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The production of adrenocorticotropic hormone by non-pituitary carcinomas has been documented in several tumors, most frequently small cell carcinoma of the lung, islet cell carcinomas of the pancreas, thymomas and carcinoids. Electron microscopy of these tumors reveals typical membrane-limited "neurosecretory" granules. Confirmation of the granules as adrenocorticotropin (ACTH) requires the use of OsO4 as a primary fixative to give the characteristic cored granule appearance in conjunction with immunohistochemical demonstration of the hormone peptide. Because of the rarity of ectopic ACTH production by mammary carcinomas and the absence of appropriate ultrastructural studies in the two examples of such ectopic hormone production in the literature of which we are aware (1,2), we present biochemical and ultrastructural data from a carcinoma of the breast with apparent ACTH production.The patient had her primary tumor in the right breast in 1969. The tumor recurred as visceral and subcutaneous metastases in 1976 and again in 1977.

This study corroborates previous reports which suggested the efficacy of estrogen receptor (ER) analysis in predicting responses of patients with metastatic mammary carcinoma to hormonal therapeutic manipulation. The predictive value of multiconcentration titration and sucrose density gradient analyses of ERs and progesterone receptors (PRs) are compared. The predictive value of ER analyses can be improved by the discrimination of 8S versus 4S binding species or by the use of PR analysis in combination with ER analysis. The tumor-associated antigen, carcinoembryonic antigen (CEA), is evolving as an important quantitative aid in evaluating the clinical responses of patients receiving hormonal therapy.

Cystosarcoma phyllodes is an unusual breast neoplasm that rarely metastasizes. Most series report chemotherapy, radiation, and hormonal therapy to be ineffective. Three patients were treated with cisplatin and etoposide combination chemotherapy with effective palliation in two patients. Radiation therapy was effective in controlling symptomatic metastasis in all three patients. Hormonal therapy was ineffective in two patients despite the presence of positive hormone receptors. Chemotherapy and radiotherapy may be more effective in the treatment of this tumor than has been reported, although there is no apparent role for hormonal therapy. Functional hormone receptors are probably not present.

Using direct immunofluorescence, lesions from 266 human breast specimens were studied for the presence of IgA, IgM, or IgG localization. The lesions included benign elements from 66 subcutaneous mastectomy specimens in which the absence of simultaneous breast malignancy was documented, primary breast carcinomas from 153 mastectomy specimens, and 47 biopsies containing metastatic breast cancer. A statistically significant association of IgA and IgM with benign lesions was contrasted to the association of IgG with malignant lesions. In both primary and metastatic lesions, IgG localization was associated with estrogen-receptor-poor primary cancers as compared with estrogen-receptorrich primary cancers. Among primary breast cancer patients, IgG localization in the tumor correlated with relative lymphopenia. A shorter disease-free interval was noted in association with IgG localization among the metastatic breast lesions. No statistically significant association between stage of disease and immunoglobulin presence was demonstrable. Moderate-to-severe intraductal epithelial hyperplasias were more often associated with immunoglobulin G localization than were other benign lesions. Cancer 48:69-75, 1981. EVERAL STUDIES have suggested a role of the host S immune response in the natural history of mammary car~inoma.~~,~~ The breast is a component of the secretory immune system, concentrating immunoglobulins in breast A differential concentration of immunoglobulins in benign vs. malignant lesions of the breast has been suggested.s,20,21 The accumulation of immunoglobulin A (IgA) and immunoglobulin M (IgM) in the mammary gland have been shown to be induced by hormones.23 In the present study the localization of IgA, IgG, and IgM observed in various breast lesions was compared with the estrogen receptor content of the tissues. Benign and malignant lesions were examined to determine if immunoglobulin localization may characterize primary and metastatic breast cancers as contrasted to benign breast lesions.

Confusion exists concerning the influence of pregnancy on survival in patients with malignant melanoma. To evaluate this problem a retrospective computer-aided study was performed of women in the child-bearing years treated for Stage I cutaneous melanoma at the Duke University Comprehensive Cancer Center. Fifty-eight women were identified who had melanoma arise during pregnancy (Group 1) and 43 patients were noted who became pregnant within 5 years of diagnosis of their melanoma (Group 2). Appropriate control groups matched for the clinical variables of age, primary site, and stage of disease and the pathologic variables of Clark's Level, tumor thickness, ulceration, and histologic type were selected from the cohort of 2938 melanoma patients seen at Duke. Actuarial survivals for Group 1 and 2 patients did not differ from their respective controls, although the small number of deaths in each group resulted in wide confidence intervals. When actuarial disease-free intervals were plotted, there was a significant difference beween women who had melanoma develop during pregnancy when compared to their controls (P = 0.04). In a multivariate regression analysis, after adjustment for the influence of the more significant prognostic factors for Stage 1 melanoma, including Clark's Level, ulceration, and tumor thickness, the effect of pregnancy on disease-free interval became more apparent (P = 0.02). No difference in actuarial disease-free interval was noted in the melanoma patients who elected to become pregnant within 5 years of diagnosis (P = 0.31). A multivariate regression analysis confirmed this finding. These data indicate that although an intercurrent melanoma during pregnancy has a worse prognosis than the control groups, once a woman has been diagnosed as having a cutaneous melanoma, a subsequent pregnancy has no effect on recurrence rate or survival. Cancer 55:1340-1344, 1985.

3 histochemical techniques for estrogen binding localization in tissue section were compared to sucrose density gradient analyses for estrogen receptor in 186 breast carcinomas. Apparent localization to epithelial elements was noted using 6-BSA-Fluor-CMO-17-beta-estradiol 17-BSA-Fluor-TSC-estrogen and polyestradiol phosphate/anti-estradiol antibody methods. The correlation between the histochemical methods and standard sucrose density gradient techniques was poor for the polyestradiol antibody method and the 6-BSA-Fluor-CMO-17-beta-estradiol technique. While an improved correlation was observed with the 17-BSA-Fluor-TSC-estrogen compound the compounds binding was not effectively blocked by preincubation with diethylstilbestrol. This failure to show convincing saturability of binding combined with problems of extraction of soluble receptor proteins in the aqueous incubation media and washes from the cells rendered permeable by cryostat sectioning indicates that several areas will require clarification before histochemical techniques can begin to be considered as a method for estrogen "receptor" analysis in the clinical evaluation of breast neoplasms. (Authors modified)

Menstrual cycle dependent variations in cytosol levels of estrogen receptor (ER), progesterone receptor (PR), and two breast cyst fluid glycoproteins, gross cystic disease fluid protein (CDP) and nonreceptor progesterone binding protein (PBP), were demonstrated in epithelial-enriched “normal” breast tissues from 56 premenopausal women. Criteria for normalcy were: (1) normal menstrual history; (2) absence of drug use or debilitating disease; (3) normal adrenal, ovarian and pituitary function; and (4) no clinical, gross or histologic evidence of breast disease. Highest mean levels of CDP (8180 ± 2850 ng/mg protein) and PBP (17750 ± 6320 ng/mg protein) were noted during the follicular phase (days 8–14) of the menstrual cycle, while lowest levels of CDP (450 ± 260) and PBP (1810 ± 380) were observed during the luteal phase (days 15–20). Both CDP and PBP had peak values on days 10–12 with a smaller peak on days 20–23. The number of samples with ER > 3 fmole/mg protein (8/14; 57%) and mean ER level (7.5 ± 2.9 fmole/mg protein) were significantly higher during the proliferative phase (days 3–7) than during other menstrual phases. Maximum ER values occurred on days 5–8. The greatest number of samples with PR > 3 fmole/mg protein (5/15, 33%) and highest mean levels of PR (36 ± 27.8 fmole/mg protein) were noted during the follicular phase of the menstrual cycle. These data demonstrate that the normal human breast has menstrual cycle variations of CDP and PBP which may be useful as markers of sex steroid receptor integrity. These data also documented that appreciable ER levels were found during the proliferative phase with low levels at other times in the menstrual cycle.

A patient with gonadal dysgenesis who developed endometrial carcinoma in her 31st year of estrogen therapy is discussed in relation to thirteen previously reported cases of carcinoma of the uterus in patients with Turner's syndrome. The pattern of steroid receptor proteins in the endometrial carcinoma was found to correlate with the degree of differentiation of the tumor as assessed by light and electron microscopy. The findings reflect a potential for continued hormonal responsiveness of the tumor.

Estrogen and progesterone receptor determination in breast cancer is of significance in determining a patient's potential response to hormonal manipulation. One practical limitation to this procedure has been availability of material for receptor assay. We describe 12 patients in whom quantitative estrogen and/or progesterone receptor analysis was accomplished utilizing tumor cells obtained from malignant effusions. The ability to obtain quantitative steroid receptor data on material derived from malignant effusions provides an effective source for this important biochemical parameter in patients in whom no other tumor tissue is available for study.

Melanomas from 20 patients were evaluated for estrogen and progesterone receptors. No restriction as to patient's age, sex, race, or menstrual status was made. Fifteen of the tumors were melanin producing. Of the 20 tumors examined, seven contained more than 3 fm/mg protein of specifically inhibitable estrogen binding. None of the tumors reported here demonstrated either a 4S or 8S binding protein as shown by sucrose density gradient analysis. All tumors in which estradiol binding was observed were melanin producing, whereas none of the amelanotic melanomas (five tumors) bound this steroid. Purified tyrosinase appeared to mimic the estrogen binding detected in melanoma cytosols, as demonstrated with the dextran-coated charcoal technique. Although the binding of estradiol to tyrosinase was inhibited by DOPA, the binding of estradiol to estrogen receptor preparations was not. These studies represent an extension of previous studies of sex steroid binding in melanomas and suggest that gradient analysis and DOPA inhibition studies should be included in the evaluation of the estrogen binding phenomenon in human melanoma.

Using a modification of the histologic grading system of the NSABP, we observed a trend towards higher levels of estrogen (E2R) and progesterone receptor (PR) content in well (grade I) and moderately (grade II) differentiated mammary carcinomas. This relationship between receptor content and histologic grade is enhanced by considering estrogen and progesterone receptor simultaneously. The rank correlation between the quantitative levels of E2R and PR was 0.74 among histologic grade I tumors and 0.64 among histologic grade II tumors. Among the grade III carcinomas, the majority of tumors displayed either a paucity of measurable receptor or a divergence between levels of estrogen versus progesterone receptor (r = 0.19). The use of ultrastructural evaluation of features of differentiation is discussed in the evaluation of grade III tumors and in the evaluation of specific histologic types of mammary carcinoma.