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Women previously treated for primary operable breast cancer are at increased risk of developing cancer in the contralateral breast, but the clinical significance of this development is unclear. The purpose of this study was to assess the impact of synchronous bilateral breast cancer or the development of a metachronous contralateral breast primary on the prognosis. In a series of 3210 women age < or = 70 years treated between 1975 and 1995 for primary operable breast cancer, 106 were identified to have bilateral breast cancer. Of these women, 26 were noted to have synchronous bilateral breast primaries (0.8%), and 80 developed a contralateral breast cancer after treatment for an initial primary breast cancer. Using life-tables analysis, there was a significant difference in survival between women with unilateral breast cancer, those with synchronous bilateral breast cancers, and those with metachronous contralateral breast with survivals at 16 years of 53.8%, 42.4%, and 60.1%, respectively (p < 0.0001), from the date of the diagnosis of the first primary tumor. There was no difference in survival seen between the three groups when survival was calculated from the date of diagnosis of the second primary in cases of metachronous contralateral breast cancer (p = 0.31). When contralateral breast cancer was incorporated as a time-dependent covariate in a Cox multivariate model together with the three factors used to determine the Nottingham Prognostic Index (invasive tumor size, grade, and lymph node stage), contralateral breast cancer continued to be a significant prognostic determinant (p = 0.02). The survival of women with synchronous bilateral breast cancer or metachronous breast cancers diagnosed within 2 years of the original primary was worse than those with unilateral disease. However, the time duration to metachronous contralateral breast cancer did not have prognostic significance in a multivariate model compared with the prognostic features of the original primary.

Current classification systems for borderline lesions of the breast including epithelial hyperplasia, atypical hyperplasia, and ductal carcinoma in situ fall short of the ideal. They present pathologists with problems of recognition or clear distinction and clinicians with difficult management choices. In addition, recent evidence indicates that different pathogenetic lesions are present in some categories. This article presents a brief critical appraisal of the existing classifications and offers suggestions for revision using a model of pathogenetic lineage.

The mammographic appearances of 86 invasive lobular carcinomas were compared with those of 86 invasive ductal carcinomas of no special type matched for age, size and stage. There was no significant difference in the frequency of a mammographic abnormality consistent with malignancy between the lobular carcinoma (90%) and ductal carcinoma (96%) groups. A spiculate mass was the commonest feature in both groups (69% and 63%, respectively). There were no differences in the imaging features of masses in the two groups. In the lobular carcinoma group any mammographic abnormality was more likely to be seen on only one view and calcifications were less frequently observed. Multiple lesions were more frequent in the ductal carcinoma group. However, although these differences appeared to reach statistical significance, as they were only apparent in a study with a large number of comparisons, it is unlikely that these differences are practically significant. Analysis of the lobular invasive group failed to demonstrate any significant differences in the imaging features of the classical and mixed sub-types, a spiculate mass being the most common single abnormality in both. No mammographic differences of practical use to distinguish invasive lobular from invasive ductal carcinoma of no special type were demonstrated.

The expression of oestrogen receptor protein (ER) was examined in 151 cases of symptomatic or screening detected pure ductal carcinoma in situ (DCIS) of the breast by immunocytochemical assay (ERICA), in formalin-fixed paraffin-embedded tissue, with the monoclonal antibody H 222 (Abbott). Forty-eight tumours (31.8%) of cases were ER positive. Twenty-seven (17.9%) of cases showed high level ER expression and 21 (13.9%) of cases showed low level ER immunoreactivity. Significant associations of positive tumour ER immunoreactivity and non-comedo architecture chi 2 = 6.76; (d.f. = 1): P < 0.001, small cell size chi 2 = 4.49; (d.f. = 1): P = 0.034, higher S-phase fraction chi 2 = 4.71; (d.f. = 1): P = 0.03 and lack of c-erbB-2 protein overexpression chi 2 = 7.96; (d.f. = 1): P < 0.01 were identified. No significant associations of ER expression and patient age, histological grade of necrosis in DCIS, or DNA ploidy were found. ER expression is detectable in less than one third of symptomatic and screening detected cases of DCIS, implying that endocrine therapy of DCIS may be a more appropriate form of management for morphological subtypes of DCIS which show higher rates of oestrogen receptor expression, particularly those of non-comedo and small cell type.

The immunohistochemical expression of the p53 gene protein was examined in a consecutive series of 143 cases of pure ductal carcinoma in situ (DCIS) of the breast. Expression of wild-type and/or mutant p53 protein was detected in 36 (25.2%) of the cases examined, as evidenced by positive nuclear staining with the monoclonal antibody DO 7. Thirty-four (35.8%) of the large cell cases showed p53 protein expression compared with two (4.1%) of the small cell cases (chi 2 = 15.3 [df = 1], P < .001). p53 Protein expression also was associated with an increased histologic degree of necrosis, with a nearly significant association of negative tumor estrogen receptor status and p53 protein expression. No significant association of p53 protein expression and c-erbB-2 protein expression was seen. Immunohistochemical expression of p53 protein is present in approximately 25% of DCIS cases and is confined almost exclusively to large cell DCIS, a morphologic subtype of in situ breast carcinoma thought to be more biologically aggressive. Expression of p53 protein may be important in the neoplastic progression of DCIS, reflecting the acquisition of p53 gene mutations in large cell DCIS cases. Therefore, p53 may be implicated in mammary tumor evolution from in situ to invasive disease.

The expression of p53 protein, oestrogen receptor protein, epidermal growth factor receptor (EGFR) and overexpression of the c-erbB-2 oncoprotein was examined in a series of 149 primary symptomatic breast carcinomas. Expression of p53 was present in 62 of 146 cases (42.5%) of the invasive carcinoma and one of three cases (33.3%) of ductal carcinoma in situ (DCIS) examined. Statistical associations of tumour oestrogen receptor positivity and lack of p53 protein expression, chi 2 = 19.78 (d.f. = 1), P less than 0.001, positive tumour p53 status and poor tumour grade; chi 2 = 14.1 (d.f. = 2), P less than 0.001, EGFR expression chi 2 = 7.07, (d.f. = 1), P less than 0.01 and tumour c-erbB-2 protein overexpression; chi 2 = 4.61 (d.f. = 1), P = 0.032 were identified. Expression of p53 is rare in invasive lobular carcinoma of classical type (8.3% of cases examined) in contrast to other common types of mammary carcinoma. Non-significant trends of p53 protein expression and increased regional tumour recurrence; chi 2 = 3.20 (d.f. = 1), P = 0.074 and also poorer patient survival; chi 2 = 3.76 (d.f. = 1), P = 0.053 were identified. p53 protein expression is a common event in human breast cancer and is present in both DCIS and invasive mammary carcinoma. Abnormal expression of p53 protein is a feature of both in situ and invasive breast carcinoma, implying that the abnormal p53 protein expression may be implicated in the early stages of mammary carcinoma progression.

The overexpression of the c-erbB-2 oncoprotein is now thought by most authors to be associated with adverse prognosis in breast carcinoma. In this study, we investigate the relationship between overexpression of the c-erbB-2 oncoprotein and nuclear size by morphometry in a series of 150 human breast carcinomas, comprising 65 cases of ductal carcinoma in situ (DCIS) and 85 cases of invasive adenocarcinoma. The mean nuclear size for c-erbB-2 positive cases of DCIS was 54.8 micron 2 and invasive carcinoma was 52.1 micron 2 respectively, in contrast with 41.6 micron 2 and 42.5 micron 2 for c-erbB-2 negative cases of DCIS and invasive carcinoma respectively. Flow cytometric examination of DNA in a subset of 91 of these tumours showed no association between tumour cell aneuploidy and c-erbB-2 overexpression. S-phase fraction could be calculated on 20 cases of DCIS and 48 invasive carcinomas. There was a strong association between c-erbB-2 overexpression, S-phase fraction (p less than 0.001) and proliferative index (p less than 0.001) in 20 cases of DCIS. A weak association of S-phase fraction and c-erbB-2 overexpression was seen in 48 invasive carcinomas (p = 0.047). This study confirms the subjective impression that there is a relationship between large tumour cell nuclear size and an overexpression of the c-erbB-2 oncoprotein, and also shows an association with increased tumour cell proliferation.

Ninety-eight consecutive patients with primary operable breast cancer and an initial diagnosis of no regional lymph node metastases as assessed by conventional light microscopy were studied. Immunohistological staining of routine lymph node sections was assessed using two monoclonal antibodies: CAM 5.2 (Becton Dickinson) with specificity for low molecular weight cytokeratin, and NCRC-11 (CRC Laboratories, Nottingham) with specificity for epithelial mucin antigen. Positive staining for occult metastases was seen in nine patients with CAM 5.2 and in eight of these nine with NCRC-11. At a follow-up out to 14 years, there was no difference in overall survival, in recurrence-free survival, or in frequency of or time to presentation of local or regional recurrences between occult metastasis-positive and occult metastasis-negative patients. This study concludes that while immunohistological staining of routine lymph node sections increases the diagnostic yield of metastases, it is not to be recommended as this increase is of no useful clinical value.

One-hundred-and-seventy-one patients with invasive lobular carcinomas have been matched with 342 patients with non-lobular invasive carcinomas for lymph node stage, tumour differentiation and patient age on a one to two basis. The two groups were investigated for differences in prognostic factors, survival, disease-free interval, metastatic patterns, receptor status, response to endocrine therapy after distant metastases and bilateral cancer rates. Patients with lobular carcinomas survived significantly longer than patients with carcinomas of no specific type, particularly in survival from the time of diagnosis of distant metastases; lobular carcinomas more often responded to endocrine treatment for systemic disease. Lobular cancers had a significantly higher rate of local recurrence, particularly after treatment by excision and breast irradiation. No differences were found between the two groups with respect to regional or distant recurrence rates, distant organ involvement patterns, distant metastatic free intervals and receptor status. Bilateral cancer was more frequent in patients with lobular carcinoma.

Seventy seven patients with metastases from an invasive lobular carcinoma of the breast have been compared with 72 consecutive metastatic ductal carcinomas. There was no difference in the metastatic free interval between the two groups. A distinct pattern of clinical presentation of metastases was seen; hepatic (P = 0.01) and peritoneal metastases (P = 0.0003) occurred more commonly in lobular tumours. Bilateral cancers were more common in the lobular group (P = 0.01). No difference was seen in terms of meningeal and pulmonary metastases. Survival after metastases was significantly longer in patients with metastatic lobular carcinoma (P = 0.02).

Using archival paraffin wax embedded tumour we have investigated histological grade, DNA ploidy, S phase fraction and proliferative index in 74 patients with symptomatic ductal carcinoma in situ (DCIS) of the breast. Nine patients developed local recurrence, six invasive in character. No patients with the cribriform subtype of DCIS developed local recurrence. The cribriform subtype showed a significantly lower rate of DNA aneuploidy and a lower proliferative index than the other subtypes. Cribriform tumours were almost exclusively well differentiated in contrast with the comedo and solid variants. Our results suggest the cribriform variant is less aggressive than other subtypes of DCIS. This has possible implications for management of these lesions.

A cohort of 36 cases of advanced breast carcinoma were included in the study. DNA ploidy, histological grade, and immunoreactivity for carcino-embryonic antigen (CEA), carcino-embryonic antigen with normal cross-reacting antigen (CEA/NCA), and to NCRC-11 were assessed in primary breast carcinomas and metastases from the ovary and axillary lymph nodes. Changes in these variables between primary tumours and their metastases were found in 44 per cent of cases for DNA ploidy, 44 per cent of cases for histological grade, 17 per cent of cases for immunoreactivity to NCRC-11, 28 per cent of cases for CEA, and 56 per cent of cases for CEA/NCA immunoreactivity, respectively. Alteration of one factor appeared to be independent of changes in other factors. The development of clones with metastatic potential does not appear to be related to consistent changes in any one of the factors examined and suggests that none of these factors would be of prognostic value in advanced breast carcinoma.

Microdochectomy has been the accepted treatment for single-duct nipple discharge. Review of 97 consecutive patients undergoing microdochectomy between 1980 and 1987 revealed a total of eight patients with ductal carcinoma in situ. All of these had pre-operative mammography, results of which were highly suspicious of malignancy in six patients. Tiny foci of ductal carcinoma in situ were found in the two patients with normal mammograms. We suggest an expectant policy in cases where the mammogram is normal, omitting routine microdochectomy.