Prognosis of Japanese metastatic renal cell carcinoma patients in the cytokine era: a cooperative group report of 1463 patients.

BACKGROUND: Incidence rate of renal cell carcinoma (RCC) differs among countries. The rates of Asian countries are lower than those of countries in North America or Europe but are exceptionally high in Japanese males. Approximately 30% of patients with RCC have metastasis at initial diagnosis, and another 30% have metastasis after nephrectomy. Clinical studies of risk factors in patients with metastatic RCC (mRCC) are mainly based on data from non-Asian patients. OBJECTIVES: We aimed to investigate the prognosis of Japanese patients and their prognostic factors. DESIGN, SETTING, AND PARTICIPANTS: The subjects of this study were 1463 patients who were clinically diagnosed with RCC with metastasis in 40 Japanese hospitals between January 1988 and November 2002. MEASUREMENTS: The primary end point was overall survival calculated from first diagnosis of mRCC to death or last follow-up. We also investigated the relationship between survival and clinical features. RESULTS AND LIMITATIONS: The median overall survival time was 21.4 mo. The estimated survival rates at 1, 3, 5, and 10 yr were 64.2%, 35.2%, 22.5%, and 9.1%, respectively; they contrasted with data from the United States of 54%, 19%, 10%, and 6%, respectively for the same periods. A high percentage of patients had undergone nephrectomy (80.5%) and metastasectomy (20.8%), both of which were shown to prolong survival. CONCLUSIONS: The median survival time in the present study was approximately twice as long as that of previous studies from North America or Europe. Early diagnosis of metastasis, nephrectomy, metastasectomy, and cytokine-based therapy seemed to improve the prognosis of RCC patients in the present study.

Reclassification of the current tumor, node, metastasis staging in pT3 renal cell carcinoma.

OBJECTIVES: Although the tumor, node, metastasis (TNM) staging classification of renal cell carcinoma (RCC) was last modified in 2002, pT3 staging has continued to be debated. It has been suggested that direct adrenal gland involvement and pT3b with pT3a should be reclassified. This study accordingly explores reclassification of the current 2002 TNM staging in pT3 RCCs. METHODS: A total of 111 patients with pT3 RCC who underwent radical nephrectomy at our institution between March 1972 and February 2006 were enrolled in this study. Histological samples were reviewed by a single pathologist. Disease-specific survival was compared according to reclassification as pT3a with perirenal fat involvement only (pT3a-fat), pT3a with adrenal gland involvement (pT3a-ad), pT3b without pT3a factors (pT3b-only), pT3b with pT3a factors (pT3b with pT3a), or pT3c. RESULTS: Seven patients were identified as having pT3a-ad and 20 patients as having pT3b with pT3a. The mean disease-specific survival times in pT3a-fat and pT3b-only were significantly longer: 124.1 +/- 13.2 (SE) months and 70.9 +/- 9.1 (SE) months, respectively, compared with 24.7 +/- 6.7 (SE) months in pT3a-ad (P = 0.0004 and 0.0010, respectively), and 25.0 +/- 4.4 (SE) months in pT3b with pT3a (P = 0.0009 and 0.0032, respectively). On multivariate analysis, the presence of direct ipsilateral adrenal gland involvement was recognized as a predictor of poor prognosis (P = 0.0331). CONCLUSIONS: Direct ipsilateral adrenal gland involvement for patients with pT3a, and perirenal fat or adrenal gland involvement for patients with pT3b should be reclassified nearly to pT4.

Prognostic impact of perirenal fat or adrenal gland involvement in patients with pT3b renal cell carcinoma.

OBJECTIVES: To analyze the prognostic impact of the pT3a factors, perirenal fat or adrenal gland involvement, in patients with pT3b renal cell carcinoma (RCC). METHODS: A total of 43 patients with pT3b RCC who underwent radical nephrectomy, with complete resection of tumor thrombus, at our institution from March 1972 to September 2005 were enrolled in this study. The presence of pT3a factors was reviewed, and the disease-specific survival was compared according to the reclassification as pT3b only or pT3b with pT3a. RESULTS: After review by a single pathologist, 23 patients (53.5%) were identified as having pT3b only and 20 patients (46.5%) as having pT3b with pT3a. The mean disease-specific survival time in those with pT3b only was significantly longer at 70.9 +/- 9.1 (SE) months compared with 25.0 +/- 4.4 (SE) months in those with pT3b with pT3a (P = 0.0032). On univariate analyses, the presence of pT3a factors (P = 0.0065), preoperative metastasis (P = 0.0025), surgical specimens positive for lymph node metastasis (P = 0.0183), and spindle cell factor (P = 0.0233) were recognized as predictors of a poor prognosis. CONCLUSIONS: The presence of perirenal fat or adrenal gland involvement in patients with pT3b RCC renders the prognosis significantly worse. Careful postoperative examination should be required, along with reclassification for Stage pT3b with pT3a in RCC.

[A case report: small cell carcinoma transformed from transitional cell carcinoma of the urinary bladder].

A 72-year-old man presented with gross hematuria. Cystoscopy showed a non-papillary tumor at the right side of the posterior wall. Transurethral resection of the bladder tumor (TURBT) was performed. Pathologic findings demonstrated superficial transitional cell carcinoma (TCC). However, recurrent tumors were detected at the same location after 69 months' follow up. TURBT was done for the biopsy and pathologic examination showed muscle-invasive TCC. After two courses of neoadjuvant chemotherapy (MVAC), we performed radical cystectomy with Hautmann's continent reservoir. Pathologic findings revealed small cell carcinoma without any TCC features. Immunohistochemical staining using chromogranin A and synaptophysin was positive in the latest TURBT and the radical cystectomy specimens. We report a case of primary small cell carcinoma transformed from TCC of the urinary bladder.

[8-month neoadjuvant hormonal therapy before radical prostatectomy for high-risk prostate cancer].

PURPOSE: To evaluate the clinicopathological outcomes of 8 months of neoadjuvant hormonal therapy (NHT) prior to radical prostatectomy for high-risk prostate cancer. PATIENTS AND METHODS: A multi-institutional prospective trial was performed between July 2000 and May 2003 involving high-risk prostate cancer patients without metastasis, including 21 who received 8 months of NHT before radical prostatectomy. High-risk group was defined as clinical stage > or =T2c and/or prostate-specific antigen (PSA) >20 ng/ml and/or Gleason score > or =8. PSA values were considered elevated (biochemical failure) if values of 0.1 ng/ml or greater were obtained. RESULTS: Median of initial PSA levels before prostate biopsy was 27.6 ng/ml (8.5-80.7 ng/ml), and median of pre-operative PSA levels after NHT was 0.28 ng/ml (0.02-4.2 ng/ml). There were 5 patients (23.8%) with lower limit of PSA detection (less than 0.02 ng/ml) in 8 months after NHT. The clinical T stage was T1c in 9 patients (42.9%), T2a-b in 8 patients (38.1%), T2c in 3 patients (14.3%), and T3a in 1 patient (4.8%). The median follow-up was 25 months (range 4 to 37). There were 2 patients (9.5%) in pT0, 5 patients (23.8%) with positive surgical margin, 5 patients (23.8%) with extracapsular extension (ECE) and 3 patients (14.3%) with seminal vesicle involvement (SVI). Biochemical failure was occurred in 9 of 21 (42.9%) including of one pT0. Range of time to postoperative biochemical failure was 2 to 25 months (median 6 months) and most of biochemical failure was found within 12 months after surgery. Biochemical failure rate was significantly higher in patient with positive SVI (p = 0.0308) and higher in patients with pre-operative PSA levels of more than 0.1 ng/ml (p = 0.0836), positive ECE (p = 0.0545) and positive surgical margin (p = 0.0545). CONCLUSION: Biochemical failure was frequent after this combined treatment, even in a pT0 case. Long-term follow-up of patients is needed to assess the impact of this therapy on mortality.

Predicting the presence and side of extracapsular extension: a nomogram for staging prostate cancer.

PURPOSE: We developed a model to predict the side specific probability of extracapsular extension (ECE) in radical prostatectomy (RP) specimens based on the clinical features of the cancer. MATERIALS AND METHODS: We studied 763 patients with clinical stage T1c-T3 prostate cancer who were diagnosed by systematic needle biopsy and subsequently treated with RP. Candidate predictor variables associated with ECE were clinical T stage, the highest Gleason sum in any core, percent positive cores, percent cancer in the cores from each side and serum prostate specific antigen (PSA). Receiver operating characteristic (ROC) analyses were performed to assess the predictive value of each variable alone and in combination. We constructed and internally validated nomograms to predict the side specific probability of ECE based on logistic regression analysis. RESULTS: Overall 30% of the patients and 17% of 1,526 prostate lobes (left or right) had ECE. The areas under the ROC curves (AUC) of the standard features in predicting side specific probability of ECE were 0.627 for PSA, 0.695 for clinical T stage on each side and 0.727 for Gleason sum on each side. When these features were combined predictive accuracy increased to 0.788. The highest value (0.806) was achieved by adding the percent positive cores and the percent cancer in the biopsy specimen to the standard features. The resulting nomograms were internally validated and had excellent calibration and discrimination accuracy. CONCLUSIONS: Standard clinical features of prostate cancer in each lobe-PSA, palpable induration and biopsy Gleason sum-can be used to predict the side specific probability of ECE in RP specimens. The predictive accuracy is increased by adding information from systematic biopsy results. The predictive nomograms are sufficiently accurate for use in clinical practice in decisions such as wide versus close dissection of the cavernous nerves from the prostate.

The addition of interleukin-6 soluble receptor and transforming growth factor beta1 improves a preoperative nomogram for predicting biochemical progression in patients with clinically localized prostate cancer.

PURPOSE: Several preoperative prostate cancer nomograms have been developed that predict risk of progression using pretreatment prostate-specific antigen (PSA) level, clinical stage, and biopsy Gleason grade. We describe the development and performance of a new nomogram. The nomogram adds new markers to the standard clinical predictors that reflect the biologic behavior of prostate cancer: pretreatment plasma levels of interleukin-6 soluble receptor (IL6SR) and transforming growth factor beta1 (TGF-beta1). PATIENTS AND METHODS: Between November 7, 1994 and December 22, 1997, 714 patients with stage cT1c to cT3a prostate cancer and no prior therapy were treated with radical prostatectomy at the Methodist Hospital, Houston TX. Plasma levels of IL6SR and TGF-beta1 were measured in banked preoperative plasma. With these data, a nomogram was developed to predict the probability of PSA progression within 5 years of surgery. The nomogram was validated with bootstrapping to assess its discrimination and calibration performance. RESULTS: In the multivariable Cox model, PSA (P =.004), IL6SR (P <.001), TGF-beta1 (P <.001), primary Gleason grade (P <.002), and secondary Gleason grade (P =.029) were associated with PSA progression, whereas clinical stage (P =.696) was not. The nomogram seemed to be well calibrated and had a bootstrap-corrected area under the receiver operating characteristic curve (ie, concordance index) of 0.83. For comparison, a nomogram that omitted IL6SR and TGF-beta1 achieved a concordance index of only 0.75. CONCLUSION: We found that pretreatment plasma levels of IL6SR and TGF-beta1 improved the ability to predict biochemical progression by a prognostically substantial margin. A nomogram including the pretreatment levels of these molecular markers, along with standard clinical markers, has been developed and internally validated.

[The 1992 TNM classification of T2 prostate cancer predicts pathologic stage and prognosis better than the revised 1997 classification].

PURPOSE: In the 1997 the TNM staging system for prostate cancer was changed, reclassifying, T2 cancers from 3 groups (T2a, less than one half of one lobe; T2b, one lobe; and T2c, both lobes) to 2 groups (T2a, one lobe; and T2b, both lobes), combining the 1992 T2a and T2b into the 1997 T2a subclassification. We investigated the pathological stage and prognosis of cancers in the 1992 and 1997 subclassification to determine whether this change was warranted. MATERIAL AND METHODS: We studied a consecutive series of 555 patients with clinical stage T2 prostate cancer treated with radical prostatectomy (RP) between 1983 and 1998. We analyzed the clinical, pathological features and PSA non-progression rate after prostatectomy for patients classified according to the 1992 and the 1997 TNM system. Median follow-up was 51.3 months. RESULTS: In the 1992 TNM system T2a tumors were more likely to have a low PSA (5.8 versus 7.2 and 8.1 ng/ml, p = 0.034, p = 0.012), be confined to the prostate (67% versus 45% and 40%, p < 0.001 for both), be poorly differentiated (48% versus 63% and 66%, p = 0.002 for both) and have a low cancer volume (1.22 versus 2.27 and 2.63 cm3, p = 0.005 for both) than T2b and T2c tumors. But there were no significant differences between T2b and T2c. Reflecting these results, the patients with T2a cancer had a significantly better prognosis with 82 +/- 4% PSA non-progression rate at 5 years compared to 68 +/- 4% of patients with T2b and 73 +/- 4% of patients with T2c (p = 0.007, p = 0.048, respectively). In the 1997 TNM system T2a tumors were also different from T2b tumors in terms with the frequency of confined cancer (54% versus 40%, p = 0.006) and cancer volume (1.78 versus 2.63 cm3, p = 0.013). However, the those differences were smaller than those in 1992 system. There were no significant differences between 1997 T2a and T2b cancers in the serum PSA level and the frequency of a poorly differentiated cancer. In fact, the 5-years recurrence-free survival rate for patients with T2a (73 +/- 3%) was identical to that for T2b cancer. In a Cox proportional hazard regression analysis, however, neither the 1992 nor the 1997 TNM staging subclassifications of T2 cancers were independent predictor of PSA non-progression when the age of patient, serum PSA level and biopsy Gleason grade were included in the analysis. CONCLUSION: Since a palpable tumor less than half of one lobe (1992 T2a) has a distinctly different pathological and prognostic significance compared to T2b and T2c cancers, the T2a subclassification should be retained in future revisions of TNM staging system. However, because the digital rectal examination provides limited information, both PSA results and histological grade in a biopsy specimen should be incorporated into future revision of the TNM staging system.

[Prognostic value of serum immunosuppressive acidic protein in renal cell carcinoma].

BACKGROUND: To determine whether the immunosuppressive acidic protein (IAP) could be a useful marker for renal cell carcinoma (RCC), serum IAP levels were compared with clinicopathological features in RCC patients. Furthermore, IAP cutoff level to predict the recurrence was determined using receiver operating characteristics (ROC) curve analysis. PATIENTS AND METHODS: Between January 1994 and December 1998, pretreatment serum IAP was measured in 123 consecutive patients with PCC at Kitasato University Hospital. Ninety-eight patients were received radical surgery and 86 patients were performed as clinically curable renal cell carcinoma (pT1-pT3N0M0). ROC curve analysis was utilized to set the cutoff value of IAP for prediction of cancer recurrence. Significance of prognostic factors in RCC recurrence was analyzed by Cox proportional hazard model. RESULTS: The mean age of the 123 patients was 58.6 years (range 33 to 90, median 59). The mean follow-up period was 24.8 months (range 1 to 78, median 26). The median IAP levels were 447 ug/ml in stage I, 629 ug/ml in stage II, 588 ug/ml in stage III and 1,150 ug/ml in stage IV (p < 0.05). Tumor size and venous involvement were significantly associated with IAP concentrations (p < 0.05). However, tumor grade did not correlate with IAP level. Of 86 patients with clinically curable tumor, 79 patients were disease-free after median follow-up of 27 months. Using ROC curve analysis, IAP cutoff level for prediction of cancer recurrence was set at 620 ug/ml. Disease-free survival rate in patients with preoperative IAP levels of 620 ug/ml or lower was 98.5% (67/68) at 27 months postoperatively, whereas that in patients with IAP greater than 620 ug/ml was 75.0% (12/18). This difference was statistically significant (p < 0.05). Results of multivariate analysis revealed that preoperative IAP and pT stage were statistically significant factors for tumor recurrence after radical surgery (p < 0.05). CONCLUSIONS: The present study indicates that preoperative IAP level is a useful prognostic marker in patients with RCC. In particular, patients with clinically curable tumors (pT1-3N0M0), whose preoperative IAP levels greater then 620 ug/ml may have high risk for recurrence after radical nephrectomy.

Clinical significance of p53, mdm2, and bcl-2 proteins in renal cell carcinoma.

OBJECTIVES: To improve our understanding of the clinical relevance of p53, mdm2, and bcl-2 protein overexpression in renal cell carcinoma, we retrospectively investigated the immunohistochemical expression of p53, murine double minute 2 (mdm2), and bcl-2 and the relationship of this expression to clinicopathologic characteristics. p53 regulates the transcription of downstream effectors such as the oncoprotein mdm2, and bcl-2 has been shown to inhibit apoptosis triggered by wild-type p53. METHODS: The expression of p53, mdm2, and bcl-2 protein was studied by immunohistochemical methods in paraffin-embedded nephrectomy specimens from 112 patients whose clinicopathologic data confirmed renal cell carcinoma. RESULTS: The expression of the p53 and bcl-2 protein was recognized in 15 (13.4%) and 52 (42.0%) cases, respectively; the expression of the mdm2 protein, however, was seen in only 2 cases (1.8%). No correlation was noted between these three proteins and any clinicopathologic parameters, except p53 expression and Stage T1-2/T3-4 (P = 0.0208). However, in multivariate analysis, stage (hazard ratio 3.586; P = 0.0002), expression of p53 (hazard ratio 6.090; P = 0.0126) and of mdm2 (hazard ratio 22.016; P = 0.0156), and coexpression of p53/mdm2 (hazard ratio 6.146; P = 0.0005) demonstrated a statistically significant effect on prognosis by proportional hazards regression tests. CONCLUSIONS: Our results indicate that stage, p53 expression, mdm2 expression, and coexpression of p53/mdm2 are useful to predict the clinical outcome in patients with renal cell carcinoma.