Grade Transitional Cell Carcinoma Research Articles

Human papillomavirus associated with bladder cancer

Recently published data have suggested a link between active human papillomavirus (HPV) infection and the development of bladder cancer. This study was undertaken to test for HPV genomic material in the tumors of patients without evidence of ongoing viral infection. Twenty-three consecutive patients with clinical evidence of intravesical neoplasia and no history of HPV infection or clinical evidence of intercurrent disease, underwent cystopanendoscopy and biopsy as part of the routine evaluation and treatment of their tumor. Routine pathologic evaluation and southern blot analysis of biopsy material were done to establish the presence or absence of HPV DNA in the bladder tumors. Twenty-one tumors were identified by routine histology: 20 were low-to-moderate grade transitional cell carcinomas; 1 was found to be squamous cell carcinoma; 1 patient had moderate dysplasia; and 1 patient had evidence of inflammation. Four of the 20 transitional cell tumors (20%) were found to contain HPV DNA. In addition, the patients with dysplasia and cystitis were also shown to have HPV genomic material in their biopsy specimens. Viral types 6 11 , 16 18 , and 31 33 were found. The 20 percent incidence of HPV genomic material in bladder tumors from patients without clinical evidence of viral infection is in keeping with the observations of other investigators. We present the implication of these findings within the context of our current understanding of viral oncogenesis in the urinary bladder.

Immunohistochemical Analysis of c‐erbB‐2 Oncogene Product and Epidermal Growth Factor Receptor Expression in Human Urinary Bladder Carcinomas

Expression of the product of the c-erbB-2 gene, a proto-oncogene related to, but distinct from c-erbB-1 encoding the epidermal growth factor receptor (EGF-R), was investigated in human urinary bladder carcinomas. In addition, levels of EGF-R and transferrin receptor were also analyzed using an immunohistochemical approach, and the results compared with histological pattern and grading, and tumor staging. Increased expression of c-erb B-2 product was found in 32% of cases (7/22), a positive reaction being observed in 60% of transitional cell carcinoma (TCC) Grade 3 lesions (3/5), 20% of Grade 2 TCCs (2/10) and 100% of adenocarcinomas (AC) (2/2), but in none of the cases of squamous cell carcinoma (SCC). Although no statistical correlation with staging was evident, TCCs or SCCs of high grade and stage often showed EGF-R-positive staining, whereas other well differentiated lesions and normal bladder epithelium were generally negative. Most cases of urinary bladder carcinoma were positive for the transferrin receptor, which was not detected in normal bladder. The results thus suggested that a positive reaction for c-erbB-2 product is correlated with TCC histological grading or AC morphology. A high intensity of EGF-R staining in human bladder carcinomas may be associated with poor differentiation and invasion, whereas transferrin receptor expression might reflect tumor growth.

Observer variability in histopathological reporting of transitional cell carcinoma and epithelial dysplasia in bladders.

Sections from 90 urinary bladder biopsy specimens were examined by 11 consultant histopathologists with varying experience to determine the appropriateness of existing pathology terminology. Analysis with kappa statistics showed fair to good agreement in the grading and staging of transitional cell carcinoma. There was also reasonable agreement in the diagnosis of high grade dysplasia in random biopsy specimens from the urothelium adjacent to the neoplasm, but very poor agreement for lesser degrees of dysplasia. It is concluded that the present classification of bladder carcinomata is reliable and that pathologists can determine stage with a high degree of reproducibility and grade with a fair degree of reproducibility.

Conservative Treatment of Diffuse Carcinoma in situ of the Bladder with Repeated Courses of Intravesical Therapy

We present a series of 13 patients with diffuse carcinoma in situ (CIS) of the bladder who failed an initial induction course of intravesical therapy with Mitomycin C, thiotepa, doxorubicin or Bacillus Calmette Guérin (BCG). Cystectomy, although indicated, was, for various reasons, not performed after the first failure of intravesical therapy and all patients were subsequently treated topically with the same or different agents. Of the 7 patients treated with 2 induction courses, 6 showed a complete response during a follow-up period of 24 to 42 months. Although 1 patient initially responded completely, he developed invasive transitional cell carcinoma (TCC) Grade IV 30 months later. Among the 3 patients who underwent 3 induction courses, 2 had a complete response at 42 and 60 months of follow-up and 1 developed TCC Grade IV with muscle invasion 18 months later. Two of the 3 patients treated with 4 induction courses are free of disease at 48 and 57 months; the third developed low grade, low stage TCC. This experience suggests that the majority of patients with CIS who fail initial treatment usually respond to further treatment with the same or a different drug. The question as to whether a second course of intravesical therapy, subsequent to failure of the first course, should be given before cystectomy requires further investigation.

Cancer of the urinary bladder: current concepts and future

Recent research trends on carcinoma of the bladder with special references to the current concepts of its pathogenesis, the basic problems on its diagnosis and treatment were reviewed and discussed. 1) The transitional epithelium as the origin of transitional cell carcinoma (TCC) is understandable as an intermediate of squamous and glandular epithelium and the biology on the basal cells is seemed to be the most interesting. 2) Multistage carcinogenesis theory is adapted in the carcinoma of the urinary bladder and the research will be directed to clarify mechanisms to maintain the dormant cell in the state and to develop new technology for quantitative analysis of its promoters and antipromoters. 3) Grading of TCC by the conventional histology is not adequate in the future that new objective criteria to evaluate the structural atypia is expected other than the current DNA analysis by flow cytometry. 4) Endoscopy for diagnosis of the bladder carcinoma should be available to observe whole urinary system and the recorded images should be analyzed by the objective method developed by new technology. 5) New direction of the treatment of the bladder carcinoma will be headed to find a BRM as an antipromoters in the short range strategy.

Immunohistochemical study of tissue polypeptide antigen (TPA) in human urinary bladder tumors

The immunohistochemical study of tissue polypeptide antigen (TPA) was performed by Avidin-Biotin-Peroxidase complex method (ABC method) in the human bladder tumors. Thirteen bladder tumors (4 cases with transitional cell carcinoma grade 1, 6 cases with grade 2 and 3 cases with grade 3; 7 cases with pTa, 3 cases with pT1 and 3 cases with pT3) were subjected to this study. Prior to the experiment, it was confirmed that the TPA reactivity was not diminished by the tissue fixation with buffered formalin within 72 hours. Bladder tumors of grade 1 and 2 were strongly stained for TPA, whereas bladder tumors of grade 3 appeared to be stained weakly. There were no relationships between TPA stainings and the tumor staging, and between the TPA stainings and the prognosis of the patients. We have concluded that the TPA staining might be a useful method for determination of the bladder tumor grading.

Morphological and immunohistochemical characteristics of a cell line originated from noninvasive human bladder transitional-cell carcinoma.

A cell line (IG) was derived from a noninvasive transitional cell carcinoma grade II. The cells were propagated in vitro for 9 months, had a low proliferative capacity, formed tumor nodules, and showed four characteristic morphological stages. Primary epithelial-like cells were characterized as stage I; fibroblast-like cells with loss of contact inhibition of growth as stage II; fibroblast-like cells with long cytoplasmic projections, massive glycosaminoglycan content and tumor nodule formation as stage III; and, as stage IV, granulated stellate cells. The cell culture progressed cytologically from well-differentiated stage I to less-differentiated stage IV. The four stages were confirmed and examined by electron microscopy. Immunoreactivity for fibronectin, keratin, epithelial membrane antigen and carcinoembryonic antigen shown by the cell line and the tissue indicates that the cell line represents the original cell population in the tumor. Glycosaminoglycan production by these cells was found to be responsible for the formation of tumor nodules which appeared in culture at the same time as the patient had developed an invasive bladder tumor. Glycosaminoglycans were observed as a massive accumulation intracellularly and extracellularly, as rods or thick slices in layers of adherent vesicles and granules covering the cell culture. Normal bladder epithelial cells and fibroblasts grew in monolayer, showed contact inhibition of growth, were devoid of intracellularly accumulated glycosaminoglycans and produced uniform extracellular matrix different from that of IG cells.

Epithelial membrane antigen as an immunohistochemical marker for transitional cell carcinoma of the urinary bladder.

Epithelial membrane antigen (EMA) was immunohistochemically localized in transitional cell carcinomas of the bladder to clarify EMA staining pattern's relationship to the histological grading and staging of tumors and patient prognosis. Formalin-fixed, paraffin-embedded sections from 101 patients with bladder carcinoma were stained by the indirect immunoperoxidase method. In the lower histological grade and stage of transitional cell carcinoma, the localization of EMA was restricted to the luminal surface of the superficial cells. Membrane and cytoplasmic staining of EMA was frequently found in the intermediate and basal layers of the tumor cells, and the incidence of cytoplasmic staining increased with advancing grade and stage. Stromal staining was frequently observed in cases of higher grade and stage. In addition, these distribution patterns of EMA were well correlated with patient survival. Thus, we differentiated three types of EMA distribution: a luminal type, with very good prognosis; a cytoplasmic type, with fair prognosis; and a stromal type, with relatively poor prognosis. These findings suggest that EMA distribution in bladder cancer could be a valuable indicator for histological grading or staging in pathological diagnosis and for predicting the survival of bladder cancer patients.

The significance of urothelial dysplasia as diagnosed by cup biopsies.

A prospective study was carried out in which four quadrant cold cup biopsies of the bladder were taken from patients with either a bladder tumour (57) or irritative bladder symptoms (44), and a control group (23). Five histopathological patterns were recognized: normal urothelium, mild, moderate and severe dysplasia, and carcinoma in situ (CIS). In the control group, 22 of the 23 patients had normal urothelium, giving a 4% incidence of mild dysplasia. Of the 57 patients with all stages and grades of transitional cell carcinoma, 38 (67%) had dysplastic urothelium. This association is significant (P less than 0.01, chi-squared). Thirty-seven patients had Ta or T1 tumours, and 24 (65%) of these had dysplasia, including four (11%) with CIS. Twenty patients had T2-T4, Grade 111 tumours and 14 (70%) of these had dysplasia, including five (25%) with CIS. There was no statistical difference between these two groups. The recurrence rate was evaluated for all patients presenting with a first bladder tumour. Seventy-three percent of patients with normal cup biopsies remained recurrence free during a mean follow-up of 3 years (s.d. 1.15 years). Of patients with dysplastic urothelium, 72% remained recurrence free over a mean follow-up of 3.25 years (s.d. 1.23 years). Hence, the presence of dysplasia did not predict the likelihood of tumour recurrence. Thirty patients had dysuria or suprapubic pain for which there was no explanation. Sixteen (53%) had dysplasia on cup biopsy including three (10%) with CIS (P less than 0.01, chi-squared). It seems clear, therefore, that the dysplasia was the cause of these symptoms.(ABSTRACT TRUNCATED AT 250 WORDS)

Morphologic quantitation of nuclear size in various grades of transitional cell carcinoma of urinary bladder

Quantitative morphometry was used to characterize the different grades of human bladder transitional cell carcinoma. When histograms were constructed using data obtained, lower grade tumors were easily differentiated from tumors with higher grade. There is the further suggestion that low-grade tumors which progress to an aggressive stage demonstrate the pattern of high-grade malignancy early in their development, thus identifying which tumors may ultimately require radical surgery.

Study on Cytology of Urinary Transitional Cell Carcinoma

In 1962, Umiker reported the difficulty of cytological diagnosis of voided urine, especially in class III group. Up to the present, it seems that this problem has been not resolved.We performed a statistical analysis and a karyomethric examination using available materials for cytology of Sakai Municipal Hospital from 1974 to 1977. Our statistical data were similar to Umiker's. In 84% we observed desquamated cell clusters in the voided urine of patients with transitional cell carcinoma. Consequently we conducted a karyometry on cells in clusters in the voided urine of patients with transitional cell carcinomas grade III, II, I and false positive. Totally 33 patients were karyometrically examined.The discriminant point between transitional cell carcinoma grade I and grade II was determined by the comparison of nuclear sizes (p<0.01). In examination of two more cells in a transitional cell cluster, if the sum of long diameter and short diameter of a tumor cell nucleus is 2.5 times larger than that of lymphocyte, the cell cluster is considered to belong to transitional cell carcinoma grade II or grade III. The comparison of the nuclear diameters among them, however, did not seem to be easy under microscope. Therefore we tried to convert the length to the dimensions concerning the discriminant point, using the ratio of long diameter/short diameter of the tumor cell nucleus with the size of discriminant point, that of the lymphocyte's nucleus of average size in the urine and the discriminant value of the sum of long and short diameters of tumor cell nucleus.Consequently, in case that observed more than two cells 6 times larger than a lymphocyte's nucleus in a transitional cell cluster, we suspected transitional cell carcinoma grade II or III. But in microscopic examination, when we put lymphocyte's figure on a tumor cell nucleus in the above condition, we are just able to place four lymphocytes on it, because we cannot put six figures of almost circle like lymphocyte on an elliptical figure like a nucleus of transitional cell carcinoma without an unfilled space.In this study the renewed transitional cells with clear cell dysplasia, renal tubular epithelium and glandular epithelium were excluded out of the karyometric examination of transitional cell carcinoma. Additionally we studied on the features of nuclei in all groups of transitional cell carcinomas grade III, II, I, false positive and negative respectively.The result concerning the karyometrical differentiation between transitional cell carcinoma grade I and grade II should be evaluated as a preliminary one, because the condition of desquamated cells, e. g. shrinkage, swelling, or other degenerative changes, could not be uniform as long as we would use the voided urine as materials and because the number of cases examined karyometrically were not enough to settle the conclusion. So we continued to confirm the above results in the practice of urine cytology almost for two years.In other words, we conducted supplementarily the urinocytological examination cytology from January 1978 to October 1979 on the basis of the above results.As result, we obtained more accurate information of urinary cytology in class V, IV, II follow up, II and I. In fact, a correct diagnosis could be made 94% in class V, IV and 83% in class H follow up, while the former 86%, the latter 55% in the previous data. However a correct diagnosis rate became lower in class III.The result in class III suggests that it is very difficult to distinguish between transitional cell carcinoma grade I and hyperplasia of non-malignant transitional epithelium only by the estimation of nuclear sizes.

膀胱の癌肉腫 (結合腫瘍) の1例

A 61-year-old man was seen on September, 9, 1975 with the chief complaint of intermittent gross hematuria of 4 years' duration and burning on urination for the past 2 months. Cystoscopy disclosed a large sessile tumor involving the left lateral wall of the bladder. A total cystectomy with ileal loop urinary diversion was performed on October 23, 1975.The surgical specimen demonstrated the co-existence of a solid, necrotic tumor 7×6×5cm. in size and a papillary tumor 3×4×2cm, in size. On microscopic examination the former was identified as myxomatous leiomyosarcoma, the latter as transitional cell carcinoma grade 3. The two components collided in some areas and invaded each other. Consequently the pathological diagnosis was carcinosarcoma (collision tumor) of the urinary bladder.Two months after the operation, urethral bleeding reappeared and an induration in the pendulous urethra was noted. As biopsy revealed sarcomatous elements, the penis was amputated and the urethra was removed.On May 13, 1976, he died with the local recurrent lesion and pulmonary metastasis, showing no response to telecobalt irradiation and chemotherapy. No autopsy was done.The literature was reviewed and the clinicopathology of the carcinosarcoma of the bladder was discussed.

膀胱拡大術の臨床研究

We previously reported in “A Study on Cystoplasty by Regeneration of Contracted Bladder Using Novectane (Liquid Synthetic Resin)-sprayed Thin Paper (1) and (2)” that we had conducted cystoplasty by regeneration in various cases of contracted bladder Among these cases there was a case in which the bladder capacity increased from 20cc to 400cc.The period of observation after operation on these cases was from 18-30 months. Favorable results have been maintained in all the cases.In this paper we report on a case in which this method of cystoplasty was applied to tumor of bladder. Case 1 was a 40-year-old male. For about 3 months macroscopic hematuria was present without subjective symptoms. Clinical observations by cystogram in prone position revealed a large filling defect as shown in Fig. 1 by the arrow.The cystoscopy revealed a large tumor surrounding the vertux of the bladder. The operation was performed under the spinal anesthesia.As shown in Fig. 2, we excised 4/5-5/6 of the bladder together with a part of the peritoneum, leaving the neck of the bladder, the trigone of the bladder and the ureteral orifices on both sides. As shown in Fig. 2, the ureteral catheters were inserted from the ureteral of ifices on both sides. This ureteral catheter was removed immediately after excision of the bladder. Then a porous Nelaton catheter No. 15 was inserted into the bladder transurethrally. This method of cystoplasty is the same as that used for cystoplasty of Contracted Bladder. The prepared Novectane sprayed thin paper bladder was sutured to the residual bladder by interrupted sutures using 00 cutgut as shown in Fig. 4. The peritonuem was sutured by interrupted No. 4 silk sutures. We placed the drain on both sides of the artificial bladder and finished this operation by suturing the fascia and skin.The excised bladder is shown in Fig. 3. The arrow indicates the tumor. The microscopic pathological findings showed that there was a third grade transitional cell carcinoma. The operation time was about 2 hours. We continued the extraction of urine by Nelaton catheter by an aspirator for about 5 days. After 7 days we removed all the sutures and replaced the Nelaton catheter with a bag catheter. Then the patient was allowed to walk. After about 3 weeks the artificial bladder fell off from the regenerated granulation bladder wall. After we had extracted the artificial bladder transurethrally, we made the patient urinate by himself.Clinical observations by cystogram are given in Figs. 5, (1), (2), (3), and (4). An almost normal cystogram pattern was observed after a month in this case. The residual urine was about 40cc. The cystograms revealed a remarkably increased capacity with the lapse of time. But after a month the cystogram showed a Vesico-Ureteral reflux. This reflux is observed in the cystogram even after a year.This was an instructive and difficult case, since all the 15 pieces of No. 4 silk suture used for suturing the peritoneum appeared in the bladder and remained as foreign materials as shown by the arrow in Fig. 6. Therefore we extracted all the silk sutures transurethrally. In this method of cystoplasty the cutgut should be used, even for suturing the peritoneum. The entire bladder wall was covered with normal regenerated mucous membrane after 5 months as shown in Fig. 7.Natural urination at one time was 350-400cc, 15 months after cystoplasty. Residual urine was less than 30cc. The volume of liquid at maximum desire to urinate was 270cc when the inner pressure of the bladder was 21-30mmHg, 5 months after the cystoplasty. The volume of liquid at maximum desire to urinate was 290cc when the inner pressure of the bladder was 40mmHg 12 months after the cystoplasty.Urine analysis in this case revealed protein +-±, sediment white cell +-±, red cell +, and bacteria-This patient was treated neither by chemotherapy nor by the radiation thera