Faculty Bibliography

We have studied six cases of choriocarcinomas in the female by conventional cytogenetic analysis and by in situ hybridization using a 12p painting probe, and found evidence for chromosome 12 abnormalities in two of them. Abnormalities of chromosome 12 are a common occurrence in genitourinary tumors of the female, but their significance is not known. We discuss the present findings in relation to those in malignant ovarian germ cell tumors (MOGCTs).

Cells respond to certain soluble factors that bind to cell surface receptors possessing intrinsic tyrosine kinase activity. Overexpression of these molecules has been associated with tumor progression. Enhanced prostatic cancer cell growth in vitro has been reported in the presence of certain growth factors. To characterize the patterns of expression of the epidermal growth factor receptor (EGFr) and transforming growth factor-alpha (TGF alpha), we studied tissue from 107 prostate specimens using immunohistochemistry. We observed that epithelial cells of normal (n = 4) and benign prostatic (n = 56) tissues express EGFr but were unreactive for TGF alpha, while stroma cells in these tissues express TGF alpha but not EGFr. However, coexpression of EGFr and TGF alpha was identified in 22 of 46 prostatic adenocarcinomas studied. These results suggest that the major mode of action of EGFr/TGF alpha in normal and benign prostate is that of a paracrine or juxtacrine loop, the ligand being expressed in the stroma cells and the receptor in the epithelial cells. Since a subset of prostatic carcinomas coexpressed the ligand and the receptor in their tumor cells, it is suggested that an independent autocrine signaling mechanism may occur and grant a selective advantage for the growth of prostate cancers.

Neoadjuvant total androgen ablation therapy leads to involutional changes in prostatic carcinoma and may have the potential to downstage operable prostate cancers. We studied 27 clinically localized prostatic carcinomas after 3 months of combined treatment with a luteinizing hormone-releasing hormone agonist, goserelin acetate, and the antiandrogen flutamide, followed by radical retropubic prostatectomy, for changes in the serum prostate-specific antigen (PSA) level, changes in prostatic volume, therapy-induced histopathologic changes, DNA ploidy, and proliferative activity. Ten hormonally untreated, grade-matched prostatic adenocarcinomas served as controls. The mean pretherapy serum PSA level was 17.5 ng/ml, and posttherapy PSA levels were all < 4.0 ng/ml, with 18 men having undetectable levels. The mean reduction in prostatic volume following hormonal therapy was 37% (range 16-52%). Pathologic staging confirmed 20 pT2N0, six pT3N0, and one pT3N1. All prostates showed residual adenocarcinoma (extremely focal in seven cases [26%] with loss of glandular architecture, cytoplasmic vacuolization, and nuclear pyknosis. High-grade adenocarcinoma was nondiploid in 25% of hormonally treated prostates and 80% of 10 untreated controls. Immunostaining for proliferating cell nuclear antigen showed > 10% nuclear reactivity in 33% of treated carcinomas and 90% of untreated carcinomas. In conclusion, 3 months of neoadjuvant androgen ablation for localized prostatic carcinoma significantly lowers serum PSA and prostatic volume and produces involutional changes in residual carcinomas that mimic high-grade disease. However, pretreated carcinomas have predominantly a diploid DNA content and low proliferative activity as opposed to untreated carcinomas. Thus, grading of pretreated adenocarcinomas by conventional methods may be misleading. Preoperative total androgen ablation has a profound effect on a subset of prostatic carcinoma cells, possibly by facilitating programmed cell death.

We investigated the prevalence and clinical relevance of p53 nuclear overexpression, as detected by antibody PAb1801 and immunohistochemistry, in 33 patients with carcinoma in situ of the bladder. Median followup was 124 months. Disease progressed in 16 patients (48%) during followup. The association between p53 nuclear overexpression and tumor progression was assessed by multivariate analysis, controlling for possible confounding variables, such as patient age and sex, presence of associated stage Ta bladder tumor and adjuvant bacillus Calmette-Guerin therapy. Patients were stratified into 2 groups according to the per cent of tumor cells displaying p53 nuclear overexpression: group 1-18 with less than 20% tumor cells positive and group 2-15 with 20% or more tumor cells positive. Disease progressed in 3 patients (16.7%) in group 1 and in 13 (86.7%) in group 2 (p < 0.0001). Detection of p53 nuclear overexpression in 20% or more tumor cells was the only independent marker of tumor progression in univariate and multivariate analyses (p = 0.004, adjusted relative risk 8.6, 95% confidence interval 2 to 40). Death specifically from bladder cancer was also associated with this altered pattern of p53 expression (p = 0.01, Fisher's exact test). We conclude that p53 nuclear overexpression is an early event in bladder cancer, occurring in 48% of cases of carcinoma in situ of the bladder. Our results also suggest that p53 nuclear overexpression offers significant clinical information and may be a useful tool in the selection of therapy for patients with carcinoma in situ of the bladder.

A tumor mass resected from the anterior bladder wall of a 68-year-old woman displayed unusual histologic features: sheets of hepatoid cells merging focally with a secondary glandular pattern of adenocarcinoma. Intracytoplasmic hyaline globules and bile production within the solid areas supported the impression of hepatocytic differentiation. Immunoreactivity for alpha-fetoprotein (AFP) and alpha-1-antitrypsin and a striking canalicular immunostaining pattern for carcinoembryonic antigen and epithelial membrane antigen all indicate hepatocellular differentiation within this bladder tumor. This represents a case of a hepatoid adenocarcinoma located in the urinary bladder. The use of the term 'hepatoid' in the literature is reviewed and the reported cases are grouped into two distinct categories of tumors: (1) germ cell tumors with focal hepatoid areas and (2) true hepatoid adenocarcinomas that meet histologic and immunohistochemical criteria for hepatocellular differentiation. AFP-producing tumors without any other feature of hepatocellular differentiation should not be considered as hepatoid tumors. This classification of hepatoid tumors is likely to be important in elucidating the histogenesis and clinicopathologic features of these unusual neoplasms

Epidemiological studies show an increased risk of bladder cancer associated with tobacco smoking and occupational exposures. Certain carcinogens in tobacco and occupational exposures cause DNA damage and may produce specific mutations. TP53 is considered a common target for carcinogenic agents, and mutations of this gene are reported to be the most frequent nuclear abnormalities in human cancer. In order to investigate the relationship between tobacco smoking, occupations, and altered patterns of p53 expression, we have analyzed a group of 109 incident patients with superficial transitional cell carcinoma of the bladder. We assessed p53 nuclear overexpression by the use of anti-p53 antibody PAb1801 and immunohistochemistry, and identified 45 of 109 patients (41%) displaying p53-positive phenotype. We observed a significant association between the number of cigarettes smoked per day and p53 nuclear overexpression (p = 0.02). The odds ratios were 2.3 for those smoking 1-2 packs per day and 8.4 for smoking more than 2 packs per day. Similar estimates were obtained after controlling for age, sex, and race. Elevated odds ratios were also observed for dye-/ink-related (odds ratio = 2.0; 95% CI, 0.4-9.4) and cooking-related occupations (1.8, 0.6-5.0), although those were not statistically significant. These data support the hypothesis that certain carcinogens derived from cigarette smoking and occupations may induce TP53 mutations, which in turn are involved in early steps of bladder carcinogenesis.

Renal myxomas are rare neoplasms. Seven cases have been reported, of which only two are convincingly diagnosed as myxoma; the remaining cases exhibit features of sarcoma, fibroepithelial polyp, or myxolipoma. We report two additional cases; one in a 52-year-old man and another in a 68-year-old woman. They were discovered incidentally by radiological examination. The resected kidney in both patients contained a well-demarcated gelatinous intraparenchymal tumor, which consisted of occasional slender spindle cells scattered in an abundant myxoid stroma, closely resembling myxomas of other sites. The tumor cells showed immunoreactivity for vimentin but not for S-100 protein, epithelial membrane antigen (EMA), CAM 5.2, HHF-35, or smooth muscle actin. Ultrastructural features were of fibroblast-like cells with an elaborate network of cytoplasmic processes. The differential diagnosis of myxoid tumors of the kidney includes myxoid variants of renal sarcomas and carcinomas, renomedullary interstitial cell tumors, and fibroepithelial polyps. It is important to recognize the existence of a renal myxoma, to avoid confusing this benign tumor with the malignant neoplasms with secondary myxoid features that may involve the kidney.

To determine the chronology of p53 mutation in the gastric carcinogenic sequence, we studied p53 overexpression in premalignant lesions, including 17 adenomatous polyps (10/17 surrounded by intestinal metaplasia and 11/17 harboring foci of adenocarcinoma or severe dysplasia), and 18 hyperplastic polyps (4/18 with focal adenomatous changes). Immunohistochemistry with PAb 1801 monoclonal antibody was performed on archival material; p53 nuclear staining was seen in 10/17 adenomas, but was limited to the foci of adenocarcinoma in three cases. Five adenomas with foci of severe dysplasia or carcinoma were nonreactive. Intestinal metaplasia, normal gastric mucosa, and 14/18 hyperplastic polyps were nonreactive. p53 Reactivity observed in four hyperplastic polyps was limited to adenomatous foci. These results suggest that p53 overexpression occurs in dysplastic epithelium of precancerous gastric lesions. Its absence in chronic atrophic gastritis with intestinal metaplasia suggests it is a relatively late event in the gastric carcinogenic sequence