicopathologic and molecular features of CCPRCC, and compare it with more common kidney cancer subtypes.Design, setting, and participantsWe identified 89 CCPRCC patients and compared their clinicopathologic features with 1120 localized clear cell renal cell carcinoma (ccRCC) and 129 type 1 papillary renal cell carcinoma (pRCC) patients.Outcome measurements and statistical analysisNonparametric statistical testing was used to compare relevant features between tumor types. Overall, cancer-specific survival (CSS) and metastasis-free survival estimates were calculated from initial diagnosis using the Kaplan-Meier method. Patients with ipsilateral multifocal disease were explored further. A subset of CCPRCC tumors underwent genomic analysis and were compared with other RCC subtypes.Results and limitationsA higher proportion of female (45% vs 32%) and African-American (19% vs 3%) patients were observed in the CCPRCC cohort than in the ccRCC and pRCC cohorts. CCPRCC tumors also had increased odds of presenting with additional ipsilateral masses (odds ratio [OR]: 4.41 [confidence interval {CI}: 2.34, 8.15], p < 0.001) and bilateral disease (OR: 4.80 [CI: 2.40, 9.59], p < 0.001) compared with ccRCC tumors. On molecular analysis, CCPRCC tumors showed fewer somatic aberrations and a greater degree of mitochondrial DNA depletion. In multifocal CCPRCC tumors, histologic concordance among the different renal cell carcinoma masses was estimated at 44% (7/16), and none of the individuals presenting exclusively with CCPRCC tumors developed metastatic disease after 5 yr. In contrast, multifocal tumors with CCPRCC and other nonconcordant histologies were more likely to experience adverse outcomes (CSS, log rank p = 0.034).ConclusionsCCPRCC is characterized by distinct molecular and epidemiologic features that could be used to refine current diagnostic approaches. Although their clinical course is generally indolent, multifocal CCPRCC tumors represent a unique diagnostic challenge. In this context, single-mass biopsies could miss concomitant aggressive disease, with a potential negative impact on patient outcomes. Furthermore, high discordance rates in multifocal CCPRCC tumors have important clinical implications in management.Patient summaryWe explored the molecular and clinical features of clear cell papillary renal cell carcinoma (CCPRCC) relative to other kidney cancer subtypes. While CCPRCC generally conveys a good prognosis, additional caution should be taken when it is diagnosed using biopsy if multiple kidney masses are present.     

Renal cell carcinoma

Approximately 85% of all malignant tumors of the kidney are renal cell carcinomas (RCC). Sonography is the leading examination for early detection of kidney tumors. The treatment of RCC has been enriched in recent years by new therapeutic options for localized and metastatic cancer. The classification of RCC is based on TNM and UICC criteria. The so-called Motzer criteria are being increasingly employed to assess prognosis and monitor therapy and as the basis for reaching decisions on choosing the type of systemic treatment.     

乳头状肾细胞癌临床分析

目的：总结分析乳头状肾细胞癌的临床特点,提高其诊治水平.方法：回顾性分析2003～2009年收治的乳头状肾细胞癌的临床资料.并与同期53例肾透明细胞癌比较.结果：乳头状肾细胞癌组患者年龄57.3（47～78）岁,皆为男性,占同期肾细胞癌9.4%.就诊时3例无症状,2例出现肉眼血尿,1例双侧腰痛伴腹部包块.肿瘤平均最大径为6.6（2.6～16.0）cm,未见多中心病灶.TNM分期：T1a N0 M0 3例,T1b N0 M0 1例,T2 No M0 2例 病理分型I型3例,Ⅱ型3例 Fuhrman分级Ⅱ级2例,Ⅲ级4例.与肾透明细胞癌相比,乳头状肾细胞癌好发于男性,影像学检查不具备恶性肿瘤特征,确诊有赖于病理和免疫组织化学检查.临床分期皆为I期或Ⅱ期.就诊时无一例出现远处转移.结论：乳头状肾细胞癌在临床表现上与肾透明细胞癌相似,但在影像学表现、病理形态及生物学行为上均与肾透明细胞癌有所不同.根治性肾切除术是目前首选治疗方式.靶向治疗有可能成为转移性乳头状肾细胞癌治疗的新方向.     

Genetic pathways involved in carcinogenesis of clear cell renal cell carcinoma: genomics towards personalized medicine

What's known on the subject? and What does the study add? Sporadic clear cell Renal Cell Carcinoma (ccRCC) is dominated by nutations of the VHL gene located on chromosome 3p in up to 90% of cases. This gene plays a critical role in hypoxia response, including stimulation of neoangiogenesis. Since 2006, anti‐angiogenci therapies targeting this pathway are used in metastatic patients with objective response rate as high as 45%. However, these treatments don't target directly the tumour cell, allowing the potential for disease progession despite treatment. Large scale analysis recently showed that substantial genetic heterogeneity exists in ccRCC. Associated alterations include genes implicated in methylation regulation in 15% of cases, underlying the importance of epigenetic modifications, and truncating mutations in chromatin remodelling complex PRMB1 in 41% of cases. Systematic screening of these tumours is a way to fully determine the somatic genetic architecture of RCC in order to improve tumour classification, to develop prognostic and predictive markers and to target new molecular pathways involved in carcinogenesis. ? A critical review is provided of the recent progress in oncogenetics applied to renal cell carcinoma (RCC) by highlighting our current understanding of the genetic pathways involved in carcinogenesis and its current and future clinical application. ? RCC comprises a model of translational research because an improved understanding of molecular pathways has led to several targeted therapy options for patients with metastatic RCC. ? Alteration of the product of the Von Hippel–Lindau gene/hypoxia inductible factor/vascular endothelial growth factor pathway is well characterized in carcinogenesis and is the target of the current therapies for metastatic RCC. ? However, substantial genetic heterogeneity exists in this cancer and current treatments do not target directly the tumour cell. ? Improving overall survival still remains a challenging objective but, currently, there is a lack of prognostic and predictive biomarkers for response to treatment. ? Further information is awaited from the genomic approach to tumour classification, prognostic markers and predictive indicators of response to the treatment, as well as the personal susceptibility of developing RCC when exposed to risk factors. ? Recent technological developments, such as large‐scale analysis and high‐speed sequencing, will allow the systematic screening of tumours to fully determine the somatic genetic architecture of RCC.     

Renal cell carcinoma 2005: new frontiers in staging, prognostication and targeted molecular therapy

PURPOSE: Renal cell carcinoma (RCC) has traditionally been staged using a purely anatomical staging system. Although current staging systems provide good prognostic information, data published in the last few years has led to significant controversies as to whether further revisions are needed and whether improvements can be made with the introduction of new, more accurate and predictive prognostic factors not currently included in traditional staging systems. This review highlights such controversies and provides an update on current staging modalities, prognostic factors and targeted molecular therapy for RCC. MATERIALS AND METHODS: A comprehensive review of the peer reviewed literature was performed on the topic of current staging modalities, validated prognostic factors, predictive nomograms, molecular markers and targeted molecular therapy for RCC. RESULTS: A staging system for malignant disease such as RCC uses various characteristics of tumors to stratify patients into clinically meaningful categories, which can be used to provide patients with counseling regarding prognosis, select treatment modalities and determine eligibility for clinical trials. The TNM staging system is currently the most extensively used one. However, it has undergone recent systematic revision due to rapidly emerging data from longer patient followup. The identification of various histological and symptomatic factors has led groups at many centers to develop more comprehensive staging systems that integrate these factors and include patients with metastatic and local disease. While integrated staging systems have improved RCC staging, the recent discovery of molecular tumor markers is expected to revolutionize RCC staging in the future and lead to the development of new therapies based on molecular targeting. CONCLUSIONS: Staging systems for RCC serve as a valuable prognostic tool. Several new patient and tumor characteristics have been reported to be important prognostic factors and they have been integrated into current staging systems. In addition, the field of RCC is rapidly undergoing a revolution led by molecular markers and targeted therapies. With this information urologists will be updated with the most current and comprehensive staging strategies, and be provided with a glimpse of the molecular and patient specific staging and treatment paradigms that will in our opinion transform the future management of this malignancy.     

Effect of papillary and chromophobe cell type on disease-free survival after nephrectomy for renal cell carcinoma

Background The clinical staging of renal cortical tumors traditionally has not evaluated the potential effect of histological subtypes on survival. Evidence suggests that conventional clear cell renal cell carcinoma (RCC) and nonconventional clear cell RCC (chromophobe and papillary) have different metastatic potential. Using a large renal tumor database, we examined the effect of tumor histology on the pattern of metastasis and patient survival. Methods All patients with nonmetastatic renal cortical tumors undergoing partial or radical nephrectomy were identified from a renal tumor database between July 1989 and July 2002. Kaplan-Meier and Cox regression tests were used for statistical analysis. Results Analysis revealed 1057 patients: 794 with conventional clear cell RCC, 157 with papillary RCC, and 106 with chromophobe RCC. Metastasis occurred in 95 conventional clear cell RCC, 9 papillary RCC, and 6 chromophobe RCC. Metastasis occurred in 95 conventional clear cell RCC, 9 papillary RCC, and 6 chromophobe RCC with a median follow-up of 34.6, 43.0, and 33.2 months, respectively. Using log-rank analysis, chromophobe and papillary RCC were associated with an improved disease-free survival at 5 years (P=.009 and .015, respectively). Multivariate analysis revealed tumor size, stage, and chromophobe histology as significant variables for disease progression. Conclusions Renal cortical tumors have distinct histological subtypes with varying degrees of metastatic potential. Conventional clear cell RCC, which comprises two thirds of renal cortical tumors presenting with localized disease, has a less favorable outcome when compared with papillary and chromophobe RCC. Controlling for size and stage, chromophobe, and not papillary, RCC was a significant variable for disease progression compared with conventional clear cell RCC. Knowledge of renal cortical tumor histological subtype is critical for projecting prognosis, tailoring follow-up strategies, and designing clinical trials. Presented at the 56th Annual Cancer Symposium, Society of Surgical Oncology, San Diego, CA, March 5–9, 2003.     

Current status of targeted therapy for advanced renal cell carcinoma

The treatment of metastatic renal cell carcinoma (mRCC) has recently evolved from being predominantly cytokine-based treatment to the use of targeted agents, which include sorafenib, sunitinib, bevacizumab (plus interferon alpha [IFN-α]), temsirolimus, everolimus, pazopanib, and most recently, axitinib. Improved understanding of the molecular pathways implicated in the pathogenesis of RCC has led to the development of specific targeted therapies for treating the disease. In Korea, it has been 5 years since targeted therapy became available for mRCC. Thus, we now have broader and better therapeutic options at hand, leading to a significantly improved prognosis for patients with mRCC. However, the treatment of mRCC remains a challenge and a major health problem. Many questions remain on the efficacy of combination treatments and on the best methods for achieving complete remission. Additional studies are needed to optimize the use of these agents by identifying those patients who would most benefit and by elucidating the best means of delivering these agents, either in combination or as sequential single agents. Furthermore, numerous ongoing research activities aim at improving the benefits of the new compounds in the metastatic situation or their application in the early phase of the disease. This review introduces what is currently known regarding the fundamental biology that underlies clear cell RCC, summarizes the clinical evidence supporting the benefits of targeted agents in mRCC treatment, discusses survival endpoints used in pivotal clinical trials, and outlines future research directions.     

RCC5基因在肾透明细胞癌中的表达及临床意义

目的明确RCC5在肾透明细胞癌（ccRCC）组织中的表达水平及其对肾癌患者预后的影响。方法通过荧光定量PCR方法对54对ccRCC患者标本（包括癌组织和癌旁正常组织）的RCC5mRNA进行分析;并运用免疫组化对82对配对的癌组织和癌旁正常组织切片及161例癌组织切片进行染色;运用统计学方法分析RCC5的表达量和患者的临床特点之间关系。结果荧光定量PCR结果显示92.59%（50/54））的肾癌组织中RCC5表达水平明显高于癌旁正常组织（P〈0.001）;82对癌组织及癌旁正常组织切片免疫组化显示,92.68%（76/82）的癌组织RCC5表达水平高于癌旁正常组织（P〈0.001）;同时发现RCC5的表达水平与性别、肿瘤直径、病理分期、分级、TNM分期和复发率相关;RCC5高表达的患者预后一般较低表达者差,多元分析显示RCC5表达上调是ccRCC的独立预后因素。结论 RCC5的表达水平和ccRCC预后之间存在明显相关性;研究发现RCC5表达上调的患者预后较差,RCC5可能是一个新颖并且有临床价值的预后标志物。     

Treatment of Advanced and Metastatic Renal Cancer: A Revolution?

ContextA significant proportion of patients with renal cell carcinoma (RCC) will experience recurrence or tumour progression after surgical treatment. Nowadays, several treatment options, including immunotherapy and targeted therapies, are available for management of advanced and metastatic RCC.ObjectiveThis paper aims to give an overview of the current treatment options for patients with advanced and metastatic RCC.Evidence acquisitionThis paper is based on a presentation given at the 6th Meeting of the European Society of Oncological Urology 2009, held in Istanbul, Turkey. Data were retrieved from recent review articles, original articles, and abstracts on the treatment of advanced and metastatic RCC.Evidence synthesisThe potential role of adjuvant vaccines in treatment of patients with advanced RCC after nephrectomy has been suggested. With regard to the newly developed targeted agents for treatment of metastatic clear-cell RCC, sunitinib and bevacizumab plus interferon-α (INF-α) seem promising as first-line therapy for good- and intermediate-risk patients. Temsirolimus appears to be effective as first-line treatment in metastatic RCC (mRCC) patients with poor prognosis. Sorafenib and everolimus should be considered as second-line therapy in mRCC patients. Some targeted therapies have also demonstrated clinical activities in patients with metastatic non–clear-cell RCC. Although grade 1 and grade 2 treatment-related adverse events were common with targeted therapies, most were manageable. The effect of targeted agents in earlier stage disease is currently under investigation. Cytokine therapy was associated with a modest survival benefit in mRCC. A combined analysis, however, suggested that cytoreductive nephrectomy might improve survival in patients with mRCC treated with interferon immunotherapy.ConclusionsMore research on the use of adjuvant vaccines in treating patients with advanced RCC is warranted. Although the management of metastatic disease has undergone a revolution in recent years, a lot of questions still need to be answered.     

甲状腺乳头状癌术后复发靶向治疗进展

甲状腺乳头状癌术后复发仍是临床中的常见问题。一些肿瘤信号通路的激活与基因突变会促使甲状腺癌发生发展，导致肿瘤易复发、碘难治甚至去分化。复发性甲状腺乳头状癌一旦发生去分化或远处转移，病人预后不容乐观，包括手术、促甲状腺激素抑制治疗及放射性碘治疗在内的常规治疗对这些病人帮助甚微，靶向治疗成为目前难治性复发甲状腺乳头状癌的新型治疗手段。目前靶向治疗主要包括多靶点酪氨酸激酶抑制剂治疗、放射性再敏疗法、免疫疗法等，但临床证据尚显不足，同时带来的不良反应也不容忽视。更具针对性地为各种基因类型甲状腺癌病人提供个性化治疗是未来发展的方向。     

Review of current treatment of sacral chordoma

Chordoma is a relatively rare, locally aggressive tumor which is known to arise from embryonic remnants of the notochord and to occur exclusively along the spinal axis, with a predilection for the sacrum. Although chordoma typically presents as a single lesion, a few cases of metastasis have been reported and the prognosis of such patients may be poor. Chordomas are slowly growing tumors with insidious onset of symptoms, making early diagnosis difficult. Recent improvements in imaging have provided valuable information for early diagnosis. The optimal treatment for sacral chordoma is en bloc sacral resection with wide surgical margins. Improvement in surgical techniques has widened the opportunities to provide effective treatment. However, the effects of adjuvant treatment options are still both unclear and controversial. Substantial progress has been made in the study of molecular‐targeted therapy. The authors review the current surgical and adjuvant treatment modalities, including molecular‐targeted therapy, available for management of sacral chordoma.     

Comparisons of outcome and prognostic features among histologic subtypes of renal cell carcinoma

Our objective was to compare cancer-specific survival and to examine associations with outcome among the histologic subtypes of renal cell carcinoma (RCC). We studied 2385 patients whose first surgery between 1970 and 2000 was a radical nephrectomy for sporadic, unilateral RCC. All RCC tumors were classified following the 1997 Union Internationale Contre le Cancer and American Joint Committee on Cancer guidelines. There were 1985 (83.2%) patients with clear cell, 270 (11.3%) with papillary, 102 (4.3%) with chromophobe, 6 (0.3%) with collecting duct, 5 (0.3%) with purely sarcomatoid RCC and no underlying histologic subtype, and 17 (0.7%) with RCC, not otherwise specified. Cancer-specific survival rates at 5 years for patients with clear cell, papillary, and chromophobe RCC were 68.9%, 87.4%, and 86.7%, respectively. Patients with clear cell RCC had a poorer prognosis compared with patients with papillary and chromophobe RCC (p <0.001). This difference in outcome was observed even after stratifying by 1997 tumor stage and nuclear grade. There was no significant difference in cancer-specific survival between patients with papillary and chromophobe RCC (p = 0.918). The 1997 TNM stage, tumor size, presence of a sarcomatoid component, and nuclear grade were significantly associated with death from clear cell, papillary, and chromophobe RCC. Histologic tumor necrosis was significantly associated with death from clear cell and chromophobe RCC, but not with death from papillary RCC. Our results demonstrate that there are significant differences in outcome and associations with outcome for the different histologic subtypes of RCC, highlighting the need for accurate subtyping.     

Histologic subtype of metastatic renal cell carcinoma predicts response to combined immunochemotherapy with interleukin 2, interferon alpha and 5-fluorouracil

OBJECTIVES: Combined immunochemotherapy with interleukin 2 (IL-2), interferon alpha (IFN-alpha), and 5-fluorouracil (5-FU) is an established first-line therapy for metastatic renal cell carcinoma (RCC). However, data on histologic parameters predictive of clinical benefit are rare. In this study, we evaluated the response to immunochemotherapy in the main histologic subtypes of renal cell carcinoma and performed a subgroup analysis of inoperable patients. METHODS: From 164 patients treated with one or two cycles of combined immunochemotherapy, radical nephrectomy had revealed 22 cases of papillary RCC (pRCC; 13.4%) and 131 cases of clear cell RCC (ccRCC; 79.9%). In the remaining 11 (6.7%) their disease was inoperable. The overall response rates were evaluated according to World Health Organization criteria. RESULTS: For ccRCC and inoperable disease, responses of 34.4% and 27.3% after one cycle and 28.8% and 16.7% after two cycles, respectively, were noted. In contrast, no patient with pRCC showed any response after two cycles of combined immunochemotherapy. CONCLUSIONS: No objective response was seen in patients with pRCC. Hence, the use of immunotherapeutic agents must be questioned in this histologic subtype.