Are morphological criteria sufficient for the identification of circulating tumor cells in renal cancer?

BACKGROUND: Single circulating tumor cells (CTCs) or circulating tumor microemboli (CTMs) are potential biomarkers of renal cell cancer (RCC), however studies of CTCs/CTMs in RCC are limited. In this pilot study we aimed to evaluate a novel blood filtration technique suited for cytomorphological classification, immunocytochemical and molecular characterization of filtered, so called circulating non-hematologic cells (CNHCs) - putative CTCs/CTMs - in patients with RCC. METHODS: Blood of 40 patients with renal tumors was subjected to ScreenCell filtration. CNHCs were classified according to cytomorphological criteria. Immunocytochemical analysis was performed with antibodies against CD45, CD31 and carbonic anhydrase IX (CAIX, a RCC marker). DNA of selected CNHCs and respective primary tumors was analysed by array-CGH. RESULTS: CNHC-clusters with malignant or uncertain malignant cytomorphological features - putative CTMs - were negative for CD45, positive for CD31, while only 6% were CAIX positive. Array-CGH revealed that 83% of malignant and uncertain malignant cells did represent with a balanced genome whereas 17% presented genomic DNA imbalances which did not match the aberrations of the primary tumors. Putative single CTCs were negative for CD45, 33% were positive for CD31 and 56% were positive for CAIX. CONCLUSIONS: The majority of CNHC-clusters, putative CTMs, retrieved by ScreenCell filtration may be of endothelial origin. Morphological criteria seem to be insufficient to distinguish malignant from non-malignant cells in renal cancer.

Comparison of the 2002 and 2010 TNM classification systems regarding outcome prediction in clear cell and papillary renal cell carcinoma.

AIMS: A novel version of the tumour-node-metastasis (TNM) classification system for renal cell carcinoma (RCC) was introduced in 2010, although the prognostic significance with regard to different histological subtypes has not been explored. Therefore, the aim of our study was to compare the predictive ability of the 2002 and 2010 versions of the TNM classification system for clear cell and papillary RCC. METHODS AND RESULTS: Data from 2263 consecutive clear cell and 309 papillary RCC patients, operated at a single tertiary academic centre, were evaluated. According to TNM 2010, statistically significant differences for cancer-specific survival (CSS) were observed for pT1a versus pT1b (P < 0.001) and pT3a versus pT3b (P < 0.004) in clear cell RCC; and pT1b versus pT2a (P = 0.002) and pT3b versus pT3c (P = 0.046) in papillary RCC. The c-index for CSS in clear cell RCC was 0.74 and 0.73, and in papillary RCC 0.79 and 0.78, for the 2002 and 2010 versions of the TNM classification system, respectively. CONCLUSIONS: According to our data, the predictive ability of the 2010 version of the TNM classification system regarding CSS is not superior to the 2002 version, either in clear cell or in papillary RCC.

Does preoperative platelet count and thrombocytosis play a prognostic role in patients undergoing nephrectomy for renal cell carcinoma? Results of a comprehensive retrospective series.

PURPOSE: To evaluate the still controversially discussed prognostic role of preoperative platelet level (PPL) and thrombocytosis (TC) in patients who undergo surgery for renal cell carcinoma (RCC) based on the largest patient series reported to date. METHODS: A total of 3,139 patients, who underwent radical or nephron-sparing nephrectomy at four centres, were subdivided based on a threshold for preoperative platelets of 400 × 10(9) cells/L. Univariate and multivariable Cox regression analyses were applied to determine the prognostic influence of PPL and TC on cancer-specific survival (CSS) for patients with localized and metastatic disease at presentation. RESULTS: Group 1 (PPL ≤ 400/nl) and Group 2 (PPL > 400/nl) included 2,862 (91 %) and 277 patients (9 %), respectively. With a median follow-up (FU) of 69.5 months (IQR: 35-105), CSS of all patients after 5 years was 84.6 % in Group 1 versus 53.4 % in Group 2 (p < 0.001). At multivariable analysis, TC (HR:1.337; p = 0.007) and continuous PPL (HR:1.001; p = 0.002) independently predicted a decreased survival. However, integration of these parameters into multivariable models for the entire study group and for patients with localized tumours did only result in marginal improvement of the model quality (0.66 and 1.04 %, respectively). Interestingly, neither TC (p = 0.257) nor PPL (p = 0.132) significantly influenced survival in M1 patients. CONCLUSIONS: Preoperative TC turned out an independent predictor for decreased CSS in patients undergoing surgery for localized RCC. However, significant improvement of multivariable models comprising standard clinical and pathological parameters by the inclusion of TC is not achieved. In metastatic disease, TC did not reveal an independent influence on CSS.

Predictive ability of the 2002 and 2010 versions of the Tumour-Node-Metastasis classification system regarding metastasis-free, cancer-specific and overall survival in a European renal cell carcinoma single-centre series.

OBJECTIVE: To compare the predictive ability of the Tumour-Node-Metastasis (TNM) classification systems for renal cell carcinoma (RCC) using three different endpoints: metastasis-free (MFS); overall (OS); and cancer-specific survival (CSS). PATIENTS AND METHODS: Data from 2739 consecutive patients with RCC, who underwent surgery at a single academic centre, were evaluated using multivariate Cox proportional models, Harrell's concordance (c)-index and by applying decision curve analysis (DCA) with regard to MFS, OS and CSS. RESULTS: According to TNM 2010, significant differences for MFS were observed for pT1a vs pT1b, pT1b vs pT2a, pT3a vs pT3b and pT3b vs pT3c stages, respectively (all P < 0.05). With regard to OS, significant differences could be observed in pT1a vs pT1b and pT3a vs pT3b stages, respectively (all P < 0.05). The c-index for CSS, OS and MFS was slightly higher for the 2002 than for the 2010 version of the TNM classification system. Non-inferiority of the 2002 TNM system is supported by the results of the DCA. CONCLUSION: According to our data, the predictive ability of the 2010 version of the TNM classification system regarding three different clinical endpoints is not superior to the 2002 version of this staging system.

Trends of stage, grade, histology and tumour necrosis in renal cell carcinoma in a European centre surgical series from 1984 to 2010.

AIMS: To analyse renal cell carcinoma (RCC) stage, grade, histology and necrosis migration in a large European centre series over the last 27 years. METHODS: The pathology reports of 2739 consecutive patients with RCC who underwent nephrectomy from 1984 to 2010 at the institution of the authors were systematically re-evaluated. Patients were pooled into five time groups according to the date of surgery: group 1: 1984-1989, group 2: 1990-1994, group 3: 1995-1999, group 4: 2000-2004 and group 5: 2005-2010, respectively. Changes in pT categories according to WHO 2010 classification, tumour grade, histological subtype and presence of tumour necrosis (TN) were evaluated. RESULTS: Small pT1a tumours were found in 62/485 (12.8%) and 312/639 (48.8%) patients in groups 1 and 5, respectively (p<0.001). Advanced tumour stages (pT3a-4) were found in 306/485 (63.1%) and 171/639 (26.8%) patients in groups 1 and 5, respectively (p<0.001). The number of grade 3/4 tumours increased from 62/485 (12.7%) and 130/639 (20.3%) in groups 1 and 5, respectively, whereas the number of grade 1 tumours decreased over time (p<0.001). There has been a significant histological migration for the chromophobe subtype from 1.1% to 4.3% (p=0.002). The frequency of the presence TN decreased from 41.7% in group 1 to 32.7% in group 5 (p<0.001). CONCLUSIONS: In contrast to data from Australia but similar to data from US cohorts, a statistically significant stage migration towards small RCCs was observed in this European cohort. Significant changes in tumour grade, histological subtype and TN were also observed.

Renal cell carcinoma stage migration in a single European centre over 25 years: effects on 5- and 10-year metastasis-free survival.

PURPOSE: To assess renal cell carcinoma (RCC) stage migration in a large European academic centre series over 25 years and its possible impact on patients' metastasis-free survival. METHODS: The pathology reports of 2,333 consecutive patients with RCC who underwent nephrectomy from 1984 to 2006 at our institution were systematically re-evaluated. Patients were pooled into four groups according to the date of surgery: group 1: 1984-1989, group 2: 1990-1995, group 3: 1996-2001 and group 4: 2002-2006, respectively. Changes in pT-categories over time and the impact on 5- and 10-year metastasis-free survival were evaluated. RESULTS: Organ-confined (pT1 and pT2) tumours were found in 191/502 (38.0 %) and 372/535 (69.5 %) surgical specimens in groups 1 and 4, respectively (p < 0.001). This stage migration was mainly the result of an increase in pT1a tumours (overall: 32.6 %) from 12.5 % in group 1 to 45.8 % in group 4 and a decrease in pT3a tumours (overall: 24.1 %) from 46.6 % in group 1 to 11.0 % in group 4 (p < 0.001). The mean tumour size decreased from 6.7 cm in group 1 to 4.8 cm in group 4 (p < 0.001). In 2,152 patients with non-metastatic RCC, median follow-up was 76.2 (interquartile range: 36.2-133.9) months. Five- and 10-year metastasis-free survival probabilities were 78.7 and 71.9 % in group 1, 85.3 and 80.0 % in group 2, and 86.9 and 82.7 % in group 3, respectively. Five-year metastasis-free survival in group 4 was 90.3 % (p < 0.001). CONCLUSION: A statistically significant stage migration towards organ-confined RCC was observed in the cohort studied. This stage migration was accompanied by a significant improvement in metastasis-free survival comparing the period 1984-1989 and following time periods.

Prognostic value of the Leibovich prognosis score supplemented by vascular invasion for clear cell renal cell carcinoma.

PURPOSE: We assessed whether supplementing the Leibovich prognosis score with vascular invasion would improve prognostic value to predict metastatic disease in patients with nonmetastatic clear cell renal cell carcinoma. MATERIALS AND METHODS: We retrospectively evaluated the pathology records of 1,754 patients with nonmetastatic clear cell renal cell carcinoma treated with surgery between 1984 and 2006 at a single tertiary academic center. The Leibovich prognosis score was supplemented by additional scoring for vascular invasion. Metastasis-free survival was assessed using the Kaplan-Meier method for each score category. A Cox regression model was used for multivariate testing. Predictive accuracy was determined by the Harrell concordance index and decision curve analysis. RESULTS: Median followup was 84 months. Ten-year metastasis-free survival probability for a score of 0 to 1 and 2 to 8 or greater was 95%, 83%, 78%, 81%, 69%, 51%, 15% and 13%, respectively. The concordance index was 0.792 compared to 0.778 from our external validation of the Leibovich prognosis score using routine pathological findings (p <0.05). Decision curve analysis also favored the predictive ability of the novel model. CONCLUSIONS: Adding vascular invasion improved the predictive accuracy of our validation data by 1.4% over that of the Leibovich prognosis score. Patients with a score of 7 or greater had a more than 85% probability of metastatic disease at 10 years. Thus, they could be considered candidates for adjuvant treatment trials.

Histologic tumor necrosis is an independent prognostic indicator for clear cell and papillary renal cell carcinoma.

Histologic tumor necrosis (TN) has been reported to indicate a poor prognosis for different human cancers. In papillary renal cell carcinoma (RCC), data regarding the prognostic impact of TN are conflicting. We retrospectively studied the pathology records of 2,333 consecutive patients who underwent nephrectomy from 1984 to 2006 at a single tertiary academic center. In multivariate analyses regarding clear cell RCC, the presence of histologic TN was an independent negative prognostic factor for metastasis-free (hazard ratio [HR], 2.32; confidence interval [CI], 1.86-2.9; P < .001) and overall (HR, 1.52; CI, 1.31-1.76; P < .001) survival. Regarding papillary RCC, the presence of histologic TN represented an independent predictor of metastasis-free (HR, 5.22; CI, 2.2-12.5; P < .001) and overall (HR, 1.69; CI, 1.11-2.58; P = .015) survival. Our findings suggest that the presence of TN is an independent predictor of clinical outcome in clear cell and papillary RCC. Thus, histologic TN might be a reliable prognostic indicator and should, therefore, routinely be examined during pathologic analysis of RCC specimens.

External validation of the Leibovich prognosis score for nonmetastatic clear cell renal cell carcinoma at a single European center applying routine pathology.

PURPOSE: The Leibovich prognosis score was developed as a prognostic tool for metastatic disease after radical nephrectomy for clear cell renal cell carcinoma using pathology review. However, this scoring system has never been externally validated. We externally validated its prognostic accuracy using routine pathology reports. MATERIALS AND METHODS: We retrospectively evaluated data from the routine pathology records of 1,754 consecutive patients with nonmetastatic clear cell renal cell carcinoma operated on between 1984 and 2006 at a single tertiary academic center. Clear cell renal cell carcinoma cases were categorized as 0 to 11 by the Leibovich prognosis score and further stratified into low, intermediate and high risk groups. Metastasis-free survival was assessed using the Kaplan-Meier method. To evaluate the prognostic impact a multivariate Cox regression model was used and prognostic accuracy was determined using Harrell's concordance index. RESULTS: Median followup was 82 months (IQR 39-142). Metastasis developed in 375 of the 1,754 patients (21.4%). The 10-year metastasis-free survival rate for Leibovich scores in our study ranged from 95% for scores of 0 and 1 to 12% for scores of 8 or greater. Pathological T stage, N stage, low tumor grade, large tumor diameter and histological tumor necrosis were independent predictors of metastasis-free survival (p <0.001). Harrell's concordance index was 0.778. CONCLUSIONS: Risk prediction by the Leibovich prognosis score using routine pathological results was comparable to that of the original data based on pathology review. Our data support using the Leibovich prognosis score in clinical practice for followup decisions and patient selection for adjuvant treatment trials.

External validation of the Mayo Clinic stage, size, grade, and necrosis (SSIGN) score for clear-cell renal cell carcinoma in a single European centre applying routine pathology.

BACKGROUND: The stage, size, grade, and necrosis (SSIGN) score has been created as an outcome prediction tool for clear-cell renal cell carcinoma (ccRCC) using review pathology. OBJECTIVE: We evaluated the prognostic accuracy of the SSIGN score model using routine pathology records. DESIGN, SETTING, AND PARTICIPANTS: We retrospectively evaluated pathology records of 1862 consecutive ccRCC patients with complete data including follow-up who had been operated between 1984 and 2006. INTERVENTION: Surgical treatment of patients with ccRCC. MEASUREMENTS: TNM stage, largest tumour diameter, tumour grade, and presence of histologic tumour necrosis were recorded. ccRCC were categorised according to the SSIGN-score algorithm as 0-15. Cancer-specific survival (CSS) was assessed using the Kaplan-Meier method for individual SSIGN-score categories (scores 0-1 and > or =10, respectively, were combined). For evaluation of the prognostic impact of stage, size, grade, and necrosis regarding CSS, a multivariate analysis using a Cox regression model was performed, and for assessment of prognostic accuracy, Harrell's concordance index was performed. RESULTS AND LIMITATIONS: Median tumour diameter was 5.0 cm (range: 0.6-22 cm). Tumour necrosis was noted in 607 tumours (32.6%). Median follow-up was 72.5 mo (range: 0-281 mo); 359 of 1862 patients (19.3%) died of RCC. Ten-year CSS rates for respective SSIGN scores in our study ranged from 96.5% (scores 0-1) to 19.2% (scores > or =10). pT categories, lymph-node status, distant metastases, high tumour grade (size > or =5 cm), and necrosis were each independent predictors of CSS. The Harrell's concordance index was 0.823. Limitations included smaller sample sizes in higher risk categories and limited numbers of patients at risk after 10 yr. CONCLUSIONS: Outcome prediction with the SSIGN score using routine pathology records was comparable to the original data based on review pathology. Combining scores into five categories improved discrimination. Our data support the routine use of the SSIGN score in clinical practice with regard to follow-up decisions and patient selection for adjuvant trials.