Prognostic factors in bladder cancer. A pathologic, immunohistochemical, and DNA flow-cytometric study.

Pathologic grade and stage, immunohistochemical analysis of eight cell and tumor markers, and DNA ploidy were studied in 36 cases of bladder cancer to determine the features of value in assessment of patients' survival. Tumors of high grade and advanced stage correlated with DNA aneuploidy, whereas low grade and early stage correlated with DNA diploidy when simultaneously evaluated with survival. In addition, blood group isoantigen A correlated with DNA ploidy in deceased patients, whereas blood group isoantigen H and oncogene-related protein p21 correlated with DNA ploidy in surviving patients. Despite the relatively small number of cases studied, these results suggest that pathologic grade and stage and immunohistochemical analysis of blood group isoantigens A and H and oncogene-related protein p21 hold additional value in the prediction of bladder cancer survival when evaluated simultaneously with DNA ploidy.

Second malignant tumors following treatment during childhood and adolescence for cancer.

Many pediatric and adolescent cancer patients are treated with carcinogenic chemotherapeutic agents and radiation therapy to achieve permanent control of their malignancy. These modalities may induce a new cancer in the successfully treated patient. To identify disease and treatment factors which increased the risk of occurrence of a second malignant tumor following modern treatment for cancer during childhood or adolescence, we reviewed the courses of 1,406 previously untreated patients who were less than 20 years of age at diagnosis and were treated at Roswell Park Cancer Institute between January 1, 1960 and December 31, 1989. Eighteen patients developed a second malignant tumor, including two meningiomas, 2.65-25.65 years after diagnosis of the first cancer. The actuarial risk of a second malignant tumor was 5.6% at 25 years after diagnosis. Using Cox proportional hazards modelling, we identified prior therapy with BCNU (P = 0.0055) and doxorubicin (P = 0.0254) as the only factors that were significantly associated with the risk of a second malignant tumor. Three second malignant tumors of the central nervous system occurred following treatment with a nitrosourea. Successfully treated patients must be carefully followed to identify treatment related malignant tumors at an early stage.

Cell and tumor markers' immunohistochemistry in transitional cell carcinoma of the bladder.

A wide range of cell and tumor markers including the blood group-related isoantigens A, B, O(H) and T-Ag, the cell markers DCA(F36/22) and epithelial membrane antigen (EMA), and the oncogene-related proteins RAP-5p21 and ORP-p21 were investigated by means of immunohistochemistry in selected biopsies from 36 bladder cancer patients with the aim of ascertaining which are of value in patients' survival. A heterogeneous distribution of positivity was found for each marker. In addition, EMA immunostaining correlated significantly (p < 0.05) with patient survival. We conclude that immunohistochemical detection of EMA may provide additional prognostic information in bladder cancer patients.

Prognostic factors in survival of bladder cancer.

Clinical and pathologic data of 36 patients with transitional cell carcinoma of the bladder were investigated to determine the significance on patient survival of these factors: pathologic grade and stage; the immunohistochemistry of eight cell and tumor markers; nuclear DNA flow cytometric parameters; and patient smoking status. The bivariate and multivariate statistical analysis significantly correlated patient survival rates with the immunohistochemical expression of blood group, isoantigens A (P less than 0.05), O(H) (P = 0.001), the oncogene-related protein ORP-p21 (P less than 0.05), the pathologic grade and stage (P = 0.002), and the tumor DNA ploidy (P less than 0.05). Smoking status correlated aneuploidy (P less than 0.05) and tumor expression of ORP-p21 (P less than 0.05) with the patient survival rate. Despite the relatively small number of patients in this study, the results suggest that the clinicopathologic variables are significant factors in survival of bladder cancer.

Locally recurrent endometrioid adenocarcinoma of the prostate after radical prostatectomy.

Endometrioid carcinoma of the prostate is considered a variant of classical prostatic ductal carcinoma. Endometrioid carcinoma variant often has the unique clinical presentation of gross hematuria. The propensity of this tumor to spread within the urothelium makes local failure of curative therapy commonplace. We present 2 representative cases with a review of followup surveillance procedures and treatment options for the local recurrence once identified.

Malignant phyllodes tumor of prostate.

A case of malignant phyllodes tumor of the prostate, with clinical course of recurrence and pulmonary metastasis is described in a thirty-eight-year-old man. Histologically the tumor was characterized by a fibrosarcoma-like pattern with adjacent changes of fibroadenoma and phyllodes type of prostatic atypical hyperplasia. The pathology, histogenesis, differential diagnosis, and the role of immunohistochemistry in the diagnosis and demonstration of its components is reviewed.

Inhibition of implantation of murine bladder tumor by thiotepa in cauterized bladder.

This study was designed to determine the role of immediate intravesical instillation of single dose thiotepa post transurethral resection of bladder tumor in the prevention of recurrence by tumor implantation, using murine bladder tumor line 2 and 201 C3H/He mice. Previous studies have suggested implantation may take place as early as the first hour and reach its maximum in 24 hours after resection of bladder tumor. An in vitro dose response curve of MBT2 to thiotepa was established by treatment with various concentrations of thiotepa of 0.00, 0.01, 0.21, 0.44, and 1.91 mg./ml. In a group of 201 mice, the bladder was catheterized with a 24G angiocatheter, and a fine copper wire was inserted through the lumen. The bladder was cauterized by touching the wire with a Bovie coagulator for four seconds at the lowest setting. All bladders were instilled with 1 x 10(6) cells of murine bladder tumor line 2, followed by instillation of 1.91 mg./ml. of thiotepa with various time delays per treatment group. The bladder implantation rates were 30.4% (17/56), 3.4% (2/59), 6.5% (2/31) and 26.9% (7/26) in the control, immediate, one-hour delay and 24-hour delay groups, respectively. The urethral implantation rates were 21.4% (12/56), 0% (0/59), 6.5% (2/31) and 0% (2/26), respectively. The overall implantation rates (bladder, urethra, or both) were 42.9% (24/56), 3.4% (2/59), 6.5% (2/31) and 25.9% (7/27), respectively. Implantation rates were significantly higher in the control and 24-hour delay groups than in the immediate and one-hour instillation groups (p less than 0.05, Fisher Exact Test). We conclude from this animal model that intravesical instillation of single dose thiotepa, to be effective, should be initiated within the first hour after tumor resection, since it dramatically decreased the incidence of bladder and urethral implantation.

Comparative evaluation of National Prostatic Cancer Treatment Group and Gleason systems for pathologic grading of primary prostatic cancer.

Multivariable analysis was used to investigate the relationship between risk of disease progression or death in patients who were treated with adjuvant therapy after definitive treatment for prostatic adenocarcinoma and the components of the National Prostatic Cancer Treatment Group (NPCTG) and Gleason systems for pathologic grading of prostatic cancer. Data were available for 203 patients who were treated on NPCTG Protocols 900 and 1,000, which involve surgical and radiation therapy as definitive treatment. Since less than 10 per cent of these patients have died, analysis of survival was not attempted. The study focus was progression-free survival, which is the minimum of time to progression or death. The analysis demonstrates that a new measure, the NPCTG score (the sum of the glandular and nuclear grades) is superior to the previously reported NPCTG grade (the maximum of the two grades). In addition, the Gleason score is somewhat superior to the new NPCTG score. All of this, however, applies only to the primary tumor and not the nature of any present or future metastatic lesions.

Papillary adenoma of the prostatic urethra.

Six patients with papillary adenoma of the prostatic urethra are described. Their ages ranged from 39 to 70 years old. Two of them showed evidence of clinical recurrence 1 year after treatment. The pathological features as well as the immunohistochemical demonstration of prostate specific antigen (PSA) and prostatic acid phosphatase (PAP) are illustrated. A brief review of the literature is discussed with special emphasis on the histogenesis and nature of this lesion.

Prostate cancer grading: the NPCP system.

The use of the NPCP grading system does not contradict the principle that an accurate prediction of tumor volume, presence, and extent of metastases, therapeutic response, and clinical behavior of prostate cancer cannot be entirely based on the grade of the disease at the time of initial diagnosis. The morphology of prostate cancer, like any other cancer, is probably no more than one of a group of parameters that are decisive for the prediction of the biology and clinical course of the disease. Nevertheless, the present data support the premise that the NPCP system of grading prostate cancer, among others, is a very helpful indicator of the extent and behavior of prostate malignancy. Table 6 illustrates the correlation between grades and stages of prostatic carcinoma that can be drawn from the preceding data.

The addition of chemotherapy to hormonal therapy for treatment of patients with metastatic carcinoma of the prostate.

Patients with advanced prostate carcinoma that had been stabilized by orchiectomy (ORCH) or hormone therapy for at least 3 months, were randomized to either diethylstilbestrol (DES) alone or DES plus Cytoxan or DES plus Emcyt. A total of 188 patients were randomized between July, 1976 and February, 1982 of which 161 were evaluable for objective response to treatment. Objective response rates, response duration, or survival experiences were not demonstrably different between treatment arms, either for all patients or within good or poor prognosis groups determined by initial pain or acid phosphatase level. Subjective improvements in performance status were small for each treatment. Pain relief was somewhat greater in the chemotherapy-hormone combinations than in the DES/ORCH, but the advantage was not statistically significant. Side effects were primarily nausea and vomiting and leukopenia, mostly in the DES + Cytoxan arm. The duration of stabilization prior to entry did not influence response overall, although there were opposing trends within each of the two chemotherapy arms. The premise for combining antitumor agents with hormones before hormone failure is still felt to be a more logical approach than waiting for the ultimate hormone failure, and a combination of hormones plus two antitumor agents is being evaluated in a subsequent ongoing trial where a more rigid design limits the duration of the preentry period of hormone stabilization.

Comparison of estramustine phosphate, methotrexate and cis-platinum in patients with advanced, hormone refractory prostate cancer.

In this clinical trial of men with advanced prostatic cancer no longer responsive to hormone therapy 189 were randomized to receive estramustine phosphate, methotrexate or cis-platinum. Response evaluations were done in 158 cases. Objective response rates (complete, partial or stabilization of disease) were 34 per cent for estramustine phosphate, 36 per cent for cis-platinum and 41 per cent for methotrexate. Subjective parameters indicated a substantial advantage for pain improvement with methotrexate or cis-platinum over estramustine phosphate. Probabilities of continued response indicated some advantage for methotrexate and median response durations at this time were twice as long for methotrexate (32 weeks) as for cis-platinum (16 weeks), with estramustine phosphate intermediate (23 weeks). Survival rates for the original treatment randomization groups were not different at this time. Side effects of estramustine phosphate consisted primarily of nausea and vomiting and/or anorexia but to a lesser extent than with cis-platinum. These effects were somewhat less for methotrexate, for which the major side effects were stomatitis and leukopenia, as well as hepatic toxicity reflected by elevated serum glutamic oxaloacetic transaminase levels. Other side effects of cis-platinum were less than for methotrexate (no stomatitis), except for signs of renal toxicity (elevations in blood urea nitrogen and serum creatinine), which were greater. Methotrexate had a relatively high level of activity against metastatic, progressive, hormone nonresponsive prostatic cancer, with side effects that were substantial but manageable.

A comparison of estramustine phosphate versus cis-platinum alone versus estramustine phosphate plus cis-platinum in patients with advanced hormone refractory prostate cancer who had had extensive irradiation to the pelvis or lumbosacral area.

Single and combination chemotherapy was compared in a clinical trial for men with advanced, metastatic prostate cancer who had received prior pelvic irradiation and had had progression of disease despite hormonal therapy. The 149 patients were randomized to receive estramustine phosphate or cis-platinum alone or in combination. Of the 149 patients 25 (17 per cent) were excluded from the study but 124 were evaluated for response and survival. Entry variables were distributed similarly among patients in each treatment arm. There were no complete or partial responders but there were nearly twice as many patients whose disease was stabilized (33 per cent) on the combination regimen compared to estramustine phosphate (18 per cent) and about a third more than for cis-platinum (21 per cent). Analysis of survival revealed some advantage for patients on combination therapy. Major toxicities for all treatments were nausea and vomiting (62 to 88 per cent) and accompanying anorexia (72 to 95 per cent). Azotemia developed in 45 per cent of the patients receiving combination therapy. In addition an elevation in serum creatinine occurred in 22 per cent of the patients receiving combination therapy and in 17 per cent of those receiving cis-platinum alone. Myelosuppression occurred infrequently.

A comparison of hydroxyurea, methyl-chloroethyl-cyclohexy-nitrosourea and cyclophosphamide in patients with advanced carcinoma of the prostate.

This is the fifth completed randomized clinical trial of the National Prostatic Cancer Project. There were 125 patients with histologically confirmed relapsing clinical stage D prostatic cancer randomized to receive hydroxyurea, methyl-chloroethyl-cyclohexy-nitrosourea or cyclophosphamide. All patients had received and failed previous hormonal therapy. Patients whose disease progressed after 12 weeks on the initial therapy were crossed over or randomized to receive an alternate drug. There were 98 patients available for comparison of treatments. Objective responses included patients with complete or partial regression as well as stable disease. The response rates were 35 per cent for cyclophosphamide, 30 per cent for methyl-chloroethyl-cyclohexy-nitrosourea and 15 per cent for hydroxyurea. Subjective response parameters included improvement in performance status and relief of pain. Pain was improved in a fifth of the patients on each treatment area. Methyl-chloroethyl-cyclohexy-nitrosourea and hydroxyurea showed activity in advanced prostatic cancer patients but at the expense of excessive toxicity. Cyclophosphamide continues to be the most active single agent in this type of patient, particularly with regard to duration of response and survival. There was a statistically demonstrable advantage for cyclophosphamide over hydroxyurea and a marginal advantage over methyl-chloroethyl-cyclohexy-nitrosourea in survival experience.

Comparison of estramustine phosphate and vincristine alone or in combination for patients with advanced, hormone refractory, previously irradiated carcinoma of the prostate.

There were 121 men with hormonally refractory metastatic cancer of the prostate who were randomized to receive estramustine phosphate or vincristine, or the combination of these 2 agents. All patients had received prior radiation therapy (greater than 2,000 rad). There were 90 patients who could be compared for response. The objective response rates (partial regression or stabilization of disease) for the 3 treatment groups were 26 per cent for estramustine phosphate, 24 per cent for estramustine phosphate plus vincristine and 15 per cent for vincristine. Subjective parameters varied little among the 3 regimens. The median duration of response for those responding to estramustine phosphate was similar (20 weeks) to that for vincristine (22 weeks) and greater than that for the combination (13 weeks). The probability of survival did not differ significantly for patients randomized to each of the 3 regimens. The addition of vincristine to estramustine phosphate did not enhance the response rate achieved by estramustine phosphate alone and vincristine alone produced the lowest response rate. Estramustine phosphate continues to be the most active agent in previously irradiated patients with hormonally refractory metastatic cancer of the prostate.

An unusual case of supraclavicular and colonic malakoplakia--a light and ultrastructural study.

A case of malakoplakia of the supraclavicular region and colon in a 41-year-old patient is presented. Clinical, histopathological, histochemical and ultrastructural features are described. The etiology and pathogenesis are discussed. Malakoplakia is a chronic inflammatory disorder probably due to an abnormal response to infection with Gram negative bacteria, most likely Escherichia coli or Klebsiella. The disease is characterised by the accumulation of macrophages intermixed with plasma cells and lymphocytes. The malakoplakic cells are laden with phagolysosomes which may provide a suitable biochemical environment for the deposition of calcium to form the pathognomonic Michaelis-Gutmann bodies. Ultrastructural examination enhances the accuracy of diagnosis since it highlights the presence of lysosomes, phagolysosomes, Michaelis-Gutmann bodies, and intact E. coli or their remnants.

Histologic grading of primary prostatic cancer: a new approach to an old problem.

A simple and objective system for grading prostatic carcinoma was evaluated in a retrospective analysis of 169 cases followed during a 16-year period. The system identified and separated 4 grades of increasing malignancy based on the combined evaluation of gland differentiation and nuclear anaplasia as separate but complementary factors. The system demonstrates significant correlation with mortality rates for each grade group. Retrospective evaluation of the extent of the disease at the time of initial diagnosis also indicates correlation between prostatic grades and clinical stages.