ESR1 mutant breast cancers show elevated basal cytokeratins and immune activation

Estrogen receptor alpha (ER/ESR1) is mutated in 30-40% of endocrine resistant ER-positive (ER+) breast cancer. ESR1 mutations cause ligand-independent growth and increased metastasis in vivo and in vitro. Despite the distinct clinical features and changes in therapeutic response associated with ESR1 mutations, there are no data about their potential role in intrinsic subtype switching. Applying four luminal and basal gene set pairs, ESR1 mutant cell models and clinical samples showed a significant enrichment of basal subtype markers. Among them, the six basal cytokeratins (BCKs) were the most enriched genes. Induction of BCKs was independent of ER binding and instead associated with chromatin reprogramming centered around a progesterone receptor-orchestrated topological associated domain at the KRT14/16/17 genomic region. Unexpectedly, high BCK expression in ER+ primary breast cancer is associated with good prognosis, and these tumors show enriched activation of a number of immune pathways, a distinctive feature shared with ESR1 mutant tumors. S100A8 and S100A9 were among the most highly induced immune mediators shared between high-BCKs ER+ and ESR1 mutant tumors, and single-cell RNA-seq analysis inferred their involvement in paracrine crosstalk between epithelial and stromal cells. Collectively, these observations demonstrate that ESR1 mutant tumors gain basal features with induction of basal cytokeratins via epigenetic mechanisms in rare subpopulation of cells. This is associated with increased immune activation, encouraging additional studies of immune therapeutic vulnerabilities in ESR1 mutant tumors.

Sinonasal analogue HPV related breast multiphenotypic carcinoma, a report of a case with the first description in the breast

Background High grade basal-like breast carcinomas are triple negative, express basal cytokeratins, and are known for the overall poor prognosis and aggressive behavior. HPV related multiphenotypic sino-nasal carcinoma has overlapping histology with basal-like breast carcinomas, but carry the defining feature of association with high risk HPV. Case presentation We present a case of a perimenopausal woman with a non-healing ulcerated lesion involving the nipple and breast following a trauma. Biopsy performed showed an HPV-positive basal-like carcinoma with squamous differentiation involving the breast, analogous to multiphenotypic carcinoma previously described in the sinonasal tract. Conclusion This is the first report of a case of a high- risk HPV related basal-like carcinoma with squamous differentiation, described in the literature. We highlight the morphology and immunophenotype of this lesion and its recognition when compared to other multiphenotypic lesions of the breast, and suggest that pathologists should consider HPV evaluation when encountering similar basal-like tumors involving the breast.

Expression of cytokeratins 5/6 and cytokeratin 17 in invasive breast carcinoma

Background/Aim. Cytokeratins (CK) 5/6 and 17, myoepithelial markers, are also expressed in a proportion of breast carcinomas. Breast carcinomas expressing basal epithelium cytokeratins constitute a tumor subgroup that shows common but heterogeneous morphological, genetical, and immunophenotypical features and is associated with poor clinical outcome. The aim of this study was to determine the incidence of basal expression of cytokines CK5/6 and CK17 in the tested samples of ductal invasive breast cancers, as well as to test the presence of a correlation of tumor expression of basal cytokines and clinicopathological prognostic factors: age, the level of histological differentiation, hormone receptor status, HER2 (human epidermal prowth factor receptor 2) protein expresion and HER2 gene amplification in tumorous tissue. Methods. Immunohistochemistry (IHC) was used to evaluate the CK5/6 and CK17 status of 121 ductal invasive breast cancers. The results thus obtained were compared with clinicopathological characteristics. Results. From the 117 analyzed tumor specimens, 22% and 30% were immunohistochemically positive for CK5/6 and CK17, respectively. Basal cytokeratins showed significant inverse relationship with estrogen and progesterone receptor status and HER2 protein expression. CK5/6 and CK17 immunoreactivities were directly associated with triple-negative phenotype and higher histological grade. Conclusion. Our findings are similar to reports that tumours expression of basal cytokeratins are correlated with adverse pathological parameters. Given the limited number of emerging therapeutic targets in these tumors, routine IHC identification of basal-like subtype as a poor prognostic group of breast cancer could be based on the expression of basal CKs.

An Immunohistochemical Panel to Differentiate Metastatic Breast Carcinoma to Skin From Primary Sweat Gland Carcinomas With a Review of the Literature

Context.—Approximately 25% of patients with breast cancer develop cutaneous metastases. Sweat gland carcinomas (SGCs) account for about 0.05% of all cutaneous neoplasms. Cutaneous metastases of breast carcinoma (CMBCs) (especially the ductal type) can be difficult to distinguish from SGCs. Treatment and prognoses for these 2 types of tumors differ radically, making accurate histologic diagnosis crucial. Although a few studies attempt to differentiate these entities employing immunohistochemical (IHC) studies (some of which we review here), to date, no panel of IHC stains exists, to our knowledge, to distinguish these entities. Objective.—To devise a panel of IHC stains to distinguish CMBC from SGC. Design.—Twelve cases of ductal CMBCs (11 not otherwise specified type, and 1 basal phenotype), 11 cases of SGCs (5 eccrine carcinomas, 3 porocarcinomas, and 3 microcystic adnexal carcinomas), 2 benign sweat gland neoplasm cases, and 2 primary breast cancer cases were retrieved and analyzed with the following IHC panel: mammaglobin, gross cystic disease fluid protein (GCDFP) 15, p63, basal cytokeratins (CK5, CK14, and CK17), androgen receptor, and PAX5. Results.—The p63 was only weakly expressed in 1 of 12 CMBC cases (8.3%), whereas it was strongly expressed in 10 of 11 SGC cases (90.9%) (P < .001). Basal cytokeratins demonstrated a similar immunoprofile in the SGC group, with 10 of 11 cases (90.9%) expressing all 3 markers, and a variable immunoprofile in the CMBC group with 0% (CK14) (P < .001) to 16.7% (2 of 12 cases; CK5 and CK17) (P < .001) expression. Mammaglobin was expressed in 8 of 12 cases (66.7%) of CMBC. Conclusions.—Together, these 5 IHC stains were combined to make a panel that was 100% sensitive and 91% specific in distinguishing between CMBC and SGC.