Superficial Urothelial Carcinoma Research Articles

Strong Correlation of Basement Membrane Degradation With P53 Inactivation and/or MDM2 Overexpression in Superficial Urothelial Carcinomas

Purposes We investigated the relationships between the degradation of basement membrane underlying superficial urothelial carcinomas, including carcinoma in situ and the functional p53 loss caused by inactivation of p53 and the overexpression of mdm2 oncoprotein. Materials and Methods Nuclear accumulations of p53 and mdm2 were examined immunohistochemically for 60 transitional cell carcinomas (primary lesions) and 13 accompanying (concomitant) carcinoma in situ lesions. Degradation of the basement membrane was defined as the reduction or total loss of type IV collagen expression. Whether there was up-regulation of MMP-1, MMP-2, and MMP-9 was analyzed immunohistochemically. Results The frequency of the degradation of basement membrane underlying grade 1 pTa tumors was 0%, grade 2-3 pTa tumors 57.1%, and primary CIS lesions 83.3%. Nuclear over-accumulation of p53 was found in 48.3% and of mdm2 in 23.3% of the primary tumors. In pTa-pT1 carcinomas, nuclear staining of p53, mdm2, or both was highly correlated with degradation of the basement membrane underlying carcinomas (p = 0.00002). In the CIS lesions, the association of p53 nuclear staining with the destruction of type IV collagen expression was of borderline significance (p = 0.03). When mdm2 overexpression was considered as a molecular abnormality together with p53 inactivation, the correlation with the degradation of the basement membrane was highly significant (p = 0.00006). Moreover, the functional p53 loss was strongly associated with the up-regulation of matrix metalloproteinases (MMPs) (p = 0.0005). This finding was well correlated with the strong association of basement membrane degradation with up-regulation of MMPs (p = 0.000004). Conclusions Degradation of basement membranes underlying superficial carcinomas or CIS of the urothelium was significantly related to p53 inactivation, mdm2 overexpression, or both. The expression status of mdm2 should provide better information about the progression of superficial urothelial carcinomas than the status of p53 alone.

Early clinical experience with 5‐aminolevulinic acid for the photodynamic therapy of superficial bladder cancer

To report clinical experience with intravesical instillations of 5-aminolevulinic acid (ALA) for the photodynamic therapy of superficial bladder cancer and to assess any side-effects of the treatment. Ten patients (six men and four women, mean age 62.3 years, range 42-73) with refractory superficial bladder cancer were treated with photodynamic therapy using 5 g of ALA dissolved in 30 mL sodium bicarbonate instilled intravesically. After a mean retention of 5.1 h, the bladder interior was illuminated transurethrally at radiation integrals of 15, 30 or 60 J/cm2. At integrals of 15 or 30 J/cm2 red light (635 nm) was used and at 60 J/cm2, green light (514 nm, 40 J/cm2) was combined with a subsequent application of red light (635 nm, 20 J/cm2). After 10-12 weeks, four patients had a complete remission, two a partial remission, there was no change in three and one had progressive disease. Of those patients responding, the bladder was preserved in five after a mean follow-up of 15 months (range 6-27). There were no photodermatoses or bladder shrinkage in any patient. Photodynamic therapy with intravesically applied ALA is effective in destroying superficial urothelial carcinomas of the bladder. There were no serious side-effects which could preclude further clinical testing.

Il carcinoma uroteliale della vescica pT1G3. Studio clinico-patologico e morfometrico di 26 casi trattati con BCG:Urothelial bladder carcinoma pT1G3. Clinico-pathological and morphometric study of 26 cases treated with BCG

From 1987 to 1993, 26 patients with superficial urothelial bladder carcinoma pT1G3 were observed consecutively at the Dept. of Urology of Pordenone City Hospital and the Division of Pathology of the Centro di Riferimento Oncologico di Aviano (Italy). All patients were treated with TUR and then with a course of BCG-intravesical instillations. The complete immunoprophylaxis treatment consisted of a weekly instillation of BCG for 6 weeks; then cystoscopy and urinary cytologies or random biopsies were performed. An additional 1-monthly BCG treatment for 3 months was administered to 10 disease-free patients. In 6 cases of pT1G3 recurrences, a new complete cycle of BCG was performed whereas in 10 patients with local progression, defined as muscular infiltration, a cystoprostatectomy or RT therapy was advised. Follow-up examinations, planned every 3 months for 2 years and then every 6 months for 3 years, included cystoscopy and urinary cytologies in 19 patients and cystoscopy with randomized biopsies and washing in the remaining 7 patients. Ten patients were disease-free at a mean of 34 months follow-up (range 13-65 months); 6 patients experienced recurrence at a mean of 7 months follow-up (range 3-40 months) and 10 patients local progression at a mean of 13 months follow-up (range 3-44 months). The morphometric study demonstrated that cases with average nuclear area, in the deepest part of the histological section, more or equal to 40 μm2have a threefold progression rate, compared to cases with average nuclear area less than 40 μm2(p = 0.10). Our results would indicate the possible role of morphometric evaluation of prognostically important parameters, in the clinical management of patients with pT1G3 tumours.

Detection of urinary TNF, IL 1, and IL 2 after local BCG immunotherapy for bladder carcinoma

Intravesical application of bacillus Calmette-Guérin (BCG) is highly active against recurrences of superficial urothelial bladder carcinoma. In an attempt to monitor the immunological effects of this therapy, we analyzed the urine of patients following the sixth intravessical instillation, to show the presence of the monokines TNF and IL 1 and the lymphokine IL 2. Within 24 hours following the instillation, all (n = 10) patients exhibited a strong increase in urinary cytokine secretion, which was significantly different from the control group (n = 10), with respect to TNF L929 biological assay (P less than 0.01), TNF sandwich-ELISA (P less than 0.01), IL 2 CTL 6 biological assay (P less than 0.05), IL 2 sandwich-ELISA (P less than 0.005), and IL 1 sandwich-ELISA (P less than 0.05), but not to the IL 1 fibroblast biological assay. The maximum urinary secretion varied between individual patients and different cytokines, but was generally found within 2 to 8 hr after the instillation. A persistent high urinary activity was demonstrated in BCG-treated patients for IL 2 in sandwich-ELISA. These results reflect the local inflammatory response to BCG and suggest an immunomodulatory mode of action against urothelial carcinoma cells. Elucidation of the possible role of each urinary cytokine against this cancer warrants further investigations.

Tumor-associated mononuclear cell infiltrate and recurrence rate in the superficial urothelial carcinoma of the urinary bladder

Investigation on the absence or presence of malignancy-associated mononuclear cell infiltration in correlation to the recurrence rate after topic adriamycin chemotherapy was made in 53 patients with a superficial urothelial carcinoma of the urinary bladder after transurethral resection. The tumor recurrence rate, after an average observation period of 2.8 years, was 55%. Malignancy-associated mononuclear cell infiltration was found in 18 cases (34%) and of these, 6 (33%) showed recurrence. Absence of cell infiltration was found in 35 cases (66%) and of these, 23 (66%) showed recurrence. In those tumors which showed recurrence, cell infiltration was absent in 83%, whereas it was absent in only 46% of the tumors without recurrence.