Prognostic variables in invasive breast cancer: contribution of comedo versus noncomedo in situ component.

BACKGROUND: Many invasive breast cancers are accompanied by a variety of noninvasive components. Histological distinctions have been made between these components, but to understand their importance, it is essential to examine their molecular biology. METHODS: Proliferative indices, oncoproteins, and steroid receptor expression were compared for invasive breast cancers containing comedo-type ductal carcinoma in situ (n = 35), noncomedo-type ductal carcinoma in situ (n = 34), and pure invasive cancers (n = 49). Ploidy, S-phase fraction, Ki-67 staining, estrogen receptor (ER), progesterone receptor (PR), and the expression of HER-2/neu and epidermal growth factor receptor (EGFR) were evaluated in these tumors. RESULTS: The comedo-invasive subgroup differed significantly from the noncomedo-invasive subgroup, demonstrating significantly higher mean ploidy (1.6 vs. 1.3; p = 0.0156), S-phase fraction (7.9% vs. 4.3%; p = 0.0066), Ki-67 staining (20.3% vs. 12.0%; p = 0.0058), and HER-2/neu values (2,247 fm/mg vs. 1,014 fm/mg; p = 0.0412) and lower ER (76 fm/mg vs. 339 fm/mg; p = 0.006) and PR values (99 fm/mg vs. 265 fm/mg; p = 0.0608). A higher percentage of comedo-invasive carcinomas demonstrated aneuploidy 71%; p = 0.0158), elevated levels of S-phase fraction (75%; p = 0.0016) and Ki-67 staining (55%; p = 0.0512), overexpression of HER-2/neu oncogene (47%; p = 0.0011), and were ER negative (35%; p = 0.0148), PR negative (47%; p = 0.0073) when compared to noncomedo-invasive carcinomas. Comedo-invasive and noncomedo-invasive tumors were comparable for nodal status and tumor size, but differences were noted for tumor differentiation and percentage of tumors that were > 1 cm. Comedo-invasive tumors were predominantly poorly differentiated (60 vs. 32%) and were > 1 cm (94 vs. 77%, p < 0.05). RESULTS: Comedo-invasive cancers were comparable to pure invasive cancers for ploidy, S-phase fraction, Ki-67 staining, and ER, PR, and EGFR expression. However, comedo-invasive carcinomas had greater HER-2/neu overexpression when compared to pure invasive tumors (47 vs. 19%; p = 0.0359). CONCLUSIONS: These results are consistent with the hypothesis that comedo carcinoma is a more aggressive type of ductal carcinoma in situ and may have independent prognostic value when seen in association with infiltrating ductal carcinoma. In invasive tumors, comedo carcinomas are associated with poor prognostic factors, including higher ploidy, S-phase fractions, Ki-67 staining, negative ER and PR status, poorer differentiation, larger tumors, and presence of HER-2/neu oncogene overexpression.

Ethnic differences in risk and prognostic factors for breast cancer.

BACKGROUND: Poor survival among African American patients with breast cancer has been attributed to low socioeconomic status and lack of access to health care. However, Hispanics of equivalent socioeconomic status and health care access exhibit much higher survival rates, almost comparable to whites. This suggests that biologic differences play a role in differences in breast cancer survival in addition to socioeconomic and health care access factors. METHODS: The authors studied clinical and molecular differences between patients with breast cancer of different ethnicity to determine biologic explanations for the observed differences in survival. Consecutive patients scheduled for breast biopsies were identified preoperatively and were interviewed. Blood was withdrawn for serum marker measurements, and tumor specimens collected at frozen section diagnosis were analyzed by flow cytometry, hormone receptor concentration, tumor grade, and Ki-67 nuclear antigen, HER-2/neu, and epidermal growth factor oncoprotein expression. RESULTS: Age, age at menarche, number of lymph nodes with metastasis, estrogen and progesterone receptor levels, ploidy status, S-phase, Ki-67, HER-2/neu expression, tumor grade, epidermal growth factor receptor expression, lipid-associated sialic acid (LASA), and carcinoembryonic antigen level were not significantly related to ethnicity. African Americans presented at a significantly more advanced stage and with significantly larger tumors. They were significantly heavier and had a significantly higher mean Quetelet's index and a significantly higher number of pregnancies and number of live births. Whites and Hispanics were significantly older at menopause. CONCLUSIONS: The molecular indices associated with breast cancer prognosis do not differ significantly among whites, African Americans, and Hispanics, suggesting that the reported differences in survival among these groups are not due to biologic differences in breast cancer among ethnic groups.

Image cytometric deoxyribonucleic acid analysis of urine specimens as an adjunct to visual cytology in the detection of urothelial cell carcinoma.

We evaluated image cytometric deoxyribonucleic acid ploidy analysis of urine sediments as an adjunct to visual cytology in the detection of urothelial cell carcinoma. Both procedures were performed on 384 specimens obtained from voided urine (78%), bladder washings or by catheterization. Of these specimens 235 came from patients with active urothelial cell carcinoma, 23 from patients with currently inactive urothelial cell carcinoma and 126 from patients with benign disorders of the urinary tract. Visual cytology classified 171 specimens as positive for urothelial cell carcinoma, 143 as negative and 70 as atypical but diagnostically ambiguous. Sensitivity was 72.3% (170 of 235) and specificity was 99.3% (148 of 149, with atypical and negative specimens grouped together). The slides were then restained for ploidy analysis. Each of the deoxyribonucleic acid histograms of the 170 true positive and the 129 true negative specimens was described by a set of order statistics. These sets were entered into a multivariate discriminant analysis. The discriminant function obtained was then applied to the 70 ambiguous specimens. As a result 27 of these specimens, all from patients with active urothelial cell carcinoma, were reclassified as positive. Sensitivity was increased to 83.8% (197 of 235), with no loss of specificity. Image cytometry is a useful adjunct to visual cytology for the detection of bladder cancer in urine sediments.

Newer diagnostic techniques for bladder cancer.

As described in the above paragraphs, efforts in the areas of immunology, cytogenetics, molecular biology, and cytopathology have been applied to the problems urologists face in treating the individual patient with bladder cancer. It is hoped that continued investigations in these disciplines will not only lead to earlier diagnosis of bladder cancer and better prediction of tumor behavior but will further our understanding of the molecular basis of oncogenesis.

Flow cytometric determination of nuclear DNA content in benign adrenal pheochromocytomas.

Nuclear DNA content of paraffin-embedded tissue from 19 clinically benign adrenal pheochromocytomas and 18 control adrenal glands was analyzed using flow cytometry. All control adrenal glands and 6 pheochromocytomas were diploid. Four tumors were tetraploid. Nine were aneuploid with relative DNA indices in the near diploid range in 2, in the peritriploid range in 5, and in the near tetraploid range in 2. These results indicate that aneuploid DNA content is a frequent occurrence in benign adrenal pheochromocytomas. Aneuploidy per se is not a specific marker of malignancy in these tumors as has been suggested by previous reports.

Flow cytometric analysis of nuclear DNA from adrenocortical neoplasms. A retrospective study using paraffin-embedded tissue.

Nuclear DNA content of paraffin-embedded tissue from 48 adrenocortical neoplasms, 18 histologically normal control adrenal glands, and five hyperplastic adrenal glands was analyzed retrospectively using flow cytometry. Aneuploidy was compared with morphologic criteria as a predictor of recurrence. All 18 controls, five hyperplastic glands, and 39 neoplasms were diploid. Nine neoplasms were aneuploid. Compared with their diploid counterparts, aneuploid neoplasms were more likely to weigh more than 50 g (P less than 0.0001) and to have three or more histologic features of carcinoma (P less than 0.0001). Thirty-six neoplasms were followed clinically for at least 2 years (range 24 to 120 months, mean = 64.6 months) or until local recurrence, metastasis, or death. Five were clinically malignant. Neoplasms which recurred or metastasized were more apt to be aneuploid (P less than 0.005) than those showing no evidence of further disease during the follow-up period. They were also more likely to weigh more than 50 g (P less than 0.005) and to have three or more histologic features of carcinoma (P less than 0.0025). However, neither aneuploidy, large size, nor unfavorable histology result was a consistent feature in every malignant neoplasm. Flow cytometric DNA content analysis appears to be as effective a predictor of clinical outcome as size and histology and may be of particular value when the morphologic features are ambiguous.

Malignant lymphomas and the acquired immunodeficiency syndrome. Evaluation of 30 cases using a working formulation.

Malignant lymphomas occurring in 29 homosexual men and one thalassemic woman with the acquired immunodeficiency syndrome or the acquired immunodeficiency syndrome-related complex are reported using a working formulation for non-Hodgkin's lymphomas (NHLs). The patients' ages ranged from 25 to 59 years, with an average age of 42 years. Ninety percent of the cases were extranodal; 67% were exclusively extranodal. One case of Hodgkin's disease was encountered. All NHLs were of the diffuse types in both the intermediate- and high-grade categories, with the largest single group (49%) being of the diffuse, large, follicular-center-cell types. The NHLs in this series were classifiable as B-cell neoplasms and were aggressive as evidenced by markedly reduced median survivals. The morphological diagnosis as defined in the working formulation, especially for the intermediate-grade lesions, offered little significant prognostic information.

Interaction of arterial cells. I. Endothelial cells alter cholesterol metabolism in co-cultured smooth muscle cells.

Results of previous in vivo experiments indicated that the presence of arterial endothelium modifies cholesteryl ester (CE) metabolism and the retention of low density lipoproteins (LDL) in injured arteries. We describe herein the effects of bovine arterial endothelial cells (ENDO) on the CE cycle, fluid phase endocytosis, and cell proliferation in co-cultured bovine arterial smooth muscle cells (SMC). Following several days of cultivation on confluent SMC, ENDO were removed from SMC by treatment of the co-cultures with 1.0% collagenase (type II). Removal of only ENDO from the co-culture dishes was confirmed by immunofluorescent staining for Factor VIII antigen, hemotoxylin-eosin staining, and biochemical analyses. We observed that ENDO grown to 75% confluency on confluent SMC induced: 1) a reduction of CE hydrolysis as a result of decreased lysosomal CE hydrolytic activity in SMC as compared to SMC cultured alone; and 2) an increase in the rate of incorporation of labeled oleate into CE as a result of increased acyl CoA:cholesterol O-acyltransferase activity in SMC as compared to SMC cultured alone. Neither endothelial cell-derived culture media (ECDM) nor fibroblasts modulated CE metabolism in co-cultured SMC. Additional experiments showed that the presence of endothelial cells or ECDM decreased the proliferation of co-cultured SMC by 50%, but enhanced the endocytotic rate of labeled sucrose into SMC threefold. Results of experiments described herein demonstrate that, in addition to providing a thrombo-resistant surface and regulating permeability, endothelial cells may also serve to modulate cholesteryl ester metabolism in smooth muscle cells derived from the arterial wall.

Diagnostic pathology in the acquired immunodeficiency syndrome. Surgical pathology and cytology experience with 67 patients.

We report the pathologic findings in specimens submitted for histologic and cytologic evaluation from 67 patients with the acquired immunodeficiency syndrome. A wide variety of opportunistic pathogens were identified in 41 patients. Mycobacterium avium-intracellulare evoked only a mild host response: granulomas, if present, were poorly formed. Biopsy specimens showing cytomegalovirus gastroenteritis required sections at multiple levels to demonstrate inclusions. Combined histologic and cytologic evaluation can increase the diagnostic yield in pulmonary and esophageal infections. Kaposi's sarcoma was found in biopsy specimens from 29 patients. Early lesions were often extremely subtle, yet distinct from, benign vascular proliferations in involuted lymph nodes. Malignant lymphoma was diagnosed in ten homosexual men who were suspected of having the acquired immunodeficiency syndrome. The lymphomas were characterized by B-cell origin, a diffuse pattern, frequent extranodal presentations, and an aggressive clinical course with prominent central nervous system involvement.

Loss of HLA-DR expression by human epidermal cells after growth in culture.

These studies present evidence that when human epidermal cells are grown in culture they lose both the ability to stimulate the proliferation of allogeneic T lymphocytes in vitro and their expression of HLA-DR antigens. Our results also show that epidermal cells incubated with anti-HLA-DR serum lose their ability to stimulate the proliferation to allogeneic T lymphocytes in a mixed skin cell-lymphocyte reaction.

Congenital pulmonary arteriovenous fistula producing pulmonary arterial steal syndrome.

This report describes a congenital pulmonary arterial steal syndrome manifested as cyanosis and acidosis in a newborn. A fistulous connection between the right pulmonary artery and a large, anomalous right common pulmonary vein stole blood from the pulmonary arteries. The anomaly was suspected because of a pericardiac shadow on frontal and lateral chest films, substantiated by M-mode echocardiogram, confirmed at cardiac catheterization with angiocardiography, and analyzed at postmortem examination.

Syphilitic aortic aneurysm presenting with the superior vena cava syndrome.

In a 65 year old man with hemoptysis, chest pain, weight loss, clubbing of the digits and a large mediastinal mass, the superior vena cava syndrome developed. He was treated for malignancy with radiation therapy and corticosteroids, but he died shortly after his admission to the hospital. Autopsy revealed syphilitic aortitis with an aneurysm of the ascending aorta compressing the superior vena cava and right mainstem bronchus. The postmortem serology corroborated the morphologic findings of tertiary syphilis. In this report we emphasize the important, although now uncommon, association between the superior vena cava syndrome and aneurysm of the aorta.