William M. Murphy

Renal disease after mitomycin C therapy.

Fourteen patients with adenocarcinoma of the gastrointestinal tract and pancreas treated with mitomycin C(MMC) and 5‐fluorouracil (5‐FU) had renal impairment 6‐11 months from the beginning of MMC therapy. Two clinical entities were recognized: an acute fulminating renal failure that was rapidly fatal and a chronic slowly progressive renal impairment. The first entity showed a microangiopathic hemolytic profile with anemia, thrombocytopenia, and erythrocyte fragmentation. Light microscopy and electron microscopy examination of the kidney revealed a primary vascular disease with musculomucoid intimal hyperplasia of arteries and rare fibrin thrombi in arterioles. Interstitial fibrosis, tubular atrophy, and widespread glomerular necrosis were also seen. The disease was ultimately fatal within three to four weeks.

Flow Cytometry Versus Urinary Cytology in the Evaluation of Patients with Bladder Cancer

We compared the roles of urinary cytology and flow cytometry in the evaluation of patients with bladder cancer in clinical practice situations at a large general hospital. Specimens included 105 bladder washings from patients being followed for urothelial carcinomas and 28 control washings from individuals undergoing cytoscopy for other reasons. Flow cytometry and cytology were performed on aliquots of the same specimen in all bladder cancer samples. When carcinoma was present at the time of specimen collection it was detected by positive cytology in 75 per cent and deoxyribonucleic acid aneuploidy in 78 per cent of the cases. Combination of flow cytometry and urinary cytology increased the diagnostic yield to 95 per cent. Flow cytometry was slightly more sensitive than urinary cytology for detection of abnormalities in specimens from noninvasive and untreated tumors but the only statistically significant difference between the 2 procedures occurred among specimens from treated invasive cancers in which flow cytometry was a less sensitive method than cytology. Abnormal deoxyribonucleic acid ploidy was documented in a few specimens from noncancer-bearing patients having diseases associated with high urothelial cell turnover rates but the concomitant urinary cytology was negative for neoplasia. When used in conjunction with urinary cytology, flow cytometry was a valuable procedure in the followup of patients with bladder cancer. The diagnostic yield with this combination was such that flow cytometry and cytology may be used to reduce the frequency of cystoscopy and biopsy during clinical management in selected situations.

Aspiration biopsy of the kidney. Simultaneous collection of cytologic and histologic specimens

Aspiration biopsy of mass lesions of the kidney is a diagnostic procedure whose potential benefit to patients with equivocal radiologic findings, suspected metastases, palpable flank masses, nonfunctioning kidneys and even cortical cysts has not been fully explored. Over the past 7 years 163 renal aspiration specimens from 152 patients have been examined. Diagnostic yield was enhanced by use of modified “fine” needles with notched tips so that tissue fragments for histology as well as smears for cytology were obtained in 89% of solid tumors. The availability of aspirated tissue contributed significantly to pathologic classification and often spared patients additional surgery for confirmation of the cytologic diagnosis. Among the 152 cases, there were 35 with renal cell carcinomas, a sufficient number for detailed semiquantitative evaluation of their cytologic features. The remaining cases comprised metastatic carcinomas, lymphomas, transitional cell carcinomas, oncocytomas, cortical cysts, and miscellaneous conditions, e.g., abscesses, nonfunctioning kidneys, and hematomas. Overall, the aspiration biopsy determined the nature of the renal mass in 141 cases (93%). False‐negative interpretations were due to insufficient diagnostic material in all but one instance. There was one false‐positive result.

Flow Cytometry of Deparaffinized Nuclei Compared to Histological Grading for the Pathological Evaluation of Transitional Cell Carcinomas

Recent developments in flow cytometric analyses have resulted in a practical method to examine the deoxyribonucleic acid ploidy of various tissues, including bladder cancers. Although the technique provides information not readily available from usual pathological examinations, its value as a diagnostic test in clinical urology remains to be investigated. We confirm previous reports that flow cytometry can be performed on tissues stored in paraffin and demonstrate a positive correlation among deoxyribonucleic acid ploidy, histological grade and clinical outcome in patients with transitional cell carcinoma. Nevertheless, deoxyribonucleic acid ploidy offered no more prognostic information than histological grading alone when these tests were performed on the initial bladder tumors in 63 patients.

Bladder Cancer Induced by Noncarcinogenic Substances

Chemical carcinogenesis is currently regarded as a complicated series of events requiring initiation and promotion in specific sequences. Carcinogens are thought to be chemicals which can induce both initiation and promotion so that few if any additional host or environmental factors are required in the production of neoplasms. Most experimental studies to date have investigated bladder cancer using these highly active agents and the role of other substances in urothelial neoplasia has not been emphasized. We have examined the role of a variety of solutions, including water and saline, in pilot studies of urothelial carcinogenesis using the ALZA mini-pump for continuous infusion. Bladder tumors indistinguishable morphologically from papillary transitional cell carcinomas were induced. Although experimental induction of bladder cancer with powerful carcinogens may completely overwhelm host defenses and result in more and higher grade neoplasms, similar tumors may occur after exposure to substances not generally considered to be carcinogenic. This process, which probably requires cofactors and host-chemical interaction, may be more representative of environmental carcinogenesis than systems using powerful carcinogens and should be further investigated.

The morphologic effects of mitomycin C in mammalian urinary bladder.

This investigation was intended to determine the morphologic changes of mitomycin C. It is part of a series of experiments designed to evaluate the cytologic and histologic effects of topical chemotherapeutic agents using the FANFT experimental model system in mice. The results for mitomycin C are very similar to those previously reported for thio‐tepa. They indicate that these chemicals produce few, if any, drug‐specific light microscopic alterations. Rather, mitomycin C and thio‐tepa apparently act as toxic substances, causing increased exfoliation, degeneration, and necrosis of urothelial cells. The implications of these findings and suggestions for future investigations are discussed.

Kappa light chain nephropathy

Percutaneous renal biopsies from 4 patients with clinically unsuspected kappa light chain nephropathy were studied using light, immunofluorescence, and electron microscopy. The diagnosis in each case was established by demonstrating monoclonal kappa light chain deposits in basement membranes and basement membrane-like structures of glomeruli, tubules, and blood vessels by immunofluorescence microscopy. Characteristic electron dense deposits occurred in every case but the intensity and distribution of electron densitites did not correlate with the immunofluorescence findings. When light chain aggregation occurred, as evidenced by the distribution of electron dense deposits, it was proportional to the amount of basement membrane-like material as if these immunoglobulins had a particular affinity for structures chemically related to basement membranes. Although active tubulointerstitial lesions were prominent in all biopsies, there was considerable variation in glomerular pathology with only 1 case exhibiting the typical nodular glomerulosclerosis. Correlation of the light, immunofluorescence, and electron microscopic findings in these cases suggests that the pathogenesis of kappa light chain nephropathy is related to light chain nephrotoxicity directed to basement membrane-like structures with subsequent alterations in hemodynamics and structural renal damage.

The Prognostic Value of DNA Ploidy Combined With Histologic Substaging for Incidental Carcinoma of the Prostate Gland

Although current methods of histologic substaging for incidental prostatic carcinoma are useful, they offer only general indications of potential tumor behavior. To further define the biologic tendencies of stage A cancers, an examination was made of the role of DNA ploidy combined with histologic staging in archival material selected to achieve both a representative sample and long-term follow-up. With histology alone, 36% of stage A2 cancers and 9% of Al neoplasms were progressive. Adding DNA flow cytometry to histology resulted in a significant improvement in the capacity of pathologic evaluation to predict outcome. Progression occurred in 67% of aneuploid stage A2 prostate cancers and in none of the nonaneuploid stage Al tumors. Despite current limitations in the interpretation of DNA histograms from archival tissue, flow cytometry has significant potential in the pathologic evaluation of incidental prostatic carcinomas. (