Microstaging of pT1 transitional cell carcinoma of the bladder. Does it really differentiate two populations with different prognoses? (pT1 subcategory)

INTRODUCTION: Our objective was to evaluate the feasibility and value of microstaging in pT1 transitional cell carcinoma (TCC) of the bladder in a well-defined group of patients treated with transurethral resection (TUR) only. MATERIALS AND METHODS: The clinical records of 152 patients who underwent TUR for the treatment of primary superficial TCC of the bladder between 1983 and 1997 were reviewed. Patients with primary carcinoma in situ and who received adjuvant intravesical treatments were excluded from study. We subclassified the pT1 tumors into two groups according to muscularis mucosae (MM) invasion (pT1 and pT1b). The recurrence and progression rate of cancers was analyzed according to the stage, grade, multiplicity and tumor size. Mean follow-up was 68 months. Estimation of the cumulative distribution of the disease-free interval in separate groups was calculated according to the Kaplan-Meier method. Multivariate analysis of the data was performed by using Cox regression method. A value of p < 0.05 was taken to be statistically significant with odds ratios. RESULTS: Of the 152 patients, tumor stage was pTa in 62 (40.8%) patients and pT1 in 90 (59.2%) patients. Among those pT1 tumors, MM was identified in 50 (55.5%) of cases (pT1a = 34, pT1b = 16). In the remaining 40 (44.5%) patients, MM could not be assessed. Kaplan-Meier analysis revealed that recurrence and progression were statistically significant for stage, multiplicity and grade of tumor. However, multivariate analysis revealed that stage was the only prognostic factor for recurrence and progression (p = 0.0001). CONCLUSION: The present study underscores the fact that pT1b tumors have a distinct natural history. If initial conservative treatment is selected, the patients must be followed very cautiously.     

International validation of the prognostic value of subclassification for AJCC stage pT3 upper tract urothelial carcinoma of the renal pelvis

Study Type – Prognosis (inception cohort) Level of Evidence 2a What's known on the subject? and What does the study add? Tumour stage is a powerful predictor of clinical outcomes and the most important factor driving clinical decision‐making after radical nephroureterectomy (RNU) in upper tract urothelial carcinoma (UTUC). It has been suggested that renal pelvic pT3 subclassification into microscopic infiltration of the renal parenchyma (pT3a) versus macroscopic infiltration or invasion of peripelvic adipose tissue (pT3b) has strong prognostic value. This is an external validation study of the prognostic value of pT3 subclassification of renal pelvic UTUC in a large international cohort of patients treated with RNU. pT3b UTUC is associated with features of aggressive tumour biology, disease recurrence and cancer‐specific mortality. However, pT3 subclassification is not an independent predictor of clinical outcomes.

OBJECTIVE

• ? To externally validate the prognostic value of subclassification of pT3 renal pelvic upper tract urothelial carcinoma (UTUC) in a large international cohort of patients treated with radical nephroureterectomy (RNU).

PATIENTS AND METHODS

• ? The RNU specimens with pT3 UTUC of the renal pelvis from 284 patients at 11 centres located in Asia, North America and Europe were retrospectively evaluated. All specimens were reviewed by genitourinary pathologists at each institution. Tumours were categorized as pT3a (microscopic infiltration of the renal parenchyma) or pT3b (macroscopic infiltration of the renal parenchyma and/or infiltration of peripelvic adipose tissue).

RESULTS

• ? Overall, 148 (52%) tumours were classified as pT3a and 136 (48%) as pT3b. Patients with pT3b disease were more likely to have high‐grade tumours and sessile tumour architecture (all P≤ 0.02). Patients with pT3b tumours were at increased risk of disease recurrence (5‐year estimates: 55% versus 42%, P= 0.012) and cancer‐specific mortality (CSM) (5‐year estimates: 48% versus 40%, P= 0.04). Lymph node status, tumour architecture and tumour grade were independently associated with disease recurrence, whereas lymph node status, tumour architecture and lymphovascular invasion were independently associated with CSM. Subclassification of pT3 tumours was not associated with recurrence or CSM in multivariable analyses.

CONCLUSION

• ? Patients with pT3b UTUC were more likely to have tumours with aggressive pathological features and were at higher risk of disease recurrence and CSM after RNU compared with patients with pT3a disease. However, the pT3 subclassification did not remain an independent predictor of disease recurrence or CSM after controlling for tumour grade, lymph node status, tumour architecture and lymphovascular invasion.

     

The presence of carcinoma in situ at radical cystectomy increases the risk of urothelial recurrence: Implications for follow-up schemes

Introduction

To evaluate the incidence of carcinoma in situ (CIS) in patients treated with radical cystectomy (RC) due to bladder cancer and to assess its effect on recurrence and survival rates.

Impact of several histopathological prognosticators and local tumour extension on oncological outcome in pT3b/c N0M0 renal cell carcinoma

OBJECTIVE

To investigate the prognostic relevance of different histopathological features and local tumour extension in patients with pT3b/c N0M0 renal cell carcinoma (RCC), as recently new proposals of reclassifying tumour fat invasion in pT3b/c RCC have been made but the effect of other histopathological tumour characteristics and combinations thereof with tumour invasion has yet to be determined in these patients.

PATIENTS AND METHODS

Between 1990 and 2006, 1943 patients underwent surgical treatment for renal tumours in our institution, of which 175 patients (8.7%) had pT3b/c RCC. After exclusion of 57 patients (32.6%) with lymph node and/or distant metastases at the time of diagnosis, 118 (67.4%) remained for retrospective analysis. Different histopathological features and local tumour extension were studied for their association with cancer‐specific‐survival (CSS) and progression‐free‐survival (PFS) by univariate and multivariate analyses. Histopathology was reviewed and revised according to the 2002 Tumour‐Nodes‐Metastasis (TNM) classification system by one pathologist (S.B.). CSS and PFS were estimated by the Kaplan–Meier method.

RESULTS

Follow‐up data were obtained from 110 patients at a median (range) of 3.2 (0.3–16.1) years. In univariate analysis, microvascular invasion (MVI) and capsular invasion increased the risk of tumour progression by 2.05‐ and 2.72‐times (P = 0.037 and P < 0.001). Overall, tumour fat invasion (TFI) and the presence of areas composed by cells with eosinophilic cytoplasm were associated with a higher risk of progression (P = 0.001 and P = 0.011) and reduced CSS (P = 0.037 and P = 0.017). In multivariate analysis, MVI and capsular invasion were associated with a two‐fold increased risk of dying from cancer (hazard risk ratio, HR 2.22, P = 0.045 and HR 2.31, P = 0.011). TFI in general (P = 0.004) and specifically coexistent perirenal fat invasion (PFI) and renal sinus fat invasion (RSFI) were associated with a three‐fold increased risk of developing tumour progression (HR 3.36, P = 0.001). The 10‐year CSS and PFS rates were 39% and 36% for all patients, 47% and 45% for pT3b/c RCC with no PFI or RSFI, and 25% and 10% for PFI + RSFI.

CONCLUSION

Patients with pT3b/c RCC with MVI, capsular invasion, TFI and especially PFI + RSFI, have a markedly reduced prognosis compared with patients with pT3b/c RCC without these features. When these results are corroborated by additional studies and external validation, modification of the TNM classification system would be a sensible consequence.     

CANCER SPECIFIC SURVIVAL FOR PATIENTS WITH pT3 RENAL CELL CARCINOMA—CAN THE 2002 PRIMARY TUMOR CLASSIFICATION BE IMPROVED?

PURPOSE: The 2002 primary tumor classification for renal cell carcinoma (RCC) does not distinguish between patients with tumor thrombus involving the renal vein only and those with inferior vena cava tumor thrombus below the diaphragm. We evaluated the association of tumor thrombus level and fat invasion with outcome to determine if further subclassification would improve the prognostic accuracy of the current classification. MATERIALS AND METHODS: We studied 675 patients treated with radical nephrectomy or nephron sparing surgery for pT3a (206, 30.5%), pT3b (422, 62.5%), pT3c (19, 2.8%) or pT4 (28, 4.2%) RCC at the Mayo Clinic between 1970 and 2000. Associations with outcome were evaluated using Cox proportional hazards regression. RESULTS: There were 531 deaths from RCC at a median of 1.5 years following nephrectomy. Patients with pT3b RCC and level I, II or III tumor thrombus were significantly more likely to die of RCC compared to patients with pT3b RCC and level 0 tumor thrombus (risk ratio 1.62, p <0.001). Patients with peripheral perinephric or renal sinus fat invasion were also more likely to die of RCC compared to patients without fat invasion (risk ratio 1.87, p <0.001). Therefore, patients with pT3 RCC were reclassified into 4 groups as thrombus level 0 without fat invasion, fat invasion only, thrombus level 0 with fat invasion or thrombus level I, II or III without fat invasion, and thrombus level I, II or III with fat invasion or thrombus level IV. This reclassification significantly improved prediction of death from RCC compared with the current classification (c indexes of 0.61 versus 0.55, respectively). CONCLUSIONS: Further subclassification of the primary tumor classification for patients with pT3 RCC improved prognostic accuracy.     

Initial high-grade T1 urothelial cell carcinoma: feasibility and prognostic significance of lamina propria invasion microstaging (T1a/b/c) in BCG-treated and BCG-non-treated patients

OBJECTIVES: This study aimed to determine the prognostic value of depth of lamina propria invasion in initial high-grade T1 bladder tumors. Secondary aims were to evaluate the prognostic significance of concomitant carcinoma in situ (CIS) and the impact of bacillus Calmette-Guérin (BCG) treatment as well as to assess the feasibility of microstaging by pathologists in a community setting. PATIENTS AND METHODS: Ninety-seven tumors were available for study and were substaged according to invasion superficial to, into or beyond the muscularis mucosae (MM) (T1a, T1b, T1c). Outcomes were compared by chi-square analysis. Recurrence-free and progression-free survival estimates were obtained by Kaplan-Meier analysis. BCG treatment impact and prognostic significance of CIS were also evaluated (Cox regression). RESULTS: T1 subclassification was possible in 87% (85/97) of cases: 38 (39.1%) T1a, 10 (10.3%) T1b, and 37 (38.1%) T1c; in 12 patients (12.4%) substaging was not possible. Mean age was 66.4 years and mean follow-up was 53 months. Recurrence rates were similar for all groups. By contrast, the progression rate for deep lamina propria-invasive tumors, i.e. T1b and T1c, was 34% (16/47) in comparison to 8% (3/38) for T1a (p=0.016). Progression-free intervals were significantly different in patients with (T1b, T1c) or without (T1a) deep lamina propria involvement (p=0.003), regardless of BCG treatment (p=0.02). BCG-treated patients (67 cases) showed a slight trend towards a better outcome, but differences were not significant. CIS was associated with more than 50% of cases that progressed. On multivariate analysis, depth of invasion and CIS remained two independent prognostic factors, increasing the hazards ratio of progression to 4.47 and 3.19 respectively. CONCLUSIONS: The depth of invasion in the TURB specimens is an independent prognostic factor for T1 bladder cancer even in BCG-treated patients. Associated CIS significantly increases the risk of progression in these patients. The percentage of cases that can be substaged according to the depth of lamina propria involvement increases over time with the collaboration between urologists and pathologists. Consequently, we support that routine pathological assessment of the level of MM invasion in patients with stage T1 bladder cancer should be included in the histopathological report.     

Prognostic risk stratification of pathological stage T2N0 bladder cancer after radical cystectomy

Study Type – Therapy (individual cohort) Level of Evidence 2b What’s known on the subject? and What does the study add? Patients with urothelial carcinoma of the bladder (UCB) and pathological (p) stage T2N0 disease exhibit a range of clinical outcomes with an overall estimated 10–25% experiencing recurrence and death after radical cystectomy (RC). Nomograms to prognosticate UCB post‐RC have been developed in heterogeneous datasets of patients across different stages and do not address factors unique to pT2N0 disease. A user‐friendly prognostic risk model was devised for patients with pT2N0 UCB undergoing RC based on residual pathological stage at RC (pT2a, pT2b, OBJECTIVE ? To stratify risk of pathological (p) T2N0 urothelial carcinoma of the bladder after radical cystectomy (RC) based on pathological factors to facilitate the development of adjuvant therapy trials for high‐risk patients.

PATIENTS AND METHODS

? The study comprised 707 patients from a database of patients with pT2N0 urothelial carcinoma of the bladder who had undergone RC and not received perioperative chemotherapy. ? The effect of residual pT‐stage at RC, age, grade, lymphovascular invasion and number of lymph nodes removed on recurrence‐free survival was evaluated using Cox regression analyses. A weighted prognostic model was devised with significant variables.

RESULTS

? The median follow up was 60.9 months. In multivariable analyses, residual disease at RC (pT2a: hazard ratio (HR) 1.740, P = 0.03; for pT2b: HR 3.075, P < 0.001; both compared with P = 0.09) and lymphovascular invasion (HR 2.234, P < 0.001) were associated with recurrence‐free survival (c = 0.70). ? Three risk groups were devised based on weighted variables with 5‐year recurrence‐free survival of 95% (95% CI 87–98), 86% (95% CI 81–90) and 62% (95% CI 54–69) in the good‐risk, intermediate‐risk and poor‐risk groups, respectively (c = 0.68). The primary limitation is the retrospective and multicenter feature.

CONCLUSIONS

? A prognostic risk model for patients with pT2N0 bladder cancer undergoing RC with generally adequate lymph node dissection was constructed based on residual pathological stage at RC, grade and lymphovascular invasion. ? These data warrant validation and may enable the selection of patients with high‐risk pT2N0 urothelial carcinoma of the bladder for adjuvant therapy trials.     

Carcinoma urotelial de tracto urinario superior: 114 casos con largo seguimiento

PurposeUpper urinary tract urothelial carcinoma (UUTUC) represents 5% of all urothelial tumors and has uncertain prognostic. Exist few series which describes clinical-pathological parameters of tumor progression. The aim of this study is to evaluate clinical and pathological parameters and determine their value as prognostic factors of tumor progression and cancer-specific survival.Material and methodsRetrospective analysis of 114 cases of radical nephroureterectomy or partial ureterectomy collected between 1991 – 2004. Variables analyzed were age, sex, pathological tumor stage, histological tumor grade, CIS, tumor localization, multiplicity, bladder cancer history, pathological nodes and adjuvant chemotherapy. Spearman test was used for correlations. The probabilities of progression free survival and cancer-specific survival were calculated using Kaplan-Meier curves. In the multivariate analysis forward stepwise Cox regression was performed.ResultsPathological stage was: 15 pTa, 25 pT1, 26 pT2, 32 pT3 and 16 pT4. There were 10 G1 (9%), 52 G2 (45.5%) and 52 G3 (45.5%). Fifteen patients presented pathological nodes at the moment of diagnosis. Fourteen percent of 114 patients received adjuvant treatment (Platin-based regimen). Mean follow-up: 74.8 months; 30.7% of the patients developed tumor progression. Death from the disease: 24.6%. Five-years overall and cancer-specific survival: 59.3% and 72.9%, respectively. Five-year progression-free survival: 68%. Mean time of tumor progression: 12.2 months and 23.3 months for cancer-specific death. In the multivariate analysis the independent predictive variables of death and tumor progression were histological grade and pathological stage.ConclusionsWe demonstrated that histological grade and pathological stage constitute independent prognostic factors of tumor progression and cancer-specific survival in UUTUC.     

Evaluation of HER2 protein overexpression in non-muscle-invasive bladder cancer with emphasis on tumour grade and recurrence

Objectiveto evaluate the prognostic value of HER2 expression in non-muscle invasive bladder transitional cell carcinoma (TCC) with special emphasis in the high grade population.Materials and methods (patients)Tissue microarrays (TMA) were performed with representative TUR-B specimens from 84 patients with non-muscle invasive bladder TCC (40 pT1GII and 44 pT1GIII) treated in our institution. Depth of invasion and grade were uniformly assigned by the same pathologist who performed blind immunohistochemical analysis with Hercep test: 3+ was considered strong positive HER2 overexpression. Other clinico-pathological variables were also assessed.ResultsHER2 protein overexpression was detected in 30/44 (68.2%) pT1GIII lesions and predicted recurrence in this subgroup of bladder TCC (p < 0.01). Negative HER2 expression was detected in 26/40 (65%) cases with pT1GII TCC, and this condition was more frequent in unifocal tumours, without angiogenesis, with low recurrence rate and without progression. Recurrence-free survival can also be anticipated by HER 2 expression within pT1GII tumours (p < 0.01).ConclusionHER2 expression using Hercep test may be useful to predict recurrence in non-muscle invasive bladder TCC. The potential application of this study, especially regarding prediction of response to BCG, should be prospectively confirmed in multi-institutional trials.     

Prognostic significance of non-papillary tumor morphology as a predictor of cancer progression and survival in patients with primary T1G3 bladder cancer

Objective  To investigate the prognostic significance of tumor morphology in relation to progression and survival in patients with primary T1G3 bladder cancer (BC) Methods  After review of pathology, 194 patients who were diagnosed with primary T1G3 BC after clinically complete transurethral resection between 1989 and 2005 were seen. Of these patients, 144 underwent surveillance and 50 underwent immediate cystectomy. Tumor morphology (gross and microscopic) in addition to other clinicopathological factors such as tumor size, multifocality, lymphovascular invasion (LVI), carcinoma-in-situ (CIS), intravesical therapy, and the absence of proper muscle were evaluated with regard to recurrence, progression, upstaging, and survival. In addition, correlations between tumor morphology and other factors were analyzed. Results  Median follow-up was 52.5 months. Five-year cancer-specific survival rates were 92.1% for entire cohort, 95.6% for surveillance group, and 84.0% for immediate cystectomy group, respectively. During surveillance, recurrence and progression were noted in 43.1, 13.2%, respectively. Of the potential prognostic factors analyzed, non-papillary morphology (both gross and microscopic) was a significant parameter of progression and intravesical therapy was significantly predictive of recurrence. After immediate cystectomy, 34% were upstaged. Non-papillary morphology and the absence of proper muscle were related to upstaging. For entire patients, non-papillary morphology and the absence of proper muscle were also significant predictors of patient’s survival (P = 0.048, HR = 4.826, and P = 0.007, HR = 5.663, respectively). Non-papillary tumors were significantly related to the presence of LVI and CIS compared to papillary tumors. Conclusions  Non-papillary tumor morphology was a predictor of cancer progression and survival in patients with primary T1G3 BC.     

Upper urinary tract transitional cell carcinoma: location is not correlated with prognosis

Study Type – Therapy (case series) Level of Evidence 4 What's known on the subject? and What does the study add? Tumour location has been shown to be of prognostic importance in UUT‐TCC, with tumours of renal pelvis having a better prognosis than ureteral tumours. Patients from Balkan Endemic Nephropathy (BEN) areas had a higher frequency of pelvis tumours. Also, we found that belonging to a BEN area is an independent predictor of disease recurrence.

OBJECTIVE

• ? To identify the impact of tumour location on the disease recurrence and survival of patients who were treated surgically for upper urinary tract transitional cell carcinoma (UUT‐TCC).

PATIENTS AND METHODS

• ? A single‐centre series of 189 consecutive patients who were treated surgically for UUT‐TCC between January 1999 and December 2009 was evaluated.
• ? Patients who had previously undergone radical cystectomy, preoperative chemotherapy or contralateral UUT‐TCC were excluded.
• ? In all, 133 patients were available for evaluation. Tumour location was categorized as renal pelvis or ureter based on the location of the dominant tumour.
• ? Recurrence‐free probabilities and cancer‐specific survival were estimated using the Kaplan–Meier method and Cox regression analyses.

RESULTS

• ? The 5‐year recurrence‐free and cancer‐specific survival estimates for the cohort in the present study were 66% and 62%, respectively.
• ? The 5‐year bladder‐only recurrence‐free probability was 76%. Using multivariate analysis, only pT classification (hazard ratio, HR, 2.46; P= 0.04) and demographic characteristics (HR, 2.86 for areas of Balkan endemic nephropathy, vs non‐Balkan endemic nephropathy areas; 95% confidence interval, 1.37–5.98; P= 0.005) were associated with disease recurrence
• ? Tumour location was not associated with disease recurrence in any of the analyses.
• ? There was no difference in cancer‐specific survival between renal pelvis and ureteral tumours (P= 0.476).
• ? Using multivariate analysis, pT classification (HR, 8.04; P= 0.001) and lymph node status (HR, 4.73; P= 0.01) were the only independent predictors associated with a worse cancer‐specific survival.

CONCLUSION

• ? Tumour location is unable to predict outcomes in a single‐centre series of consecutive patients who were treated with radical nephroureterectomy for UUT‐TCC.

     

Risk factors for positive findings in patients with high‐grade T1 bladder cancer treated with transurethral resection of bladder tumour (TUR) and bacille Calmette‐Guérin therapy and the decision for a repeat TUR

Study Type – Therapy (case series) Level of Evidence 4

OBJECTIVE

To determine factors predictive of positive findings at the 3‐month follow‐up evaluation (after transurethral resection of bladder tumour [TUR] and bacille Calmette‐Guérin [BCG] therapy) in patients with initial high‐grade (HG)T1 bladder cancer, and to assess the depth of lamina propria (LP) invasion and effectiveness of BCG therapy.

PATIENTS AND METHODS

In all, 138 patients with initial HGT1‐transitional cell carcinoma (TCC) were prospectively assigned, after TUR + BCG and according to depth of LP invasion, to a postBCG‐TUR (T1b) or cystoscopy/cytology (T1a) at 3 months. Any finding at 3 months was considered positive. The predictive value of 11 clinical and pathological variables was assessed by chi‐squared, Mann–Whitney U and multivariate logistic regression.

RESULTS

Of the 138 patients (14 women, mean age 69 years), 42% had T1a and 58% T1b TCC. Tumour size and carcinoma in situ (CIS) were significantly associated with positive findings and present in 26% (36/138) of the patients. The postBCG‐TUR (T1b cases), was positive in 31% (25/80), including seven infiltrating tumours. On multivariate analysis, again a tumour size of >3 cm (odds ratio, OR, 7.02) and associated CIS (OR 5.4) were significantly related to a positive postBCG‐TUR. A secondary finding was that at 20.3 months; patients with T1a TCC, who did not undergo a repeat TUR, did not have increased progression; only 3% (two of 58) had progressed compared with 21% (17/80) of those with T1b/c TCC (P < 0.002).

CONCLUSIONS

In initial HGT1‐TCC, tumour size and CIS were predictive factors of positive findings at 3 months after the initial TUR + BCG therapy. Patients with HGT1‐TCC invading the LP (T1b TCC) had a seven times higher risk of a positive repeat TUR if the initial tumour was >3 cm and a five‐fold increased risk if associated with CIS. The repeat TUR after BCG therapy allowed confirmation of complete resection and pathological evaluation of the BCG response. Although data are still preliminary, the strategy of performing a repeat TUR only in cases with LP involvement, i.e. T1b TCC, did not increase the risk of progression in cases with T1a TCC.     

Primary Ta high grade bladder tumors: Determination of the risk of progression

PurposeTaG3 bladder cancer is an under-investigated disease and because of its rarity it is commonly studies together with T1G3 disease. We sought to exclusively study TaG3 disease and to determine the factors associated with disease progression.Material and methodWe retrospectively studied patients with primary TaG3 bladder cancer. Progression to ≥pT1 and pT2 were analyzed using Cox and competing-risk regression analyses.ResultsOf 3,505 consecutive patients with nonmuscle invasive bladder cancer, 285 patients had primary TaG3 without concomitant carcinoma in-situ. Progression to ≥pT1 occurred in 21 patients (7.4%). In a multivariable competing-risk regression analysis, intravesical Bacillus Calmette-Guerin (BCG) was significantly associated with a lower risk of progression to ≥pT1 (HR 0.23, 95%CI 0.08–0.64, P = 0.005). Recurrence in the first year of diagnosis was significantly associated with an increased risk of stage progression to ≥pT1 (HR 7.81, 95%CI 2.50–24.44, P < 0.001). Progression to ≥T2 was observed in 9 patients (3.2%). In univariable competing-risk regression analyses, intravesical BCG was significantly associated with a lower risk of progression to ≥pT2 (HR 0.11, 95%CI 0.04–0.47, P = 0.003). On the other hand, recurrence in the first year of diagnosis was significantly associated with an increased risk of stage progression to ≥T2 (HR 7.12, 95%CI 1.50–33.77, P = 0.013). In a subgroup of 199 patients who were treated with BCG, there was no statistically significant association between tumor recurrence in the 1^st year of diagnosis and stage progression to ≥pT1 (P = 0.14) or ≥pT2(P = 0.19).ConclusionPatients with TaG3 bladder cancer are considered high risk but if appropriately treated with BCG that risk is considerably mitigated. Our data support that TaG3 without concomitant carcinoma in-situ should not be considered as aggressive as T1G3 as it has a lower risk of progression to muscle-invasive bladder cancer. Recurrence in the first year after diagnosis is the strongest predictor of progression to muscle-invasive bladder cancer.     

A histopathologic investigation of PGE(2) pathways as predictors of proliferation and invasion in urothelial carcinomas of the bladder

INTRODUCTION AND OBJECTIVES: The pattern of arachidonate acid (AA) transformation in tumor cells has been shown to play a role in determining tumor cell invasiveness. AA is released from membrane phospholipids by cPLA(2). Then it is metabolized into prostaglandins and PGE(2) especially via cyclooxygenase pathways. PGE(2) production seems to be necessary for rendering the cells invasive. We aimed to characterize cPLA(2), cyclooxygenase 2 (COX2) and prostaglandine E synthase (PGES) expression in human transitional carcinoma (TCC) of the urinary bladder and correlate with the Ki-67 proliferating marker. METHODS: Formalin-fixed human TCC tissues (n=54) obtained from TURB or cystectomies were evaluated for cPLA(2), COX2, PGES and Ki-67 expression using specific antibodies. There were 6 CIS, 9 pTaG1, 9 pTaG3, 10 pT1G3 and 10 pT2G3. 10 normal bladder tissues were also evaluated. Control slides were incubated without primary antibodies and treated in a similar way. RESULTS: cPLA(2), COX2 and PGES were not expressed in the 10 normal tissues. In the same normal tissues, Ki-67 expression was observed only in 1% of the cells. However, cPLA(2) was expressed in 1/6 CIS, 1/9 pTaG1, 3/9 pTaG3, 6/10 pT1G3 and 2/10 pT2G3. COX2 was expressed in 0/6 CIS, 0/10 pTaG1, 2/9 pTaG3, 3/10 pT1G3 and 1/10 pT2G3. PGES was expressed in 4/6 CIS, 0/9 pTaG1, 4/9 pTaG3, 2/10 pT1G3 and 5/10 pT2G3. Ki-67 expression was 39.5% for CIS, 6.5% in pTaG1, 37% in pTaG3, 34.5% in pT1G3 and 55% in pT2G3. If we consider it a positive result when at least one enzyme was expressed, there were 5/6 CIS positive, 1/9 pTaG1 positive, 9/9 pTaG3 positive, 10/10 pT1G3 positive and 10/10 pT2G3 positive. Also the Ki-67 is more often expressed in cells with high grade tumor. CONCLUSIONS: These results suggest that (i). not only COX2 is involved in the tumorogenesis of the TCC but also cPLA(2) and PGES, (ii). there is relationship between the AA metabolic PGE(2) pathway expression and the aggressiveness of the TCC of the urinary bladder.     

Subclassification of pT3 urothelial carcinoma of the renal pelvicalyceal system is associated with recurrence-free and cancer-specific survival: proposal for a revision of the current TNM classification

Background

The clinical course of pT3 upper tract urothelial carcinoma (UTUC) is highly variable.

Objectives

The aim of the current study was to validate the clinical and prognostic importance of pT3 subclassification in the renal pelvicalyceal system in a large international cohort of patients.

Design, setting, and participants

From a multi-institutional international database, 858 renal pelvicalyceal tumors treated with radical nephroureterectomy (RNU) were systematically reevaluated by genitourinary pathologists. Category pT3 pelvic tumors were categorized as pT3a (infiltration of the renal parenchyma on a microscopic level only) versus pT3b (macroscopic infiltration of the renal parenchyma and/or infiltration of peripelvic adipose tissue).

Intervention

RNU.

Measurements

Associations of pT3 subclassifications with clinicopathologic features were assessed with the chi-square test. Prognostic impact was assessed with the log-rank test and multivariable Cox regression analyses.

Results and limitations

Of 858 patients with renal pelvicalyceal tumors, 266 (31%) had pT3 disease. Of these, 146 (54.9%) were classified as pT3a and 120 (45.1%) as pT3b. Compared with pT3a, pT3b cancers were associated with higher tumor grade, nodal disease, and tumor necrosis. Ten-year recurrence-free (pT3a 58% vs pT3b 38%; p < 0.001) and cancer-specific (pT3a 60% vs pT3b 39%; p = 0.002) survival rates were lower for patients with pT3b disease. In multivariable analyses, classification pT3b was an independent predictor of both disease recurrence (hazard ratio [HR]: 1.8, p = 0.003) and cancer-specific mortality (HR: 1.7; p = 0.02). The major limitation is the retrospective character of the study.

Conclusions

Subclassification of pT3 renal pelvicalyceal UTUC helps identify patients who are at increased risk of disease progression and cancer-related death. Further research may help assess the value of subclassification and its inclusion in future editions of the American Joint Committee on Cancer–International Union Against Cancer TNM classification system.     

Impact of diabetes mellitus on recurrence and progression in patients with non-muscle invasive bladder carcinoma: a retrospective cohort study

Objective: The aim of the present study was to investigate the relationship between diabetes mellitus (DM) and tumor features in patients with non‐muscle invasive bladder cancer (NMIBC). Methods: Data from 251 patients who underwent transurethral resection (TUR) for NMIBC from January 2000 to June 2010 were analyzed retrospectively. Patients were divided into two groups: Group I, 159 patients (63%) who did not have DM at the time of surgery; and (ii) Group II, 92 patients (37%) who had DM at the time of surgery. Recurrence‐ and progression‐free survival was assessed in both groups. Preoperative HbA1c levels, as parameter of glycemic control, were determined in Group II patients, with patients divided into two subgroups: (i) HbA1c ≥7.0%; and (ii) HbA1c <7.0%. The clinical features of the bladder tumor were compared in these two subgroups. Results: Compared with Group I, Group II patients were older and had a higher rate of hypertension, recurrence, and progression (P < 0.05). Univariate survival analysis showed that gender, DM, smoking, and serum creatinine were associated with recurrence‐free survival (P < 0.05), whereas DM, stage, grade, intravesical instillation, and serum creatinine were associated with progression‐free survival. In multivariate survival analysis, DM was found to be an independent factor for recurrence‐ (hazard ratio [HR] 2.11; 95% confidence interval [CI] 1.4–3.2; P = 0.001) and progression‐free survival (HR 9.35; 95% CI 3.1–28.6; P = 0.001). Furthermore, patients with HbA1c ≥7.0% exhibited a significantly higher rate of multiplicity (P = 0.001), tumor grade (P = 0.03), and intravesical treatment (P = 0.04). Conclusions: In conclusion, DM seems to be an independent predictor of recurrence‐ and progression‐free survival in NMIBC patients. Further prospective studies are needed to establish the prognostic significance of postoperative glycemic control in this patient population.     

Oncological outcomes of pathologically organ-confined,lymph node-positive prostate cancer after radical prostatectomy

BackgroundThe aim of this study was to investigate the impact of lymph-node involvement on oncological outcomes in patients with pathologically organ-confined prostate cancer (pT2 CaP) after radical prostatectomy (RP).MethodsWe retrospectively analyzed 9,631 pT2 CaP patients who underwent RP at a single institution between 1998 and 2018. Kaplan-Meier plots and Cox regression models (CRMs) assessed biochemical recurrence (BCR)-free survival and metastasis-free survival (MFS) according to N-stage. In subgroup analyses of N1 patients, Kaplan-Meier plots and CRMs were stratified according to adjuvant treatment.ResultsOf 9,631 pT2 staged patients, 241 (2.5%) harbored lymph-node metastases after RP (pN1). The median follow-up was 60.8 months. No pT2 N1-staged patient died due to CaP. The 5-year BCR-free survival rates were 54.7 vs. 88.4% in pT2 N1 vs. pT2 N0 patients, respectively (P < 0.001). The 5-year MFS rates were 92.5 vs. 98.9% in pT2 N1 vs. pT2 N0 patients, respectively (P < 0.001). Within pT2 N1 patients, presence of ≥3 positive lymph nodes was an independent risk factor for BCR (hazard ratio [HR] 3.4, P < 0.001) and for metastatic progression (HR 1.7, P = 0.04). Finally, 3-year BCR-free survival was improved in pT2 N1 patients treated with adjuvant radiation therapy (87.1% vs. 63.7% for patients who received other treatment options [P < 0.001]).ConclusionPatients with pathologically organ-confined but lymph node-positive CaP exhibited favorable oncological outcomes after RP. Presence of ≥3 positive LNs predicted higher rates of BCR and metastatic progression. In consequence, in pT2 N1 patients treated with RP with ≥3 positive LNs, adjuvant treatment may be considered.9     

The prognostic role of the pathological T2 subclassification for prostate cancer in the 2002 Tumour-Nodes-Metastasis staging system

OBJECTIVE

To evaluate the prognostic role of the 2002 Tumour‐Nodes‐Metastasis (TNM) pT2 subclassification for biochemical recurrence (BCR) after radical prostatectomy (RP) for prostate cancer.

PATIENTS AND METHODS

The 1997 TNM staging system is based on one subdivision for organ‐confined prostate tumours (T2a, unilateral; T2b, bilateral involvement). The 2002 TNM staging system subdivides unilateral involvement into T2a (half of one lobe or less) and T2b (more than one half of one lobe), while bilateral involvement is classified as T2c. In all, 542 patients were treated with RP at our institute; the RP specimens were completely embedded and histopathologically evaluated for Gleason grade, tumour volume and anatomical extent, and were staged according to the 2002 TNM staging criteria. Patients were followed for a median of 39.5 months. BCR was defined as two subsequent increasing prostate‐specific antigen (PSA) levels of >0.10 ng/mL. Kaplan‐Meier and proportional hazards regression analyses were used to evaluate the univariable and multivariable prognostic effect of tumour stage.

RESULTS

According to the 2002 TNM staging system, 360 specimens were found to have pT2 tumours; 79 (22%) of the RP specimens were staged as pT2a and 281 (78%) as pT2c; no pT2b specimens were identified. Patients with unilateral involvement (pT2a) had a 5‐year risk of BCR of 13%, while those with bilateral involvement (pT2c) had a risk of 23% (log rank test, P = 0.056). Patients with pT2c disease were more likely to have a larger tumour volume (Mann–Whitney U‐test P < 0.001) and positive surgical margins (Fishers’ exact test, P = 0.001)than those with pT2a tumours. Mann–Whitney U‐tests showed no differences between the groups for preoperative PSA levels (P = 0.167). Also, the RP Gleason score was no different between groups (Pearson chi‐square, P = 0.807). In the multivariable analyses, positive surgical margins appeared to increase the risk of BCR (hazard ratio 4.4, 95% confidence interval 2.5–7.9); pT2c vs pT2a had only a marginally (insignificant) additional effect (1.3, 0.6–2.7).

CONCLUSION

The absence of a true unilateral pathological T2b tumour in a series of 360 pT2 RP specimens questions the relevance of substaging unilateral disease. The limited differences in BCR and in pathological features of unilateral vs bilateral pT2 prostate cancer justify modifying the TNM staging system to one with no subclassification of pT2 disease, or at most as only one subdivision into unilateral (T2a) and bilateral (T2b) disease, combining the T2b and T2c substages.     

Impact of lymph node metastasis on survival in patients with pathological T1 carcinoma of the ampulla of vater

To determine the prognostic factors for patients with pathological T1 (pT1) carcinoma of the ampulla of Vater, 36 consecutive patients with carcinoma of the ampulla of Vater who underwent surgery were retrospectively analyzed in terms of clinicopathological features. The overall 5-year Kaplan-Meier survival in all patients was 50.2%, and the median survival of all patients was 64.0 months. Factors favorably influencing a long-term outcome were the absence of lymph node metastasis (P<0.0001), the absence of ulcer formation of the tumor (P=0.0062), and the absence of tumor invasion into the duodenum (P = 0.0025) and the pancreas (P=0.0098). In a multivariate analysis, lymph node metastasis was the only predictor of survival (P=0.0023). In the pT1 stage patients, 20% of the patients had lymph node metastasis, and their survival was statistically poor compared to the pT1 patients without lymph node metastasis (P=0.017). As for survival after the operation, there was no significant difference between pancreatoduodenectomy and pylorus-preserving pancreatoduodenectomy.     

The presence of extracapsular extension is associated with an increased risk of death from prostate cancer after radical prostatectomy for patients with seminal vesicle invasion and negative lymph nodes

ObjectivesDetermining clinicopathologic features that stratify the risk of disease progression in patients with seminal vesicle invasion at radical prostatectomy remains critical for patient counseling, clinical trial enrollment, and the judicious application of secondary therapies. Then, we evaluated the prognostic significance of concomitant extracapsular extension (ECE) in patients with seminal vesicle invasion and negative lymph nodes at radical prostatectomy.MethodsWe identified 1,132 patients who underwent prostatectomy between 1987 and 2009 and were found to have pT3bN0 disease. Median postoperative follow-up was 10.6 years (interquartile range, 5.9–15.3). Survival was estimated using the Kaplan-Meier method and compared for patients with and without ECE with the log-rank test. The association of ECE with outcome was evaluated using Cox proportional hazards regression models.ResultsA total of 693 (61%) patients were noted to have ECE. Compared with pT3bN0 patients without ECE, patients with pT3bN0 tumors and ECE had a significantly worse 15-year biochemical recurrence-free survival (29% vs. 39%; P<0.001), systemic progression-free survival (71% vs. 81%; P<0.001), cancer-specific survival (80% vs. 89%; P<0.001), and overall survival (50% vs. 63%; P<0.001). On multivariate analysis, the presence of ECE was associated with significantly increased risks of systemic progression (hazard ratio [HR], 1.56; P=0.006), death from prostate cancer (HR, 1.71; P=0.01), and all-cause mortality (HR, 1.35; P=0.007). Meanwhile, adjuvant hormonal therapy, which was received by 334 patients (29.5%), was associated with significantly decreased risks of systemic progression (HR, 0.50; P=0.0004) and cancer death (HR, 0.57; P=0.03), but not all-cause mortality (HR, 0.81; P=0.09). Limitations included retrospective design and nonstandardized application of secondary treatments.ConclusionsThe presence of ECE in patients with pT3bN0 prostate cancer is associated with increased risks of systemic progression and cancer death. Pending validation, ECE may be incorporated into risk stratification or staging classification or both. Meanwhile, these patients continue to represent ideal candidates for adjuvant therapy trials.