Classification Of Renal Cell Carcinoma Research Articles

Evaluation of Morphologically Unclassified Renal Cell Carcinoma with Electron Microscopy and Novel Renal Markers: Implications for Tumor Reclassification

Despite progress in the classification of renal cell carcinomas (RCC), a subset of these carcinomas remains unclassified (RCC-U). Patients with RCC-U usually present at a late stage and have a poor prognosis. Several studies have attempted to extract new classifications of newly recognized renal carcinomas from the group of RCC-U. However, to date, no studies in the literature have attempted to characterize the RCC-U with unrecognizable cell types beyond the morphologic evaluation on H&E-stained sections. The purpose of this study was to evaluate this group of RCC-U using electron microscopy and novel renal markers. Ten cases of such RCC-U were identified for this study. At the ultrastructural level, they did not show typical morphology that resembled any of the well-studied, recognizable subtypes of RCC. However, they did reveal features of renal tubular epithelial differentiation. The histologic, ultrastructural, and immunophenotypic features indicated that these tumors are poorly differentiated renal epithelial tumors, possibly derived from the proximal nephron, with an immunohistochemical profile similar to high-grade clear cell RCC. It is, therefore, proposed that this group of renal carcinomas be renamed “poorly differentiated renal cell carcinoma, not otherwise specified.” The current study showed that PAX-8 and carbonic anhydrase IX are reliable markers for this novel group of renal carcinoma, and that electron microscopy is an important adjunct in the evaluation of new and unusual renal entities.

Contemporary approach to diagnosis and classification of renal cell carcinoma with mixed histologic features

Renal cell carcinoma (RCC) is an important contributor to cancer-specific mortality worldwide. Targeted agents that inhibit key subtype-specific signaling pathways have improved survival times and have recently become part of the standard of care for this disease. Accurately diagnosing and classifying RCC on the basis of tumor histology is thus critical. RCC has been traditionally divided into clear-cell and non–clear-cell categories, with papillary RCC forming the most common subtype of non–clear-cell RCC. Renal neoplasms with overlapping histologies, such as tumors with mixed clear-cell and papillary features and hybrid renal oncocytic tumors, are increasingly seen in contemporary practice and present a diagnostic challenge with important therapeutic implications. In this review, we discuss the histologic, immunohistochemical, cytogenetic, and clinicopathologic aspects of these differential diagnoses and illustrate how the classification of RCC has evolved to integrate both the tumor's microscopic appearance and its molecular fingerprint.

Histopathology of Surgically Treated Renal Cell Carcinoma: Survival Differences by Subtype and Stage

Previous studies of the impact of renal cell carcinoma histopathology on survival are conflicting and generally limited to institutional analyses. Thus, we determined the role of renal cell carcinoma histopathology on the stage specific survival rate in a large population based cohort. We used the 2000 to 2005 National Cancer Institute SEER (Surveillance, Epidemiology and End Results) database to identify 17,605 patients who underwent surgery for renal cell carcinoma and met study inclusion criteria. Patients were stratified by histological subtype (clear cell, papillary, chromophobe, collecting duct and sarcomatoid differentiation) and pathological stage. We performed Cox proportional hazard modeling and Kaplan-Meier survival analysis to determine overall and cancer specific survival. Patients with papillary and chromophobe pathology were less likely to present with T3 or greater disease (17.6% and 16.9%, respectively) while patients with collecting duct and sarcomatoid variants were more likely to present with T3 or greater disease (55.7% and 82.8%, respectively) compared to those with clear cell histology (p <0.001). On multivariate analysis histology was significantly associated with overall and cancer specific survival. Patients with chromophobe pathology had improved survival (HR 0.56, 95% CI 0.40-0.78) while those with collecting duct and sarcomatoid variants had worse survival (HR 2.07, 95% CI 1.44-2.97 and 2.26, 95% CI 1.93-2.64, respectively). Renal cell carcinoma histological subtype predicts overall and cancer specific survival. Patients with collecting duct and sarcomatoid variants of renal cell carcinoma have poor survival, even those who present with low stage disease. These data suggest inherent differences in renal cell carcinoma biology and may ultimately form the basis of future histologically targeted therapies.

BAP1 loss defines a new class of renal cell carcinoma

The molecular pathogenesis of renal cell carcinoma (RCC) is poorly understood. Whole-genome and exome sequencing followed by innovative tumorgraft analyses (to accurately determine mutant allele ratios) identified several putative two-hit tumor suppressor genes including BAP1. BAP1, a nuclear deubiquitinase, is inactivated in 15% of clear-cell RCCs. BAP1 cofractionates with and binds to HCF-1 in tumorgrafts. Mutations disrupting the HCF-1 binding motif impair BAP1-mediated suppression of cell proliferation, but not H2AK119ub1 deubiquitination. BAP1 loss sensitizes RCC cells in vitro to genotoxic stress. Interestingly, BAP1 and PBRM1 mutations anticorrelate in tumors (P=3×10−5), and combined loss of BAP1 and PBRM1 in a few RCCs was associated with rhabdoid features (q=0.0007). BAP1 and PBRM1 regulate seemingly different gene expression programs, and BAP1 loss was associated with high tumor grade (q=0.0005). Our results establish the foundation for an integrated pathological and molecular genetic classification of RCC, paving the way for subtype-specific treatments exploiting genetic vulnerabilities.

Mucinous tubular and spindle cell carcinoma of the kidney

Mucinous tubular and spindle cell carcinoma (MTSCC) is a low-grade renal epithelial neoplasm that has recently been recognized as a specific entity in the 2004 World Health Organization classification of renal cell carcinoma. A 69-year-old woman was referred to our hospital because of incidental left renal tumor. Abdominal computed tomography showed a hypovascular tumor in the left kidney. Left radical nephrectomy was performed. Hematoxylin and eosin staining revealed cuboidal and oval or spindle-shaped cells in tubular and papillary patterns embedded in the myxoid stroma. Immunohistochemically, the tumor cells were positive for alpha-methylacyl-CoA racemase. On the basis of these findings, we diagnosed the patient as having MTSCC.

Papillary Renal Cell Carcinoma Is Associated With PTEN Hamartoma Tumor Syndrome

To formally study the prevalence and histologic classification of renal cell carcinoma (RCC) in a series of patients with PTEN hamartoma tumor syndrome (PHTS). We evaluated prevalence of RCC within a prospectively-accrued series of 219 patients found to have pathogenic germline PTEN mutations. Clinical data including pathology reports were requested for all participants. Slides and tumor blocks were requested for central pathology re-review and immunohistochemistry (IHC) analysis. Nine patients were identified with RCC. Based on Surveillance Epidemiology and End Results (SEER) data 0.28 RCC cases were expected for the group, giving an overall age-adjusted Standardized Incidence Ratio (SIR) of 31.7 (95% CI 15.4-58.1, P < 0.001) with a higher sex-adjusted SIR for females (46.7 vs 21.6 for males). Reported histology of each mutation positive patient's RCC was variable. However, on central pathology re-review of eight patients, six examined lesions were determined to be of papillary subhistology (pRCC), with the other two patients' tumors consistent with the initial report of chromophobe RCC (chRCC). IHC demonstrated complete loss of PTEN protein in all PTEN mutation positive patients' pRCCs and patchy positivity in one chRCC. PHTS is a hereditary syndrome newly associated with pRCC, and PTEN IHC may be a helpful screening tool to identify pRCC patients with PHTS. Physicians caring for PHTS patients should note the >31-fold increased risk for RCC and have a low threshold for investigating possible RCC in patients with relevant complaints. Renal ultrasound is not sensitive for detecting pRCC and so PHTS patients should have alternate renal imaging (CT or MRI).

Clear cell renal carcinoma with areas of chromophobe renal cell carcinoma

The classification of renal cell carcinoma (RCC) is based upon various histological features which aids in determining the treatment and prognosis. We report a unique case of RCC displaying features of predominantly clear cell RCC with areas of chromophobe RCC in an unusual edematous background. The tumor cells from chromophobe RCC were positive for Hales colloidal iron stain. On Immunohistochemistry majority of them were positive for vimentin and CD10, the markers of clear cell RCC with scattered cells positive for cytokeratin 7, marker of chromophobe RCC. It was grade 4 malignant tumor according to Fuhrman nuclear grading.

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.

Adult renal cell carcinoma with rhabdoid morphology represents a neoplastic dedifferentiation analogous to sarcomatoid carcinoma

Renal cell carcinoma (RCC) with rhabdoid morphology (RCC-RM) is a recently described variant of RCC, which has an aggressive biologic behavior and poor prognosis, akin to sarcomatoid RCC. The current World Health Organization classification of RCC does not include the rhabdoid phenotype as a distinct histologic entity. The aim of this study is to investigate whether RCC-RM represents a dedifferentiation of a classifiable-type World Health Organization RCC or a carcinosarcoma with muscle differentiation. We reviewed 168 cases of RCC obtained between 2003 and 2008. From these cases, 10 (6%) were found to have areas of classic rhabdoid morphology. Immunohistochemistry for cytokeratin, epithelial membrane antigen, desmin, CD10, and CD117 was performed in each case using the labeled streptavidin-biotin method. Rhabdoid differentiation was identified in association with conventional-type RCC (9) and with unclassifiable-type RCC with spindle cell morphology (1). In all cases, both the rhabdoid and nonrhabdoid tumoral areas were positive for cytokeratin and epithelial membrane antigen and negative for desmin. Cytokeratin positivity in the rhabdoid areas was focal. In cases associated with conventional-type RCC, CD10 was positive in both the rhabdoid and nonrhabdoid foci. CD117 was negative in these tumors. The unclassifiable-type RCC with spindle cell morphology was negative for both CD10 and CD117. The similar immunophenotype between the rhabdoid and nonrhabdoid tumoral foci supports the origin of the rhabdoid cells from the classifiable-type RCC. Areas of rhabdoid morphology do not represent muscle metaplastic differentiation. Renal cell carcinoma with rhabdoid morphology may represent a dedifferentiation of a classifiable-type RCC, similar to that of sarcomatoid differentiation. The recognition of RCC-RM is important as it allows for the inclusion of these high-grade malignancies into a category associated with poor prognosis despite lacking the spindle cell component classically identified as sarcomatoid change.

Abstract 299: CDK1 and CDK2 activity is a strong predictor of renal cell cancer recurrence

Abstract Background: We established original methods enabling simultaneous analysis of protein expressions and kinase activities of the CDK (cyclin-dependent kinase) molecules in lysate of tumor tissue in a clinical setting (C2P technology, Ishihara et al: Biochim Biophys Acta. 1741; 226-233, 2005). The clinical utility of the technology was first evaluated in breast cancer, and combination analysis of CDK1 and CDK2 activity was shown to be a significant prognostic indicator for relapse (Kim et al: Ann Oncol. 19; 68-72, 2009). The objective of our study is to evaluate the efficacy of CDK1 and CDK2 activity as a prognostic marker in human renal cell carcinoma (RCC).Methods: Surgical specimens were obtained from 125 patients with RCC without metastasis. These patients were selected randomly for this study. Protein expression and kinase activity of CDKs and cyclins were analyzed using a newly developed assay system. The system to measure the CDK specific activity (SA) is named C2Ps (Sysmex, Kobe, Japan). We then examined the specific activities of CDK1 and CDK2 and calculated CDK2/CDK1 ratio in RCC. Also, risk score (RS) was examined as described in previous study (JGH van Nes et al: Br J Cancer. 100; 494-500, 2009). Cut off value was calculated by ROC analysis.Results: 125 cases were tested, though 34 cases were excluded of low sample quality (25 cases) and of assay failure (9 cases). 91 cases were analyzed. They included 68 male and 23 female patients, ranging in age from 19 to 83 years. At a median follow up of 36 months (1-109M), tumor with low CDK2/CDK1 ratio showed significantly better 5-year progression free survival (PFS) than those with high CDK2/CDK1 ratio (88.7% vs 54.7%, P=0.00141). Also, RS enabled the classification of RCCs into high-risk and low-risk groups, patients with tumors classified as low RS showed better PFS than patients with tumors with high RS (88.7% vs 54.7%, P=0.0141).Conclusion: CDK1 specific activity of tumors and the CDK2 specific activity are both associated with recurrence and prognosis. Analysis of cyclin-dependent kinase activity in the clinical setting could be a powerful approach for predicting cancer recurrence and prognosis in RCC after surgery and has potential for use as a routine laboratory test. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 299. doi:10.1158/1538-7445.AM2011-299

968 CDK1 AND CDK2 ACTIVITY IS A STRONG PREDICTOR OF RENAL CELL CANCER RECURRENCE

You have accessJournal of UrologyKidney Cancer: Evaluation and Staging1 Apr 2011968 CDK1 AND CDK2 ACTIVITY IS A STRONG PREDICTOR OF RENAL CELL CANCER RECURRENCE Fumiya Hongo, Natsuki Takaha, Yasunori Kimura, Terukazu Nakamura, Kazuya Mikami, Satoshi Nakayama, Tomoko Matsushima, Hideaki Ishihara, Toshiyuki Sakai, and Tsuneharu Miki Fumiya HongoFumiya Hongo Kyoto, Japan More articles by this author , Natsuki TakahaNatsuki Takaha Kyoto, Japan More articles by this author , Yasunori KimuraYasunori Kimura Kyoto, Japan More articles by this author , Terukazu NakamuraTerukazu Nakamura Kyoto, Japan More articles by this author , Kazuya MikamiKazuya Mikami Kyoto, Japan More articles by this author , Satoshi NakayamaSatoshi Nakayama Kobe, Japan More articles by this author , Tomoko MatsushimaTomoko Matsushima Kobe, Japan More articles by this author , Hideaki IshiharaHideaki Ishihara Kobe, Japan More articles by this author , Toshiyuki SakaiToshiyuki Sakai Kyoto, Japan More articles by this author , and Tsuneharu MikiTsuneharu Miki Kyoto, Japan More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2011.02.936AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES We established original methods enabling simultaneous analysis of protein expressions and kinase activities of the CDK (cyclin-dependent kinase) molecules in lysate of tumor tissue in a clinical setting (C2P technology, Ishihara et al: Biochim Biophys Acta. 1741; 226–233, 2005). The clinical utility of the technology was first evaluated in breast cancer, and combination analysis of CDK1 and CDK2 activity was shown to be a significant prognostic indicator for relapse (Kim et al: Ann Oncol. 19; 68–72, 2009). The objective of our study is to evaluate the efficacy of CDK1 and CDK2 activity as a prognostic marker in human renal cell carcinoma (RCC). METHODS Surgical specimens were obtained from 125 patients with RCC without metastasis. These patients were selected randomly for this study. Protein expression and kinase activity of CDKs and cyclins were analyzed using a newly developed assay system. The system to measure the CDK specific activity (SA) is named C2Ps (Sysmex, Kobe, Japan). We then examined the specific activities of CDK1 and CDK2 and calculated CDK2/CDK1 ratio in RCC. Also, risk score (RS) was examined as described in previous study (JGH van Nes et al: Br J Cancer. 100; 494–500, 2009). Cut off value was calculated by ROC analysis. RESULTS 125 cases were tested, though 34 cases were excluded of low sample quality (25 cases) and of assay failure (9 cases). 91 cases were analyzed. They included 68 male and 23 female patients, ranging in age from 19 to 83 years. At a median follow up of 36 months (1–109 M), tumor with low CDK2/CDK1 ratio showed significantly better 5-year progression free survival (PFS) than those with high CDK2/CDK1 ratio (88.7% vs 54.7%, P=0.00141). Also, RS enabled the classification of RCCs into high-risk and low-risk groups, patients with tumors classified as low RS showed better PFS than patients with tumors with high RS (88.7% vs 54.7%, P=0.0141). CONCLUSIONS CDK1 specific activity of tumors and the CDK2 specific activity are both associated with recurrence and prognosis. Analysis of cyclin-dependent kinase activity in the clinical setting could be a powerful approach for predicting cancer recurrence and prognosis in RCC after surgery and has potential for use as a routine laboratory test. © 2011 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 185Issue 4SApril 2011Page: e390 Advertisement Copyright & Permissions© 2011 by American Urological Association Education and Research, Inc.MetricsAuthor Information Fumiya Hongo Kyoto, Japan More articles by this author Natsuki Takaha Kyoto, Japan More articles by this author Yasunori Kimura Kyoto, Japan More articles by this author Terukazu Nakamura Kyoto, Japan More articles by this author Kazuya Mikami Kyoto, Japan More articles by this author Satoshi Nakayama Kobe, Japan More articles by this author Tomoko Matsushima Kobe, Japan More articles by this author Hideaki Ishihara Kobe, Japan More articles by this author Toshiyuki Sakai Kyoto, Japan More articles by this author Tsuneharu Miki Kyoto, Japan More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Renal cell carcinoma with novel VCL–ALK fusion: new representative of ALK-associated tumor spectrum

Renal cell carcinoma represents a model for contemporary classification of solid tumors; however, unusual and unclassifiable cases exist and are not rare in children and young adults. The anaplastic lymphoma kinase (ALK) gene has recently been implicated in subsets of pulmonary, esophageal, breast, and colon cancers. These findings strengthen the importance of molecular classification of carcinomas across different organ sites, especially considering the evolving targeted anticancer therapies with ALK inhibitors. In the current study of six pediatric renal cell carcinomas, two cases exhibited structural karyotypic abnormalities involving the ALK locus on chromosomal band 2p23. Fluorescence in situ hybridization (FISH) studies were positive for an ALK rearrangement in one case, and subsequent 5′ rapid amplification of cDNA ends analysis of this tumor revealed that the 3′ portion of the ALK transcript encoding for the kinase domain was fused in frame to the 5′ portion of vinculin (VCL, NM_003373). The new fusion gene is predicted to have an open reading frame of 4122 bp encoding for a 1374-aa oncoprotein; its expression was shown by immunoblotting with anti-VCL and anti-ALK antibodies in tumor tissue lysates. Immunohistochemistry with the same antibodies demonstrated cytoplasmic and subplasmalemmal localization of the oncoprotein determined by its N-terminal VCL portion. FISH with a custom-designed VCL–ALK dual-fusion probe set confirmed the presence of the fusion in neoplastic cells and demonstrated the potential clinical utility of this approach for detecting VCL–ALK in routinely processed tissue. The five remaining pediatric renal cell carcinomas did not show ALK rearrangement by FISH or ALK expression by immunohistochemistry. The data identify the kidney as a new organ site for ALK-associated carcinomas and VCL as a novel ALK fusion partner. The results should prompt further studies to advance the molecular classification of renal cell carcinoma and help to select patients who would benefit from appropriate targeted therapies.

Use of CDK1 and CDK2 activity to predict renal cell cancer recurrence.

341 Background: We established original methods enabling simultaneous analysis of protein expressions and kinase activities of the CDK (cyclin-dependent kinase) molecules in lysate of tumor tissue in a clinical setting (C2P technology, Ishihara et al: Biochim Biophys Acta. 1741; 226-233, 2005). The clinical utility of the technology was first evaluated in breast cancer, and combination analysis of CDK1 and CDK2 activity was shown to be a significant prognostic indicator for relapse (Kim et al. Ann Oncol. 19;68-72,2009). The objective of our study is to evaluate the efficacy of CDK1 and CDK2 activity as a prognostic marker in human renal cell carcinoma (RCC). Methods: Surgical specimens were obtained from 115 patients with RCC without metastasis. These patients were selected randomly for this study. Protein expression and kinase activity of CDKs and cyclins were analyzed using a newly developed assay system. The system to measure the CDK specific activity (SA) is named C2Ps (Sysmex, Kobe, Japan). We then examined the specific activities of CDK1 and CDK2 and calculated CDK2/CDK1 ratio in RCC. Also, risk score (RS) was examined as described in previous study (JGH van Nes et al: Br J Cancer. 100; 494-500, 2009). Cut off value was calculated by ROC analysis. Results: 115 cases were tested, though 32 cases were excluded of low sample quality (30 cases) and of assay failure (2 cases). 83 cases were analyzed. They included 63 male and 20 female patients, ranging in age from 19 to 83 years. At a median follow up of 33 months (1-109M), tumor with low CDK2/CDK1 ratio showed significantly better 5-year progression-free survival (PFS) than those with high CDK2/CDK1 ratio (91.2% vs. 51.6%, p=0.0016). Also, RS enabled the classification of RCCs into high-risk and low-risk groups, patients with tumors classified as low RS showed better PFS than patients with tumors with high RS (88.9% vs. 63.9%, p=0.0488). Conclusions: CDK1 specific activity of tumors and the CDK2 specific activity are both associated with recurrence and prognosis. Analysis of cyclin-dependent kinase activity in the clinical setting could be a powerful approach for predicting cancer recurrence and prognosis in RCC after surgery and has potential for use as a routine laboratory test. No significant financial relationships to disclose.

Is There a Need to Further Subclassify pT2 Renal Cell Cancers as Implemented by the Revised 7th TNM Version?

BackgroundThe recently modified TNM classification of renal cell carcinoma (RCC) (7th edition) has implemented a subdivision of pT2 tumours into stage pT2a (>7 or ≤10cm) versus pT2b disease (>10cm). ObjectiveOur aim was to evaluate whether this subdivision of pT2 RCC is justified due to a clinical prognosis divergence between the two groups (pT2a vs pT2b) Design, setting, and participantsIn total, 5122 patients were subjected to either radical nephrectomy or nephron-sparing surgery at three centres in Germany (University Hospitals of Hannover, Homburg/Saar, and Marburg). Patients were reclassified into stage pT2a and pT2b according to the maximum tumour diameter as suggested by the 7th revised version of the TNM classification system. MeasurementsThe t test and Fisher exact test were applied to evaluate the comparability of the two groups (pT2a vs pT2b) regarding several additional patients’ and tumour-specific characteristics of known prognostic relevance for RCC. Univariable (Kaplan-Meier analysis) and multivariable statistical analyses (Cox proportional hazards regression model) were applied to identify a possible difference between the two groups (pT2a vs pT2b) regarding cancer-specific survival (CSS). Results and limitationsApplying the new TNM classification, 579 previously pT2-staged patients were divided into 445 (76.9%) with pT2a and 134 (23.1%) with pT2b tumours. Kaplan-Meier curves revealed no significant difference in CSS between pT2a and pT2b patients; 5-yr CSS was 79.0% and 74.1%, respectively (p=0.38). When applying multivariable analysis, unlike tumour grade and N/M status, pT2 subclassification failed to independently predict survival in RCC patients. ConclusionsThe new subclassification of pT2 RCC into two different subgroups as suggested by the latest modification of the TNM system does not yield additional/prognostic information.

Non-clear cell renal carcinoma: comparative analysis of the new and old histological classification in 79 cases

To compare the old classification and 2004 WHO histological classification of renal cell carcinoma, summarize the differences and possible reasons, and correct the traditional pathological concepts of kidney cancer. Specimens of 79 cases histopathologically diagnosed as non-clear cell renal cell carcinomas after radical nephrectomy during 1998 to 2005 in Tianjin Medical University Cancer Hospital were reclassified according to the 2004 WHO renal cell carcinoma histological classification system. After reclassification, there were 14 cases of clear cell renal cell carcinoma (CCRCC), 23 cases of papillary renal cell carcinoma (PRCC), 34 cases of chromophobe renal cell carcinoma (ChRCC), one collecting duct renal cell carcinoma, one unclassified renal cell carcinoma, 5 cases of mixed cell renal cell carcinoma (CCRCC + PRCC 2 cases, CCRCC + ChRCC 2 cases, PRCC + ChRCC 1 case), and one oncocytoma diagnosed. Some chromophobe renal cell carcinomas and papillary renal cell carcinomas were easier to be diagnosed as granular cell renal cell carcinoma in the past. The eosinophilic cytoplasm similar to that in the granular cells, and some confusion between PRCC and ChRCC are the main reasons. The cellular characteristic features of granular renal cell carcinoma can be found in many types of renal tumors. Granular cell renal cell carcinoma is not an independent entity, therefore, it should be removed from the histological classification of renal cell carcinoma. The diagnosis standard of mixed renal cell carcinoma (MRCC) need to be determined and consummated.

Use of CDK1 and CDK2 activity to predict renal cell cancer recurrence.

e15007 Background: We established original methods enabling simultaneous analysis of protein expressions and kinase activities of the CDK (cyclin-dependent kinase) molecules in lysate of tumor tissue in a clinical setting (C2P technology, Ishihara et al: Biochim Biophys Acta. 1741; 226- 233, 2005). The clinical utility of the technology was first evaluated in breast cancer, and combination analysis of CDK1 and CDK2 activity was shown to be a significant prognostic indicator for relapse (Kim et al: Ann Oncol. 19; 68-72, 2009). The objective of our study is to evaluate the efficacy of CDK1 and CDK2 activity as a prognostic marker in human renal cell carcinoma (RCC). Methods: Surgical specimens were obtained from 115 patients with RCC without metastasis. These patients were selected randomly for this study. Protein expression and kinase activity of CDKs and cyclins were analyzed using a newly developed assay system. The system to measure the CDK specific activity (SA) is named C2Ps (Sysmex, Kobe, Japan). We then examined the specific activities of CDK1 and CDK2 and calculated CDK2/CDK1 ratio in RCC. Also, risk score (RS) was examined as described in previous study (JGH van Nes et al: Br J Cancer. 100; 494-500, 2009). Cut off value was calculated by ROC analysis. Results: 115 cases were tested, though 32 cases were excluded of low sample quality (30 cases) and of assay failure (2 cases). 83 cases were analyzed. They included 63 male and 20 female patients, ranging in age from 19 to 83 years. At a median follow up of 33 months (1-109M), tumor with low CDK2/CDK1 ratio showed significantly better 5-year progression free survival (PFS) than those with high CDK2/CDK1 ratio (91.2% vs 51.6%, p=0.0016). Also, RS enabled the classification of RCCs into high-risk and low-risk groups, patients with tumors classified as low RS showed better PFS than patients with tumors with high RS (88.9% vs 63.9%, p=0.0488). Conclusions: CDK1 specific activity of tumors and the CDK2 specific activity are both associated with recurrence and prognosis. Analysis of cyclin-dependent kinase activity in the clinical setting could be a powerful approach for predicting cancer recurrence and prognosis in RCC after surgery and has potential for use as a routine laboratory test. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Sysmex Corporation

Histological Subtype is an Independent Predictor of Outcome for Patients With Renal Cell Carcinoma

There are significant differences in clinicopathological features among renal cell carcinoma histological subtypes but controversy exists regarding the independent impact of histological subtype on patient outcome after nephrectomy. We examined the significance of histological subtype on progression to distant metastasis and cancer specific death after nephrectomy. In a retrospective review of our institutional nephrectomy registry we identified 3,062 patients treated surgically for clear cell, papillary or chromophobe renal cell carcinoma between 1970 and 2003. We identified 2,466 patients (80.5%) with clear cell, 438 (14.3%) with papillary and 158 (5.2%) with chromophobe renal cell carcinoma. There were significant differences in age at surgery, gender, symptoms at presentation, tumor size, stage and grade, tumor necrosis, sarcomatoid differentiation and multifocality among the 3 renal cell carcinoma subtypes (p <0.01 for all). A significant difference in metastasis-free and cancer specific survival existed between patients with clear cell renal cell carcinoma and the 2 other subtypes, although no significant difference in these outcomes was identified between patients with the papillary and chromophobe subtypes. The clear cell renal cell carcinoma subtype remained a significant predictor of metastasis (HR 2.76, 95% CI 2.05-3.73) and cancer specific death (HR 1.77, 95% CI 1.38-2.26, each p <0.001) after multivariate adjustment for the features listed above. Histological subtype is an independent predictor of progression to distant metastasis and cancer specific death in patients with renal cell carcinoma.

Renal cell carcinoma in patients with end‐stage renal disease: relationship between histological type and duration of dialysis

To evaluate the clinical outcomes and histological types of renal cell carcinoma (RCC) arising in patients with end-stage renal disease (ESRD), and to analyse the relationship of histopathological features with the duration of dialysis. Clinical characteristics and outcomes of 34 patients who had a radical nephrectomy for RCC arising in ESRD between November 1994 and June 2008 were investigated. Archive paraffin-embedded tissue specimens obtained from 27 patients were histochemically and immunohistochemically analysed to determine the histopathological type. There was one death from cancer and one patient with local progression within a median observation period of 29.5 months. Acquired cystic disease (ACD)-associated RCC, clear cell-papillary RCC, mucinous tubular and spindle-cell carcinoma, and Xp11.2 translocation/TFE3 gene fusion were identified in eight, two, three and one patient, respectively. Conventional clear-cell RCC was the predominant histological type (nine of 15) in patients with a duration of dialysis of <10 years, while ACD-associated RCC was predominant (seven of 12) in those with dialysis for > or =10 years. Sarcomatoid foci were identified in three patients with dialysis for > or =10 years. Papillary adenoma was microscopically identified as a satellite tumour in 10 patients. The spectrum of histological types of RCCs arising in ESRD is distinct from that of sporadic RCCs. Patients with a longer duration of dialysis should have particular attention for progression and metastasis. Immunohistochemical profiling is efficient in the histological classification of RCCs arising in ESRD, although knowledge about genetic changes remains to be accumulated.

Diagnostic Utility of AMACR and Claudin-7 for the Classification of Renal Cell Carcinoma

Diagnostic Utility of AMACR and Claudin-7 for the Classification of Renal Cell Carcinoma

Prognostic Factors of Papillary Renal Cell Carcinoma: Results From a Multi-Institutional Series After Pathological Review

We examined papillary renal cell carcinoma prognostic variables and validated the 2002 UICC TNM staging system in a multicenter analysis. From 10 urological institutions in Germany followup data were collected on a total of 675 patients with papillary renal cell carcinoma. Central pathological review was done to validate external histopathological diagnoses. The Kaplan-Meier method was used to derive cumulative cancer specific and overall survival, and the log rank test was used to compare the curves of 2 or more groups. For multivariate analysis of prognostic factors Cox regression analysis was done. All proportional hazard assumptions were systemically verified using the Grambsch-Therneau test. Cancer specific survival was significantly related to TNM stage and histological grading on univariate and multivariate analyses. Five-year cancer specific survival in pT1b cases was significantly shorter than in pT1a cases (90.0% vs 98.3%, p = 0.017). No significant difference was found between pT1b and pT2 tumors. Patients with pT3 or greater disease were at high risk for metastasis (50.6%) while metastatic disease associated with pT2 or less tumors occurred in 7.8% (p <0.0001). After metastatic disease was present the prognosis was poor with 7.2% 5-year cancer specific survival. Age was associated with poor prognosis in the subgroup with pT3 or greater tumors on univariate analysis (p = 0.026) but not on multivariate analysis. In its current form the 2002 UICC TNM staging system is not applicable to papillary renal cell carcinoma. Clinical and radiological followup should be offered at frequent intervals to patients with venous thrombus and/or locally advanced disease. The role of age remains unclear but should not be underestimated in risk stratification after surgery.