Comparative carcinogenicity of N-butyl-N-(3-carboxypropyl)-nitrosamine and N-butyl-N-(4-hydroxybutyl)nitrosamine for the urinary bladder of (C57BL/6 X DBA/2)F1 mice.

The carcinogenicity of N-butyl-N-(3-carboxypropyl)-nitrosamine [CAS: 38252-74-3; 4-(N-butyl-N-nitrosamino)butyric acid] in male and female (C57BL/6 X DBA/2)F1 mice was determined. N-Butyl-N-(3-carboxypropyl)nitrosamine given in the drinking water at a concentration of 3 mM (0.056%) for 13 weeks induced only carcinoma of the urinary bladder in both sexes. At 22-28 weeks, the incidences of bladder cancer in the male and female mice were 100 and 88%, respectively. These bladder tumors were classified histologically according to the frequency (%) of tumor type: pure transitional cell carcinoma, 42%; mixed (transitional cell carcinoma with squamous or glandular differentiation, or both), 28%; squamous cell carcinoma, 27%; and carcinoma in situ, 3%. No significant sex differences were observed. In comparative studies, the incidence of bladder cancer was 100% for both sexes after administration of 3 mM (0.052%) N-butyl-N-(4-hydroxybutyl)nitrosamine [CAS: 3817-11-6; 4-(butylnitrosoamino)-1-butanol] in the drinking water. The frequency of pure transitional cell carcinoma was 47%, which was not significantly different from that observed for the carboxypropyl compound. The frequencies of other types of bladder carcinoma induced by N-butyl-N-(4-hydroxybutyl)nitrosamine were the following: mixed, 8%; squamous cell carcinoma, 42%; and carcinoma in situ, 3%.

Inhibition of N-n-butyl-N-(4-hydroxybutyl)nitrosamine-induced urinary bladder cancer in rats by administration of disulfiram in the diet.

The objective of this study was to determine if disulfiram would influence the induction of urinary bladder cancer in rats given N-n-butyl-N(4-hydroxybuty)nitrosamine (BHBN). Adult male Wistar rats were divided into: Group 1, control diet, 30 rats; Group 2, control diet plus 0.025% BHBN in the drinking water, 60 rats; Group 3, control diet containing 0.5% disulfiram, 30 rats; and Group 4, control diet containing 0.5% disulfiram plus 0.025% BHBN in the drinking water, 60 rats. The animals were kept on these regimens for 15 weeks and then were transferred to and maintained on control diet. The average total intake of BHBN was 1.21 g/rat for Group 2 and 1.23 g/rat for Group 4. The cumulative incidences of bladder cancer at 25 weeks after initial exposure to BHBN were: Group 1, 0 of 9; Group 2, 27 of 27; Group 3, 0 of 9; and Group 4, 0 of 27. At termination of the experiment (32 to 42 weeks), the final bladder cancer incidences were: Group 1, 0 of 30 (0%); Group 2, 57 of 57 ()00%); Group 3, 0 of 24 (0%); and Group 4, 7 of 55 (13%). Except for a carcinoma of the renal pelvis in one rat in Group 2 and the bladder tumors in Groups 2 and 4, tumors were not detected in other organs of any of these rats. It was concluded that disulfiram significantly inhibited the induction of bladder cancer in rats exposed to BHBN. The mechanism of action of disulfiram in this process is under investigation.

Incidental carcinoma of the prostate. How much sampling is adequate?

A prospective study of 386 consecutive transurethral prostatic resections from 383 patients with clinically benign glands was undertaken to determine the optimal sampling of chips required for the histologic detection of all clinically significant prostatic carcinomas. Cancers were graded according to two systems and staged by counting involved chips as well as estimating volume density. All Stage A2 prostatic carcinomas were detected by histologic examination of 6 g of randomly selected chips. Although additional tumors were detected in direct proportion to the amount of tissue examined, they were small, well-differentiated, Stage A1 lesions. Histologic sampling of 12 g of randomly selected prostatic chips detected almost 90% of incidental carcinomas, including all clinically significant neoplasms.

Influence of dose of N-methyl-N-nitrosourea on the induction of urinary bladder cancer in rats.

N-methyl-N-nitrosourea (MNU) was instilled by a urethral catheter into the urinary bladders of female Wistar rats in weekly doses of 0.5 mg for 1, 2, 3 and 4 weeks. At 75 weeks after the initial dose of MNU, the incidences of bladder cancer were 0, 7, 50 and 64% for the total doses of MNU of 0.5, 1.0, 1.5 and 2.0 mg, respectively. Control rats instilled with 0.9% NaCl only for 1--4 weeks did not develop bladder cancer by 75 weeks. Higher doses of MNU of 4.0 and 6.0 mg, given weekly in 0.5 mg amounts for 8 and 12 weeks, respectively, induced a higher incidence (nearly 90%) of urinary bladder cancer in rats at 22--28 weeks. However, it was shown that control rats given 12 weekly installations of solvent only developed a significant number (33%) of bladder cancers by 22--28 weeks.

Current status of urinary cytology in the evaluation of bladder neoplasms.

Pathologic examination of urinary specimens is increasingly recognized as an essential component of detection and monitoring for patients with bladder neoplasms. Among the available techniques, urinary cytology is the most useful. The current status of urinary cytology can be summarized as follows: 1. The demand for urinary cytology is steadily increasing as clinicians have realized the limitations of cystoscopy and even biopsy for monitoring bladder cancer patients, especially those having carcinoma in situ or receiving topical therapy. 2. Urinary cytology is currently an essential procedure for monitoring all patients with urothelial neoplasms and, if consistently used, can actually decrease the frequency with which patients need to be subjected to cystoscopy. 3. Even in moderately experienced hands, urinary cytology can detect almost all high-grade urothelial neoplasms. 4. The cytologic interpretation of low-grade transitional cell neoplasia requires expertise. These cells lack many of the features of malignancy, a source of confusion for the diagnostician but a positive factor for the patient since neoplasms composed of these cells are almost never aggressive. 5. The most useful type of urinary specimen for routine diagnostic interpretation is freshly voided, randomly collected urine. Catheterized specimens and bladder washings may yield more and better preserved cells, but no patient should be catheterized solely to obtain diagnostic material. 6. Preservation of urinary specimens in alcohols is not necessary unless prolonged storage is contemplated. Refrigeration to prevent bacterial growth and inhibit further cellular degeneration is required, however. 7. Cytologic details are best displayed with membrane filtration but other types of processing are adequate. The computer-programmed cytocentrifuge is currently most popular. 8. Optimal recognition of cytologic details requires some form of Papanicolaou staining; Romanovsky dyes are less desirable. 9. Urothelial cells with nuclear:cytoplasmic ratios of 1:2 or less should not be interpreted as malignant regardless of the degree of anaplasia of their nuclei. 10. Papillary aggregation is not a reliable feature of low-grade neoplasia in urinary samples. 11. Using appropriate criteria, the differential diagnosis of urothelial neoplasia versus the reactive/regenerative/reparative changes secondary to urinary stones can almost always be accomplished. 12. Alkylating agents such as Cytoxan, thio-TEPA, and mitomycin C produce characteristic but nonspecific changes in urothelial cells. These changes rarely mimic those of carcinoma. The diagnosis of urothelial neoplasia need not be confounded by previous treatment. 13. Flow cytometry and digitized image analysis are currently used for diagnostic interpretations of urinary specimens in selected centers. Their routine use must await further refinements in instrumentation and the formulation of more searching questions.

The pagetoid variant of urothelial carcinoma in situ.

The frequency, distribution, and clinical significance of pagetoid changes in urothelial carcinoma in situ (CIS) were studied in over 600 tissue slides from 102 patients followed for a mean period of over 4 years. Results indicate that pagetoid changes are unusual, randomly distributed, and never widespread. These changes occur in a histologic setting of CIS and apparently never appear as the initial lesion, even in cases in which CIS is the primary or only neoplasm. Patients manifesting pagetoid CIS had essentially the same progression and survival rates as patients without pagetoid changes. Our data suggest that this histologic pattern represents a peculiar reaction to injury confined to small areas of urothelium in susceptible hosts.

The histogenesis of clear cell adenocarcinoma of the lower urinary tract. Case series and review of the literature.

Clear cell adenocarcinoma of the lower urinary tract is a rare neoplasm whose histogenesis has not been thoroughly investigated. We have examined six specimens of clear cell adenocarcinomas collected from three institutions using histological, histochemical, and immunohistochemical techniques. Results indicate that almost all clear cell adenocarcinomas of this region express morphological and antigenic features, suggesting müllerian differentiation, and that müllerian differentiation is not a feature of either nonclear cell adenocarcinomas or normal female paraurethral glands. Including the authors' six specimens, 46 specimens have been reported in the available English literature. The accumulated experience confirms the initial impression that these tumors develop predominantly in the urethras of women and occur over a wide age range. Despite high stage at diagnosis, most patients have been alive with no evidence of disease when reported, a prognosis that seems to apply regardless of length of follow-up.

An in vitro model for testing biocompatibility of endodontic materials to bone.

Calvaria from 6-day old mice labelled 4 days previously with 45CaCl2 were divided into test and control halves and each half cultured separately in vitro. Eluents from four endodontic materials, endomethasone, zinc oxide/eugenol, AH26 and gutta-percha were added separately to the culture medium of each test half. After 24 and 48 h culturing periods, the 45CaCl2 in the media and calvaria was measured by a standard liquid scintillation counting technique and a resorption ratio between test and control halves was computed. This ratio, based on cell mediated resorption, was an indication of toxicity of soluble components of each endodontic material. In accordance with the literature, endomethasone was found, with our method, to be the most toxic and gutta-percha the least toxic of the materials tested. This shows that our model can be used to test the toxicity of other biomaterials to bone cells in vitro.

Prostate cancer. The problem of prognostic factors.

The assessment of factors that might predict the future behavior of a neoplasm is one of the principal responsibilities of pathologists. This activity is of pivotal importance and should be critically evaluated. The value of information describing the features of cancer to the care of any particular patient cannot be assumed. It must be understood in light of the nature of prostatic carcinoma and the actual direct benefit to the patient of the information. Prognostic factors represent dynamic information that may change over time. Mechanisms for ongoing evaluation of the value of these data should be instituted by each practice setting, lest the accumulation of unnecessary information create adverse financial conditions for the practice.

ASCP survey on anatomic pathology examination of the urinary bladder.

The American Society of Clinical Pathology Quality Management Practice Review Committee is sponsoring publication of a series of articles commenting on procedures used by pathologists during the examination of various surgical specimens. Committee-sponsored survey results serve as the basis for discussion and commentary by an expert in the field. Although this information may prove useful in forming a practice parameter, it is not the intention of the author or the committee to identify this information as a practice parameter. The publication of this article does not necessarily represent the opinions or endorsement by the ASCP Board of Directors.

Determination of baseline values for urinary carcinoembryonic antigen-like substances.

Carcinoembryonic antigen-like substances were measured in urine samples from 236 apparently healthy, asymptomatic individuals. Twenty-four-hour collections were submitted by 177 subjects, and random specimens were collected from 59 others. In addition to CEA measurements, bacterial colony counts and cytologic examinations were performed on the latter. Baseline values were established for males and females and data were analyzed for the effects of age, smoking, time of collection, and bacterial colonization. Results indicated that levels of CEA-like substances in the urine could be greatly altered by bacterial conlonization. Lesser effects were noted with age and time of collection. Smoking had no demonstrable effect. These variables should be considered for meaningful interpretation of urinary CEA values of patients suspected of urothelial malignancy.

IgA nephropathy. A comparative study of the clinicopathologic features in children and adults.

A comparative study of the clinicopathologic features of IgA nephropathy in 24 children and 46 adults was undertaken. In children, microscopic hematuria was present in all cases and was associated with gross hematuria in 83% and proteinuria in 58%. In adults, microscopic hematuria was present in 91%, gross hematuria in 25%, and proteinuria in 80%. During followup, renal failure was recorded among 5.5% of children and 10% of adults. Biopsy specimens were obtained from all patients and were examined by light, electron, and immunofluorescence microscopic technics. Morphologic changes in the glomeruli were classified according to the degree of mesangial hypercellularity, sclerosis, and crescent formation into four groups. The most common glomerular pattern in children was diffuse, mesangial hypercellularity, while mesangial proliferation associated with focal segmental glomerulosclerosis predominated among adults. These observations suggest that glomerular morphology correlates with age at diagnosis and influences the clinical outcome of the disease.

Nephrotic syndrome with mesangial-cell proliferation in children--a distinct entity?

Various morphologic patterns have been identified in renal biopsies of children with the idiopathic nephrotic syndrome. Children with focal segmental glomerulosclerosis have clinicopathologic features sufficiently distinct to warrant a separate subclassification. "Immunoglobulin M (IgM) nephropathy" and other morphologic patterns are less well defined. The clinicopathologic characteristics of eight patients with the nephrotic syndrome, increased mesangial cellularity on renal biopsy, and hematuria (mesangioproliferative nephropathy) were evaluated. Response to standardized prednisone therapy was poor. Of the seven children followed for 7-29 months, only two were in remission at the time of writing, and each of these had had one prior relapse. The eighth patient was lost to follow-up after one month. Although the number of patients studied was small, there was a strong correlation between degree of mesangial-cell proliferation and failure of primary treatment. As concepts of the pathogenesis of idiopathic nephrotic syndrome in children continue to evolve, the mesangioproliferative lesion should be recognized and marked for further study.

Epithelial foot-process effacement in patients with proteinuria.

In an effort to determine the pattern of foot-process effacement or "fusion" in proteinuria, quantitative measurements were performed on human tissue from patients with urinary protein excretion exceeding 0.5 g/d. Serial electronmicrographs were analyzed and the results related to both quantitative urinary protein and underlying disease. Although foot-process effacement was widespread, it was never universal. Some portions of glomeruli were morphologically normal in every case. The proportion of effaced foot processes did not vary directly with the level of urinary protein. With the possible exception of focal glomerulosclerosis, the primary disease did not appear to influence the amount of effacement.

Aluminum-containing dense deposits of the glomerular basement membrane: identification by energy dispersive X-ray analysis.

Heavy metals, including gold, mercury, lead, bismuth, and cadmium, have the potential to cause renal disease. With the development of X-ray microanalysis, these heavy metals can now be identified in tissue deposits. This report describes a case of renal failure, probably related to dysproteinemia, in which granular, electron-opaque dense deposits were present in the glomerular basement membranes. Energy dispersive X-ray analysis demonstrated that these dense deposits contained aluminum. An analysis of this patient's history in relation to the current knowledge of aluminum metabolism suggests that the aluminum deposition occurred secondary to previous glomerular injury. This case emphasizes the need to utilize heavy metal identification technology whenever granular, electron-opaque dense deposits are identified and represents, to our knowledge, the first study to document aluminum deposits within the glomerular basement membrane of humans.

Sampling of radical prostatectomy specimens. How much is adequate?

Prostate glands from 52 patients with clinical stage B carcinoma were examined using two sampling techniques. After fixation and conization of the apical portions, each gland was serially sectioned with sections mounted whole on oversized glass slides and examined for pathologic features of prognostic importance. A second examination was subsequently conducted on the same tissue using only alternate sections. No differences in tumor type, grade, Gleason score, multiplicity, or capsular penetration were detected in 75% of cases. The discrepancies that did occur were most often minor variations in multiplicity and Gleason score. Of the 20 glands with capsular penetration observed with the serial sectioning method, 17 (85%) were detected using alternate sectioning. The surgical margin was involved in two of the three invasive foci that would have been missed. Although the topography is better displayed, the authors' examinations indicated no significant advantage to whole mount sections compared with sections mounted on standard-sized glass slides. Considering the most effective use of resources, as well as the current modalities available for patient monitoring, the results support the use of an alternate sectioning method for pathologic examination of specimens removed for clinically localized prostate cancer.

Osteogenic differentiation associated with x-ray therapy for adenocarcinoma of the prostate gland.

A case of osteogenic differentiation in a prostate gland associated with high-dose x-irradiation for adenocarcinoma is reported. Heterologous cancerous elements in adults are extremely unusual in the prostate and their occurrence after treatment has rarely been documented. The relationship of this lesion to the primary glandular neoplasm is discussed.

Sickle-cell disease and poststreptococcal acute glomerulonephritis.

The cases of three children with sickle-cell hemoglobinopathy and acute poststreptococcal glomerulonephritis are described and discussed. Light and electron microscopic findings in three cases, and immunofluorescence microscopic findings in two are described. Since proliferative glomerulonephritis of either poststreptococcal or non-poststreptococcal etiology may be seen in patients who have sickle-cell disease, immunofluorescence and/or electron microscopic examination is essential for accurate diagnosis.

Prostatectomy tissue for research: balancing patient care and discovery.

The application of modern technology in basic research often requires fresh tissue from human organs. The acquisition of this tissue challenges the anatomic pathologist to balance the needs of the basic scientist with the requirements of quality patient care. Our experience indicates that fresh tissue adequate for research can be obtained from neoplastic prostate glands without compromising patient care. The process requires dedicated, knowledgeable individuals and extensive documentation. Potential problems include low yield for research studies, loss of all residual carcinoma, compromise of the specimen margin, and unforeseen costs. Best collaborations occur in situations in which basic scientists and anatomic pathologists establish a working relationship and develop a mutually supportive means of funding.

Primary primitive neuroectodermal tumor of the kidney. Case report and review of the literature.

Small cell tumors are a heterogeneous group of neoplasms with similar morphologic features. They include lymphomas, carcinomas with variable degrees of neuroendocrine differentiation, rhabdomyosarcomas, and neuroblastomas. The authors describe a rare case of primitive neuroectodermal tumor (PNET) located in the kidney that was thoroughly studied with modern diagnostic techniques, including expression of protein P 30/32 MIC2 with the antibody 013 with subsequent demonstration of a genetic translocation consistent with t(11;22). The literature on small cell tumors of the kidney, with special emphasis on PNET, is reviewed.