Most Basal-like Breast Carcinomas Demonstrate the Same Rb-/p16+ Immunophenotype as the HPV-related Poorly Differentiated Squamous Cell Carcinomas Which They Resemble Morphologically

Basal-like carcinomas (BLCs) are one of 5 distinct groups of invasive breast carcinomas defined by gene expression profiling (GEP).11,14,15 These groups are luminal A and luminal B (defined by significant expression of estrogen-related and luminal epithelium-related genes), HER-2 positive (defined by a low expression of estrogen-related genes and high expression of HER-2–related genes), normal breast-like (defined by high expression of adipose tissue/myoepithelium-related genes and low expression of luminal epithelium-related genes), and basal-like (defined by low expression of estrogen receptor (ER) and HER-2–related genes and high expression of myoepithelium-related genes). BLC typically affect young patients, demonstrate rapid clinical growth, preferentially metastasize hematogenously to lung and brain as opposed to lymph nodes, are associated with BRCA1 gene mutations, and are associated with poor outcome.8,11,14,15,26,37 BLC comprise approximately 15% to 20% of all breast carcinomas, and the majority of ER −, progesterone receptor (PR) −, HER-2 − breast carcinomas [(“triple-negative carcinoma”) (TNC)]. Although BLCs are currently defined by GEP, an ER −, PR −, HER-2 − immunophenotype with expression of cytokeratin 5/6 (CK 5/6) and/or epidermal growth factor receptor (EGFR) is a useful immunohistochemical (IHC) surrogate for BLC. It is estimated that this IHC phenotype is 100% specific and 76% sensitive for BLC as defined by GEP.31 The morphologic features which distinguish breast carcinomas with a BLC GEP from other breast carcinomas have been described by multiple groups. Several of the more distinctive features include a pushing, noninfiltrative border; a ribbonlike architecture surrounding central necrosis; cellular, solid tumor areas with minimal desmoplasia; small basaloid cells and larger polygonal cells with sharp borders resembling poorly differentiated squamous cell carcinoma (SCC); and a high proliferative index.16,27 Interestingly, all the above morphologic features also distinguish poorly differentiated human papilloma virus (HPV)-related SCCs of the oropharynx, penis, and vulva18,46 from non–HPV-related SCCs arising in these sites. HPV is usually not involved in the pathogenesis of the better differentiated, more keratinizing SCCs of the latter sites (Fig. 1). FIGURE 1 HPV-related squamous cell carcinomas of the oropharynx (HPV SCCs) mimic BLCs of the breast. HPV-related SCC of the tonsils feature ribbonlike, cellular areas of basaloid cells surrounding geographic areas of necrosis (A, B). In contrast, a non–HPV-related ... Diffuse expression of p16, which normally inhibits cyclin-dependent kinases and thus blocks proliferation, is an excellent immunochemical surrogate for SCCs harboring high-risk HPV. The explanation stems from the fact that HPV E7 protein inactivates the retinoblastoma (Rb) tumor suppressor, a potent suppressor of the G1-S cell cycle transition. Rb inhibits p16 transcription through a negative feedback loop between p16 and Rb; as a result, p16 levels are paradoxically high in these highly proliferative tumors, resulting in diffuse, strong p16 immunoreactivity. This phenomenon has been termed “abrogated response to cellular stress,” as expression of p16 is normally a protective reaction to cellular stress which inhibits proliferation and initiates senescence.17 Diffuse p16 immunoreactivity is useful diagnostically for delineation of HPV-related high-grade intraepithelial neoplasia.2,23,24,32,41 HPV E6 protein also inactivates p53 in these cancers, further compromising the G1-S cell cycle checkpoint. Given the overlap of distinguishing morphologic features between BLC of the breast and HPV-related SCCs of the oropharynx, penis, and vulva, one might hypothesize that similar genes might be inactivated in each cancer. Indeed, inactivating p53 mutations have been reported to be more frequent in BLC than in other subtypes of breast cancer,8 which parallels the inactivation of p53 by HPV E6 protein in SCCs. However, the Rb/p16 status of BLC of the breast has not been assessed. In this study, we examine the Rb/p16 status of BLC of the breast, and other unclassifiable triple negative breast carcinomas, in comparison to luminal and HER-2–positive breast carcinomas. We correlate expression of these markers with proliferative activity, as well as p53 and HPV status.