Laser scanning cytometry quantification of estrogen receptors in breast cancer.

OBJECTIVE: To describe the laser scanning cytometry (LSC) processing and analysis developed for the quantitative analysis of estrogen receptor (ER) content in routine paraffin sections of breast carcinomas. STUDY DESIGN: Histologic sections of archival, paraffin-embedded tissues from 30 breast carcinomas were labeled for ER with fluoresceinated monoclonal antibody. ER expression was quantified by LSC and expressed as percent positive tumor cells and as histogram distributions of receptor expression per cell. Duplicate sections of the same tumors were stained for ER by a conventional immunoperoxidase reaction and percent positive tumor cells counted visually. RESULTS: Percent ER-positive tumor cells by LSC of immunofluorescence-stained sections correlated well with conventional (visual) counts of immunoperoxidase-stained duplicate sections when the latter were categorized as low, intermediate or high percent of positive cells. In addition, the marked variation in relative number of ER binding sites per cell could be quantified by LSC and displayed in histogram distribution. CONCLUSION: LSC measurements are fast and objective and can be carried out on sections of paraffin-embedded tissue after routine processing in the pathology laboratory. In addition, LSC data provide the relative number of ER binding sites per unit of DNA; that may reveal clinically significant skewed distributions or subpopulations of tumor cells.

Breast cancer after breast augmentation with silicone implants.

BACKGROUND: Although epidemiological studies have failed to demonstrate an increased incidence of breast cancer in women who had undergone prior prosthetic augmentation mammoplasty (PAM), it has been reported that when breast cancer arises in this group it presents mostly in a palpable form and at a more advanced stage. This is thought to be secondary to suboptimal mammographic evaluation caused by the masking effect of the implant. This study was undertaken to determine, in our experience, whether breast cancer arising in women who had undergone PAM could be detected in a prepalpable form by mammography and whether it presented at a more advanced stage as compared with nonaugmented women with breast cancer. METHODS: The charts of 22 patients, treated by at least one of the authors, in whom 23 breast cancers developed after PAM (group A) were retrospectively reviewed. The comparison groups consisted of 611 nonaugmented patients who underwent 636 procedures for the treatment of primary breast cancer at our institution (group B) and the surveillance, epidemiology, and end results (SEER) data (group C). Parameters studied were mode of detection, tumor size, axillary lymph node involvement, and histopathology. RESULTS: No significant differences between the groups were found in mean tumor size (group A vs. group B), the incidence of preinvasive cancer (group A vs. group B) or axillary lymph node involvement (group A vs. group B and group A vs. group C). Breast-preserving surgery was performed significantly less in augmented patients (group A vs. group B). CONCLUSION: We conclude that prepalpable and preinvasive breast cancer can be detected in the PAM patient by mammography and that the stage of presentation in this group is not significantly different than in nonaugmented patients. Total mastectomy is preferred over breast-preserving procedures for the treatment of breast cancer in the PAM patient.

Prognostic significance of cellular immunity to autologous breast carcinoma and glycoprotein 55.

Using a skin window (SW) procedure, we evaluated post-operative cell-mediated immunity (CMI) to autologous breast cancer with reference to its prognostic significance, the nature of the immunogen, and the therapeutic implications. It appears that SW reactivity to autologous breast cancer is prognostically favorable per se and is independent of the prognostic significance of the nuclear grade of the cancer cells; SW reactivity to autologous breast cancer reflects CMI to a determinant(s) that is expressed by glycoprotein 55, the principal envelope glycoprotein of the RIII-murine mammary tumor virus; the glycoprotein 55-like CMi determinant(s) is more regularly expressed by preinvasive than by invasive breast cancers; tumor antigenicity and host reactivity may vary independently; and postoperative monitoring of CMI to autologous breast cancer is prognostically and therapeutically important.

Phase II trial of fludarabine phosphate (F-Ara-AMP) in patients with advanced breast cancer.

Eighteen patients with advanced breast cancer were entered into a phase II study of fludarabine phosphate. Fludarabine phosphate was given by continuous infusion for 5 days, at a starting dose of 20 mg/m2 per day for patients previously treated with two or more regimens and 25 mg/m2 per day for minimally treated patients with less than two prior regimens; therapy was repeated every 3-4 weeks. Of the 18 patients, 11 had undergone more than two prior regimens and 7 patients had undergone one prior regimen. One patient achieved a partial response (PR) for 22 months. Myelosuppression was the most common toxicity observed. Four patients developed mild nausea and vomiting and two developed a nonspecific dermatitis that resolved spontaneously. No renal, hepato-, or neurotoxicity was observed. Our study demonstrates that in heavily pretreated patients, fludarabine phosphate given on this schedule has minimal efficacy in treating advanced breast cancer. This drug might possibly have shown more activity in a previously nontreated patient population. However, patients with advanced breast cancer, who have not undergone previous treatment are not often encountered.

Modified radical mastectomy.

Surgical management in the treatment of potentially curable breast cancer has changed from a radical to a more conservative approach. The most common procedure used at the present time is the modified mastectomy, which is discussed in detail in this article.

The effect of pregnancy on the prognosis of carcinoma of the breast following radical mastectomy.

During the interval from 1940 to 1970, 41 patients treated for primary operable carcinoma of the breast had subsequent pregnancies. Of 27 patients with axillary nodes negative for tumor, nine had first trimester abortions and 14 had pregnancies occur less than two years following mastectomy. Fourteen patients had axillary nodes positive for tumor, seven having first trimester abortions and eight pregnancies having occurred within two years of mastectomy. No detrimental effect of subsequent pregnancy could be demonstrated, even among patients with positive axillary nodes or among those whose pregnancies occurred less than two years following mastectomy. Abortion could not be demonstrated to improve the survival rate. We conclude that pregnancy need not be avoided or terminated among those patients who are apparently free of a recurrence after undergoing treatment for carcinoma of the breast.

Estrogen receptor protein in visceral metastases from breast carcinoma.

Estrogen receptor protein assays were done on 1,243 tissue specimens, 34 of which represented metastases from primary breast carcinoma to parenchyma of liver, lung or brain. Eight of these specimens contained significant amounts of estrogen receptor protein. Most (4 of 5 evaluable cases) of the ERP-positive patients responded to endocrine ablation, as compared with 13 percent (2 of 16 evaluable cases) of the ERP-negative patients. We conclude that biopsy of liver and lung metastases may be useful in some circumstances and that endocrine manipulation frequently provides palliation when these metastases are ERP-positive.

Estrogen receptor protein in breast cancer as a predictor of recurrence.

Estrogen receptor protein (ERP) determinations of primary cancers of 1034 patients with primary breast cancer were done. ERP-positive patients tended to have a lower recurrence rate and had significantly improved survival. This difference was most apparent in patients with four or more axillary nodes involved. ERP-positive patients who recurred had a better survival. ERP did not influence response that adjuvant chemotherapy, nor did the presence of progesterone receptor or femtomole level of ERP affect recurrence.

Leukocyte migration inhibition among breast cancer patients in response to various oncogenic viruses.

The direct leukocyte migration inhibition (LMI) test was done with leukocytes from healthy women and from patients with primary operable breast cancer, benign breast disease, or head and neck cancer. Purified preparations of murine mammary tumor virus (MuMTV), Mason-Pfizer monkey virus (MPMV), and murine leukemia virus (MuLV) were used. For each virus, the lowest 10th percentile of the LMI responses of controls was used to discriminate positive from negative responses. Leukocytes from 46 of 94 (49%) breast cancer patients responded to MuMTV, which was significantly different from each of the other test groups: Positive reactions were observed in only 9 of 67 (13%) healthy persons, 2 of 32 (6%) patients with benign breast tumors, and 2 of 20 (10%) patients with head and neck cancer. Although leukocytes from 29% of the breast cancer patients responded to MPMV, this response did not significantly differ from that observed in healthy women (14%), in patients with benign disease (20%), or in patients with head and neck cancer (20%). The leukocytes from the breast cancer patients were not reactive to MuLV. LMI tests to both MuMTV and extracts of MCF-7 cultured breast cancer cells were done in 36 breast cancer patients and 40 healthy women simultaneously. Of the breast cancer patients, 75% responded to MuMTV and/or MCF-7 antigen as compared to 18% of the controls (P less than 0.005). These data suggest that leukocytes from breast cancer patients are presensitized to MuMTV and antigen(s) present in MCF-7 breast cancer cell line, but not to MPMV or MuLV.

A clinicopathologic study of atypical lesions of the breast further follow up.

On the assumption that both the lobular and intraductal atypical lesions of the breast are precancerous in nature, a group of 572 such patients have been closely followed during the past 12 years. Thirty-four patients eventually developed cancer during this period. The cumulative incidence of breast cancer was 7.74% at 10 years in the group of patients with atypical lesions only and 16.15% at 10 years in the patients with atypical lesions in one breast and cancer in the contralateral breast. The transformation of this probable precancerous state into cancer apparently takes a long interval of time.

Melanoma of the nipple and areola.

Fourteen primary melanomas arising in the nipple and areola of the breast were treated by mastectomy and axillary dissection. Four patients had axillary lymph node metastases and all were dead within 3 years of their operation, while the 10 patients with no axillary node involvement were free from recurrent disease 5 years after their operation. On the basis of clinical and anatomical studies, it is suggested that a wide local excision without mastectomy is adequate for the treatment of nipple and areola melanomas.

Noninvasive breast carcinoma: frequency of unsuspected invasion and implications for treatment.

One hundred twenty-nine biopsies from 121 patients with a frozen or paraffin section diagnosis of noninvasive breast carcinoma were studied. Eight women had bilateral noninvasive carcinoma. Seven biopsies reported as intraductal on frozen section contained invasive carcinoma on paraffin section. Of the remaining 122 biopsies proven to have noninvasive carcinoma on paraffin section, 39 (34%) were reported at frozen section and as noninvasive carcinoma, 24 (20%) as atypical and 59 (48%) as benign. Intraductal carcinoma (IDC) was identified more often at frozen section (45%) than was lobular carcinoma in situ (19%). Among 41 patients who had bilateral carcinoma with invasive disease in one breast, 76% of contralateral noninvasive carcinoma was LCIS. After excisional biopsy, carcinoma was found in 56% of 103 mastectomy specimens, including invasive carcinoma in 6% of breasts with IDC and 4% with LCIS. Residual noninvasive carcinoma was usually of the same type found at biopsy (90% IDC and 88% LCIS) and involved quadrants other than the biopsy site in 33% with IDC and in 80% with LCIS. When the frozen or paraffin section diagnosis of a generous excisional biopsy was noninvasive breast carcinoma, there was a substantial risk that foci of the same type of noninvasive carcinoma were also present in other quadrants. However, occult foci of invasive carcinoma were quite infrequent and the risk of axillary metastases was very low. Adequate treatment for noninvasive carcinoma requires elimination of all residual foci of noninvasive disease. At present this can best be accomplished by total mastectomy if the operation is properly performed. To insure removal of the axillary extension of the breast and for staging, in continuity dissection of the lowest axillary lymph nodes is also prudent.

Cutaneous melanoma of the breast.

A study of 115 cutaneous melanomas of the breast demonstrated that these neoplasms follow different metastatic patterns than do primary carcinomas of the breast and require a different therapuetic approach. Lesions located below a 3 cm from the clavicle metastasized exclusively to the axillary nodes regardless of location. None of 19 internal mammary node chains examined histologically contained tumor deposits. Microstaging of the primary lesion correlated closely with prognosis and lymph node metastasis. Treatment by mastectomy (radical, modified, extended radical) offered no advantage over local excision of the primary plus axillary dissection. The latter procedure is recommended for all cutaneous melanomas of the breast which require node dissection. Mastectomy is not indicated unless the breast is in the field of wide local excision. Internal mammary node dissections are not indicated.

Epidemiology of breast carcinoma: Age, menstrual status, and exogenous hormone usage in patients with lobular carcinoma in situ.

Lobular carcinoma in situ (LCIS) of the breast is a neoplastic condition associated with premenopausal women and it is largely for this reason that LCIS has been considered to be an estrogen-dependent lesion. In this report we present the results of a study of age at diagnosis, menstrual status, and exogenous hormone usage in 59 women with LCIS and in 190 patients with duct carcinoma. When LCIS was associated with duct carcinoma, 46% of patients were postmenopausal and in the group that also had infiltrating lobular carcinoma 71% were postmenopausal. Nine of 39 (23%) patients whose only carcinoma was LCIS were postmenopausal, 56% were premenopausal and 21% were menopausal. Seven of the nine postmenopausal women had never used a hormone-containing medication. In a comparison group with only duct carcinoma, 59.4% were postmenopausal and 35.2% had taken a hormone preparation. The high proportion of postmenopausal patients with LCIS leaves considerable doubt as to whether all lesions termed LCIS are equally dependent on estrogens at all stages in their evolution. We found no evidence to link LCIS with exogenous hormone usage in postmenopausal women. Prospective studies of hormone levels in patients with LCIS and in their relatives may provide an explanation for persistence of the lesion in postmenopausal women and could aid in identifying women at risk of developing invasive carcinoma.

Male breast cancer: a clinicopathologic study of 97 cases.

From 1949 through 1976, 97 men have been treated at Memorial Hospital for primary operable breast cancer. Seven per cent had intraductal carcinoma. Of the patients with invasive carcinoma 30% were pathologic stage I, 54% stage II, and 16% stage III. Fourty-six per cent had pathologically negative axillary lymph nodes. The most common type of tumor was infiltrating duct carcinoma. Fourty per cent of the patients had microscopic gynecomastia. None of the eight patients with intraductal or intracystic carcinoma died of cancer. Survival of the entire group of men with invasive carcinoma was 40% after ten years. The ten year survival for men with negative nodes was 79%, for men with positive nodes 11%. Comparison with a series of 304 women with breast cancer operated on at Memorial Hospital in 1960 revealed no difference with regard to incidence of positive axillary lymph nodes or stage of disease. There was, however, a significantly lower survival rate for men. This poorer prognosis was limited to those men with pathologically positive axillary nodes.

Prognostic significance of tumor emboli in intramammary lymphatics in patients with mammary carcinoma.

Approximately 20% of patients with invasive mammary carcinoma who do not have axillary metastases develop recurrent carcinoma within 10 years of initial therapy. There is clearly a need to identify those patients most likely to develop recurrences in this group since they may benefit from adjuvant therapy. This study was undertaken to evaluate the prognostic significance of intramammary lymphatic tumror emboli in patients with invasive breast carcinoma who did not have lymph node metastases. Twenty-three such patients treated in 1974 and 15 from 1964 were compared with matched groups of control patients who did not have lymphatic emboli. About 43% of patients with lymphatic emboli and 4% of those without emboli followed for 5 or more years in the 1964 group developed distant metastases (p less than 0.001). Local recurrences were found in only one study patient and one control in the entire series of 1964 and 1974 patients. The results suggest that among patients without axillary metastases, the finding of tumor cells in lymphatic spaces within the breast is associated with a substantial risk of distant metastases but not local recurrence.