Myoepithelial Lesions of the Breast

Clinical Presentation

AMEs occur in patients of similar age with breast carcinoma. It's mostly presented as a breast mass. The lesions may be palpable depending on their size and location. Occasionally, they are seen as small masses on mammographic imaging.

Gross Pathology

AMEs of the breast have been well documented. Some of these tumors are described as either myoepitheliomas or leiomyosarcomas in earlier literature. The bulk of the English-language literature, though, indicates that AMEs present as breast masses (on average 2 to 3 cm) in the same age range as for patients with breast carcinoma. They are firm to rubbery, and generally circumscribed, but can mimic carcinoma grossly with infiltrative borders. Benign AMEs are usually small, slow-growing round or lobulated masses, while malignant transformed AMEs are usually larger, fast-growing masses with infiltrative borders.

Microscopic Pathology

AMEs have a biphasic cytoarchitecture composed of tubular structures lined by luminal epithelial cells, surrounded by proliferating myoepithelial cells that have spindle cell, polygonal cell shapes often with clear cytoplasm, or with squamous differentiation ( Fig. 17.2A to D ). These two types of cells can be arranged in tubular, lobulated, spindle cell, adenosis, and papillary or mixed-growth patterns. It is helpful to keep in mind that AMEs and intraductal papillomas represent opposite ends of a spectrum of intraductal proliferations of the breast. Cytological atypia, mitosis, necrosis, and border status are commonly use to separate AMEs from malignant AMEs, and the term atypical AME has been proposed to classify those lesions that lack all the histological features of malignant AMEs ( Table 17.2 ). There are two main histological patterns for malignant AMEs: (1) tumors consisting in part of typical AMEs but that merge with areas of obviously invasive malignant cells; and (2) neoplasms that have the overall architecture of an AME but that, on close examination, are found to contain foci of cellular atypia and increased mitotic activity. These two patterns of malignant AME exhibit the same clinical behavior and should be distinguished from benign AMEs. The authors have encountered a few of the latter, which we believe could be considered "malignant" AMEs ( Fig. 17.3A to H ). AMEs with areas of carcinoma, AdCC, and undifferentiated carcinoma have been reported as well.

IHC Analysis

As a biphasic tumor, the epithelial component will be positive for epithelial markers such as AE1/AE3 and CAM5.2, while the myoepithelial component should be positive for myoepithelial markers such as p63, smooth muscle myosin heavy chain (SMM-HC), calponin, ad smooth muscle actin (SMA). However, as cytological atypia increase, the distinction between epithelial and myoepithelial cells becomes less obvious and cells may show aberrant expression patterns not correlating with their morphological cell types.

AMEs are usually triple negative—that is, estrogen receptor negative (ER–), progesterone receptor negative (PgR–), and human epidermal growth factor receptor-2 negative (HER2–)—with variable labeling for the proliferating marker Ki-67: usually lower in benign AME and higher in malignant AME. ER can be weakly and/or focally positive in the epithelial component of AME. HER2 amplifications are never reported in AME, but they can occur in coexisting ductal carcinoma and coexisting apocrine metaplasia.

Pareja et al recently reported that a highly specific monoclonal antibody (SP174) can detect HRAS Q61R mutation with 100% specificity in ER– AME.

Differential Diagnosis

Morphologically and immunohistologically, AMEs should be distinguished from other biphasic lesions of the breast, including low-grade adenosquamous carcinoma ( Fig. 17.4A to C ), adenoid cystic carcinoma, and other sclerosing and papillary lesions.

Because of the marked differences in tumor aggressiveness and therapy, benign AME should be clearly distinguished from the spindle cell variant of metaplastic carcinoma of the breast ( Fig. 17.4D to F ; see Chapter 25 of Metaplastic Carcinoma). Moreover, closely related examples of malignant AME, myoepithelial carcinoma, AME with carcinoma, and AME with undifferentiated carcinoma are scattered throughout the literature. The histological, ultrastructural, and immunohistochemical (IHC) features of these malignant AMEs overlap greatly with spindle cell variants of metaplastic carcinoma; indeed, the distinctions between these malignant entities are poorly defined and not likely reproducible, and may have more academic than practical value.

A peculiar variant of ductal carcinoma in situ (DCIS) has been described that is characterized by intraductal growth of carcinoma cells having clear cell and spindle cell myoepithelial differentiation and should be differentiated from AME. Also, the epithelial component of an AME surrounded by the spindle myoepithelial component can be mistaken for invasive carcinoma in a desmoplastic stroma. Adding to this pitfall, if apocrine metaplasia is present, it may exhibit immunoreactivity for HER2. Finally, less well-developed benign myoepithelial lesions are encountered, such as myoepitheliosis (periductal proliferation of eosinophilic myoepithelial cells) or adenomyoepithelial adenosis (periductal proliferation of clear myoepithelial cells), which can mimic invasive carcinoma as well.

Molecular Alterations

AMEs display fewer copy number alterations and fewer mutational burdens than conventional invasive breast carcinomas; also, homozygous deletions and gene amplifications are uncommon, which are often associated with malignant phenotypes.

AMEs appear to have gene alterations associated with ER status. In ER+ AMEs, there are frequent activating mutations with PIK3CA or AKT1; in ER– AMEs, up to 60% have HRAS Q61 hotspot mutations, which often coexist with PIK3CA or PTK3RI mutations.

AMEs are also genetically related to other epithelial-myoepithelial lesions of the salivary glands. For example, up to 50% of salivary lesions also have coexisting HRAS Q61 hot-spot mutations and PIK3CA mutations, which are commonly present in ER– AMEs. Also, a subset of ER+ AMEs have HMGA2-WIFI fusion, which is commonly seen in PA, suggesting that this subset of AMEs might be related to PA.

Malignant AMEs are shown to be associated with epidermal growth factor receptor (EGFR) amplifications as well.

Treatment and Prognosis

AMEs comprise a spectrum of diseases ranging from benign to malignant, although the vast majority have thus far been considered benign. Among the 27 cases reported by Tavassoli, only two cases recurred, and none metastasized.

Loose and colleagues reported six cases of AME including two malignant examples. Both malignant examples had high mitotic rates (11 to 14/10 HPF) and cytologically malignant cells. The metastasizing example showed the biphasic features of typical AMEs; the other example showed spindle cell morphology as the malignant sarcomatous component. Van Dorpe and coworkers described rare cases of AME giving rise to AdCC, which is an example of epithelial-myoepithelial carcinoma. Foschini and coworkers reported six cases of invasive breast carcinoma with unusual morphological features. The ages of the female patients ranged from 46 to 79 years (mean age, 60.5 years). All tumors had areas typical of an AME. In three of the patients, adenomyoepithelioma gradually merged with low-grade adenosquamous carcinoma. In the other three patients, a sarcomatoid carcinoma was associated with adenomyoepithelial areas. The morphological spectrum of salivary gland–type breast tumors including AME was reviewed recently by Foshini et al.

The treatment for AME is largely based on its morphological diagnosis. Generally, a benign AME needs local excision only; an atypical or recurrent AME requires local excision with a wide margin; and a malignant AME needs excision with wide margins or mastectomy plus or minus radiation. If carcinoma arises from the AME, systematic therapy should also be considered according to the guideline for in situ or invasive carcinoma treatment.

Clinical Presentation

AdCC of the breast closely resembles AdCC of salivary gland origin, but it is much less common, only accounting for approximately 0.1% of all breast carcinomas. AdCC occurs in adult women of the same age group as for mammary carcinoma (i.e., mean age 50 to 63 years; range 25 to 80 years). Rare cases have been reported in men. AdCC usually presents as a discrete, firm mass, often located in the retroareolar region. They can be detected by mammography and some could be present for 10 years or more. Occasionally, AdCC may be found as an incidental finding in the breast. AdCC of the breast has an indolent clinical course, with very rare nodal and distant metastasis.

Electron microscopic studies have revealed AdCC from both the breast and salivary gland share the same diverse cell types. This likely reflects the common ectodermal “sweat gland” origin of both the breast and salivary gland. Indeed, breast glands and salivary glands are tubuloacinar exocrine glands that can manifest as tumors with similar morphological features but differ in incidence and clinical behavior. Salivary gland–like tumors of the breast are of two types: tumors with myoepithelial differentiation and those devoid of myoepithelial differentiation. The first and more numerous group comprises a spectrum of lesions ranging from benign AME and PA, low-grade malignant such as AdCC, low-grade adenosquamous carcinoma, and atypical AME, to high-grade malignant lesions such as metaplastic carcinoma and malignant AME. The second group comprises lesions that have only recently been recognized, such as acinic cell carcinoma, oncocytic carcinoma of the breast, and the rare mucoepidermoid carcinoma.