Maurice M. Black

Association of atypical characteristics of benign breast lesions with subsequent risk of breast cancer

A retrospective case‐control study was carried out to determine to what degree atypical changes in the mammary duct system are associated with increased risk of developing breast cancer. A previously developed grading system was used by one of us (MMB) to describe the morphological atypicality in a series of benign breast lesions. Our primary finding is that a woman with some degree of ductular atypia in a benign lesion is subject to a risk of developing breast cancer 5 times that of a woman with no evidence of atypical changes. The implications of this finding regarding treatment require further study.

Prognosis in breast cancer utilizing histologic characteristics of the primary tumor

A study was made of the inter‐relationships and prognostic significance of structural characteristics found in primary breast cancers and their associated axillary lymph nodes. The prognostically favorable characteristics included the following. For the primary tumor: nuclear differentiation of the cancer cells, diffuse lymphoid cell infiltrations (LI), and perivenous lymphoid cell infiltrations (PVI). For the axillary lymph nodes: sinus histiocytosis (SH). Perivenous lymphoid cell infiltrations (PVI) in the primary tumor are found to be as important a prognostic factor as SH in the axillary lymph nodes; these two characteristics are found to be positively associated. Evaluation of the nuclear grade (NG), LI, and PVI in the primary tumor allows for the definition of prognostically significant patient groupings. LI is found to occur primarily in assoication with cancer cells having a low (anaplastic) nuclear grade, and to be positively associated with follicular hyperplasia (FH) in the lymph nodes. We also found a positive association between the cellular responses to areas of in situ carcinoma and the cellular responses to accompanying invasive breast cancer. These findings add to our general understanding of immunogenicity of breast cancer tissue. They also provide a progonstic system for classifying breast cancer patients on the basis of the microscopic characteristics of the primary tumor and surrounding breast tissue. The latter system should be of value in comparing the therapeutic benefits of various treatments.

Prognostic significance of microscopic structure of gastric carcinomas and their regional lymph nodes

The correlation of structural features in the tumor and the regional lymph nodes with patient survival is confirmed in a study of 600 Norwegian patients with gastric cancer. Follicular hyperplasia in the regional nodes and lymphoid infiltration of the tumor are associated with longer survival, as are favorable nuclear grade and tumor grade determinations. Each of these factors is also associated with a more favorable extent of disease. In contrast with breast cancer, sinus histiocytosis of the regional lymph nodes is infrequently seen. The prognostic influence of the aforementioned factors could not be explained by taking histologic type into account. This study provides further evidence in support of a tumor‐host interaction wherein a significant component of host response is mediated by lymphoreticuloendothelial system.

Further observations on prognostic factors in cancer of the female breast

A series of nearly 900 Norwegian women with cancer of the breast provides further evidence of the prognostic significance of the structural characteristics of the tumor and the lymph nodes, e.g., nuclear grade and sinus histiocytosis. The percentage of patients with evidence of a histiocytic reaction in the lymph nodes was found to depend on the number of nodes examined. Among patients with at least 6 nodes available for review, one third exhibited a histiocytic reaction. In the group in which 6 or more nodes were examined, the percentage of nodes with metastases is a powerful prognostic factor. In the presence of at least one favorable factor, such as a small tumor, histiocytic reaction in the nodes, or favorable nuclear grade, the survival of patients with metastases in less than one third of the axillary nodes is similar to survival of patients with no nodal metastases. The relationship of histologic type to other structural characteristics was investigated. Mucinous tumors had a high percentage with favorable nuclear grade. Medullary tumors had a high percentage with unfavorable nuclear grade, but the influence of this factor on survival was counterbalanced by the presence of lymphoid infiltrate in the tumor. The findings in this study suggest that more intensive study of the dynamic interactions between cancer and the lymphoicticulocndothelial system will provide insight into the behavior of human cancer.

Correlation of cell‐cycle kinetics, hormone receptors, histopathology, and nodal status in human breast cancer

DNA ploidy and percent of (%S‐phase) S‐phase cells were determined from the DNA content distribution of 21 benign and 76 malignant (69 primary, 7 metastatic) breast tumors using flow cytometry. All of the benign tumors were diploid, whereas 89% of the malignant tumors had measurable aneuploidy. Multiple stem‐lines were observed in approximately 10% of the malignant tumors. The ploidy distribution of the malignant tumors was bimodal with an increased frequency of tumors with a near diploid DNA index (DI), and a second group with DI ranging from triploid to tetraploid. The percentage of cells in S‐phase ranged from <1% to 37.4%. DI and %S were significantly higher in poorly differentiated duct carcinomas, medullary carcinomas, and recurrent tumor metastases. DI and %S were also significantly higher in estrogen‐receptor‐negative tumors. There was no correlation between DI or %S and the extent of axillary nodal metastases. However, within the groups of node‐negative and node‐positive patients, DI and %S were not randomly distributed but were significantly correlated with degree of nuclear differentiation. Both parameters were higher in poorly differentiated tumors compared with well‐differentiated tumors, indicating significant intrastage heterogeneity in tumor ploidy and proliferation characteristics. Determination of the prognostic significance of DI and %S will require a longer follow‐up time.

Histone Staining with Ammoniacal Silver

Under controlled conditions, ammoniacal silver (A-S) stains the bands of Dipteran salivary gland chromosomes in a precise and selective manner. Such staining is dependent upon the histone content of the band, as shown by the effects of selective extraction and blocking of the histones. The effects of qcid extraction and HONO solution on the A-S staining of different bands suggest that specific genes may have particular histones associated with them.

Prognostic factors in cancer of the female breast. II. Reproducibility of histopathologic classification

The reproducibility of histopathologic classification of breast tumor tissue (nuclear grade) and of axillary lymph nodes (sinus histiocytosis) has been evaluated. In 2 independent readings, an experienced observer assigned 70% of tumor tissue slides and 70% of lymph node slides to the same classification. Two other pathologists agreed fairly well with the classification by the experienced observer. Nuclear grade and sinus histiocytosis were found to be related to patient survival on the basis of classification by each of the 3 pathologists.

Cellular hypersensitivity to breast cancer. Assessment by a leukocyte migration procedure

Cellular hypersensitivity against autologous and homologous breast cancer was evaluated by means of a leukocyte migration procedure. The antigens employed were cryostat sections of breast tissue. The relative leukocyte migration in the presence of the antigen as compared with migration without antigen was termed the migration index (MI), and used to quantify the response. The cryostat sections were also used for parallel studies of cellular hypersensitivity against autologous breast cancer by means of the skin window procedure. Both procedures demonstrated a stage‐response relationship against autologous breast cancer; in situ < Stage I < Stage II. Both procedures demonstrated the persistence of hypersensitivity in patients who were apparently free of cancer more than 2 years postoperatively. Cross reactivity (MI procedure) was uncommon against homologous invasive breast cancer, but was found in approximately half of the tests against homologous in situ carcinoma tissue. Such reactivity against homologous in situ carcinoma was observed in Stage II patients as frequently as in Stage I patients. The data corroborate our previous observations on the unique antigenicity of in situ carcinoma and emphasize the need for careful correlations between clinicopathologic findings and in vitro measurements.

Cellular responses to autologous breast cancer tissue: Correlation with stage and lymphoreticuloendothelial reactive

Cellular responses to autologous benign and malignant breast tissue were studied by means of a modified skin window procedure, using cryostat sections of autologous breast tissue mounted on coverslips as the antigen. The coverslips were applied to microabrasions of the skin for 28 to 33 hours. The cellular exudates on such windows were evaluated in terms of: type of mononuclear cell response, total basophil count, and the occurrence of basophil‐associated mononuclear (BAM) cell aggregates. Distinctive types of basophil‐associated aggregations were seen in response to autologous cancer tissue but not to autologous benign breast tissue. Elevated basophil counts and BAM responses were more frequent postmastectomy (≥30 days) than during the perioperative period (< 14 days). Elevated basophil counts and BAM responses postoperatively (≥30 days) were found more frequently in Stage I than in Stage II patients and more frequently in patients showing lymphoreticuloendothelial reactions in their axillary lymph nodes and primary tumors than in patients without such structural features. The findings support previous conclusions regarding the immunologic significance of sinus histiocytosis of axillary lymph nodes and further implicate immunologic phenomena in the biological behavior of human breast carcinoma.

Palpable axillary lymph nodes in cancer of the breast: Structural and biologic considerations

The presence of bilaterally palpable axillary lymph nodes was previously found to be a prognostically favorable clinical sign. This study has sought to determine whether patients having bilaterally palpable lymph nodes are characterized by distinctive features in their homolateral nodes and primary tumors. The authors collected groups of cases according to the presence or absence of metastases to axillary lymph nodes and the palpability of their homolateral and heterolateral nodes. The superior survival of patients with bilaterally palpable lymph nodes was most closely correlated with superior sinus histiocytosis reactivity of the homolateral lymph nodes. The findings are discussed in relation to the concept of tumor‐host interactions and the therapeutic implications.