An intronic variant of the TGFBR1 gene is associated with carcinomas of the kidney and bladder

TGF-beta signaling is frequently perturbed in many human cancers, including renal cell carcinomas (RCCs) and transitional cell carcinomas (TCCs) of the bladder. Genetic alterations of the TGF-beta type 1 receptor (TGFBR1) may contribute to these perturbations. We therefore examined variations in the TGFBR1 gene by PCR, SSCP and RFLP in carcinomas of the urinary system and in tissues from noncancer, age-matched controls. A G-->A variant 24 bp downstream of the exon/intron 7 boundary of the TGFBR1 gene (Int7G24A) was evident in patients with RCC (46.5%, n = 86) and bladder and upper urinary tract TCC (49.2%, n = 65) significantly more frequently than in age-matched controls (28.3%, n = 113, p < 0.002 by chi2 test). Moreover, 8 homozygous variant carriers were found in the cancer groups, whereas not a single homozygous variant carrier was found in the control group. The Int7G24A allele (both heterozygous G/A and homozygous A/A carriers) was associated with increased RCC incidence (OR = 2.20, 95% CI 1.22-3.96) and TCC incidence (OR = 2.45, 95% CI 1.89-3.16). One somatic mutation of serine to phenylalanine at codon 57 of the TGFBR1 gene was confirmed in an upper urinary tract TCC. In conclusion, the Int7G24A variant in the TGFBR1 gene is significantly more frequent in patients with RCC and TCC than normal age-matched controls, suggesting that it may represent a risk factor for the development of kidney and bladder carcinomas.     

Immunohistochemical evaluation of nonspecific cross reactive antigen and carcinoembryonic antigen (CEA) in urinary bladder carcinoma

The immunohistochemical expression of CEA in formalin-fixed paraffin sections in urinary bladder carcinomas was compared to the use of polyclonal anti-CEA antiserum (P-CEA), NCA-absorbed anti-CEA (NCA-aCEA) and monoclonal antibody to CEA (M-CEA). The urinary bladder carcinomas examined consisted of 19 cases of transitional cell carcinoma (TCC) and 7 cases of squamous cell carcinoma (SCC). Both TCC and SCC were positive for CEA with the use of P-CEA and NCA-aCEA, and the degree of staining was markedly dependent on the grade of malignancy in TCC. However, the reaction to M-CEA was generally very weak or negative in TCC and SCC. In SCC, the staining reaction was confined to keratinized foci and not found in all malignant tumour cells when polyclonal CEA antiserum was used. These findings indicate that positive reactions seen with conventional CEA antibodies (P-CEA and NCA-aCEA) are possibly related to NCA and that urinary bladder carcinoma may contain relatively more NCA than true CEA.     

Immunohistochemical demonstration of carcinoembryonic antigen (CEA) and its correlation with grading and staging on tissue sections of urinary bladder carcinomas

In 150 transitional cell carcinomas (TCC) of the urinary bladder, 50 each of Grades 1, 2, and 3, the content of carcinoembryonic antigen (CEA) was examined immunocytochemically and correlated to grading and staging. Fifty-seven percent of the TCC contained CEA-positive tumor cells. Their distribution in tumor tissue is described. They were found in 24% of Grade 1 cases, in 72% of Grade 2 carcinomas, and in 76% of Grade 3 tumors. None of the Grade 1 cases contained more than 10% CEA-positive cells, whereas 34% and 40% of the Grade 2 and 3 tumors, respectively, revealed more than 10% CEA-positive tumor cells. According to the correlation found between grading and staging, the percentage of TCC containing CEA-positive tumor cells was 34% in pTA, 59% in pT1, and 80% in pT2/3 tumors. The results show a correlation between CEA content of tumor tissue and histopathologic malignancy in TCC of urinary bladder.     

G1 checkpoint protein and p53 abnormalities occur in most invasive transitional cell carcinomas of the urinary bladder.

The G1 cell cycle checkpoint regulates entry into S phase for normal cells. Components of the G1 checkpoint, including retinoblastoma (Rb) protein, cyclin D1 and p16INK4a, are commonly altered in human malignancies, abrogating cell cycle control. Using immunohistochemistry, we examined 79 invasive transitional cell carcinomas of the urinary bladder treated by cystectomy, for loss of Rb or p16INK4a protein and for cyclin D1 overexpression. As p53 is also involved in cell cycle control, its expression was studied as well. Rb protein loss occurred in 23/79 cases (29%); it was inversely correlated with loss of p16INK4a, which occurred in 15/79 cases (19%). One biphenotypic case, with Rb+p16- and Rb-p16+ areas, was identified as well. Cyclin D1 was overexpressed in 21/79 carcinomas (27%), all of which retained Rb protein. Fifty of 79 tumours (63%) showed aberrant accumulation of p53 protein; p53 staining did not correlate with Rb, p16INK4a, or cyclin D1 status. Overall, 70% of bladder carcinomas showed abnormalities in one or more of the intrinsic proteins of the G1 checkpoint (Rb, p16INK4a and cyclin D1). Only 15% of all bladder carcinomas (12/79) showed a normal phenotype for all four proteins. In a multivariate survival analysis, cyclin D1 overexpression was linked to less aggressive disease and relatively favourable outcome. In our series, Rb, p16INK4a and p53 status did not reach statistical significance as prognostic factors. In conclusion, G1 restriction point defects can be identified in the majority of bladder carcinomas. Our findings support the hypothesis that cyclin D1 and p16INK4a can cooperate to dysregulate the cell cycle, but that loss of Rb protein abolishes the G1 checkpoint completely, removing any selective advantage for cells that alter additional cell cycle proteins.     

Proliferative activity is the most significant predictor of recurrence in noninvasive papillary urothelial neoplasms of low malignant potential and grade 1 papillary carcinomas of the bladder

BACKGROUND: Recurrence of transitional cell carcinoma of the bladder cannot be predicted accurately by traditional criteria alone. This study examined the value of cell proliferative activity, morphometry, and expression of p53, c-erbB-2, and bcl-2 oncogenes in predicting recurrence of superficial papillary urothelial neoplasms of low malignant potential (LMP) and Grade 1 (G1) papillary carcinomas of the bladder. METHODS: Sixty-two patients (mean age, 62 years) with newly diagnosed superficial pTa bladder tumors (19 LMP, and 43 G1) were analyzed retrospectively. All patients underwent transurethral resection (TUR). Median follow-up was 69 months. Serial sections from formalin-fixed, paraffin-embedded material at initial TUR were stained with monoclonal antibodies (MoAbs) DO7, CB11, and bcl-2-124. Cell proliferation was assessed by MIB-1 MoAb, the quantity of argyrophilic nucleolar organizer region-associated proteins (AgNORs), and mitotic count. RESULTS: Of the 62 patients, 42 (67.7%) had one or more recurrences. Recurrence rates were higher in MIB-1 (P < 0.0001) and p53 immunopositive cases (P = 0.02), when the mitotic count was greater than 5 (P = 0.004), and in G1 carcinomas (P = 0.04). In univariate analysis, the disease-free period was shorter for MIB-1 (P < 0.0001) and p53 immunopositive (P = 0.0001) cases, for cases with high AgNOR quantity (P = 0.04), mitotic count greater than 5 (P = 0.01), and in G1 carcinomas (P = 0.002). In multivariate analysis, only MIB-1 immunoreactivity retained independent prognostic significance. CONCLUSIONS: Despite the small cohort, the results confirm the prognostic value of cell proliferation and p53 expression in patients with bladder neoplasms. The results also indicate that MIB-1 immunopositivity is the most significant predictor of recurrence and disease-free survival in superficial LMP and G1 papillary bladder carcinomas.     

Various urinary properties in bladder tumor patients

Urinary electrolytes, pH, urea nitrogen, creatinine, uric acid and osmolarity were measured in patients with bladder tumors and compared with those of a control group. There were 41 bladder tumor patients ranging in age from 29 to 87 (average 64) years with a male:female ratio of 32:9. According to histopathological classification of the bladder tumors, there were 34 transitional cell carcinomas (TCC) (21 G1, 10 G2, 3 G3), four squamous cell carcinomas, two adenocarcinomas and one inverted papilloma. The control group comprised 29 patients ranging in age from 35 to 80 (average 63) years with a male:female ratio of 26:3. Four urine samples were collected from each patient: early morning on the day of admission, just after admission, early morning on the day of return to hospital after temporary discharge, immediately after return to hospital after temporary discharge. The results indicated that the urinary Ca2+ and uric acid values were significantly lower in the bladder tumor group than in the control group. The urinary pH tended to be somewhat higher than in the control group, and the pH values tended to be especially high in the TCC G3 patients. There were differences in the various urinary properties between the TCC G1 and G2 and the TCC G3 patients.     

Carcinogenicity of uracil, a nongenotoxic chemical, in rats and mice and its rationale.

In Experiment 1, groups of thirty 6-wk-old male and female F344 rats were given diets containing 0 (control) or 3% uracil for 104 wk. In the uracil-treated groups, carcinomas, in particular transitional cell carcinomas, developed in the urinary bladder of 90% of the males and 19% of the females. Squamous cell carcinomas also developed in 10% of the males, but not in females. Striking findings were that calculi were present in the urinary bladder of almost all males, but in only 30% of the females, and that induction of urinary bladder carcinomas was related to the presence of calculi. In Experiment 2, groups of thirty 6-wk-old male and female C57BL/6 x C3H F1 mice were given a diet containing 0 (control) or 3% (from Wk 1 to Wk 6) and 2.5% (from Wk 7 to Wk 96) uracil. The total observation period was 96 wk. In the uracil-treated groups, transitional cell carcinomas developed in 76% of the females and 8% of the males. Squamous cell carcinomas developed in only 8% of the males. In Experiment 3, 6-wk-old male F344 rats were given diets containing 3% uracil, 3% uracil plus 5% or 10% NaCl, or 10% NaCl for 36 wk and then diet without chemicals for a recovery period of 4 wk. The incidences of carcinomas and calculi of the urinary bladder were 75% and 81% in the group given uracil alone, 6% and 6% in the group given uracil plus 5% NaCl, and both zero in the group given uracil plus 10% NaCl. Thus, the present study showed that the inductions of urinary bladder carcinomas by uracil, a nongenotoxic compound, in rats and mice showed sex differences and were related to the presence of calculi in the urinary bladder.     

环氧化酶-2 在膀胱癌组织及尿脱落细胞中的表达和意义

 目的 探讨COX-2在膀胱癌组织中的表达，了解尿脱落细胞COX-2表达在膀胱癌早期诊断中的价值。方法 应用免疫组化技术检测48例膀胱移行细胞癌组织、免疫细胞化学技术检测40例膀胱移行细胞癌患者和30例非肿瘤患者尿脱落细胞COX-2的表达。结果 膀胱移行细胞癌组织COX-2阳性表达率为72．9％，对照组正常膀胱黏膜无表达。COX-2的表达与膀胱癌临床分期显著相关(P<0．05)，不同病理分级膀胱癌的表达差别无显著性意义。非肿瘤患者尿脱落细胞无COx-2表达，膀胱癌尿脱落细胞COX-2免疫细胞化学检测阳性率为67．5％，明显高于常规尿细胞学的37．5％(P<0．05)，尤其对于G1级和Ta～T1期的低级、早期肿瘤，尿脱落细胞COX-2免疫细胞化学检测与常规尿细胞学检查相比，具有显著性意义(P<0．05)。结论 COX-2在膀胱移行细胞癌的发生发展中起重要作用，与肿瘤的浸润、转移相关。尿脱落细胞COX-2表达检测特异性高，可作为早期诊断膀胱癌的一种标志物。     

Overexpression of cyclooxygenase-2 in squamous cell carcinoma of the urinary bladder.

Epidemiological studies indicate that the development of squamous cell carcinoma of the urinary bladder is closely associated with chronic inflammation of the urinary tract, but the underlying mechanism is unknown. Cyclooxygenase (COX)-2 is involved in tumorigenesis in many tumors. The purpose of this study was to investigate the role of COX-2 in squamous cell carcinoma of the urinary bladder by immunoblot and immunohistochemical analyses. COX-2 protein was undetectable in normal bladder samples, but was expressed in 29 of 29 (100%) squamous cell carcinomas and in 8 of 8 (100%) squamous metaplasias. The expression of COX-2 showed intense, homogenous cytoplasmic immunostaining in squamous cell carcinomas. In contrast, COX-2 was heterogeneously expressed in 6 of 12 (50%) cases of transitional cell carcinoma of the bladder combined with squamous cell carcinoma, consistent with previous findings. We provide the first evidence that COX-2 is expressed in squamous cell carcinomas of the urinary bladder and in the precursor lesions, indicating its involvement in the development of this type of malignancy.     

Carcinomas of the renal pelvis associated with smoking and phenacetin abuse: p53 mutations and polymorphism of carcinogen-metabolising enzymes

Phenacetin abuse and smoking are established risk factors for transitional cell carcinomas of the urinary tract. In the present study, we analysed exposure and the clinical course of patients who underwent nephrectomy for transitional cell carcinoma of the renal pelvis. PCR-SSCP of archival, paraffin-embedded histological sections followed by direct DNA sequencing revealed that 29 of 89 (33%) renal pelvic carcinomas contained a p53 mutation. Double mutations were found in 4 tumours and triple mutations in 1 tumour. The incidence of p53 mutations was significantly higher in tumours with grades 3 and 4 than in those with grades 1 and 2 and higher in invasive than in non-invasive tumours. Furthermore, patients with carcinomas carrying a p53 mutation showed poorer survival than those without mutation. The type of p53 mutation in renal pelvic carcinomas was similar to that reported for bladder cancer, G:C→A:T transition mutations being most frequent (45%, 33% of these at CpG sites), followed by G:C→T:A and G:C→C:G transversions. The incidence and type of p53 mutation did not differ significantly in patients with a history of phenacetin abuse, smoking or neither of these habits. This was also true for G:C→T:A transversions (17.5% of mutations), which are considered typical of smoking-induced carcinomas at other sites, e.g., lung, oral cavity and oesophagus. Our results indicate that the frequency and pattern of p53 mutations are similar in transitional cell carcinomas of the bladder and the renal pelvis and do not reflect exposure to phenacetin and/or smoking. The frequency of genetic polymorphism in genes coding for carcinogen-metabolising enzymes (CYP1A1, NAT1, GSTT1 and GSTM1) was also independent of exposure. Although the sample size of our study does not allow definite conclusions, these data are compatible with chronic tissue damage as a causative factor in the evolution of urothelial carcinomas rather than pointing to a direct mutagenic effect of phenacetin and tobacco-specific carcinogens. Int. J. Cancer (Pred. Oncol.) 79:531–536, 1998.© 1998 Wiley-Liss, Inc.     

尿液核基质蛋白22在膀胱移行上皮癌筛检中的价值

目的：评价尿核基质蛋白22(NMP22)在膀胱移行上皮癌筛检中的意义。方法：采用酶联免疫法检测28例膀胱移行上皮癌、25例泌尿系良性疾病和10例泌尿系非移行上皮癌患者尿NMP22水平，并与尿脱落细胞学检查进行比较。结果：膀胱移行上皮癌患者尿NMP,,中位值为66．5u／ml，明显高于泌尿系良性疾病和非移行上皮癌，与肿瘤分期、分级、数目无关，以10u／ml为临界，诊断膀胱癌敏感性为85．7％，特异性为60％，尿脱落细胞学检查敏感性为32．1％，特异性为100％。结论：尿NMP22检测膀胱移行上皮癌敏感性、特异性均较高，可用于膀胱移行上皮癌的筛选和术后随访。     

Results of the UFT sensitivity test using human urogenital cancers transplanted subcutaneously and under the subrenal capsule of nude mice

Experimental chemotherapy with UFT was performed against human urogenital cancers, transplanted subcutaneously and under the subrenal capsule (SRC) of nude mice. The tumor take with subcutaneous assay was confirmed in 21 cell lines of human neoplasms, which consisted of 9 renal cell carcinomas, 5 renal pelvic carcinomas, 1 ureteral carcinoma, 3 carcinomas of the urinary bladder, 2 prostatic carcinomas and 1 testicular tumor. On the other hand, the tumor take with subrenal capsule assay was confirmed in 17 of the neoplasm, which consisted of 7 renal cell carcinomas, 4 renal pelvic carcinomas, 4 carcinomas of urinary bladder, 1 prostatic carcinoma and 1 testicular tumor. UFT was administered, starting on Day 14 for subcutaneous transplantation and starting on Day 0 for SRC assay. The dose of UFT was the same as clinical dose for both subcutaneous transplantation and subrenal capsule assays. Treatment with UFT was performed for 6 weeks in subcutaneous transplantation assay and for 4 weeks in subrenal capsule assay. Effect of UFT was evaluated by the inhibition rate (IR) calculated by the mean tumor weights of both treated and untreated groups. Responses to the treatment in subcutaneous transplantation and subrenal capsule assays were judged as effective when the IR were higher than 58% and 20%, respectively. Responses rates of UFT in subcutaneous transplantation and subrenal capsule assays were 43% and 82%, respectively.     

Human papilloma virus and p53 expression in bladder cancer in Egypt: Relationship to schistosomiasis and clinicopathologic factors

The aim of the current study was to compare the role of p53 and human papillomavirus (HPV) in schistosomiasis-related and schistosomiasis-unrelated carcinoma of the urinary bladder. To achieve this aim, we investigated 114 bladder carcinomas for p53 oncoprotein expression by immunohistochemistry and for human papillomavirus by in situ hybridization technique. The results revealed that 64 tumors (56.1%) were schistosomiasis-associated. Sixty seven (58.8%) were transitional cell carcinomas and 32 (28%) were squamous cell carcinomas. The remaining 15 tumors (13.2%) included adenocarcinomas and sarcomatoid carcinomas. In both schistosomiasis-associated and non-associated carcinomas, p53 oncoprotein expression was significantly higher in poorly differentiated tumors. However, it was significantly higher in locally more invasive tumors in the schistosomal carcinomas only. HPV types 16/18 could be detected in 1 of the 114 bladder carcinomas (0.95%), which was schistosomiasis-related squamous cell carcinoma in situ. These results suggest that p53 immunohistochemistry can be a prognostic factor in both schistosomal and nonschistosomal bladder cancer. More importantly, HPV does not seem to play a role in the pathogenesis of either type of bladder cancer in our country.(Pathology Oncology Research Vol 12, No 3, 173–178) An erratum to this article is available at .     

Reversibility of proliferative lesions and induction of non-papillary tumors in rat urinary bladder treated with phenylethyl isothiocyanate

Phenylethyl isothiocyanate (PEITC), generally thought to be a chemopreventive agent for various kinds of genotoxic carcinogens, has been found to induce rat urinary bladder carcinomas in our laboratory. To cast light on the underlying mechanisms, the reversibility of urothelial proliferative lesions and the frequencies of H-ras and p53 mutations in the induced rat urinary bladder tumors were investigated. F344 male rats were given diet containing 0.1% PEITC for 48 weeks and then killed, or for 32 weeks and then returned to normal diet without supplement for 1, 3, 7 days or 16 weeks before death. At 7 days after withdrawal of PEITC treatment, carcinomas were observed in only two of 24 rats but a high incidence of dysplasias was evident. Furthermore, 16 weeks after withdrawal, seven of 12 (58.3%) rats had carcinomas. In addition, carcinomas were induced in 11 of 12 (91.7%) rats continuously receiving PEITC for 48 weeks. Most of the carcinomas were characterized as of non-papillary transitional cell type with occasional squamous cell differentiation and/or glandular components. Bromodeoxyuridine labeling indices (LIs) were increased by PEITC administration even in normal-looking epithelium. After withdrawal of treatment, LIs in simple and papillary or nodular (PN) hyperplasias were markedly decreased and these lesions gradually disappeared, while values for dysplasias and carcinomas, which persisted, were only slightly decreased. A silent point mutation was found in H-ras in one of 12 tumor samples (8.3%), whereas seven (58.3%) had mutations in p53. These results indicate that PEITC itself is a carcinogen for the rat urinary bladder, and that while the simple and PN hyperplasia induced by PEITC are reversible, dysplasia is irreversible with the potential to give rise to non-papillary carcinomas with frequent p53 mutations.     

Conversion from low grade to high grade of rat urinary bladder carcinomas

The present study was conducted to test if low-grade carcinomas induced by a single dose of N-methyl-Nitrosourea (MNU) can be converted to high-grade carcinomas by a second identical dose of the carcinogen. The heterotopically transplanted rat urinary bladder system was used. Four wk after heterotopic bladder transplantation, the recipient male Fischer 344 rats were divided into 2 groups. The first group received 0.25 mg of MNU into heterotopically transplanted rat urinary bladder; the second group (controls) received 0.9% NaCl solution. At week 29 of the experiment, 1/3 of the animals from each group were killed for histological examination of the heterotopically transplanted rat urinary bladders. The remaining animals from each group were divided into 2 subgroups, the first receiving 0.25 mg MNU and the second, 0.9% NaCl solution. All animals were killed at 50 wk of the experiment. MNU-induced carcinomas at week 29 were all of low histological grade and were noninvasive. Longer follow-up without a second carcinogen administration resulted in both an increase in tumor incidence (P less than 0.005) and more tumors per bladder (P less than 0.001), but high-grade invasive carcinomas were rare. The second dose of MNU administered at the stage when low-grade carcinomas were prevalent (week 29) resulted in a significant increase in invasive high-grade carcinomas (P less than 0.01). Our data are consistent with the view that the second carcinogen administration induces a new mutation(s) within low-grade carcinomas which leads to invasive carcinomas.     

Tissue-specific markers in flow cytometry of urological cancers. III. Comparing chromosomal and flow cytometric DNA analysis of bladder tumors

Thirty-seven transitional-cell carcinomas (TCC) of the urinary bladder were analyzed by DNA flow cytometry (FCM). After labelling of the cell suspensions with antibodies to cytokeratin, the cytokeratin-positive cells and the non-epithelial cytokeratin-negative cells could be analyzed separately. After estimation of S- and G2M phase, 3/17 cases (18%) with a normal DNA index showed elevated proliferative levels, among cytokeratin-labelled suspensions only. Of these 17 cases, 14 showed chromosomal abnormalities. The remaining 20 cases were abnormal, irrespective of the technique used. Although immuno-labeling of tumor cells for cytokeratin in FCM increases the sensitivity of this method in detecting aneuploid tumors or tumors with high proliferation fractions, the discriminating power of chromosomal analysis of TCC is greater than FCM.     

Telomerase activity in bladder cancer, bladder washings and in urine

With only a few exceptions, the ribonucleoprotein telomerase has been found in malignant, but not in benign tissues. Telomerase is thus a potentially new diagnostic marker. Carcinoma of the urinary bladder is the most frequent malignant tumor of the urinary tract and, after prostatic carcinoma, the second most common malignancy of the genitourinary system. In order to evaluate the diagnostic capabilities of telomerase in bladder carcinomas, four cell lines derived from human urothelial carcinomas of the bladder, 75 tissue samples from bladder carcinomas, eight tissue samples of normal bladder urothelium, 40 bladder washings and 30 urine samples were examined for telomerase activity. The four cell lines derived from urothelial carcinoma of the bladder (F975, 582, SCaBER, UM-UC-3) all exhibited high telomerase activity and were thus used as positive controls. Telomerase activity was found in nearly all (96%) tissue samples obtained from histologically confirmed urothelial carcinoma of the bladder. None of the normal tissue samples examined showed telomerase activity. Telomerase activity was similarly found in 73% of bladder washings in patients with histologically confirmed bladder carcinoma. There were no false positive results. The determination of telomerase activity in bladder washing samples thus represents a new diagnostic method for detection of tumor cells in rinsing media. Because of the early inactivation or degradation of telomerase there was no detection of the enzyme in native urine in the present study.     

Morphology and therapeutic strategies for neuroendocrine tumors of the genitourinary tract

BACKGROUND: Although many articles have been published regarding neuroendocrine tumors (NET) and neuroendocrine carcinomas of both low- and high-grade malignancy (NEC) of the genitourinary tract, the histologic diagnosis and therapeutic strategies for treating these entities remains difficult. In the current study the author discusses the significant differences between NET and NEC of the urinary bladder and the prostate, including therapeutic consequences. METHODS: Four hundred eighty neoplasms of the urinary bladder and prostate with a small cell pattern were analyzed not only on slides stained with hematoxylin and eosin but also by means of immunohistochemical stains demonstrating a neuroendocrine origin. The avidin-biotin complex method was used with the following markers: MIB-1, chromogranin A (Chr A), synaptophysin (SNP), cytokeratin (CK) 34betaE12, CK20, androgen receptor (AR), and prostate specific antigen (PSA). RESULTS: Twenty tumors of the urinary bladder and 26 of the prostate demonstrated a diffuse neuroendocrine pattern. Only two patients were found to have a low-grade NEC of the prostate with a low proliferative index but strong expression of neuroendocrine markers. All other patients with small cell neuroendocrine carcinomas of the bladder and prostate demonstrated extremely high proliferation activity (>80%) and expressed Chr A and SNP. CK34betaE12, 20, PSA, and AR were not found to be expressed. The mean survival time was 6.9 months. Fourteen of 20 patients with NEC of the urinary bladder died of the disease and 19 of 24 patients with prostatic NEC died. The therapy for urinary bladder NEC was repeated transurethral resection and antiandrogen therapy was given for NEC of the prostate. Only one patient was treated with chemotherapy, which to the author's knowledge currently is the only treatment for NECs of the genitourinary tract. CONCLUSIONS: Undifferentiated carcinomas of the urinary bladder and prostate should be analyzed not only by means of hematoxylin and eosin but also by immunohistochemical staining for Chr A and SNP to demonstrate a neuroendocrine origin. Because the prognosis of small cell NECs is very poor, pathologists should indicate in their final report the peculiarities of small cell NECs of the prostate and the urinary bladder with special emphasis on different therapeutic strategies.     

Urinary bladder lesions after the Chernobyl accident: immunohistochemical assessment of p53, proliferating cell nuclear antigen, cyclin D1 and p21WAF1/Cip1.

During the 11-year period subsequent to the Chernobyl accident, the incidence of urinary bladder cancer in Ukraine has increased from 26.2 to 36.1 per 100,000 population. Cesium-137 (137Cs) accounts for 80-90% of the incorporated radioactivity in this population, which has been exposed to long-term, low-dose ionizing radiation, and 80% of the more labile pool of cesium is excreted via the urine. The present study was performed to evaluate the histopathological features and the immunohistochemical status of p53, p21WAF1/Cip1, cyclin D1 and PCNA (proliferating cell nuclear antigen) in urinary bladder mucosa of 55 males (49-92 years old) with benign prostatic hyperplasia who underwent surgery in Kiev, Ukraine, in 1995 and 1996. Group I (28 patients) inhabiting radiocontaminated areas of the country, group II (17 patients) from Kiev city with less radiocontamination and a control group III (10 patients) living in so-called "clean" areas of Ukraine were compared. In groups I and II, an increase in multiple areas of moderate or severe dysplasia or carcinoma in situ was seen in 42 (93%) of 45 cases. In addition, two small transitional cell carcinomas were found in one patient in each of groups I and II. Nuclear accumulation of p53, PCNA, cyclin D1, and to a lesser extent p21WAF1/Cip1, was significantly increased in both groups I and II as compared with the control group III, indicating possible transformation events or enhancement of repair activities, that may precede the defect in the regulatory pathway itself, at least in the G1 phase of the cell cycle. Our results suggest that early malignant transformation is taking place in the bladder urothelium of people in the radiocontaminated areas of Ukraine and that this could possibly lead sometime in the future to an increased incidence of urinary bladder cancer.