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AIM: Inflammation in carcinoma of the breast may represent an immune response to the tumour, but there is evidence that this response is impaired. Inflammation may also stimulate tumour growth by releasing proteolytic enzymes and angiogenic factors. Prognostic studies have produced conflicting results, but most investigators have not evaluated the different patterns of inflammation. The aim of this study was to test the hypothesis that moderate or marked diffuse inflammation is associated with a better prognosis. We also tested the 'danger model', which suggests that necrosis is necessary for an effective immune response. METHODS AND RESULTS: On multivariate analysis of women with stage 1 and 2 tumours (n = 679, median follow-up of 9.8 years), survival was independently associated with diffuse inflammation (relative risk 0.43, 95% confidence interval 0.24, 0.77, P =0.005) in addition to histological grade, axillary lymph node status, tumour size and oestrogen receptor status. The presence or absence of tumour necrosis did not have a clear effect on the relationship between survival and diffuse inflammation. CONCLUSIONS: Moderate or marked diffuse inflammation in breast cancer is associated with a better prognosis, suggesting that the immune effects of the inflammation predominate over the protumour effects.

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The grade of recurrent in situ and invasive carcinoma occurring after treatment of pure ductal carcinoma in situ (DCIS) has been compared with the grade of the original DCIS in 122 patients from four different centres (The Royal Marsden Hospitals, London and Sutton, 57 patients; Guy's Hospital, London, 19 patients; Nottingham City Hospital, 31 patients and The Royal Liverpool Hospital, 15 patients). The recurrent carcinoma was pure DCIS in 70 women (57%) and in 52 women (43%) invasive carcinoma was present, which was associated with an in situ element in 43. In all, 19 patients developed a second recurrence (pure DCIS in 11 and invasive with or without an in situ element in eight). The majority of invasive carcinomas followed high-grade DCIS. There was strong agreement between the grade of the original DCIS and that of the recurrent DCIS (kappa=0.679), which was the same in 95 of 113 patients (84%). The grade of the original DCIS showed only fair agreement with the grade of recurrent invasive carcinoma (kappa=0.241), although agreement was stronger with the pleomorphism score of the recurrent carcinoma (kappa=0.396). There was moderate agreement, in recurrent invasive lesions, between the grade of the DCIS and that of the associated invasive element (kappa=0.515). Other features that showed moderate or strong agreement between the original and recurrent DCIS were necrosis and periductal inflammation. The similarity between the histological findings of the original and subsequent DCIS is consistent with the concept that recurrent lesions represent regrowth of residual carcinoma. In addition, although agreement between the grade of the original DCIS and that of any subsequent invasive carcinoma was only fair, there is no suggestion that low-grade DCIS lesions progress to higher grade lesions or to the development of higher grade invasive carcinoma. This is in agreement with immunohistochemical and molecular data indicating that low-grade and high-grade mammary carcinomas are quite different lesions.

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The oestrogen receptor (ER) status of 2660 patients with primary breast cancer has been related to the effect of different adjuvant systemic therapies on survival. However, as patients in the various treatment groups also had different prognostic features comparison between treatments was difficult. Over 90% of patients receiving tamoxifen (Tam) were postmenopausal compared with <20% of those receiving chemotherapy (CT). The latter had more positive nodes (85% vs 54%) and grade III tumours (54% vs 30%) than the Tam group. The combined CT and Tam group had similar characteristics to the CT alone group. The current reported increase in the proportion of women with ER+ tumours is explained by immunohistochemical analysis of ER and screening programmes. ER status was unrelated to survival in patients with small, low grade, node-negative tumours which was no different from that expected for age-matched women taken from the general population. The value of adjuvant treatment in these patients is therefore questionable. In those given any adjuvant treatment, survival of women with ER+ tumours was prolonged, with the greatest effect being seen in those receiving Tam. Patients with ER- tumours benefited from CT but the addition of Tam to CT improved survival only in those with ER+ tumours. ER status is now established as a major predictive factor for treatment selection in primary disease. Studies of prognostic and predictive markers may be invalidated by use of adjuvant therapy and selection criteria for different treatments. Survival will be influenced by both tumour biology and therapy. This important consideration must be remembered when analysing new markers, particularly in small studies.

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The significance of occult metastases in axillary lymph nodes in patients with carcinoma of the breast is controversial. Additional sections were cut from the axillary lymph nodes of 477 women with invasive carcinoma of the breast, in whom no metastases were seen on initial assessment of haematoxylin and eosin stained sections of the nodes. One section was stained with haematoxylin and eosin, and one using immunohistochemistry with two anti-epithelial antibodies (CAM5.2 and HMFG2). Occult metastases were found in 60 patients (13%). The median follow-up was 18.9 years with 153 breast cancer related deaths. There was no difference in survival between those with and those without occult metastases. Multivariate analysis, however, showed that survival was related to tumour size and histological grade. This node-negative group was compared with a second group of 202 patients who had one involved axillary node found on initial assessment of the haematoxylin and eosin sections; survival was worse in the patients in whom a nodal metastasis was found at the time of surgery. Survival was not related to the size of nodal metastases in the occult metastases and single node positive groups. Some previous studies have found a worse prognosis associated with occult metastases on univariate analysis, but the evidence that it is an independent prognostic factor on multivariate analysis is weak. We believe that the current evidence does not support the routine use of serial sections or immunohistochemistry for the detection of occult metastases in the management of lymph node negative patients, but that the traditional factors of histological grade and tumour size are useful.

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Ninety-eight minimal breast cancers (MBCs) diagnosed between 1975 and 1990, and all originally considered to be invasive were found, on review, to form three groups: (a) 28 predominantly invasive carcinomas < or = 10 mm ('predominant invasive'); (b) 48 predominantly ductal carcinoma in situ (DCIS) lesions with definite foci of invasion each < or = 10 mm ('predominant DCIS'); and (c) 22 DCIS without evidence of invasion ('pure DCIS'). Tumour histology and immunohistochemical expression of Ki-67, c-erbB2, p53, oestrogen receptor (ER), progesterone receptor (PR), and Bcl-2 were compared. The major finding was the contrasting features in the two invasive groups, with significant differences in their extent of invasion (P < 0.0001), tumour grade (P = 0.03), DCIS type (P = 0.008) and in marker expression. In the predominant invasive group, the infiltrative component was usually greater than 5 mm, low-grade and associated with well-differentiated DCIS. Expression of Ki-67, c-erbB2 and p53 was generally low, and that of ER, PR and Bcl-2 high. The predominant DCIS group in contrast had a much smaller, commonly high-grade, invasive component, usually with poorly differentiated DCIS and the reverse pattern of marker expression. Although not significant, survival of patients in the predominant invasive group was slightly better. These findings suggest that invasive MBCs should perhaps be treated as separate entities, in order to aid more appropriate selection of treatment.

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In an attempt to explain the difference in outcome between British and Japanese women with breast cancer we have compared histopathological features, expression of c-erbB2 and p53 proteins and clinical outcome of 191 British (Anglo) women with 171 Japanese women treated between 1979 and 1980. The Japanese patients were significantly younger than the Anglo patients, while in premenopausal women the latter had significantly smaller tumors. The proportion of tumors expressing c-erbB2 and p53 proteins was similar in both populations. c-erbB2 positivity was significantly associated with positive lymph node status and with poorly differentiated carcinomas. Duration of relapse-free and overall survival was significantly longer in the Japanese women than in the Anglo women. Women with c-erbB2-negative tumors had a longer overall survival than women with c-erbB2-positive tumors and this difference was accentuated when patients were stratified according to country of origin. Japanese women with c-erbB2-negative tumors had the best outcome, whereas the Anglo women with c-erbB2-positive tumors had the worst. There was no relationship between p53 status and any histopathological features or clinical outcome. Differences in the expression of c-erbB2 and p53 do not explain the better outcome experienced by Japanese breast cancer patients.

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The increased detection of ductal carcinoma in situ (DCIS) by mammographic screening and the more widespread use of breast-conserving surgery have led to a search for histological features associated with the risk of recurrence. In a case control study of 141 patients with long follow-up, we compared the ability of five morphological classifications to predict recurrence after local excision. A significant correlation was not found between recurrence and growth pattern when a traditional classification based on architecture was used nor with necrosis when a scheme based principally on this feature was employed. A correlation was, however, found between recurrence and "differentiation" as defined by nuclear features and cell polarization in a classification recently formulated by the European Pathologists Working Group (EPWG), but this failed to reach statistical significance at the 5% level. A stronger and statistically significant correlation was found between nuclear grade as defined by the EPWG and recurrence when cell polarization was disregarded, using the classification currently employed by the UK National Health Service and European Commission-funded Breast Screening Programmes. This was attributable to a small number of recurring cases being downgraded as a consequence of exhibiting polarized cells. A significant correlation between histology and recurrence was also observed using the Van Nuys classification, which is based on nuclear grade and necrosis. Whether the tumor recurred as in situ or invasive carcinoma was unrelated to histological classification, as was the time course over which it occurred. These findings strongly support the use of nuclear grade to identify cases of DCIS at high risk of recurrence after local excision, but further work is necessary to determine whether nuclear grade or necrosis is more appropriate to subdivide the non-high-grade cases.

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The primary tumour grade in 115 patients with infiltrating ductal carcinoma of the breast was compared with the type of the ductal carcinoma in situ (DCIS) component and with the grade of 169 locally recurrent and metastatic lesions. 102 patients had axillary lymph node metastases at the time of primary surgery, 49 had subsequent recurrences and 36 had both. There was concordance of grade between the primary tumour and axillary lymph node metastases and with subsequent locally recurrent and metastatic lesions. The type of the DCIS component was also significantly associated with the grade of the infiltrating component. No evidence of progression of tumour grade between these phases of mammary carcinoma was found.

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The clinicopathological characteristics of breast cancer in 95 women between the ages of 24 and 45 years with a family history of breast cancer were compared with tumours from 329 women with sporadic disease matched for age and year of diagnosis. There was a trend for the family history patients to have slightly smaller tumours (mean size 2.49 cm) than the controls (mean 3.04 cm) (Mann-Whitney test, P = 0.09). A significantly greater proportion of the familial cases had grade III infiltrating ductal carcinoma than did the controls (40% vs 27%; chi2(1) = 5.64, P = 0.02). Despite this, there were more cases of operable node-negative disease among the study group than among the controls (48% vs 32%; chi2(1) = 8.2, P = 0.004). There was a highly significant survival advantage for patients with a family history (chi2 = 22.4, P < 0.001). Five- and 10-year survival rates were 92% and 87% for those with a family history compared with 70% and 54% for those in the control group. This survival advantage was maintained when patients with operable disease only were considered. In multivariate analysis, which included age, tumour size, stage, histological grade and family history, family history was an independent predictor of favourable prognosis and, in a Cox model, was associated with a relative risk of survival of 6.11 (95% CI 2.81-13.28). These results suggest that familial breast cancer has a more favourable clinical course than the more common sporadic forms of the disease.

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Experimental studies suggest that cyclin D1 is a potential oncogene but in clinical studies of invasive breast cancer, overexpression of cyclin D1 is found to be associated with oestrogen receptor (ER) expression and low histological grade, both markers of good prognosis. Immunohistochemistry has been used to examine the relationship between cyclin D1 expression and differentiation in 36 cases of ductal carcinoma in situ (DCIS) and the interrelationship between expression of cyclin D1, its associated protein product of the retinoblastoma gene (pRb), and ER, in this group of cases. The expression of these markers has also been examined in nine cases of atypical ductal hyperplasia (ADH) and these results have been compared with the levels of expression seen in DCIS. Cyclin D1 overexpression was found in 23/36 (64 per cent) cases of DCIS and, in contrast to invasive carcinoma, there was no relationship with either differentiation or ER expression. The level of pRb expression was significantly associated with cyclin D1 expression (rS = 0.49, P = 0.001) and only two cases (6 per cent) were pRb-negative. There was no association between pRb and differentiation of DCIS or ER status. In contrast to DCIS, only one case of ADH showed overexpression of cyclin D1 (Mann-Whitney U-test, P = 0.02). All cases of ADH were ER-positive and showed moderate pRb staining, similar to that seen in well-differentiated DCIS. These results provide further evidence that overexpression of cyclin D1 plays a role early in carcinogenesis.

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The clinico-pathological features of 7 cases of adenomyoepithelioma of the breast with features suggestive of malignancy are presented. There was a high incidence of local tumour recurrence, in 2 cases as high-grade infiltrating carcinoma of the breast of no special type ("ductal", grade III). One patient died as the result of a clinically diagnosed cerebral metastasis. Histological examination of the primary breast tumours reveals two main patterns: (1) tumours consisting in part of typical adenomyoepitheliomas but which merge with areas of obviously invasive malignant cells and (2) neoplasms that have the overall architecture of an adenomyoepithelioma but which, on close examination, are found to contain foci of cellular atypia and increased mitotic activity. The two patterns of tumour exhibit the same clinical behaviour and should be distinguished from adenomyoepitheliomas, which are cytologically bland throughout.

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This paper outlines the changes which have occurred over the last 25 years in the methods employed for the measurement of oestrogen receptors to aid the management of women with breast cancer. Immunohistochemistry is now the method of choice and knowledge of oestrogen receptor status is being used with increasing frequency for the selection of adjuvant treatment as well as for the treatment of metastatic disease. It is essential that good quality assurance procedures are established so that results are reproducible and can be used with confidence in individual centres as well as being comparable with those produced elsewhere. A retrospective study of 170 women with metastatic breast cancer provides the basis for a discussion on the advantages and pitfalls of the immunohistochemical assay. Particular emphasis is paid to the choice of cut-off and how the results may be applied in patient management.

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AIM: To investigate the relation between angiogenesis and inflammation in invasive carcinoma of the breast. METHODS: Sections from 75 invasive carcinomas of the breast were stained using immunohistochemistry for von Willebrand factor, CD3, CD8, CD45RO, CD45RA, CD20, CD68, and c-erbB-2. Tumour vascularity was assessed by counting vessels in the three most vascular areas, and calculating the average (x 400 magnification, field 0.168 mm2). Each pattern of inflammation was scored semiquantitatively. RESULTS: The main pattern of inflammation was a diffuse infiltrate of macrophages, and to a lesser extent T cells. Perivascular and perilobular clusters of B and T cells were noted at the edge of the carcinomas, but were less prominent than the diffuse inflammation. Diffuse inflammation, particularly macrophages, was associated with high tumour grade, tumour necrosis, large tumour size, and c-erbB-2 expression. Perivascular and perilobular inflammation also increased with tumour grade. Tumour vascularity increased slightly with intensity of diffuse inflammation (Spearman's rank correlation coefficient rs = 0.17, p = 0.08), and was inversely related to perilobular inflammation (rs = -0.23, p = 0.03). CONCLUSIONS: The correlations between inflammation and vascularity were weak in this study (r2 about 0.04) and thus there was no evidence of an important relation. Discrepancies between this and other studies may be resolved by studying expression of angiogenic cytokines and proteolytic enzymes by tumour infiltrating inflammatory cells, and their relation to tumour vascularity.

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Several recent studies suggest that vascular density may be an independent prognostic indicator in invasive carcinoma of the breast. Increased vascularity has also been shown in ductal carcinoma in situ (DCIS). The prognostic significance of the inflammatory infiltrate in mammary carcinoma is more controversial, but it could affect angiogenesis by releasing angiogenic factors and digesting matrix. Vascularity and inflammation have been studied in 41 examples of pure DCIS, classified using the method of Holland et al. Immunohistochemistry was performed with antibodies to von Willebrand factor, CD3, CD8, CD45RO, CD45RA, CD20, CD68, and c-erB-2. The main pattern of inflammation was clusters of B and T cells situated either adjacent to involved ducts or in the interductal stroma. Typically, these clusters were around vessels with plump endothelium suggestive of high endothelial venules. A less prominent pattern was a diffuse stromal infiltrate of macrophages and T cells. There were two patterns of increased vascularity associated with DCIS: necklaces of vessels close to the involved ducts and vessels arranged diffusely in the interductal stroma. Each pattern of inflammation and of vascularity was graded semi-quantitatively. Increased stromal vascularity was associated with the perivascular clusters of inflammation; both were associated with c-erB-2 expression and extent of the DCIS. Necklaces of vessels were associated with the diffuse inflammation. Perivascular inflammation and c-erB-2 (but neither pattern of vascularity) were associated with poor differentiation of the DCIS. Thus, different patterns of inflammation are associated with different patterns of vessels. The clusters of B and T cells may be recruited via high endothelial venules induced by the DCIS. Cytokines released by the DCIS and/or the inflammatory cells (clusters or diffuse) may stimulate the two patterns of new vessel formation.

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Histological reports of 1869 consecutive women with invasive breast cancer have been reviewed to determine whether histological features of the tumour's were related to the patients' age. The patients, treated between 1983 and 1992, were divided into four groups, based on age. There were 148 aged < or = 39 years, 355 aged 40-49 years, 984 aged 50-69 years and 382 aged 70 years or more. The most outstanding finding was the increase in incidence of grade III infiltrating ductal carcinoma in those aged < or = 39 years (P < 0.0001). Certain tumour types, in particular lobular, were reported more frequently in the oldest age group. Additionally, there was a significant reduction of axillary lymph node metastases, vascular invasion and lymphoplasmacytic stromal reaction with increasing age, all of which were independent of tumour grade. These data suggest that there may be age-related changes in the histology of breast cancer and, in some cases, less aggressive features in the elderly. However, as the life expectancy of women over the age of 70 may be many years, treatment should be based on histological prognostic features of the primary tumour rather than age alone.

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In a series of 73 patients with mucoid breast carcinomas treated at Guy's Hospital between 1973 and 1989, 24 (33%) patients had pure mucoid lesions and 49 (67%) had mixed mucoid carcinomas. The patients with pure mucoid cancers had significantly smaller tumours and, among those in whom an axillary dissection was performed, mixed mucoid cancers were more likely to be associated with axillary nodal metastases (46% vs 14%). After long-term follow-up of 64 patients, both relapse-free and overall survival were significantly better for those with pure mucoid carcinomas, for whom the 10-year actuarial overall survival was 100%. The overall proportion of the tumour that was mucoid was also positively associated with a more favourable prognosis in patients with mixed tumours. With such a good prognosis, patients with pure mucoid carcinomas may not require systemic adjuvant therapy after adequate primary treatment.

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To examine the relationship between body weight and vascular invasion (VI) around tumours in post-menopausal women with operable breast cancer, a retrospective study was conducted of 393 patients treated in a breast unit between 1987 and 1991. Weight was measured at the time of diagnosis. Vascular invasion was recorded as being present or absent. Vascular invasion was seen in slightly more of the 50 perimenopausal patients than in the 343 post-menopausal women (44% vs 36%). In the tumour specimens from post-menopausal patients weighing <50 kg, VI was observed in 11% compared with 45% of those weighing more than 80 kg (P= 0.02). Furthermore, the 5-year survival of those with VI was 74% compared with 91% for those without (P < 0.0001). Menopausal status and body weight may influence survival in patients with breast cancer, possibly as a result of the presence of unopposed circulating oestrogens at the time of surgery. Oestrogens may alter cohesiveness of breast cancer cells and modulate secretion of proteases, thereby influencing invasive potential. Excision of tumours in such an environment may have a deleterious impact on survival.

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c-erbB-3, A recently identified member of the type I tyrosine kinase receptor family, has been shown to be overexpressed in invasive ductal carcinoma of breast. In this study, expression of the c-erbB-3 protein was examined in 57 cases of pure ductal carcinoma in situ of the breast (DCIS) by immuno-cytochemical methods. Staining was either absent (17 cases), present at levels equivalent to that found in adjacent normal tissue (20) or greater than in normal tissue (20). In most cases the pattern of staining was cytoplasmic, but in 4 cases with the most intense reaction there was also focal membrane staining. In the same series of cases, c-erbB-2 protein had previously been shown to be overexpressed in 28 of 57 cases, c-erbB-2 overexpression was correlated with normal level of c-erbB-3, and lack of c-erbB-2 expression was correlated with c-erbB-3 overexpression.

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A comparative immunohistochemical study was performed on Paget's disease of the nipple (PDN), extramammary Paget's disease (EMPD) and cutaneous superficial spreading melanoma (SSM) using antibodies to S100, NK1-C3 and HMB45, cytokeratin (CAM 5.2) and c-erb B2 oncoprotein (21N). Conventional histochemical stains for intracytoplasmic mucin and melanin were also done. Of the 20 cases of PDN, positivity was seen in 12 with S100, 16 with NK1-C3, none with HMB45, 20 with CAM 5.2 and 19 with 21N. All 5 cases of EMPD were CAM 5.2 positive and HMB45, S100 and 21N negative. Three EMPD were NK1-C3 positive. All 10 cases of SSM were S100, NK1-C3 and HMB45 positive and all were CAM5.2 and 21N negative. Mucin was demonstrable in 11 cases of PDN and all of EMPD but none of SSM. Melanin was seen in 2 PDN, 3 EMPD and all SSM cases. Identification of mucin and melanin, therefore, proved an unreliable means of distinguishing these diseases. Immunohistochemistry for cytokeratin and HMB45 appear to be the most specific markers in differentiating Paget's disease and SSM. Antibodies to c-erb B2 may also be valuable in this situation.

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