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.     

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 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.     

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.     

Impact of renal vein invasion and fat invasion in pT3a renal cell carcinoma

Study Type – Therapy (case series) Level of Evidence 4 What's known on the subject? and What does the study add? The presence of invasion of renal vein and perinephric fat are predictors of poor outcome in patients with RCC. The latest version of the TNM system included tumours exhibiting such parameters in the T3a stage, thus grouping tumours with distinct pathologic features. Our study showed that patients with RCC presenting concomitant invasion of the renal vein invasion and perinephric fat invasion have significantly worse survival rates than those showing any of the parameters separately. Therefore, we conclude that these tumours should not be grouped within T3a stage since they have significantly different outcomes.

OBJECTIVE

? To evaluate the prognostic impact of tumor fat invasion (FI) and renal vein invasion (RVI) in patients with T3a renal cell carcinoma.

PATIENTS AND METHODS

? In total, 220 consecutive patients treated for renal cell carcinoma between 1992 and 2009 were analyzed. T3a stage cases were selected. ? A single pathologist reviewed all cases.

RESULTS

? The present study cohort included 46 patients with mean follow‐up of 28.6 months, of whom 17 (36.9%) died from disease. Patients were initially divided into three groups including 24 (52.1%) of FI only, 11 (23.9%) of RVI only and 11 (23.9%) of both FI and RVI. ? In univariate analysis, no significant differences in disease‐specific survival (DSS) were noted between FI only and RVI only groups (P= 0.91). DSS was significantly worse in the FI + RVI group compared to the other groups (P= 0.02). ? When grouped into FI or RVI vs FI + RVI, DSS remained significantly lower in the group containing the parameters concurrently (P= 0.009). Progression‐free survival also was significantly lower in FI + RVI group (P= 0.01). ? Metastasis, positive lymph nodes and the presence of FI + RVI remained as isolated predictors of survival. ? Patients with FI + RVI presented a 2.6‐fold increase in risk of death from cancer and a 2.5‐fold increase in risk of disease progression (P= 0.04) compared to those with either of them alone.

CONCLUSION

? The isolated or concomitant presence of FI and RVI may be used as one of the criteria for staging in the next edition of the Tumour‐Node‐Metastasis classification because they have significantly different outcomes.     

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.     

Machine-learning approach for prediction of pT3a upstaging and outcomes of localized renal cell carcinoma (UroCCR-15)

Objectives

To assess the impact of pathological upstaging from clinically localized to locally advanced pT3a on survival in patients with renal cell carcinoma (RCC), as well as the oncological safety of various surgical approaches in this setting, and to develop a machine-learning-based, contemporary, clinically relevant model for individual preoperative prediction of pT3a upstaging.

Materials and Methods

Clinical data from patients treated with either partial nephrectomy (PN) or radical nephrectomy (RN) for cT1/cT2a RCC from 2000 to 2019, included in the French multi-institutional kidney cancer database UroCCR, were retrospectively analysed. Seven machine-learning algorithms were applied to the cohort after a training/testing split to develop a predictive model for upstaging to pT3a. Survival curves for disease-free survival (DFS) and overall survival (OS) rates were compared between PN and RN after G-computation for pT3a tumours.

Results

A total of 4395 patients were included, among whom 667 patients (15%, 337 PN and 330 RN) had a pT3a-upstaged RCC. The UroCCR-15 predictive model presented an area under the receiver-operating characteristic curve of 0.77. Survival analysis after adjustment for confounders showed no difference in DFS or OS for PN vs RN in pT3a tumours (DFS: hazard ratio [HR] 1.08, P = 0.7; OS: HR 1.03, P > 0.9).

Conclusions

Our study shows that machine-learning technology can play a useful role in the evaluation and prognosis of upstaged RCC. In the context of incidental upstaging, PN does not compromise oncological outcomes, even for large tumour sizes.     

The influence of pNx/pN0 grouping in a multivariate setting for outcome modeling in patients with clear cell renal cell carcinoma

PURPOSE: Lymphadenectomy, especially extended lymphadenectomy, is not commonly performed in patients undergoing a radical nephrectomy for clear cell renal cell carcinoma. Surgeons may sample suspicious regional lymph nodes, but the lymph node status of many patients with renal cell carcinoma remains unknown, termed stage pNx. Outcome models based on large institutional reviews have been criticized for grouping stages pNx and pN0 cases because of concern that the pNx category may include unrecognized stages pN1/pN2 disease. We evaluated cancer specific survival differences in patients with clear cell renal cell carcinoma and a lymph node stage of pNx, pN0 or pN1/pN2. MATERIALS AND METHODS: We searched the registry at our institution for patients who underwent radical nephrectomy for clear cell histology renal cell carcinoma between 1970 and 1998. Those with distant metastases at surgery were excluded from study. Clinical features obtained from the medical record included age at surgery, history of tobacco use, hypertension and symptomatic disease at presentation. A single urological pathologist reviewed all tumor specimens for nuclear grade, tumor necrosis, surgical margin status, 1997 tumor stage and lymph node status. These features were compared in patients with stages pNx and pN0 tumors. Cox proportional hazards models were used to compare cancer specific survival in univariate fashion, and after adjusting for tumor stage and grade. RESULTS: The study cohort consisted of 1,535 patients with sporadic, unilateral clear cell renal cell carcinoma who underwent radical nephrectomy. There were 600 patients (39%) with stage pNx, 870 (57%) with stage pN0 and 65 (4%) with stages pN1/pN2 tumors. At an average of 4.2 years after surgery 414 patients died of renal cell carcinoma. On univariate analysis patients with stage pN0 tumors were significantly more likely to die of renal cell carcinoma than those with stage pNx tumors (risk ratio 1.40, 95% confidence interval 1.12 to 1.75, p = 0.003). However, after adjusting for tumor stage and nuclear grade the difference in outcome for stages pNx and pN0 tumors was not statistically significant (risk ratio 1.07 95% confidence interval 0.85 to 1.34, p = 0.583). Patients with stage pNx disease were significantly less likely to be symptomatic at presentation (p = 0.002), have tumors that were less than 5 cm. (p <0.001) and of lower stage (p <0.001) and grade (p = 0.005), and to have tumors with necrosis (p = 0.024) than patients with stage pN0 disease. CONCLUSIONS: Combining stages pNx and pN0 cases to create outcome prediction models after radical nephrectomy for clear cell renal cell carcinoma is appropriate in a multivariate setting that includes tumor stage and grade. Clinical features available preoperatively and during surgery can help guide the decision to perform limited lymph node sampling. When the tumor is 5 cm. or greater, shows pathological necrosis or is advanced grade 3 or 4, lymph node sampling adds little prognostic information.     

Cytoreductive nephrectomy for metastatic renal cell carcinoma with nonclear cell histology

PURPOSE: To our knowledge the benefit of cytoreductive surgery for patients with metastatic renal cell carcinoma with nonclear cell histology is unknown. In this retrospective study we report our experience with cytoreductive nephrectomy for nonclear cell metastatic renal cell carcinoma at M. D. Anderson Cancer Center. We compared the outcomes with those in patients with clear cell metastatic renal cell carcinoma. MATERIALS AND METHODS: From 1991 to 2006, 606 patients with metastatic renal cell carcinoma underwent cytoreductive nephrectomy and they formed the basis of this report. Of these patients 92 had nonclear cell metastatic renal cell carcinoma. The remaining 514 patients had clear cell metastatic renal cell carcinoma and they formed a comparative group. Multivariate Cox regression analysis was performed to evaluate the relationship between clinical variables and histology (clear cell vs nonclear cell) on disease specific survival. RESULTS: Compared with patients with clear cell histology those with nonclear cell metastatic renal cell carcinoma were younger (p = 0.0001), and more likely to have nodal metastases (p <0.0001) and sarcomatoid features (23% vs 13%, p = 0.026). On multivariate analysis median disease specific survival in patients with nonclear cell histology was significantly worse than that in patients with clear cell metastatic renal cell carcinoma (9.7 vs 20.3 months, p = 0.0003) even after adjusting for T stage, grade, performance status, age and sarcomatoid features. Sarcomatoid features were a predictor of poor outcome in cases of clear and nonclear cell histology, although even in the absence of sarcomatoid features nonclear cell histology was associated with worse disease specific survival (p = 0.017). Interestingly although there was a significantly higher incidence of positive nodes in patients with nonclear histology (p <0.0001), this phenotype was not associated with a worse disease specific survival, as it was in those with clear cell histology (p = 0.0001). In fact, patients with node negative disease with nonclear cell histology had the worst prognosis overall in the entire group. CONCLUSIONS: Patients with nonclear cell metastatic renal cell carcinoma were younger and had a higher incidence of nodal metastases, a higher incidence of sarcomatoid features and a worse prognosis than those with clear cell histology who underwent cytoreductive surgery.     

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.     

Prognostic impact of tumor size on pT2 renal cell carcinoma: an international multicenter experience

PURPOSE: The current tumor classification for renal cell carcinoma classifies pT2 tumors as larger than 7 cm in greatest dimension and limited to the kidney. We examined the current pT2 tumor classification of renal cell carcinoma and determined whether a tumor size cutoff exists that would improve prognostic accuracy. MATERIALS AND METHODS: We studied 706 patients with pT2 renal cell carcinoma treated with surgical extirpation at 9 international academic centers. Data collected from each patient included age at diagnosis, gender, 2002 TNM (tumor, node, metastasis) stage, tumor size, nuclear grade, performance status, histological subtype and disease specific survival. Disease specific survival was evaluated with univariate and multivariate analysis. RESULTS: Median followup was 52 months. Univariate Cox regression analysis showed a significant association of tumor size with disease specific survival (HR 1.11, p<0.001). An ideal tumor size cutoff of 11 cm was identified, which led to the stratification of 2 groups with respect to disease specific survival (p<0.0001) with 5 and 10-year survival rates of 73% and 65% for pT2 11 cm or less, and 57% and 49% for pT2 larger than 11 cm, respectively. The incidence of metastases was significantly greater in the larger than 11 cm group, while Eastern Cooperative Oncology Group performance status, Fuhrman grade and histological subtype were similar. Multivariate Cox regression analysis retained tumor size as an independent prognostic factor and as the strongest prognostic factor for patients with pT2N0M0 disease. CONCLUSIONS: Our data suggest that the current pT2 classification can be improved by subclassification into pT2a and pT2b based on a tumor size cutoff of 11 cm. Patients in the proposed pT2bN0M0 group are at higher risk for death from renal cell carcinoma and should be considered for adjuvant therapies. External validation is warranted before suggesting change to the TNM classification.