Cytopathological expression of different types of urothelial carcinoma in situ in urinary bladder washings

OBJECTIVE: To evaluate and compare the cytopathological expression of the five major histological types of carcinoma in situ (CIS) in urinary bladder washings from patients with flat urothelial lesions. MATERIALS AND METHODS: Seventy-five cases of primary and secondary urothelial CIS with no concomitant tumours, and having tissue and cytological samples, were identified. Biopsies were evaluated based on the consensus classification as: large-cell pleomorphic; large-cell non-pleomorphic; small-cell; clinging; and cancerization of the urothelium. In the cytological classification the 'clinging' category was excluded, as its definition depends on the histological appearance. kappa statistics were used to evaluate the correlation between histopathology and cytology. RESULTS: More than one subtype of CIS could often be identified in both the histological and cytological specimens. Cytology often showed more subtypes than did histopathology. Statistically, there was only a moderate correlation between histopathology and cytology for recognising different patterns. CONCLUSION: Different patterns of CIS can be identified by cytology; it is important for cytologists to be aware of the cytological spectrum of CIS and not to under-diagnose monomorphic, pagetoid (cancerization) and small-cell forms. Studies on treatments for CIS and of the clinical significance of different subtypes of CIS should include both cytopathology and histopathology.     

The Relationship Among Multiple Recurrences, Progression and Prognosis of Patients with Stages TA and T1 Transitional Cell Cancer of the Bladder Followed for at least 20 years

A retrospective study was done on 176 patients with primary stages Ta and T1 bladder cancer treated between 1963 and 1972. One patient was lost to followup after 6 years, while the remainder were followed to death or for at least 20 years. In 1993, 13 patients had no evidence of disease, 39 died of bladder cancer and 123 died of intercurrent disease. Of 77 patients with a primary noninfiltrating tumor and 99 with a primary lamina propria invasive tumor 9 (11 percent) and 30 (30 percent), respectively, died of bladder cancer. Recurrences were noted on 10 or more cystoscopic studies in 16 patients and 10 died of bladder cancer 3.5 to 19 years after the primary transurethral resection. A total of 14 patients received repeated thiotepa instillations, all continued to have recurrences and 10 subsequently died of bladder cancer. Only 1 upper tract tumor was diagnosed on routine followup excretory urography. Invasive transitional cell carcinoma of the bladder developed in only 1 of 59 patients who had been tumor-free for 5 years.

The results indicate that patients with recurrences on 10 or more cystoscopic studies will continue to have recurrences until death or cystectomy. Recurrence more than 4 years after the primary tumor operation is another ominous sign. Repeated thiotepa instillations did not influence the course of the disease in patients with a history of multiple recurrences. Followup cystoscopy may be discontinued 5 to 10 years after the last recurrence, at least in patients with a solitary low grade primary tumor. Routine followup urographic studies are neither cost-effective, clinically indicated nor justified in patients with superficial bladder cancer.     

Long-Term Followup of all Patients with Muscle Invasive (Stages T2, T3 and T4) Bladder Carcinoma in a Geographical Region

Purpose

We studied the relationship between long-term survival and treatment of stages T2, T3 and T4 bladder carcinoma in an unselected patient population.

Materials and Methods

A total of 680 patients with the initial diagnosis of bladder carcinoma in 1987 to 1988 in Western Sweden was prospectively registered and followed until 1994. Of these patients 107 had stage T2 to T3 and 41 had stage T4 disease.

Results

Of the patients with stage T2 to T3 disease 30 (mean age 66) underwent radical cystectomy, 33 (mean age 75) full dose radiotherapy and 44 (mean age 81) nonradical therapy (mainly transurethral resection of the bladder). The 5-year crude survival rates were 33, 15 and 14%, respectively. Of the patients with stage T4 disease 6 (mean age 61) underwent radical cystectomy, 9 (mean age 73) full dose radiotherapy and 26 (mean age 81) nonradical therapy (mainly transurethral resection of the bladder). All except 1 patient died of disease within 4 years.

Conclusions

More than 60% of the patients in the cohort were considered unsuitable for radical cystectomy and their survival was poor, whether treated with full dose radiotherapy or transurethral resection of the bladder alone.     

Stage Ta-T1 bladder cancer: the relationship between findings at first followup cystoscopy and subsequent recurrence and progression

PURPOSE: We studied the relationship of first cystoscopy findings with recurrence and progression rates in a large, population based series of patients with bladder cancer. MATERIALS AND METHODS: All 463 patients with an initial diagnosis of stage Ta-T1 bladder cancer in western Sweden in 1987 to 1988 were followed at least 5 years. The 355 patients who were treated with transurethral resection only until repeat cystoscopy or longer were selected for this report. RESULTS: Negative first cystoscopy findings were associated with significantly decreased recurrence and progression rates for all grades, and for stage Ta and T1 tumors. However, some patients with initial high grade carcinoma (WHO 2 to 3) had stage progression despite negative first cystoscopy. On multivariate analyses first cystoscopy findings and papillary urothelial neoplasm of low malignant potential versus grades 1 to 3 but not stage and the number of tumors had prognostic significance for time to recurrence. Only first cystoscopy findings and grade had prognostic significance for time to stage progression. CONCLUSIONS: Our data support other groups who recommend a less intense cystoscopy followup schedule in patients with negative cystoscopy findings 3 months after initial transurethral bladder resection. We recommend that patients with initial papillary urothelial neoplasm of low malignant potential and low grade carcinoma (WHO 1) with negative first cystoscopy findings undergo repeat cystoscopy at month 12. In our opinion followup should not be less intense in patients with high grade carcinoma (WHO 2-3), even in those with stage pTa disease.     

Effect of indomethacin on N-(4-(5-nitro-2-firyl)-2-thiazolyl)formamide-induced urinary tract carcinogenesis

The effects of indomethacin on the urinary bladder and renalpelvis in rats treated with N-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide(FANFT) were studied. Two hundred female Sprague-Dawley ratswere divided into four groups. Group 1 received control dietwithout added chemicals. Group 2 was treated with indomethacin(1 mg/kg per day) in the drinking water throughout the experiment.Groups 3 and 4 received 0.2% FANFT in the diet for seven weeksfollowed by control diet. In addition to FANFT, Group 4 receivedindomethacin, 1 mg/kg per day, for the entire experiment. Therats were sacrificed after 92 weeks. There were no urothelialtumors in the control group, one renal pelvic tumor in the indomethacingroup, 4 tumors in the FANFT group and 10 urothelial tumorsin the FANFT ⁺ indomethacin group. The difference between Groups3 and 4 was statistically significant (P < 0.05). Moderateand severe hyperplasia of the renal pelvic and papillary epitheliumwas found in 15 of 48 rats in Group 2 (indomethacin only) ascompared with 6 of 49 control rats (P < 0.05). Moderate andsevere hyperplasia was equally frequent in Groups 3 and 4 (14and 17 animals in each group, respectively). Twenty-four ratsin Group 2 had mammary tumors as compared to 12 animals in Group1 (P < 0.01). Five of the tumors in Group 2 were adenocarcinomas.There was no difference between the number of mammary tumorsin Groups 3 and 4 (36 and 32 animals in each group, respectively).The results suggest that indomethacin enhances FANFT-inducedurinary tract carcinogenesis. Indomethacin also seems to exertsome tumorigenic activity in the mammary gland.     

Primary Small Cell Carcinoma of the Bladder: A Report of 25 Cases

Primary small cell carcinoma of the bladder is a rare condition with approximately 100 cases reported to date. An incidence of 0.7 percent small cell carcinoma was found in a total series of bladder tumors diagnosed in Western Sweden during a 2-year period. We describe 22 patients with primary small cell carcinoma followed to death or for at least 6 years. Three additional cases were diagnosed at autopsy. Of 18 patients with stages T2M0 to T4M0 cancer treated with locoregional therapy 5 (28 percent) had no evidence of disease after a median observation of 10 years (range 6 to 18) and 13 died of disease after 0.5 to 19 months (median 7.3). Two patients with metastatic disease were treated with systemic chemotherapy but died within 15 months. Two patients died shortly after the diagnostic biopsy. Our study and a review of the literature indicate that primary small cell carcinoma of the bladder is less aggressive than its pulmonary counterpart and that some patients can be cured by transurethral resection, or partial or radical cystectomy combined with radiotherapy.     

Postnatal endotoxin exposure results in increased insulin sensitivity and altered activity of neuroendocrine axes in adult female rats

OBJECTIVES: Severe postnatal infection leads to a systemic inflammatory response with release of cytokines and glucocorticoids, representing a stressful event for the newborn child. The purpose of this study was to mimic this situation and to study the effects of early postnatal endotoxin exposure of female rat pups on metabolic, endocrine and anthropometric variables in adulthood. DESIGN: Female pups were given subcutaneous injections of lipopolysaccharides (LPS; Salmonella enteriditis, 0.05 mg/kg) or vehicle 3 and 5 days after birth. RESULTS: Six hours after injection, LPS-treated rats had higher corticosterone levels than controls. As adults, LPS-exposed female rats showed increased insulin sensitivity (P<0.05), measured with the hyperinsulinemic euglycemic clamp (5 mU/kg per min). They exhibited a higher locomotor activity (P<0.05) and increased skeletal muscle mass in comparison with controls (P<0.05). Basal ACTH and corticosterone levels in LPS-treated rats were elevated (P<0.05), as were corticosterone levels after exposure to a novel environment stress (P<0.05). The adrenals were morphologically changed and enlarged (P<0.05) in LPS-exposed rats at 11 weeks of age, and a higher density of hypothalamic but not hippocampal glucocorticoid receptor protein was found in the LPS-treated rats (P<0.05). Furthermore, circulating progesterone levels were lower (P<0.05) and testosterone tended to be higher. CONCLUSION: The results indicate that postnatal exposure to LPS leads to increased insulin sensitivity in the adult female rat. In addition, LPS-treated rats showed changes in the regulation of hypothalamic-pituitary-adrenal and hypothalamic-pituitary-gonadal axes. This study suggests that postnatal exposure to an endotoxin such as LPS can induce specific programming of neuroendocrine regulation, with long-term consequences in adult life.     

Female gender is associated with higher risk of disease recurrence in patients with primary T1 high-grade urothelial carcinoma of the bladder

Purpose

An increasing body of evidence suggests gender differences in the presentation and prognosis of bladder cancer. We aimed to assess the impact of gender on outcomes in patients with primary T1 high-grade (HG) urothelial carcinoma of the bladder (UCB).

Methods

We retrospectively analysed the data from 916 patients with primary T1HG UCB from 7 tertiary care centres. Patients were treated with transurethral resection of the bladder with or without intravesical instillation therapy (IVT). Univariable and multivariable Cox regression analyses assessed the effect of gender on outcomes.

Results

Within a median follow-up of 42.8 months, 365 (39.8 %) patients experienced disease recurrence, 104 (11.4 %) progression, 59 (6.4 %) cancer-specific mortality and 190 (20.7 %) mortality of any cause. Overall, 634 (69.2 %) patients received IVT of which 234 (25.5 %) received BCG therapy. Female gender (n = 190, 20.7 %) was associated with higher risk of disease recurrence (HR:1.359;1.071–1.724, p = 0.012) in all patients and in a subgroup of patients treated with BCG therapy (HR:1.717;1.101–2.677, p = 0.017). There was no difference between genders with regard to disease progression, cancer-specific mortality and any-cause mortality. In multivariable analyses that adjusted for the effects of concomitant carcinoma in situ (CIS), tumour size, number of tumours, and IVT, gender remained an independent predictor for disease recurrence (p = 0.026) when analysed in all patients, but not in the subgroup of BCG treated patients (p = 0.093).

Conclusions

In patients with T1HG UCB, female gender is associated with higher risk of disease recurrence, but not with disease progression. This gender disparity may be due to differences in care and/or biology of UCB.     

Accuracy of the EORTC risk tables and of the CUETO scoring model to predict outcomes in non-muscle-invasive urothelial carcinoma of the bladder

Background:

The European Organization for Research and Treatment of Cancer (EORTC) risk tables and the Spanish Urological Club for Oncological Treatment (CUETO) scoring model are the two best-established predictive tools to help decision making for patients with non-muscle-invasive bladder cancer (NMIBC). The aim of the current study was to assess the performance of these predictive tools in a large multicentre cohort of NMIBC patients.

Methods:

We performed a retrospective analysis of 4689 patients with NMIBC. To evaluate the discrimination of the models, we created Cox proportional hazard regression models for time to disease recurrence and progression. We incorporated the patients calculated risk score as a predictor into both of these models and then calculated their discrimination (concordance indexes). We compared the concordance index of our models with the concordance index reported for the models.

Results:

With a median follow-up of 57 months, 2110 patients experienced disease recurrence and 591 patients experienced disease progression. Both tools exhibited a poor discrimination for disease recurrence and progression (0.597 and 0.662, and 0.523 and 0.616, respectively, for the EORTC and CUETO models). The EORTC tables overestimated the risk of disease recurrence and progression in high-risk patients. The discrimination of the EORTC tables was even lower in the subgroup of patients treated with BCG (0.554 and 0.576 for disease recurrence and progression, respectively). Conversely, the discrimination of the CUETO model increased in BCG-treated patients (0.597 and 0.645 for disease recurrence and progression, respectively). However, both models overestimated the risk of disease progression in high-risk patients.

Conclusion:

The EORTC risk tables and the CUETO scoring system exhibit a poor discrimination for both disease recurrence and progression in NMIBC patients. These models overestimated the risk of disease recurrence and progression in high-risk patients. These overestimations remained in BCG-treated patients, especially for the EORTC tables. These results underline the need for improving our current predictive tools. However, our study is limited by its retrospective and multi-institutional design.     

Early Complications and Survival Following Short-Term Palliative Radiotherapy in Invasive Bladder Carcinoma

Purpose

We studied the early side effects and survival rates after short-term radiotherapy (7 Gy. 3 times or 5 Gy. 4 times) in patients with muscle invasive bladder carcinoma.

Materials and Methods

Between 1981 and 1992, 96 patients (median age 80 years) were treated. Followup was complete until 1994 or death.

Results

Early side effects caused the hospitalization of 22 patients and may have contributed to the death of 5 elderly patients. Median survival for patients with stages, T2M0, T3M0, T4M0 and T2 to 4M + disease was 27 months, 6.3 months, 5.6 months and 2.9 months, respectively.

Conclusions

Short-term radiotherapy is of doubtful benefit to elderly patients with advanced bladder carcinoma and may even be harmful.