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Medullary carcinoma is a poorly differentiated breast cancer tumor with a high histologic grade and a paradoxically good prognosis. It accounts for only 5% of all breast cancers (1–3). Thus far, only histologic criteria are used to define this tumor type; no genetic characteristics have been identified. An alteration in the p53 gene (also known as TP53) is found in 20%– 40% of invasive breast cancers, but its status in medullary breast cancer is poorly documented. Immunochemical detection of a stable mutant p53 in nuclei of tumor cells is the most convenient assay, but the correlation of the results from such an assay with results from molecular analysis, such as sequencing, is not totally in agreement (4). The frequency of p53 mutations in breast cancer is around 20%, but immunohistochemical analysis detects p53 accumulation in 30%–40% of tumors (5,6). In the present study, we demonstrate that typical medullary breast carcinomas have a high frequency of p53 alterations (100%). We found excellent agreement between the results of the different analytical techniques that we used. We obtained specimens from 23 medullary breast carcinomas from the Institut Curie tumor bank; these carcinomas were initially registered (during the period from 1989 to 1995) as medullary carcinomas. All specimens were selected on the basis of the availability of blocks and frozen material, and two trained pathologists (B. Bouchind’homme and A. V. Salomon), who were blinded to the status of the specimens, independently reviewed each specimen during the study. As defined by Rapin et al.(3), typical medullary carcinomas display at least 75% syncytial architecture, a welldefined border, diffuse lymphoplasmocytic infiltrate, moderate or marked anisonucleosis, and absence of tubular differentiation and/or an intraductal component(2,3) (15 of our 23 specimens). Atypical medullary carcinomas (eight of our 23 specimens) have a syncytial architecture and two or three of the above criteria. We assessed the status of the p53 gene by using molecular and immunohistochemical techniques (8) (Fig. 1). For the molecular analysis, we combined direct sequencing of genetic material from tumors with a functional assay, developed by Flaman et al. (7), to ensure that all molecular changes detected were deleterious for p53 function (true mutations). Seventy-four percent (17 of 23) of tumors had a p53 mutation (Table 1). Immunohistochemical analysis showed that p53 accumulated in the 14 tumors that contained a missense mutation, one in-frame codon deletion (patient 7), or a long truncated protein (patient 3) (Table 1). Tumors expressing short truncated p53 (tumors in patients 2, 10, and 15) did not accumulate p53, since such proteins are rather unstable (Table 1). Thus, we observed 100% agreement between the molecular genomic analysis and the accumulation of p53 in the nucleus of the tumor cells. In this immunohistochemical analysis, all positive cases were intensely stained, with more than 70% of cells staining (Fig. 1). This result is very unusual for invasive breast cancer, because the staining intensity is generally quite heterogeneous. This finding is not due to technical variation, because we observed a similar heterogeneity in 328 breast tumor samples that we have analyzed recently (9). Previous studies(10–12)have suggested that the p53 alteration could occur frequently in medullary breast carcinoma, but no detai led analyses combining sequencing and immunohistochemistry have been performed; furthermore, the small number of cases reported did not enable adequate statistical evaluation. As defined by Rapin et al. (3), eight tumors were atypical medullary breast carcinomas and 15 tumors were typical medullary breast carcinomas. It is interesting that all typical medullary carcinomas harbored a p53 alteration (Table 1) (95% confidence interval [CI] 4 78%– 100%). In the eight atypical medullary carcinomas examined, only two mutations were detected, giving a frequency of 25% (95% CI4 3%–65%), a frequency similar to that in invasive breast carcinomas. Our results indicate that medullary breast carcinoma is a distinct genetic subtype of breast cancer. The observations of a high incidence of p53 alterations and an unambiguous pattern of p53 staining suggest that the genetic pathway leading to this subtype of cancer is different from that of common infiltrating breast carcinoma. To our knowledge, this is the first time that a genetic defect is able to specifically distinguish medullary breast carcinoma. It has recently been shown (13,14)that medullary breast carcinoma is found at a very high frequency (up to 20%) in patients with BRCA1associated breast cancers. The observation that BRCA1-associated tumors also have a high frequency of p53 mutation (15) suggests that there may be a relationship between alterations in the BRCA1 gene and medullary breast carcinoma, supporting the notion that a specific genetic pathway leads to this tumor type. Medullary breast carcinomas usually have a much more favorable prognosis than the poorly differentiated common invasive cancers. This behavior is para-

p53 Mutation as a Genetic Trait of Typical Medullary Breast Carcinoma