Bilharzial related, organ confined, muscle invasive bladder cancer: prognostic value of apoptosis markers, proliferation markers, p53, E-cadherin, epidermal growth factor receptor and c-erbB-2

PURPOSE: We investigated the association of the apoptosis related proteins Bcl-2, Bcl-x, Bax and Bak, p53, the adhesion molecule E-cadherin, the receptor proteins epidermal growth factor receptor and c-erbB-2, and the proliferation markers proliferating cell nuclear antigen and Ki-67 with the clinical outcome of bilharzial related transitional cell carcinoma and squamous cell carcinoma. MATERIALS AND METHODS: Cystectomy specimens from 109 patients with organ confined, muscle invasive stage, pT2pN0M0, bilharziall positive bladder cancer were examined, including 60 with squamous cell carcinoma and 49 with transitional cell carcinoma. Immunohistochemical results were correlated with tumor progression. RESULTS: In squamous cell carcinoma but not in transitional cell carcinoma the loss of epidermal growth factor receptor, Bax and Bak was significantly associated with higher histological grade (p = 0.02, 0.006 and 0.01, respectively). On univariate analysis patients with transitional cell carcinoma had a poorer prognosis than those with squamous cell carcinoma. p53 Over expression and the loss of Bak positivity were associated with shortened progression-free survival in transitional cell carcinoma (p = 0.006 and 0.04, respectively), and squamous cell carcinoma (p = 0.00001 and 0.04, respectively). In squamous cell carcinoma high tumor grade (p = 0.02) and in transitional cell carcinoma high labeling indexes for MIB-1, Bcl-x expression and c-erbB-2 positivity (p = 0.03, 0.02 and 0.04, respectively) were associated with a poorer prognosis. On multivariate analysis p53 emerged as a significant prognostic factor for each condition. Additional independent prognostic factors were proliferating cell nuclear antigen for squamous cell carcinoma, and MIB-1, Bcl-x and Bax for transitional cell carcinoma. CONCLUSIONS: Bilharzial related transitional cell carcinoma and squamous cell carcinoma of the bladder differ in interims of protein expression and prognosis. Independent prognostic factors were p53, MIB-1, Bcl-x, and Bax in the former disease, and p53 and proliferating cell nuclear antigen in the latter disease.     

Immunoexpression of p53 protein and proliferating cell nuclear antigen in penile carcinoma.

PURPOSE: We examined p53 protein and proliferating cell nuclear antigen immunoexpression as prognostic factors to the outcome of squamous cell carcinoma of the penis in 50 patients. MATERIALS AND METHODS: Penectomy and lymphadenectomy were performed in 14 patients with clinically positive nodes while 36 with cN0 disease were treated with penectomy and kept under surveillance that resulted in subsequent lymphadenectomy due to nodal relapse in 8. Of 21 patients with confirmed nodal metastases 18 died of disease. Immunohistochemical reactions were performed via the avidin-biotin-immunoperoxidase method and the results were compared with tumor pT stage, grade, nodal status and cause specific death. RESULTS: In univariate analysis proliferating cell nuclear antigen staining showed association only with nodal metastasis (p = 0.04) while p53 staining exhibited correlation with tumor pT stage (p = 0.0005), grade (p = 0.02), lymphatic spread (p = 0.02) and cause specific survival (p = 0.003). Multivariate analysis showed that p53 immunoreactivity was the only factor with prognostic significance for disease progression and cause specific survival. Tumor pT stage, grade and proliferating cell nuclear antigen staining had no significance for nodal metastases and cause specific death. CONCLUSIONS: Proliferating cell nuclear antigen staining had no prognostic value for disease progression. Since p53 over expression was associated with tumor progression and cause specific death, perhaps it should be evaluated in staging and therapeutic planning for patients with squamous cell carcinoma of the penis.     

Strong Immunohistochemical Expression of Vascular Endothelial Growth Factor Predicts Overall Survival in Head and Neck Squamous Cell Carcinoma

Background Head and neck squamous cell carcinoma (HNSCC) has high morbidity and mortality, and its relationship with tumor angiogenesis as measured by mircovessel density (MVD) or vascular endothelial growth factor (VEGF) expression has shown mixed results, with some, but not others, reporting correlation with outcome. Methods A retrospective study of 186 patients with HNSCC was performed. Patients were evaluated for MVD and VEGF and to correlate the levels with clinical parameters, including age at diagnosis, sex, site of tumor, stage, survival (disease free and overall), pathological tumor grade, and the presence of lymph node metastases. Results The 186 cancers included the following sites: oral tongue (n = 69), palate (n = 9), maxillary sinus (n = 8), floor of mouth (n = 13), oropharynx (n = 27), hypopharynx (n = 26) and larynx (n = 34). Over three-quarters of patients had advanced tumor (stage III/IV) and 58.6% had lymph node metastases. MVD and VEGF were assessed in 166 and 164 cases, respectively, but these were not correlated with site and grade. The 3-year overall and disease-free survival rates were 55.4% and 53.2%, respectively. Both univariate and multivariate survival analysis showed that advanced T stage, nodal metastasis, and strong VEGF intensity were independent adverse predictors for overall and disease-free survival. In stage IV disease, strong VEGF immunoreactivity was found to be the single adverse factor affecting the overall survival and a contributory factor for disease-free survival. Conclusions VEGF immunoreactivity is a strong predictor of adverse outcome, particularly in locoregionally advanced disease.     

Squamous cell carcinoma of the renal pelvis and ureter: incidence, symptoms, treatment and outcome

PURPOSE: Squamous cell carcinomas of the renal pelvis and ureter are rare. We report a large series of patients and compare it to patients with urothelial carcinoma. MATERIALS AND METHODS: The initial material was comprised of 808 patients with renal pelvis or ureteral cancer. A review of the histopathological material and clinical records was performed. RESULTS: Only 2 (4%) of 65 patients with squamous cell carcinoma had stage pTa/pT1/pT2 tumors compared to 460 (62%) of 743 patients with urothelial carcinoma. Median survival was much shorter for surgically treated patients with squamous cell carcinoma compared to those with urothelial carcinoma (7 vs 50 months). However, there was no significant difference in the disease specific 5-year survival rate between patients with squamous cell carcinoma and urothelial carcinoma in the same disease stage. Vascular invasion, microscopic solid tumor pattern and large tumor size had negative prognostic significance in multivariate analyses. Histopathological tumor type (squamous cell carcinoma or urothelial carcinoma) had no prognostic significance. CONCLUSIONS: The prognosis for squamous cell carcinoma is poor, but stage for stage the prognosis is not different between patients with urothelial carcinoma and squamous cell carcinoma of the renal pelvis and ureter. It can be presumed that high stage squamous cell carcinoma and urothelial carcinoma become symptomatic first at a time when the tumors already are large, deeply invasive and most often incurable. New treatment modalities are urgently needed to improve the poor prognosis in patients with advanced stage squamous cell carcinoma and urothelial carcinoma of the upper urinary tract.     

Prognostic prediction of the immunohistochemical expression of p53 and p16 in resected non-small cell lung cancer.

OBJECTIVE: p53 and p16(INK4) are the common and important tumor suppressor genes. Aberrant expression of p53 or p16 protein has been reported in various malignancies including lung cancer. Our aim was to investigate the association of p53 and p16 expression in resected non-small cell lung carcinoma (NSCLC) and evaluated their correlation with clinocopathologic features and survival. METHODS: p16 and p53 expression were detected by immunohistochemical analysis of 90 paraffin specimens of resected NSCLC, including 35 squamous cell carcinoma, 47 adenocarcinoma, and eight large cell carcinoma, between stages I and IV. The immunohistochemical study was performed using the labeled streptavidine-biotin method with anti-p53 and anti-p16 monoclonal antibodies. RESULTS: Fifty-two (57.8%) and 36 (40%) of 90 patients revealed aberrant immunostaining for p53 (p53+) and p16 (p16+), respectively. While 19 cases (21.1%) showed abnormal immunoreactivity for both p16 and p53. (p53+/p16+). There was no correlation of p53 or p16 expression with the clinicopathologic features. The Kaplan-Meier survival analysis demonstrated that patients with p16+, p53+, late stages, and nodal or distal metastasis had poor survival status (P = 0.006, 0.013, <0.001, <0.001 and 0.018, respectively). Further analysis demonstrated that p53 status was a significant prognostic factor in stage I NSCLCs (P < 0.001), and p16 status in stage I and II NSCLCs (P < 0.001, P = 0.003, respectively). Furthermore, patients whose tumors were both p53 and p16 aberrant expression had worse outcome compared with those whose tumors were both normal expression of p53 and p16 (5-year survival rate: 5 vs. 76%, P < 0.001). In Cox's regression model, the aberrant expression of p16, p53, advanced stages and combined aberrant expression of p53/p16 survived for a significant shorter period. CONCLUSIONS: The results indicated that aberrant expression of p16 and p53 are significant and independent, predictable prognostic factors for resected NSCLC, especially in early stage of NSCLCs. The worst prognosis was seen in patients whose tumors had both aberrant expression of p53 and p16. Further prospective trials may be aimed at confirming and validating these results.     

Decreased E-cadherin but not beta-catenin expression is associated with vascular invasion and decreased survival in head and neck squamous carcinomas.

OBJECTIVE: We wished to correlate the expression of E-cadherin and beta-catenin in squamous carcinomas of the head and neck to outcome and other clinicopathologic variables. STUDY DESIGN AND SETTING: This retrospective study was carried out in a tertiary care setting. The tumors of 45 patients who had their head and neck squamous carcinoma primarily treated by resection were evaluated immunohistochemically with antibodies to E-cadherin and beta-catenin. Thirty-two tumors arose in the oral cavity, 9 tumors originated in the larynx, and 4 tumors began in the hypopharynx. Patient outcome and the clinicopathologic variables of tumor site, tumor stage, cervical lymph node status, tumor differentiation, perineural invasion, and vascular invasion were correlated to immunohistochemical expression of E-cadherin and beta-catenin. RESULTS: Low expression of E-cadherin in the tumors was significantly associated with decreased overall survival (P = 0.004), disease-free survival (P = 0.007), and vascular invasion (P = 0.02) but not with other clinicopathologic variables. beta-catenin expression was not significantly associated with any of the studied clinicopathologic variables. CONCLUSION: Decreased E-cadherin but not beta-catenin expression is associated with decreased survival in patients with head and neck squamous carcinomas. SIGNIFICANCE: Detection of loss of E-cadherin expression may help predict which patients with head and neck squamous cell carcinoma will experience a worse outcome compared to patients whose tumors have not lost this tumor suppressor. EBM rating: C-4.     

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

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

Expression of Ku86 confers favorable outcome of tonsillar carcinoma treated with radiotherapy

BACKGROUND: To determine possible molecular markers for predicting radiosensitivity in squamous cell carcinoma, we have examined the relationship between pretreatment expression of the DNA damage recognition complex DNA-PK, its in vitro substrates, p53 and MDM2, local tumor control after radiotherapy (RT), and patient survival. METHODS AND MATERIALS: Formalin-fixed tumor biopsy specimens from 79 previously untreated patients with tonsillar carcinoma were analyzed by immunohistochemical methods. RESULTS: Tumors expressing high levels of Ku86 had better locoregional control in contrast to tumors expressing low levels of Ku86 (p =.023). Survival of patients with tumors expressing high levels of DNA-PKcs was significantly better than survival of patients with tumors expressing low levels of DNA-PKcs (p =.0024). p53 and MDM2 status alone did not correlate with survival of patients. However, patients with p53 tumors and high DNA-PKcs expression had significantly better survival than patients with p53+ tumors expressing low levels of DNA-PKcs (p =.0018). Furthermore, survival of patients with high expression of DNA-PKcs or Ku86 and low MDM2 levels was significantly better when compared with survival of patients with low DNA-PKcs or Ku86 and high MDM2 (p =.0017 and p =.0034, respectively). CONCLUSIONS: High expression of DNA-PKcs/Ku86 in combination with p53 negativity in tonsillar carcinoma correlates with better survival of patients. Identifying tumors with a phenotype predicting poor survival may be used to optimize treatment of patients with radioresistant tumors.     

Tissue microarray analysis of the prognostic value of E-cadherin, Ki67, p53, p27, survivin and MSH2 expression in upper urinary tract transitional cell carcinoma

OBJECTIVES: Invasive upper urinary tract transitional cell carcinoma (UUT-TCC) has a poor prognosis (survival <50% at 5 years), and tumor stage and grade often fail to predict outcome. Our purpose was to establish whether the expression of Ki67, p53, p27, E-cadherin, survivin or MSH2 can provide prognostic information in UUT-TCC. METHODS: The following data from the files of 62 patients treated for UUT-TCC over 12 years were collated: age at diagnosis, prior history of cancer, tobacco consumption, tumor stage (including surgical margins) and grade, and disease progression. Immunohistochemistry (IHC) for Ki67, p53, p27, E-cadherin, survivin and MSH2 was performed on tissue microarray sections from tumor tissue. RESULTS: Overall, 31 patients died with metastasis from UUT-TCC. Mean survival was 20+/-16 months (range 2-83). In a univariate analysis, advanced age (>68 years), high stage, and loss of E-cadherin and high Ki67 expression were associated with a poor prognosis and disease recurrence. In a multivariate analysis, the independent factors of prognosis and recurrence were E-cadherin (p=0.001; p=0.004), age (p=0.022; p=0.008), and high stage (p=0.023; p=0.008). CONCLUSIONS: E-cadherin is a useful independent prognostic factor in UUT-TCC, for use in addition to age and tumor stage. It is of particular interest to predict recurrence in patients with low grade non-invasive tumors. Ki67 expression is informative but less significant. Survivin, p53, p27 and MSH2 have no prognostic value.     

EXPRESSION OF BCL-2 AND BCL-X IN BLADDER CANCER

Purpose

TP53 and RB1 gene mutations in bladder transitional cell carcinoma (TCC) are correlated with grade, stage, recurrence, and survival and may correlate with tumor cell apoptotic potential. Overexpression of the bcl-2 and bcl-X anti-apoptotic genes has been correlated with poor prognosis and chemotherapy resistance in other systems. Similar studies have not been performed in TCC. We thus sought to determine expression of bcl-2 and bcl-X in TCC and correlate these with stage, survival and abnormal pRb or p53 expression.

Materials and Methods

Forty-two TCC samples (19 Ta and 23 locally advanced tumors) and normal urothelial controls were examined. Immunohistochemistry for p53, pRb, bcl-2 and bcl-X was performed on an automated system using indirect streptavidin biotin/horseradish peroxidase staining. Western immunoblot analysis was performed on bladder cancer cell lines to further characterize bcl-X expression. Recurrence-free and disease-specific survival were retrospectively determined. Kaplan-Meier survival curves were compared using the log rank test, and correlation of abnormal staining with stage and p53 or pRb status was determined using Fisher's exact test.

Results

Bcl-2 was expressed in less than 1% of normal urothelial cells, but moderate expression of bcl-x was found in all normal urothelial samples. Only 7.0% of TCC samples (1/19 Ta and 2/23 locally advanced tumors) demonstrated bcl-2 overexpression. Bcl-X overexpression was observed in 45.2% of TCC (8/19 Ta and 11/23 locally advanced tumors). Western blot analysis also revealed that both the long (29 kDa) anti-apoptotic form and short (19 kDa) pro-apoptotic form were overexpressed in bladder cancer cell lines and normal human urothelial cells. Bcl-X overexpression was weakly correlated with normal p53 expression (p = 0.06). There were no correlations of bcl-2 and bcl-X overexpression with abnormal p53, pRb, or tumor stage. There were no differences in recurrence-free or overall survival in patients with abnormal bcl-X staining.

Conclusions

Bcl-2 overexpression is rare in TCC. Bcl-X overexpression is common, likely reflecting its expression pattern in normal urothelium, but is not correlated with stage or abnormal p53 or pRb staining. Within the power limitations of this small study, bcl-X overexpression is not correlated with recurrence or survival.     

Prognostic significance of p53, bcl-2, and Bax expression in early breast cancer

BACKGROUND: The use of adjuvant chemotherapy in early breast carcinoma is controversial, with most advocating its use in high-risk patients as defined by specific clinicopathologic parameters. Both bcl-2 and p53, which play a role in determining tumor growth by their effects on apoptosis and cell proliferation respectively, may serve to delineate this subset more accurately. The purpose of this study was to determine the prognostic value of bcl-2, Bax, and mutant p53 in stage I breast cancer. STUDY DESIGN: A total of 75 patients with stage Ic breast carcinoma diagnosed from 1989 to 1992 were identified retrospectively and clinicopathologic parameters such as age, tumor size, estrogen receptor (ER) and progesterone receptor (PR) status, disease-free survival and overall survival obtained. Paraffin-embedded formalin-fixed tissues were immunostained with bcl-2, Bax and p53 monoclonal antibodies using a standard avidin biotin peroxidase reaction. Stained slides were evaluated by two independent pathologists for staining intensity and percentage of cells staining positively. Cox regression was used for multivariate survival analysis using the clinicopathologic parameters and molecular markers. Chi-square tests were used for frequency tables. RESULTS: Mean patient age was 58 years (range 29 to 79 years) with a median followup of 80 months from time of diagnosis. The most common histopathology was infiltrating ductal carcinoma. Neither bcl-2 nor Bax expression was associated statistically with disease-free or overall survival. Expression of mutant p53 was associated with a significant decrease in both 5-year disease-free survival (70% versus 98%, p 相似文献   

Differences in gene expression in muscle-invasive bladder cancer: a comparison of Italian and American patients

OBJECTIVE: To seek differences in gene expression in the primary muscle-invasive bladder cancers of two cohorts of patients having different survival rates. An Italian group treated by transurethral resection of the bladder tumor (TURBT) and neo-adjuvant chemotherapy using methotrexate, vinblastine, adriamycin and cisplatin (M-VAC) followed by TURBT, partial cystectomy or radical cystectomy (75% 3-year survival) was compared to an American cohort treated by radical cystectomy (51% 3-year survival). METHODS: Immunohistochemistry was used to examine the protein expression levels of three genes that act at the G1/S cell cycle checkpoint, p53, p21/waf-1/cip1 (a downstream effector gene in the p53 pathway) and Rb, plus a major inhibitor of apoptosis, Bcl-2. RESULTS: For the bladder cancers of the Italian patient cohort, there was a significantly higher rate of p53 immunopositivity (93 vs. 63%, p = 0.002) and a significantly lower rate of Rb loss (25 vs. 54%, p = 0.009). In bivariate analysis, 72% of Italian tumors were immunopositive for both p53 and p21 (p53+/p21+) vs. 49% for the American tumors. The subset of Italian patients with p53+/p21+ tumors were more frequently disease-free (stage pT0) following chemotherapy and were less likely to fail therapy than those with p53+/p21- tumors (p = 0.0357). Loss of Rb staining was associated with a decreased 5-year survival in the Italian, but not in the American patients. CONCLUSIONS: (1) Significant differences in the expression of the p53, p21 and Rb genes were found between the 2 groups of patients. (2) Italian patients with p53+/p21+ tumors had significantly lower recurrence rates after TURBT and chemotherapy than those having p53+/p21- tumors. (3) Absence of p21 immunopositivity in the Italian tumors may identify alterations in the p53 pathway that predict poor outcome.     

The role of bcl-2, p53, and ki-67 index in predicting tumor recurrence for low grade superficial transitional cell bladder carcinoma

PURPOSE: We assess the prognostic significance of bcl-2 expression, p53 mutation and ki-67 index for low grade, superficial transitional cell bladder carcinoma. MATERIALS AND METHODS: The medical records of 93 cases of primary, low grade (24 G1, 69 G2), superficial (70 pTa, 23 pT1) transitional cell carcinoma of the bladder were reviewed. Association of bcl-2, p53 and ki-67 index immunoreactivity with tumor grade and stage was examined. Prognostic significance of tumor grade, pathological stage, bcl-2 expression, p53 mutation and ki-67 index in predicting tumor recurrence was assessed. RESULTS: Of the tumors 60 (70%) had p53 mutation and 9 (10.5%) expressed bcl-2. These 2 markers did not relate to tumor grade or pathological stage. Median ki-67 index was 10.9% and positively correlated with tumor grade. Recurrence was noted in 34.9% of patients with a median followup of 26 months (range 1 to 84). The ki-67 index was the only significant prognostic indicator in univariate and multivariate analyses. This marker can further distinguish grade 2 tumors with a favorable prognosis from those with an unfavorable outcome. CONCLUSIONS: The ki-67 labeling index is an independent predictor of tumor recurrence for patients with primary superficial, low grade bladder cancers.     

p53 nuclear accumulation is not associated with decreased disease-free survival in patients with node positive transitional cell carcinoma of the bladder

PURPOSE: Although the majority of patients with node positive transitional cell carcinoma of the bladder have disease progression, a definitive subset is cured by surgery only. Nuclear accumulation of p53 has been associated with disease progression in patients with superficial transitional cell carcinoma and decreased survival in those with muscle invasive disease. We determined whether p53 status would predict survival in a cohort with nodal metastasis. MATERIALS AND METHODS: We explored the comprehensive database of all 199 radical cystectomies performed at our institution between July 1988 and September 1999. The 59 patients in this database with node positive pathology comprise our study. We performed immunohistochemical analysis of specimens using the MAB1801 antibody with greater than 20% lymph node and primary tumor nucleus staining deemed positive. Additional covariates measured included patient age, sex, pathological disease stage, adjuvant chemotherapy and nodal stage. Disease-free survival curves were generated for the various covariates and compared using the log rank test. The Cox proportional hazards technique was used to determine covariate adjusted p53 survival. RESULTS: In the cohort overall median disease-free survival was only 21 months, although 18% of patients were disease-free at 5 years. There was evidence of p53 nuclear accumulation in 54% of cases and complete agreement of nodal with bladder p53 nuclear accumulation. No significant baseline differences were noted in the covariates with respect to p53 nuclear accumulation. For stratum specific disease-free survival univariate and multivariate analyses revealed that only pathological stages p0-p2b versus p3-p4 (hazards ratio 2.86, p = 0.03), and nodal stages N2 versus N1 and N3 versus N1 (hazards ratio 3.84, p = 0.01 and hazards ratio 13.3, p = 0.0002, respectively) were significantly associated with prolonged disease-free survival, while p53 nuclear accumulation was not. CONCLUSIONS: Despite credible evidence for p53 nuclear accumulation prognostication in patients with in situ and invasive transitional cell carcinoma, this marker is not predictive of disease-free survival in node positive disease.     

Bcl-2 expression identifies patients with advanced bladder cancer treated by radiotherapy who benefit from neoadjuvant chemotherapy

OBJECTIVE: To assess the prognostic significance of Bcl-2 expression on the clinical outcome after radiotherapy for muscle-invasive bladder cancer, and to determine if it is possible to identify a subgroup of patients to whom neoadjuvant chemotherapy can be targeted to improve survival. PATIENTS AND METHODS: Immunohistochemical staining for Bcl-2 and p53 was performed on the tumours of 51 patients with stage T2-T4a NXM0 transitional cell carcinoma of the bladder who had been included in a randomized clinical trial of radiotherapy with or without neoadjuvant cisplatin. The association between positive staining and salvage cystectomy rate and overall survival was examined, with a median follow-up of 12 years. RESULTS: Bcl-2 and p53 expression was positive in 31 (61%) and 39 (76%) of the tumours, with no association between either, or with tumour stage or grade. There was no difference according to Bcl-2 positivity in the salvage cystectomy rate (P = 0.83) or survival (P = 0.68) for the 51 patients as a whole, but Bcl-2-negative patients receiving neoadjuvant cisplatin had a significantly better prognosis, with a median survival of 72 months compared to 17 months in Bcl-2-positive patients, and a 5-year survival rate of 55% (P = 0.03). CONCLUSIONS: Quantifying Bcl-2 in patients undergoing radiotherapy for advanced bladder cancer identifies those who may benefit from neoadjuvant chemotherapy. Further studies of other members of the Bcl-2 family and other proteins controlling both cell proliferation and apoptosis are warranted, to define the roles and the interactions between them that may contribute to oncogenesis and resistance to standard treatments. This may allow the targeting of specific treatments to patients known to be sensitive to them, and aid the future development of novel therapies for bladder cancer.     

Association of 8p23 deletions with poor survival in head and neck cancer.

OBJECTIVE: Allelic loss at 8p23 occurs frequently in head and neck squamous cell carcinoma. The objective of this study was to determine the prognostic importance of 8p23 loss. STUDY DESIGN AND SETTINGS: We tested 51 primary tumors and 19 lymph node metastases for loss of heterozygosity with 7 microsatellite polymorphisms at 8p23 and correlated the results with disease-free interval and disease-specific survival. RESULTS: The Kaplan-Meier analysis demonstrated statistically significant association of 8p23 allelic loss with both shorter disease-free interval and disease-specific survival. For the pN stage, the log-rank test indicated significance in correlation with the disease-free interval, whereas the pT stage showed a significant correlation with disease-specific survival. Multivariate analysis identified loss of heterozygosity at 8p23 as independent prognostic marker for disease-free interval. CONCLUSION: Our data suggest that 8p23 allelic loss is associated with poor prognosis in head and neck squamous cell carcinoma and could be useful refining diagnosis of these tumors.     

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.     

Sarcomatoid differentiation in renal cell carcinoma: a study of 101 cases

Sarcomatoid renal cell carcinoma is not a distinct histologic entity and represents high-grade transformation in different subtypes of renal cell carcinoma. It is not known whether any particular histologic type has a predilection for sarcomatoid change or whether the primary histologic type of renal carcinoma undergoing sarcomatoid change affects prognosis. Of 952 consecutively histologically subtyped renal cell carcinomas, the incidence of sarcomatoid differentiation was 8% in conventional (clear cell) renal carcinoma, 3% in papillary renal carcinoma, 9% in chromophobe renal carcinoma, 29% in collecting duct carcinoma, and 11% in unclassified renal cell carcinoma. One hundred one renal cell carcinomas with sarcomatoid change were studied, and clinicopathologic parameters were correlated with outcome. The mean age of patients was 60 years (range, 33-80 years), and the male-to-female ratio was 1.6:1. The median tumor size was 9.2 cm (range, 3-25 cm). The primary histologic subtype of the carcinoma component was conventional (clear cell) renal carcinoma in 80 cases, papillary renal carcinoma in eight, chromophobe renal carcinoma in seven, collecting duct carcinoma in two, and unclassified renal cell carcinoma in four. The sarcomatoid component resembled fibrosarcoma in 54 cases, malignant fibrous histiocytoma in 44, undifferentiated sarcoma (not otherwise specified) in three with focal rhabdomyosarcomatous component in two of them. The spindled elements accounted for 1% to 99% of the sampled tumor (median, 40%; mean 45%). The histologic grade of the spindled elements was intermediate to high in 92 cases and low in nine cases. Most cases were TNM stages III and IV (seven stage I, six stage II, 63 stage III, and 25 stage IV). Follow-up was available in 88 patients; 61 (69%) patients died of disease and had a median survival time of 19 months. Distant metastases, most frequently to the lungs, were documented in 51 (66%) of 77 patients who had available clinical information regarding distant metastasis. The disease-specific survival rate was 22% and 13% after 5 and 10 years, respectively, compared with a cohort of renal cell carcinomas without sarcomatoid change with a 5-and 10-year disease-specific survival of 79% and 76%, respectively. Kaplan-Meier survival analysis showed that tumors with high TNM stage (p = 0.0027), at least 50% sarcomatoid component (p = 0.0453), and angiolymphatic invasion (p = 0.0282) were associated with decreased survival rates. The primary histologic subtype of the carcinoma component and the type and grade of the sarcomatoid component did not affect survival. In a Cox proportional hazard regression model, TNM stage appeared to be the only significant variable in predicting outcome among renal cell carcinomas with sarcomatoid change (p = 0.018; risk ratio, 6.984 and 8.439). Compared with a cohort of renal cell carcinomas without sarcomatoid change, sarcomatoid tumors tended to present at a more advanced stage (p = 0.0001). Also, when adjusted for stage, necrosis, and tumor size, patients with tumors with sarcomatoid differentiation had a worse prognosis than did patients with tumors without sarcomatoid change (p = 0.0001). In conclusion, sarcomatoid change in renal cell carcinoma portends a worse prognosis. Because tumors with even a small component of sarcomatoid change may have an adverse outcome, this finding, when present, should be noted in the surgical pathology report.     

HPV Positive Squamous Cell Carcinoma of the Oropharynx. Are we Observing an Unusual Pattern of Metastases?

To describe the clinical, histopathologic, immunohistochemical and molecular features of human papilloma virus (HPV)+ squamous cell carcinomas of the oropharynx that had an atypical clinical course. Methods and Results: Four patients with HPV+ oropharyngeal squamous cell carcinoma (OPSCC) were identified retrospectively based on unanticipated clinical behavior. The histopathology, immunohistochemistry and molecular studies of both the primary tumor and the metastases were analyzed to look for any predictors to explain the clinical course. The four patients were all male (average age 55) who presented initially with a neck mass and had stage IVA disease. Three of the primary tumors were nonkeratinizing squamous cell carcinoma and one case was a hybrid tumor of both high-grade squamous cell carcinoma and nonkeratinizing type, and all were p16 and HPV 16/18 positive. All patients received concurrent chemoradiation as primary therapy and had a complete response. Disease-free survival ranged from 7 to 15 months and metastases in 3 patients occurred only in bone, including the sternum, humerus, clavicle, and vertebrae. In one patient, distant metastases were identified in the pancreas, liver, lung and skull base. All metastatic lesions were nonkeratinizing morphology and were p16 and/or HPV positive. Two patients died of their disease, one patient is alive with disease and one patient is disease-free. Although infrequent, unanticipated clinical outcomes can occur in HPV-related OPSCC including distant metastases and bone-only metastases. The tumor morphology of the metastases was comparable to the primary and retained p16 and HPV expression.     

Relationship of p53 and bcl-2 to Prognosis in Muscle-Invasive Transitional Cell Carcinoma of the Bladder

Purpose

We examined the presence of the p53 and Bcl-2 oncoproteins, as detected by immunohistochemistry, in muscle-invasive bladder cancer and correlated this with survival.

Materials and Methods

Formalin-fixed cystectomy specimens from 41 consecutive patients with mean follow-up of 52 months were used. Five patients were either lost to follow-up or died of other diseases and were not included in the survival evaluation.

Results

Eighteen of 36 patients died of metastatic transitional cell carcinoma. p53 immunostaining was found in 61 percent of patients. In 21 of 23 this staining was homogeneous, with more than 75 percent of cancer cells staining using a DO-1/DO-7 antibody cocktail. p53 staining was not correlated with stage (p greater than 0.25) or grade (p less than 0.10) in these invasive cancer specimens. Contrary to recent studies p53 immunostaining was not correlated with disease-specific survival. Bcl-2 immunostaining was found in 28 percent of patients and was not correlated with grade (p greater than 0.25) or disease-specific survival. No combination of p53 and Bcl-2 staining gave added predictive information.

Conclusions

Cytoplasmic Bcl-2 is found in a small percentage of these cancers and does not correlate with prognosis. Further, p53 molecular overexpression is detected in the majority of muscle-invasive bladder tumors as a field defect. However, in patients undergoing cystectomy, it does not correlate with prognosis.