Extranodal extension in regional lymph nodes is associated with outcome in patients with renal cell carcinoma

PURPOSE: The 2002 American Joint Committee on Cancer pN classification for renal cell carcinoma is based on the number of positive regional lymph nodes. We examined the associations of pathological features of lymph node metastases with patient outcome to improve the prognostic accuracy of the current classification. MATERIALS AND METHODS: We studied the records of 2,076 patients treated with radical nephrectomy for unilateral, sporadic pM0 renal cell carcinoma between 1970 and 2000. There were 34 patients with metastasis in a single regional lymph node (pN1) and 35 with metastases in more than 1 lymph node (pN2). Pathological features of lymph node metastases, including the number and percent of positive lymph nodes, total number of lymph nodes removed, grade, necrosis, extranodal extension, and largest dimension and surface area of metastases were determined by 2 urological pathologists (HHD and JCC). RESULTS: There was no statistically significant association between the pN classification and death from renal cell carcinoma (pN2 vs pN1 RR 1.05, 95% CI 0.62 to 1.79, p = 0.846). However, patients with extranodal extension were twice as likely to die of renal cell carcinoma than patients in whom metastases did not extend outside of the lymph node capsule (RR 2.02, 95% CI 1.18 to 3.45, p = 0.010). The 5-year cancer specific survival rate was 18% and 35% in patients with and without extranodal extension, respectively. CONCLUSIONS: We believe that a pN classification based on the presence or absence of lymph node metastases with a notation regarding the presence or absence of extranodal extension represents a significant improvement in the prognostic accuracy of the current pN classification.     

A protocol for performing extended lymph node dissection using primary tumor pathological features for patients treated with radical nephrectomy for clear cell renal cell carcinoma

PURPOSE: We determined the primary pathological features of clear cell renal cell carcinoma that are predictive of positive regional lymph nodes at radical nephrectomy (RN) and developed a protocol for the selective use of extended lymph node dissection. MATERIALS AND METHODS: We studied 1,652 patients who underwent RN for unilateral pM0 sporadic clear cell renal cell carcinoma between 1970 and 2000. A multivariate logistic regression model was used to determine the pathological features of the primary tumor that were associated with positive regional lymph nodes at RN. RESULTS: There were 887 (54%) patients with no positive nodes (pN0), 57 (3%) with 1 positive node (pN1), 11 (1%) with 2 or more positive nodes (pN2) and 697 (42%) who did not have any lymph nodes dissected (pNx). Nuclear grade 3 or 4 (p <0.001), presence of a sarcomatoid component (p <0.001), tumor size 10 cm or greater (p = 0.005), tumor stage pT3 or pT4 (p = 0.017) and histological tumor necrosis (p = 0.051) were significantly associated with positive regional lymph nodes in a multivariate setting. These features can be used to identify candidates for extended lymph node dissection at the time of RN. For example, only 6 (0.6%) of the 1,031 patients with 0 or 1 of these features had positive lymph nodes at RN compared with 62 (10%) of the 621 patients with at least 2 of these features. CONCLUSIONS: The primary tumor pathological features of nuclear grade, sarcomatoid component, tumor size, stage and presence of tumor necrosis can be used to predict patients at the greatest risk for regional lymph node involvement at RN.     

A new staging system for locally advanced (pT3-4) renal cell carcinoma: a multicenter European study including 2,000 patients

PURPOSE: We provide an adequate prognostic stratification for locally advanced renal cell carcinoma and propose a new TNM classification. MATERIALS AND METHODS: We analyzed clinical and pathological data on a large series of patients undergoing radical nephrectomy for pT3-4 renal cell carcinoma at 12 European centers. Cancer specific survivals were estimated using the Kaplan-Meier method. The log rank test was used for comparing survival curves and for univariate analysis. The Cox proportional hazards regression model was used for multivariate analysis. RESULTS: The analysis included 1,969 patients. Median survivor followup was 49 months. Five-year cancer specific survival was 60% for pT3a, 46.2% for pT3b, 10% for pT3c and 12% for pT4 tumors (p <0.0001). According to median survival we identified 3 prognostic groups, including 1--patients with renal vein thrombosis (117 months), fat invasion (98 months) or infradiaphragmatic vena caval thrombosis (67 months), 2--patients with adrenal invasion alone (24 months), renal vein thrombosis plus fat invasion (24 months) or infradiaphragmatic vena cava plus fat invasion (24 months) and 3--patients with renal or infradiaphragmatic caval thrombosis plus adrenal involvement (11 months), supradiaphragmatic vena caval thrombosis (12 months) or Gerota's fascia invasion (12 months). Five-year cancer specific survival rates in groups 1 to 3 were 61%, 35% and 12.9%, respectively (p <0.0001). On multivariate analysis the proposed classification had an independent prognostic value. CONCLUSIONS: Our results suggest the necessity of reclassifying locally advanced renal cell carcinoma according to the 3 described prognostic categories.     

Primary apoptosis as a prognostic index for the classification of metastatic renal cell carcinoma

PURPOSE: We identified novel biological markers of prognosis in primary histopathological specimens from patients with metastatic renal cell carcinoma. MATERIALS AND METHODS: Apoptotic indexes (terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end-labeling), proliferation rates (Ki-67 antigen), p21 (WAF1/cip1) expression and CD95 (APO-1/Fas) expression were determined in paraffin embedded nephrectomy specimens from 73 patients with histologically confirmed, progressive metastatic disease. Kaplan-Meier survival analysis, log rank statistics and 2-proportional Cox regression analysis were done to identify new risk factors in addition to conventional classification criteria, and demonstrate statistical independence. RESULTS: Multivariate analysis indicated that primary tumor apoptosis (p = 0.0116) and the interval from diagnosis to metastatic disease (p = 0.002) had a high predictive impact on overall survival after initial diagnosis. Patients were assigned to 2 risk groups, namely a poor prognosis group with a median survival of 20 months, defined by apoptosis less than 6% in the primary tumor nephrectomy specimen and a time from initial diagnosis to metastatic disease of less than 6 months, and a good prognosis group with a median survival of 56 months, defined as the absence of 1 or 2 risk factors. CONCLUSIONS: Our findings showed that primary tumor apoptosis is a novel independent predictor in patients with metastatic renal cell carcinoma at initial diagnosis. It leads to a new prognostic index in the pretreatment classification of metastatic renal cell carcinoma.     

A postoperative prognostic nomogram predicting recurrence for patients with conventional clear cell renal cell carcinoma

PURPOSE: Few published studies have simultaneously analyzed multiple prognostic factors to predict recurrence after surgery for conventional clear cell renal cortical carcinomas. We developed and performed external validation of a postoperative nomogram for this purpose. We used a prospectively updated database of more than 1,400 patients treated at a single institution. MATERIALS AND METHODS: From January 1989 to August 2002, 833 nephrectomies (partial and radical) for renal cell carcinoma of conventional clear cell histology performed at Memorial Sloan-Kettering Cancer Center were reviewed from the center's kidney database. Patients with von Hippel-Lindau disease or familial syndromes, as well as patients presenting with synchronous bilateral renal masses, or distant metastases or metastatic regional lymph nodes before or at surgery were excluded from study. We modeled clinicopathological data and disease followup for 701 patients with conventional clear cell renal cell carcinoma. Prognostic variables for the nomogram included pathological stage, Fuhrman grade, tumor size, necrosis, vascular invasion and clinical presentation (ie incidental asymptomatic, locally symptomatic or systemically symptomatic). RESULTS: Disease recurrence was noted in 72 of 701 patients. Those patients without evidence of disease had a median and maximum followup of 32 and 120 months, respectively. The 5-year probability of freedom from recurrence for the patient cohort was 80.9% (95% confidence interval 75.7% to 85.1%). A nomogram was designed based on a Cox proportional hazards regression model. Following external validation predictions by the nomogram appeared accurate and discriminating, and the concordance index was 0.82. CONCLUSIONS: A nomogram has been developed that can be used to predict the 5-year probability of freedom from recurrence for patients with conventional clear cell renal cell carcinoma. This nomogram may be useful for patient counseling, clinical trial design and effective patient followup strategies.     

Impact of tumor size on the predictive ability of the pT3a primary tumor classification for renal cell carcinoma

PURPOSE: The accuracy of the pT3a primary tumor classification for renal cell carcinoma has been questioned recently. We investigated the association of perinephric and renal sinus fat invasion with death from renal cell carcinoma independent of tumor size. MATERIALS AND METHODS: We identified 2,165 patients treated with open radical nephrectomy or nephron sparing surgery for clinically localized, sporadic pT1a, pT1b, pT2 or pT3a renal cell carcinoma between 1970 and 2002. Patients with pT3a disease were then subdivided into 3 groups according to tumor size to match the size definitions for the pT1a, pT1b and pT2 tumor classifications. RESULTS: There were 834 patients with pT1a RCC, 674 with pT1b, 494 with pT2 and 163 with pT3a RCC. At last followup 317 patients died of RCC at a median of 3.8 years following surgery. The median followup among the 1,087 patients still alive at last followup was 7.8 years (range 0 to 34). The risk ratios (95% CI) for the association between fat invasion and death from RCC among patients with tumors 4 cm or smaller, 4 to 7 cm and more than 7 cm were 6.15 (1.84-20.50, p = 0.003), 4.12 (2.50-6.78, p <0.001) and 2.13 (1.53-2.97, p <0.001), respectively. These associations remained statistically significant in a multivariate analysis that included nuclear grade and histological coagulative tumor necrosis. CONCLUSIONS: Peripheral perinephric and renal sinus fat invasion was associated with death from RCC independent of tumor size. Our data contradict reports suggesting that pT3a tumors should be reclassified according to tumor size only.     

Evaluation of the association of current cigarette smoking and outcome for patients with clear cell renal cell carcinoma

Objectives:   Cigarette smoking is a well known risk factor for the development of renal cell carcinoma (RCC); however, its association with tumor aggressiveness and patient outcome remains in question. Herein, we test the hypothesis that cigarette smoking is associated with a more aggressive phenotype and poorer outcome among patients with RCC.
Methods:   We examined data on 2242 patients treated with radical nephrectomy or nephron-sparing surgery for unilateral, sporadic, clear cell RCC at Mayo Clinic Rochester between 1970 and 2002. Associations of self-reported smoking status with death from RCC were assessed using Cox proportional hazards regression models summarized with hazard ratios (HR) and 95% confidence intervals (CI).
Results:   While former cigarette smoking was not associated with an increased risk of RCC death, current cigarette smokers were 31% more likely to die from RCC compared with non-smokers on a hazard ratio scale (HR 1.31; 95% CI 1.09–1.58; P  = 0.004). Interestingly, current smokers were more likely to present with advanced disease (i.e. later TNM stage) compared with both former and never smokers. After adjustment for TNM stage group and tumor grade, there was no longer a statistically significant increase in the risk of death from RCC for current cigarette smokers (HR 0.99; 95% CI 0.82–1.19; P  = 0.875).
Conclusions:   Patients who report current smoking at time of surgery are at increased risk of RCC death; however, this association is attenuated after adjustment for standard pathological indices and is therefore of little prognostic value. Nevertheless, the association of current smoking with more advanced disease at presentation (e.g. metastatic spread) warrants further investigation.     

pT1 substaging in renal cell carcinoma: validation of the 2002 TNM staging modification of malignant renal epithelial tumors

PURPOSE: Tumor size has been used as one of the criteria to stratify renal cell carcinoma (RCC) into different pathological stages (pT). The recent 2002 UICC/TNM classification of malignant epithelial renal tumors is modified to substratify pT1 RCC into pT1a (less than 4.0 cm) and pT1b (greater than 4.0 but less than 7.0 cm). In this study we ascertained if this stage modification has prognostic relevance. MATERIALS AND METHODS: A total of 259 consecutive radical nephrectomy specimens of organ confined RCC from 1970 to 1997 at 1 institution, including 153 of conventional RCC (CRCC), 71 of papillary RCC, 28 of chromophobe RCC, 1 of collecting duct carcinoma and 6 of RCC not otherwise specified, with a mean clinical followup of 7.5 years (median 6.4) were included in the study. RESULTS: There were 115 pT1a (44.4%), 95 pT1b (36.7%) and 49 pT2 tumors (18.9%). Disease recurrences (DR) and disease specific death occurred in 2 (1.7%) and 0 cases (0%) of pT1a, 7 (7.3%) and 5 (5.3%) of pT1b, and 16 (32.6%) and 12 (24.5%) of pT2. DR for pT1b was higher compared with pT1a (all histological subtypes RR 3.68), although this difference was not statistically significant (p = 0.106). If only CRCCs were analyzed, DR in the pT1b group was statistically higher compared with pT1a (RR 8.54, p = 0.047). Disease specific survival in pT1a could not be evaluated because no deaths occurred in this subgroup. DR and disease specific survival were significantly different between pT1b and pT2 tumors for all histological subtypes (RR 5.51, p = 0.001 and 5.49, p = 0.001) and for the CRCC subtype (RR 5.50, p = 0.001 and 5.18, p = 0.005, respectively). Using size as a continuous variable the logarithmic change in tumor size was a significant predictor of DR (RR 8.82, p = 0.001). All statistical analyses were adjusted for age and sex. CONCLUSIONS: Substaging RCC into pT1a and pT1b yields prognostically important information, validating the 2002 TNM modification for malignant renal epithelial malignancies. The substratification of pT1 is particularly useful in tumors with CRCC histology.     

TNM T3a renal cell carcinoma: adrenal gland involvement is not the same as renal fat invasion

PURPOSE: Upper pole tumors with direct extension into the adrenal gland are currently staged as pT3a tumors in the 1997 TNM staging system. To determine whether the clinical behavior of pT3a adrenal tumors differs from that of tumors with perinephric fat invasion (also stage pT3a) a retrospective analysis was performed. MATERIALS AND METHODS: Of 1,087 patients who underwent nephrectomy 27 were identified with direct adrenal involvement and 187 were identified with perinephric fat or renal sinus involvement. Variables and outcomes analyzed in each group included the percent of patients with metastatic disease at presentation, lymph node involvement, Eastern Cooperative Oncology Group score, response to immunotherapy, and median and overall survival using Kaplan-Meier curves. RESULTS: Median survival for patients with pT3a disease and perinephric or renal sinus fat involvement was 36 months with a 36% 5-year cancer specific survival rate. In contrast, patients with adrenal gland invasion had significantly worse survival at a median of 12.5 months and a 0% 5-year cancer specific survival rate (p <0.001), which was similar to median survival of those with stage pT4 disease (11 months). CONCLUSIONS: Upper pole tumors with direct extension into the adrenal gland predict significantly worse survival than similarly staged tumors with fat invasion and they have a prognosis similar to that of stage pT4 disease. While these data await external validation, consideration should be given to re-categorizing tumors with direct adrenal gland involvement as stage pT4 or in a subcategory such as pT4a.     

Tumor size predicts synchronous metastatic renal cell carcinoma: implications for surveillance of small renal masses

PURPOSE: Active surveillance of small incidental renal masses is associated with slow radiographic growth and a low risk of metastatic progression. Radiographic tumor size, in the absence of histological data, is the only prognostic indicator available when considering active surveillance. To better define the relationship between tumor size and the metastatic potential of small renal masses, we investigated whether radiographic tumor size predicts for the presence of synchronous metastases in renal cell carcinoma. MATERIALS AND METHODS: We reviewed our institutional tumor registry to identify sporadic pathologically verified renal cell carcinoma treated during an 8-year period. We analyzed data regarding primary tumor size and the presence of biopsy proven synchronous metastatic disease at presentation. All N+M0 and nonpathologically confirmed M+ disease was excluded from analysis. RESULTS: We compared 110 cases of renal cell carcinoma with biopsy proven synchronous metastatic disease at presentation to 250 controls with clinically localized renal cell carcinoma. Tumors associated with synchronous metastasis were significantly larger than localized lesions (median 8.0 cm [range 2.2 to 20.0] vs 4.5 cm [range 0.3 to 17.5], p <0.0001). The probability of synchronous metastasis increased with increasing primary tumor size (p <0.0001). There were no patients with tumors 2 cm or smaller who presented with biopsy confirmed metastatic disease and less than 5% (5 of 110) of all synchronous metastasis occurred in tumors 3.0 cm or smaller. Logistic regression models determined that the odds of synchronous metastasis increased by 22% for each 1 cm increase in tumor size. CONCLUSIONS: Radiographic tumor size is a significant clinical predictor of the presence of biopsy proven synchronous metastatic renal cell carcinoma. In our series the odds of presenting with synchronous, biopsy proven metastatic disease increased by 22% with each 1 cm increase in tumor size. A 100% odds increase, or doubling of the risk of metastasis, occurs with a 3.5 cm increase in primary tumor size. These data have important implications for extent of disease evaluations in patients with large tumors and for the active surveillance of small enhancing renal masses.     

Application of the revised Tumour Node Metastasis (TNM) staging system of clear cell renal cell carcinoma in eastern China: advantages and limitations

This study was designed to evaluate whether the revised 2010 Tumour Node Metastasis (TNM) staging system could lead to a more accurate prediction of the prognosis of renal cell carcinoma (RCC) patients. A total of 1216 patients who had undergone radical nephrectomy or partial nephrectomy for RCC from 2003 to 2011 were enrolled. All of the patients had pathologically confirmed clear cell RCC (ccRCC). All cases were staged by both the 2002 and 2010 TNM staging systems after pathological review, and survival data were collected. Univariate and multivariate Cox regression models were used to evaluate cancer-specific survival (CSS) and progression-free survival (PFS) after surgery. Continuous variables, such as age and tumour diameter, were calculated as mean values and standard deviations (s.d.) or as median values. Survival was calculated by the Kaplan–Meier method, and the log-rank test assessed differences between groups. Statistically significant differences in CSS and PFS were noted among patients in T3 subgroups using the new 2010 staging system. Therefore, the revised 2010 TNM staging system can lead to a more accurate prediction of the prognosis of ccRCC patients. However, when using the revised 2010 staging system, we found that more than 92% of patients (288/313) with T3 tumours were staged in the T3a subgroup, and their survival data were not significantly different from those of patients with T2b tumours. In addition, T2 subclassification failed to independently predict survival in RCC patients.