Associations with contralateral recurrence following nephrectomy for renal cell carcinoma using a cohort of 2,352 patients

PURPOSE: We determined the incidence of and factors associated with the development of renal cell carcinoma (RCC) in the contralateral kidney after nephrectomy for localized RCC. MATERIALS AND METHODS: Between 1970 and 2000, 2,352 patients with sporadic, localized unilateral RCC and a normal contralateral kidney underwent nephrectomy for RCC. Cancer specific survival rates were estimated using the Kaplan-Meier method. Univariate Cox proportional hazards models were used to determine associations with outcome. RESULTS: Of the 2,352 patients studied 28 (1.2%) had RCC in the contralateral kidney, including 20 with clear cell and 8 with papillary RCC. Mean time from primary surgery to contralateral recurrence was 5.2 years (median 4.8, range 0 to 18) for clear cell RCC compared with 5.6 years (median 1.3, range 0 to 21) for papillary cell RCC. Positive surgical margins (risk ratio 14.23, p = 0.010) and multifocality (risk ratio 5.74, p = 0.019) were significantly associated with contralateral recurrence following nephrectomy for clear cell RCC, while nuclear grade (risk ratio for grades 3/4 vs 1/2, 4.78, p = 0.040) was significantly associated with contralateral recurrence following nephrectomy for papillary RCC. In patients with clear cell RCC estimated cancer specific survival rates 1, 3, and 5 years following contralateral recurrence were 93.8%, 80.2% and 72.9%, respectively. CONCLUSIONS: In patients with localized RCC and a normal contralateral kidney who underwent nephrectomy for RCC positive surgical margins and multifocality were significant predictors of contralateral recurrence for clear cell RCC, while nuclear grade was a significant predictor of contralateral recurrence for papillary RCC.     

Comparison of presentation and outcome for patients 18 to 40 and 60 to 70 years old with solid renal masses

PURPOSE: We compared histological subtype, pathological features and outcome of patients with solid renal masses who were 18 to 40 years old vs patients who were 60 to 70 years old. MATERIALS AND METHODS: We conducted a retrospective review of the Mayo Clinic Nephrectomy Registry from 1970 to 2000, and identified 124 patients 18 to 40 years old and 1,067 patients 60 to 70 years old available for analysis. RESULTS: There was no significant difference in the incidence of benign solid renal masses between patients 18 to 40 years old and those 60 to 70 years old (13.7% vs 10.2%). Among patients with renal cell carcinoma (RCC), younger patients were more likely to have chromophobe RCC (13.1% vs 3.6%) and less likely to have clear cell RCC (70.1% vs 81.5%) than older patients. Among patients with clear cell RCC, younger patients were more likely to have stage pT2b or lower tumors (82.7% vs 69.9%) and a higher incidence of cystic clear cell RCC (10.7% vs 2.2%) than older patients. Younger patients had an improved cancer specific survival compared with older patients but this difference was not statistically significant (risk ratio 0.71, p =0.127). CONCLUSIONS: We found that patients 18 to 40 years old were more likely to have chromophobe and less likely to have clear cell RCC compared with patients 60 to 70 years old. We did not identify a higher incidence of papillary RCC in younger patients. Patients with clear cell RCC 18 to 40 years old had a higher incidence of low stage and cystic tumors compared with patients 60 to 70 years old, features which have been shown to have a favorable prognosis. These factors likely contributed to improved cancer specific survival for younger patients.     

Independent validation of the 2002 American Joint Committee on cancer primary tumor classification for renal cell carcinoma using a large, single institution cohort

PURPOSE: The primary tumor classification for renal cell carcinoma (RCC) was updated by the American Joint Committee on Cancer in 2002. To date the new classification has not been validated using an independent group of patients and, therefore, its accuracy for predicting patient outcome is unknown. In the current study we evaluated the 2002 primary tumor classification and compared its predictive ability with that of the 1997 classification. MATERIALS AND METHODS: We studied 2,746 patients treated with radical nephrectomy or nephron sparing surgery for unilateral, sporadic RCC between 1970 and 2000. Cancer specific survival was estimated using the Kaplan-Meier method. The predictive abilities of the 1997 and 2002 classifications were compared using the concordance index. RESULTS: There were 812 deaths from RCC a mean of 3.3 years following nephrectomy. Median followup in patients still alive at last followup was 9 years. Estimated 5-year cancer specific survival rates by the 2002 tumor classification were 97%, 87%, 71%, 53%, 44%, 37% and 20% in patients with pT1a, pT1b, pT2, pT3a, pT3b, pT3c and pT4 RCC, respectively. The concordance index for the association between the 2002 classification and death from RCC was 0.752 compared with 0.737 for the 1997 classification, indicating that the 2002 version contained more predictive ability. CONCLUSIONS: Our data suggest that the 2002 primary tumor classification with pT1 cancers subclassified into pT1a and pT1b provides excellent stratification of patients according to cancer specific survival and it has a predictive ability that is superior to that of the 1997 classification.     

Renal cell carcinoma with renal vein and inferior vena caval involvement: clinicopathological features, surgical techniques and outcomes

PURPOSE: We present a contemporary review of patients with renal cell carcinoma (RCC) in whom renal vein/inferior vena caval thrombus was treated with radical nephrectomy and thrombectomy. MATERIALS AND METHODS: A total of 220 patients underwent radical nephrectomy for RCC at our institution from 1998 to 2002. Of them 49 patients with renal vein/inferior vena caval involvement (T3b/c) were selected for review. We evaluated demographics, presenting symptoms, imaging modalities, clinical staging, pathological features, adjuvant treatment and clinical outcomes. We also evaluated surgical incisions, liver mobilization procedures, blood loss, transfusion requirements and perioperative mortality/morbidity. RESULTS: Gross hematuria was the most common presenting symptom, seen in 22 patients (45%), followed by constitutional symptoms in 8 (16%). Stage T3b/c was clinically diagnosed in 44 patients, while 2 had T2 and 2 had T4 disease. A subcostal incision was made in 30 patients, a chevron incision was made in 18, and a sternotomy and flank incision were made in 1. Liver mobilization was necessary in 13 patients and 2 required a Pringle maneuver. Cardiopulmonary bypass was performed in a single patient. Lymph node involvement was seen in 4 patients (8%) and distant metastases were present in 10 (20%). Median tumor size was 10 cm. Clear cell carcinoma was most common, as seen in 42 patients. Early (30-day) mortality in this series was 8%. At a median followup of 15 months 21 patients (43%) were without evidence of disease, 14 (29%) had disease, 8 (16%) had died of disease and 2 (4%) had died of other causes. None of the patients with lymph node involvement survived beyond 8 months after surgery. Tumor grade and T stage were found to be significant negative predictors of survival on univariate analysis. CONCLUSION: Most patients with RCC and tumor thrombus are symptomatic at presentation and metastatic disease at presentation is not uncommon. These results support the role of aggressive surgical treatment as the best initial management of these tumors. The majority of tumors can be approached and safely controlled without the need for a thoracoabdominal incision. While surgery provides modest disease-free survival, most patients should be offered immunotherapy, particularly those with advanced stage, grade, nodal involvement or metastases.     

Progression and long-term survival after simple enucleation for the elective treatment of renal cell carcinoma: experience in 107 patients

PURPOSE: We present our findings in a series of T1a renal cell carcinoma treated with elective simple enucleation, specifically reporting the incidence of local recurrence, and progression-free and disease specific survival rates. MATERIALS AND METHODS: A total of 107 patients who underwent elective nephron sparing surgery performed with simple enucleation from January 1989 to December 2000 were studied retrospectively. None of the patients had preoperative or intraoperative suspicion of positive nodes. All patients were free from distant metastases before surgery (M0). Patient status was last evaluated in July 2004. Mean (median, range) followup was 88.3 (84, 44 to 175) months. RESULTS: Pathological review according to the 2002 TNM classification showed that 95% (102 of 107) of tumors were pT1a, 4% (4 of 107) pT1b and 1% (1 of 107) pT3a. Mean (SD, median, range) tumor greatest dimension was 2.7 (0.93, 2.5, 0.6 to 5) cm. None of the patients died in the immediate postoperative period (within the first 30 days). There were no major complications such as bleeding and urinary leakage/urinoma requiring reoperation. The 5 and 10-year cancer specific survival was 99% and 97.8%, respectively. The 5 and 10-year progression-free survival was 98.1% and 94.7%, respectively. Overall 3 patients had disease progression (2.8%) of whom 2 (1.9%) were local recurrence, 1 alone and 1 associated with distant metastases diagnosed 12 months earlier. CONCLUSIONS: Simple tumor enucleation is a safe and acceptable approach for elective nephron sparing surgery. It provides excellent long-term progression-free and cancer specific survival rates, and is not associated with an increased risk of local recurrence compared with partial nephrectomy.     

An outcome prediction model for patients with clear cell renal cell carcinoma treated with radical nephrectomy based on tumor stage,size, grade and necrosis: the SSIGN score

PURPOSE: Currently outcome prediction in renal cell carcinoma is largely based on pathological stage and tumor grade. We developed an outcome prediction model for patients treated with radical nephrectomy for clear cell renal cell carcinoma, which was based on all available clinical and pathological features significantly associated with death from renal cell carcinoma. MATERIALS AND METHODS: We identified 1,801 adult patients with unilateral clear cell renal cell carcinoma treated with radical nephrectomy between 1970 and 1998. Clinical features examined included age, sex, smoking history, and signs and symptoms at presentation. Pathological features examined included 1997 TNM stage, tumor size, nuclear grade, histological tumor necrosis, sarcomatoid component, cystic architecture, multifocality and surgical margin status. Cancer specific survival was estimated using the Kaplan-Meier method. Cox proportional hazards regression models were used to test associations between features studied and outcome. The selection of features included in the multivariate model was validated using bootstrap methodology. RESULTS: Mean followup was 9.7 years (range 0.1 to 31). Estimated cancer specific survival rates at 1, 3, 5, 7 and 10 years were 86.6%, 74.0%, 68.7%, 63.8% and 60.0%, respectively. Several features were multivariately associated with death from clear cell renal cell carcinoma, including 1997 TNM stage (p <0.001), tumor size 5 cm. or greater (p <0.001), nuclear grade (p <0.001) and histological tumor necrosis (p <0.001). CONCLUSIONS: In patients with clear cell renal cell carcinoma 1997 TNM stage, tumor size, nuclear grade and histological tumor necrosis were significantly associated with cancer specific survival. We present a scoring system based on these features that can be used to predict outcome.     

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.     

Conventional (clear cell) renal carcinoma metastases have greater bcl-2 expression than high-risk primary tumors

Bcl-2 antagonizes p53-induced apoptosis and may contribute to chemoresistance. In renal cell carcinoma (RCC), the role of bcl-2 is not well-defined, though its expression is reportedly low in primary tumors and lacks prognostic value. This study evaluates patterns of bcl-2 expression in high-risk (pT(3)) primary tumors and in matched patient metastases. Immunohistochemical analysis of bcl-2 was performed on 149 cases of conventional (clear cell) RCC (112 pT(3) primaries, 37 metastases). Paraffin-embedded tissues were obtained from nephrectomies and metastatic resections. Median follow up was 48 months in the entire cohort and 69 months in living patients. We evaluated associations between bcl-2 expression and tumor recurrence or patient survival with the Cox regression test, and used the t-test and Pearson correlation methods to evaluate bcl-2 expression in primary and metastatic cases. Bcl-2 expression was observed at a higher frequency in metastases (21/37 cases; 57%) compared to primary tumors (24/112 cases; 21%; P < 0.001). The percentage of cells stained was greater in metastases than primary tumors (P = 0.003). This finding was also noted when expression in metastatic cases was compared with matched primaries (P = 0.05). Bcl-2 expression did not predict disease-free (P = 0.30), disease-specific (P = 0.90), or overall (P = 0.51) survival. Most RCC primary tumors have low-to-absent levels of bcl-2 protein, whereas most RCC metastases display greater protein levels. Bcl-2 expression in primary tumors does not predict clinical outcome. However, expression of bcl-2 protein occurs at a high frequency in RCC metastases when compared to primary tumors. It may be reasonable to target RCC patients displaying altered bcl-2 levels for molecular therapies, such as anti-bcl2, should metastatic disease develop.     

Stage-specific conditional survival in renal cell carcinoma after nephrectomy

ObjectivesConditional survival (CS) represents the probability that a cancer patient will survive some additional number of years, given that the patient has already survived for a certain period of time. CS estimates, therefore, serve as better measures of survival probability compared to standard estimates as they incorporate patient survivorship. Stage-specific CS has not been widely investigated in the context of renal cell carcinoma (RCC) after nephrectomy. We aimed to examine this phenomenon.Materials and methodsWe analyzed retrospective data on a population-based cohort of 87,225 surgically-treated RCC patients extracted from the Surveillance, Epidemiology, and End Results database (2004–2015) and on a similar validation cohort of 1,642 patients from our institution (1995–2015). 5-year cancer-specific CS estimates stratified by stage were obtained using the Kaplan–Meier method. Multivariable Cox regression analyses were performed to evaluate the possible variation in risk of cancer-specific mortality by stage at nephrectomy and with increasing postoperative survivorship.Results5-year cancer-specific survival rates at time of nephrectomy for stage I, II, III, and IV patients in the population-based cohort were 97.4%, 89.9%, 77.9%, and 26.7%, respectively. Improvement in 5-year CS was mainly observed in surviving patients with advanced-stage disease; given 1, 2, 3, 4, and 5 years of survivorship after nephrectomy, the subsequent 5-year cancer-specific survival rates were, respectively, 79.3% (+1.8% increase over previous survival probability), 81.3% (+2.5%), 83.3% (+2.5%), 84.3% (+1.2%), and 85.1% (+1.0%) for stage III, and 34.6% (+29.6%), 42.5% (+22.8%), 49.0% (+15.3%), 55.7% (+13.7%), and 58.6% (+5.2%) for stage IV. A similar trend was established in the validation cohort. Findings were confirmed upon multivariable analyses.ConclusionsCS after nephrectomy for RCC varies dramatically by stage of disease. Gains in CS over time occur primarily among patients with advanced-stage disease. Stage-specific CS estimates can help urologists better plan postoperative surveillance for RCC patients.     

Cachexia-like symptoms predict a worse prognosis in localized t1 renal cell carcinoma

PURPOSE: Although cachexia is a common sequela of advanced and metastatic renal cell carcinoma (RCC), cachexia-like symptoms may also represent a paraneoplastic finding. We assessed the prognostic significance of these symptoms in patients with stage T1 RCC. MATERIALS AND METHODS: Using the kidney cancer database at our institution 250 patients were identified who underwent partial or radical nephrectomy for T1N0M0 RCC between 1989 and 2001. The prognostic significance of the symptoms present at diagnosis and findings on preoperative laboratory evaluation were examined. RESULTS: Mean and median followup was 33 and 43 months, respectively. Malaise, weight loss, anorexia and hypoalbuminemia were cachexia related findings that were significant predictors of worse disease specific survival (DSS). DSS in patients with 1 vs greater than 1 cachexia related symptoms was not significantly different (p = 0.077). Therefore, any patient with at least 1 cachexia related finding was considered to be positive for cachexia and cachexia occurred in 37 (14.8%). Cachexia was associated with significantly worse recurrence-free survival (HR 3.03, p = 0.032) and DSS (HR 4.39, p = 0.011) even after controlling for tumor size, grade and performance status. The 5-year survival rate in patients with low grade (1 or 2) tumors with and without cachexia was 91% and 81%, respectively. The 5-year survival rate in patients with high grade (3 or 4) tumors with and without cachexia was 75% and 55%, respectively. CONCLUSIONS: Cachexia-like symptoms independently predict a worse prognosis in patients with T1 RCC. Patients with cachexia (malaise, weight loss, anorexia and hypoalbuminemia), especially when associated with high grade tumors, should be considered for clinical trials of adjuvant therapies.     

Contralateral adrenal metastasis of renal cell carcinoma: treatment,outcome and a review

OBJECTIVE: To report the surgical treatment of patients with renal cell carcinoma (RCC) metastatic to the contralateral adrenal gland and compare our experience with previous reports, as such metastases are found in 2.5% of patients with metastatic RCC at autopsy, and the role of resecting metastatic RCC at this site is not well defined. PATIENTS AND METHODS: We retrospectively identified 11 patients who had surgery for metastatic RCC to the contralateral adrenal gland between October 1978 and April 2001. The patients' medical records were reviewed for clinical, surgical and pathological features, and the patients' outcome. RESULTS: The mean (median, range) age of the patients at primary nephrectomy was 60.9 (64, 43-79) years; all had clear cell (conventional) RCC. Synchronous contralateral adrenal metastasis occurred in two patients. The mean (median, range) time to contralateral adrenal metastasis after primary nephrectomy for the remaining nine patients was 5.2 (6.1, 0.8-9.2) years. All patients were treated with adrenalectomy; there were no perioperative complications or mortality. Seven patients died from RCC at a mean (median, range) of 3.9 (3.7, 0.2-10) years after adrenalectomy for contralateral adrenal metastasis; one died from other causes at 3.4 years, one from an unknown cause at 1.7 years and two were still alive at the last follow-up. CONCLUSIONS: The surgical resection of contralateral adrenal metastasis from RCC is safe; although most patients died from RCC, survival may be prolonged in individual patients. Hence, in the era of cytoreductive surgery, the removal of solitary contralateral adrenal metastasis seems to be indicated.     

Renal cell and transitional cell carcinoma in a Japanese population undergoing maintenance dialysis

PURPOSE: We verified differences in the incidence, clinical characteristics and outcomes between patients on chronic dialysis for end stage renal disease with renal cell carcinoma (RCC) and those with transitional cell carcinoma (TCC). MATERIALS AND METHODS: Data regarding RCC and TCC were reviewed in the medical records of 6,201 patients with end stage renal disease who underwent chronic dialysis between January 1990 and June 2003 in our 38 affiliated dialysis centers, and data were compared with those reported in Australia and New Zealand. RESULTS: Among the patients RCC developed in 38 (0.61%) and TCC developed in 16 (0.26%) during maintenance dialysis. The primary renal disease was chronic glomerulonephritis in patients with RCC (68.4%) and diabetic nephropathy in patients with TCC (43.8%, p = 0.002). Mean patient age at initiation of dialysis was 45 years for those with RCC and 63 for those with TCC (p < 0.001). Mean interval from dialysis induction to tumor diagnosis was 143 months for patients with RCC and 54 months for patients with TCC (p < 0.001). Of 38 RCCs 23 (60.5%) were incidentally detected by regular abdominal imaging examinations while painless gross hematuria was the cardinal symptom in 13 (81.2%) of 16 TCCs. Overall and cancer specific survivals after tumor diagnosis were significantly superior in patients with RCC compared to those with TCC (p = 0.0001 and p = 0.0003, respectively), and the cancer specific 5-year survival was 88.9% for RCC and 29.5% for TCC. In both cancers tumor stage significantly increased the risk of cancer specific death. Compared with patients from Australia and New Zealand, the incidence of RCC was higher and that of TCC was lower in our patients (p <0.001). CONCLUSIONS: In the Japanese population on dialysis RCC is more common than TCC. Since long-term dialysis is a risk factor for RCC, regular imaging examinations may have contributed to the favorable outcome of our patients on dialysis with RCC. In contrast, the unfavorable outcome of TCC suggests the need for effective diagnostic measures for early detection of TCC in patients on dialysis.     

Renal cell carcinoma with nodal metastases in the absence of distant metastatic disease: prognostic indicators of disease-specific survival

OBJECTIVES: Outcome of patients with exclusive renal cell carcinoma (RCC) nodal metastases without distant metastases is not extensively described. We explored the ability of standard risk factors such as tumour size, Fuhrman grade, histologic subtype and symptom classification to predict renal cell carcinoma-specific survival (RCC-SS). METHODS: Analyses targeted 171 patients with RCC nodal metastases and absence of distant metastases. Univariable, multivariable, and predictive accuracy analyses addressed RCC-SS with the intent of identifying independent and most informative predictors of RCC-SS in this cohort of patients. RESULTS: Median RCC-SS was 2.3 yr. Symptom classification (61.3%, p<0.001) demonstrated the highest univariable accuracy. In multivariable analyses, symptom classification contributed the most to the combined predictive accuracy of all variables (+4.2%, p<0.001), followed by Fuhrman grade (+2.3%) and histologic subtype (+1.0%). CONCLUSIONS: Renal cell carcinoma-specific survival of patients with exclusive nodal metastases may show important variability. In presence of systemic symptoms, survival is extremely poor. Substantially better survival may be expected in patients with local or no symptoms. This observation has important implications when adjuvant therapies are considered.     

Angiogenesis and other markers for prediction of survival in metastatic renal cell carcinoma

OBJECTIVE: The treatment of metastatic renal cell carcinoma (RCC) remains a clinical challenge. Factors predicting any benefit of different therapies would therefore be useful. Angiogenesis is important in tumor progression and the development of metastases. The aim of this study in patients with distant metastases at diagnosis was to evaluate possible outcome information obtained with a number of soluble angiogenic variables in serum. MATERIAL AND METHODS: Serum samples were taken at diagnosis from 120 consecutive patients with metastatic RCC who were operated on with radical nephrectomy. Different clinicopathological variables and vascular endothelial growth factor (VEGF), vascular endothelial growth factor receptor-1 (VEGFR-1), basic fibroblast growth factor (bFGF) and erythropoietin levels in serum were compared with the clinical course. RESULTS: The median survival time for all patients was 9 months. Six patients (5%) died during the postoperative period, all of whom had a performance status (PS) of 2 or 3. None of the angiogenic factors (VEGF, VEGFR-1, bFGF, erythropoietin) gave any prognostic information, except that VEGF was associated with survival (p = 0.0234) in patients with a good PS. A number of other variables gave prognostic information in univariate analysis but, after multivariate analysis, only PS (p = 0.002), the number of metastatic sites (p = 0.003) and capsule invasion (p = 0.017) remained as independent predictive factors. CONCLUSIONS: Among predictive factors, only PS, the number of metastatic sites and capsule invasion independently predicted survival in patients with metastatic RCC, while soluble angiogenic factors in serum gave no prognostic information. Nephrectomy in patients with metastatic RCC remains controversial but long-term survival can be achieved in selected patients, especially those with a good PS.     

Follow-up guidelines for nonmetastatic renal cell carcinoma based on the occurrence of metastases after radical nephrectomy.

OBJECTIVE: To define guidelines for the follow-up management of nonmetastatic renal cell carcinoma (RCC), by assessing tumour recurrences and the clinical course in patients who had undergone radical nephrectomy. PATIENTS AND METHODS: The records of 187 patients with pT1-3, N0-X, M0 RCC who underwent radical nephrectomy between 1982 and 1997 were reviewed prospectively. Clinicopathological variables were compared with the time of first recurrence, site of metastasis and reason for diagnosis. RESULTS: Metastases were diagnosed in 98 sites in 56 of the 187 patients (30%). The risk for developing metastases increased with stage; 80% of the patients had their metastases diagnosed within 3 years (median 14.5 months) after nephrectomy. The time to first diagnosis was longer for patients with pT1 tumours and for those with skeletal metastases. The cause-specific 5-year survival rate for pT1 tumours was 95%, for pT2 87% and for pT3 tumours 37%. All patients with diploid pT1-2 RCC survived, having a survival advantage over those with aneuploid pT1-2 tumours (P=0.018). Also, pT1-2 tumours of < 5 cm were associated with better survival rates. Among 74 patients with pT3 tumours, 45 got metastases; DNA ploidy in these tumours did not influence survival. Of 30 patients with lung metastases, 28 were diagnosed during follow-up, while 25 of 26 other metastatic sites were diagnosed because of symptoms. CONCLUSIONS: The risk for tumour progression depends mainly on stage; these results indicate no need for follow-up in patients with diploid pT1-2 tumours or with aneuploid pT1 tumours of < 5 cm. For patients with aneuploid pT1-2 tumours of > 5 cm and pT3 tumours, follow-up is indicated.     

Prognostic factors and the role of neprectomy in metastatic renal cell carcinoma

The objective of this study was to evaluate the prognostic factors and role of nephrectomy in metastatic renal cell carcinoma. We reviewed 62 cases of metastatic renal cell carcinoma (RCC) at presentation to document the factors influencing the survival and to evaluate the role of nephrectomy. Sex and age of the patients, size of the primary tumour, site and number of the metastases, nephrectomy, cell type and grade of the tumour and type of the medical treatment were analyzed as prognostic factors. The age and sex of the patients, cell type and type of the medical treatment did not appear to be significant predictors of prognosis. However, improved survival was correlated with tumours ≤7 cm in diameter, low grade tumours, metastasis limited to single organ and removal of the primary tumour. When these parameters were analyzed in a combined manner patients who had undergone nephrectomy showed consistently longer survival. We suggest that nephrectomy should be considered in all patients with metastatic RCC, as long as the morbidity of the operation is predicted to be acceptable.     

Prediction of response to combined immunotherapy with interferon-α and low-dose interleukin-2 in metastatic renal cell carcinoma: Expression patterns of potential molecular markers in radical nephrectomy specimens

Objectives:   To evaluate the expression levels of multiple molecular markers in radical nephrectomy specimens from patients with metastatic renal cell carcinoma (RCC) who received combined immunotherapy with interferon-α (IFN-α) and low-dose interleukin-2 (IL-2) and to identify factors predicting susceptibility to this therapy.
Methods:   This study included 40 patients with metastatic clear cell RCC undergoing combined immunotherapy with IFN-α and low-dose IL-2 following radical nephrectomy. Expression levels of 10 markers, including Aurora-A, Bcl-2, clusterin, heat shock protein 27, heat shock protein 90, Ki-67, matrix metalloproteinase-2, matrix metalloproteinase-9, p53 and vascular endothelial growth factor, in RCC specimens were measured using immunohistochemical staining.
Results:   In this series, one, 10, 15 and 16 patients were diagnosed as showing complete response, partial response, stable disease and progressive disease, respectively. Expression levels of Bcl-2 and Ki-67 had significant impacts on the response to this therapy. Furthermore, cancer-specific survival was significantly associated with the expression levels of Ki-67 and Bcl-2 in addition to performance status, presence of metastases at diagnosis, metastatic organ and C-reactive protein on univariate analysis. Only the presence of metastases at diagnosis and Ki-67 expression level appeared to be independent predictors of cancer-specific survival on multivariate analysis.
Conclusions:   It would be useful to consider the expression levels of potential molecular markers, particularly Ki-67, in addition to clinical parameters, such as the presence of metastases at diagnosis, to select metastatic RCC patients likely to benefit from combined immunotherapy.     

Creation of a primary tumor tissue expression biomarker-augmented prognostic model for patients with metastatic renal cell carcinoma

BackgroundClinical and pathological factors alone have limited prognostic ability in patients with metastatic clear cell renal cell carcinoma (ccRCC). Bim, a downstream pro-apoptotic molecule in the PD-1 signaling pathway, has recently been associated with survival in other malignancies. We sought to determine if tissue biomarkers including Bim, added to a previously reported clinical metastases score, improved prediction of cancer-specific survival (CSS) for patients with metastatic ccRCC.MethodsPatients with metastatic ccRCC who underwent nephrectomy between 1990 and 2004 were identified using our institutional registry. Sections from paraffin-embedded primary tumor tissue blocks were used for immunohistochemistry staining for Bim, PD-1, B7-H1 (PD-L1), B7-H3, CA-IX, IMP3, Ki67, and survivin. Biomarkers that were significantly associated with CSS after adjusting for the metastases score were used to develop a biomarker-specific multivariable model using a bootstrap resampling approach and forward selection. Predictive ability was summarized using a bootstrap-corrected c-index.ResultsThe cohort included 602 patients: 192 (32%) with metastases at diagnosis and 410 (68%) who developed metastases after nephrectomy. Median follow-up was 9.6 years (IQR 4.2–12.8), during which 504 patients died of RCC. Bim, IMP3, Ki67, and survivin expression were significantly associated with CSS after adjusting for the metastases score, and were eligible for biomarker-specific model inclusion. After variable selection, high Bim (hazard ratio [HR] = 1.44; 95% confidence interval [CI] 1.16–1.78; P <0.001), high survivin (HR = 1.35; 95% CI 1.08–1.68; P = 0.008), and the metastases score (HR = 1.13 per 1 point; 95% CI 1.10–1.16; P <0.001) were retained in the final multivariable model (c-index = 0.69).ConclusionWe created a prognostic model combining the clinical metastases score and 2 primary tumor tissue expression biomarkers, Bim and survivin, for patients with metastatic renal cell carcinoma who underwent nephrectomy.     

Sarcomatoid renal cell carcinoma: an examination of underlying histologic subtype and an analysis of associations with patient outcome

A sarcomatoid component can occur in all histologic subtypes of renal cell carcinoma (RCC) and indicates an aggressive tumor. We studied 2381 patients treated with radical nephrectomy for RCC between 1970 and 2000. A urologic pathologist reviewed the microscopic slides from all tumor specimens for the presence of a sarcomatoid component, defined as a RCC with any malignant spindle cell component. All tumors with a sarcomatoid component were classified as nuclear grade 4. A total of 120 (5.0%) patients had RCC with a sarcomatoid component, including 94 who died of RCC at a mean of 1.4 years following nephrectomy (median 8 months; range 44 days to 10 years). Cancer-specific survival rates at 2 and 5 years following nephrectomy were 33.3% and 14.5%, respectively. The presence of distant metastases at the radical nephrectomy and histologic tumor necrosis were significantly associated with death from RCC among patients with sarcomatoid RCC. Patients with clear cell (conventional) RCC and chromophobe RCC were more likely to have tumors with a sarcomatoid component (5.2% and 8.7%, respectively) compared with patients with papillary RCC (1.9%). The presence of a sarcomatoid component was significantly associated with death from RCC for all three subtypes (P < 0.001). Even among patients with grade 4 clear cell RCC, the presence of a sarcomatoid component was significantly associated with outcome, both univariately (risk ratio 1.59; P = 0.010) and after adjusting for TNM stage, tumor size, and histologic tumor necrosis (risk ratio 1.46; P = 0.037).     

Treatment and prognosis of T 4 renal cell carcinoma]

BACKGROUND: We studied the cases with T 4 renal cell carcinoma (RCC) to characterize the factors associated with prolonged survival and to clarify the indication of extended nephrectomy. MATERIALS AND METHODS: The study population consisted of 53 patients (44 male and 9 female) with pT 4 RCC treated at the Yokohama City University Hospital and its affiliated hospitals from 1965 to 1994. Survival rates were analyzed with respect to clinicopathological factors (patient age, sex, symptom, tumor growing type, tumor size, histological grade, cell type, structural type, lymph node metastasis, vein invasion, distant metastasis and extended nephrectomy). RESULTS: One-year, 2-years, and 3-years survival rates of the cases with T 4 RCC were 30.4%, 16.4%, and 9.4% respectively. In univariate analysis, improved survival were correlated with no extra-urinary symptom (Logrank: p = 0.0048, Wilcoxon: p = 0.0423), no lymphnode metastasis (Logrank: p = 0.1045, Wilcoxon: p = 0.0199), no distant metastases (Logrank: p = 0.0007, Wilcoxon: p = 0.0006), and enforcement of extended nephrectomy (Logrank: p = 0.0018, Wilcoxon: p = 0.0008). In 28 cases with extended nephrectomy, improved survival was correlated with no extra-urinary symptom, no abdominal wall invasion and no distant metastases. In 5 cases with more than 3 year survival after extended nephrectomy, 4 cases were found to have no distant metastases at the time of operation. Non-operative therapy including interferon for 20 cases without extended nephrectomy were almost ineffective. CONCLUSIONS: These results indicate that if curative excision for T 4 RCC cases without distant metastases could be done, some patients might be appropriate candidates for extended nephrectomy.