In 150 surgically resected primary breast carcinomas that had axillary lymph-node metastases, we examined the incidence of loss of heterozygosity on chromosomes 16p, 16q, 17p, 17q, and 18q, point mutation of the p53 tumor-suppressor gene, nuclear immunoreaction of p53 protein, and amplifications of the c-erbB-2 and int-2 oncogenes by Southern blotting, single-strand conformation polymorphism analysis, and immunohistochemistry. We analyzed the association of these factors and conventional prognostic parameters with outcome of the patients, using Cox's univariate and multivariate analyses. The univariate analysis revealed that nuclear p53 immunoreaction, p53 mutation, and c-erbB-2 amplification as well as the number of metastatic lymph nodes, histological grade, and hormone-receptor statuses were significant prognostic indicators for both recurrence and cancer death. p53 immunoreaction was correlated more strongly with a poor prognosis than p53 mutations. The combination of p53 and c-erbB-2 effectively identified the high-risk patient group, and even among Grade 3 cases the subgroup with these alterations tended to have poorer clinical outcomes. The multivariate analysis including p53, c-erbB-2, and conventional factors. Lymph node status, grade, and p53 had independent impacts on the survival of patients. Under identical adjuvant systemic therapies, prognoses differed between the patient groups with and without alterations of p53 or c-erbB-2. Appropriate combinations of conventional factors with nuclear p53 immunoreaction and c-erbB-2 amplification would help to identify highly aggressive node-positive breast carcinomas and would aid stratification of patient groups in randomized clinical trials of adjuvant systemic therapies.

Summary Although breast carcinomas are considered to originate from glandular epithelial cells, some exhibit 'squamoid features', comprising stratification with a gradient in the nuclear-cytoplasmic ratio within individual cancer cell nests on microscopy. In parallel with a histological review of squamoid features, we immunohistochemically investigated the expression of involucrin, a marker of terminal squamous differentiation, in 223 breast carcinomas with one to three regional nodal metastases but no distant metastases and analysed their association with other clinicopathological parameters to explore their clinical and biological implications. Squamoid features and involucrin expression, detected in 22% and 27% of cases respectively, correlated with each other and were associated with high-grade atypia, a solidnest pattern, cancer cell necrosis on histology and negative oestrogen receptor status. The incidence of regional recurrences was higher in patients with involucrin expression, whereas bone metastases were less frequent in groups with squamoid features or with diffuse (> 10%) involucrin expression. Both squamoid features and involucrin expression, which were considered to be derived either from differentiation into keratinocytes or from some kind of cellular degeneration caused by high turnover rate, are suggested to influence the biological behaviour of breast cancer cells in vivo, and they may be effective in predicting the most likely recurrence sites.

The histological grade of atypia is a known prognostic indicator for breast cancer patients and correlates with many gene and chromosome alterations. To investigate the independent prognostic significance of gene and chromosome alterations in axillary node-negative (n0) breast cancers of the invasive ductal and invasive lobular types, the prevalence of eight gene and chromosome alterations and their association with histological grade and recurrence was studied in 129 consecutive patients who had undergone resection over an average follow-up period of 43.4 months. Loss of heterozygosity on 16q, 17p, 16p, 17q and 18q, p53 gene mutation and c-erbB-2 and int-2 gene amplifications were detected in 55%, 37%, 25%, 24%, 22%, 23%, 15% and 11% respectively. Individual alterations in 17p, 17q, 18q, c-erbB-2 and p53 were detected most frequently and gene and chromosome alterations tended to be accumulated in Grade 3 n0 invasive ductal/lobular carcinomas. Histological grade, 18q, int-2 and the number of these gene and chromosome alterations were significant prognostic indicators on Cox's univariate proportional hazard model, and 18q and int-2 were still significant after adjustment for histological grade. Results suggested that examination of the presence of certain gene and chromosome alterations, as well as histological grade, were effective in identifying n0 breast cancer patients at high risk of early recurrence.

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