and Aysegul A. Sahin2
Division of Pathology, Singapore General Hospital, Singapore, Singapore
The University of Texas, M. D. Anderson Cancer Center, Houston, TX, USA
Apocrine morphology is characterised by abundant eosinophilic cytoplasm containing finely granular, periodic acid–Schiff (PAS)-positive, diastase-resistant granules and moderate to large, centrally or eccentrically located nuclei with prominent nucleoli and distinctive cell borders. It is commonly observed in a wide variety of breast lesions [1–4] (Fig. 7.1), ranging from simple cysts to intraductal proliferative lesions with and without atypia and to invasive carcinoma (Fig. 7.2). The majority of apocrine breast lesions are benign and have no major clinical consequences. They are often considered normal features of the female breast after the age of 25–30 years . Some apocrine proliferations may cause diagnostic problems, however, especially when they involve pre-existing lesions such as adenosis or papilloma [3, 6]. Accurate diagnosis and classification of these lesions are important. The biologic and clinical significance of breast carcinomas with apocrine morphology remains controversial, mainly because of the subjectivity of histopathological criteria and the lack of specific biomarkers for reliable classification of this histological subtype of breast carcinoma. Identification of novel molecular markers that can define apocrine carcinoma and determine the true clinical significance of apocrine differentiation in breast cancer is an area of active research.
Apocrine metaplasia. (a) On H&E staining, apocrine cells are characterised by abundant pink, granular cytoplasm and centrally located hyperchromatic nuclei, which may have one or two prominent nucleoli. The nuclear to cytoplasmic ratio is very low. The apical portions of the cells contain coarse eosinophilic granules. These type A apocrine cells are more commonly observed than type B apocrine cells which feature abundant foamy cytoplasm. (b) Type B apocrine cells (arrows) with abundant pale to foamy cytoplasm
Apocrine change in the breast is seen in a broad range of lesions. (a) Benign microcyst with apocrine metaplasia. (b) Usual ductal hyperplasia with apocrine change. (c) Invasive apocrine carcinoma
Gross cystic disease fluid protein 15 (GCDFP-15), originally isolated from the contents of a breast cyst, is a sensitive immunohistochemical marker of apocrine differentiation. It can be used to confirm apocrine differentiation in both benign and malignant conditions (Fig. 7.3) [7, 8]. Some non-apocrine breast lesions can also be positive for GCDFP-15. Similarly, androgen receptor is a sensitive but not a specific marker of apocrine differentiation (Fig. 7.4). Today, apocrine differentiation is determined primarily on morphologic features.
Immunohistochemical staining for gross cystic disease fluid protein 15 (GCDFP-15). Almost all benign apocrine lesions and a great majority of malignant apocrine lesions show strong positivity for this marker
Immunohistochemical staining for androgen receptor in adenosis with apocrine differentiation. Though apocrine cells show strong diffuse expression of androgen receptor, only scattered non-apocrine cells are positive (arrow)
This chapter reviews histopathologic features of apocrine lesions of the breast, with an emphasis on the differential diagnosis of benign, borderline, and malignant apocrine lesions.
Benign Lesions: Apocrine Metaplasia
Apocrine metaplasia, defined as the change of the breast epithelium into an epithelium similar to that found in apocrine glands of cutaneous origin, is quite common and is observed in a variety of benign breast lesions (cystic changes, fibroadenoma, papilloma, and sclerosing adenosis) (Figs. 7.5 and 7.6). Embryologically, the breasts develop from the anlage that gives rise to apocrine glands, but apocrine glands are not basic histologic components of the breast. There are several hypotheses regarding the origin of apocrine cells in breast tissue. The presence of apocrine epithelium is generally regarded as a metaplastic or degenerative process, but some suggest that apocrine cells may be a normal constituent of glandular structures of the breast and may represent apocrine glands of cutaneous origin entrapped in breast tissue . Apocrine cells in the breast are histologically indistinguishable from apocrine cells in cutaneous apocrine glands.
Cystic duct with apocrine metaplasia. Transition from normal ductal epithelium to apocrine metaplasia is shown (arrow)
Apocrine metaplasia is a common component of breast cystic changes (left lower field) and is frequently associated with adenosis and a broad range of benign proliferative changes. An intraductal papilloma is present (right field)
Clinical and Epidemiological Features
Apocrine metaplasia is frequently found along the epithelial lining of cysts (Fig. 7.7), which can be part of breast cystic changes that may present as a palpable mass (Fig. 7.8) or be associated with microcalcifications [3–5]. There is no specific clinical feature that can be attributed to apocrine metaplasia. Apocrine metaplasia is a common histologic finding in the female breast after 25–30 years of age [3–6, 10]. It is rarely seen in women younger than 20 years, and the frequency increases with age, being highest in the fifth decade.
Cystic apocrine metaplasia. Dilated cysts are lined by apocrine cells
Cystic apocrine metaplasia. (a, b) Cystically dilated glands lined by benign apocrine epithelium. (c) Higher magnification shows that the nuclei are centrally and basally located and there is no cytologic atypia. The lumen contains eosinophilic secretory material mixed with a few degenerative cells. Rare mitoses can be identified even in benign apocrine proliferations (b, arrow)
Clusters of ducts with apocrine metaplasia may form a mass that can be identified on imaging. They may be associated with microcalcifications, which can be calcium phosphate or calcium oxalate (Fig. 7.9).
(a) Apocrine cyst. A cystically dilated gland lined by apocrine cells shows luminal pale secretions and transparent calcium oxalate. (b) Polarised microscopy shows refractility of the calcium oxalate within the lumen
There are no specific macroscopic findings associated with apocrine metaplasia. Large cystic lesions may be grossly visible and contain dark-coloured fluid.
Cystic apocrine metaplasia is composed of flat and cuboidal cells with abundant eosinophilic granular cytoplasm and round nuclei located in either the basal or central positions. The nuclei often have prominent nucleoli. The cells are typically evenly spaced and have distinct borders (Fig. 7.10).
Benign cystic apocrine metaplasia. The apocrine cyst lining may be a single layer (a) or multiple layers of apocrine cells (b). The cells are typically evenly spaced and have distinct borders
Apocrine cells lining glands usually show apical snouts projecting into the lumen (Fig. 7.11). A myoepithelial layer is easily distinguishable, but diminished or focally absent myoepithelium has been reported in benign apocrine cysts.
Benign cystic apocrine metaplasia with typical apical snouts, low (a) and higher (b) magnification
Apocrine metaplasia has a distinct histological appearance that usually does not pose diagnostic difficulty. Other benign lesions such as duct ectasia with abundant histiocytes may mimic apocrine metaplasia (Fig. 7.12
Foamy histiocytes within the duct wall and lumen may mimic apocrine metaplasia. Here, the foamy histiocytes have ample pale brown cytoplasm reflecting intracytoplasmic ceroid or lipofuscin, whereas apocrine cells have pink cytoplasm. Presence of intraluminal foam cells with identical histological appearances as those along the duct wall, together with accompanying chronic inflammation, favour a histiocytic origin
Malignant Apocrine Lesions
Apocrine Ductal Carcinoma In Situ
Apocrine-like changes are common findings in ductal carcinoma in situ (DCIS) (Figs. 7.13 and 7.14). The incidence of pure apocrine DCIS is difficult to establish in the literature because of the variable diagnostic criteria used to define apocrine differentiation [12–17]. The presence of abundant eosinophilic cytoplasm and centrally located enlarged nuclei, which are the defining histologic features of apocrine differentiation, are common findings in high-grade DCIS. High-grade apocrine DCIS, characterised by proliferation of pure apocrine cells with marked nuclear pleomorphism, high mitotic rate, and comedonecrosis, presents the least diagnostic difficulty (Fig. 7.15). Comedonecrosis is a common finding in apocrine DCIS, and some experts require the presence of necrosis to establish the diagnosis of DCIS in apocrine proliferations [14, 16]. They consider that all apocrine DCIS should be at least intermediate grade based on nuclear features. Others support classification of apocrine DCIS into categories of low grade, intermediate grade, and high grade, similar to non-apocrine DCIS (Figs. 7.16, 7.17, 7.18, and 7.19) [16, 17].
Non-apocrine ductal carcinoma in situ (DCIS) mimicking apocrine differentiation. (a) Although the cells have eosinophilic cytoplasm, this proliferation is not classified as apocrine because of the lack of other characteristics of apocrine differentiation, such as cytoplasmic granularity and ample pink cytoplasm. (b) Similarly, this in situ ductal malignant proliferation is classified as non-apocrine
High-grade ductal carcinoma in situ. (a, b) Although they have some features such as eosinophilic cytoplasm and prominent nucleoli, these cases are not classified as apocrine DCIS
Apocrine ductal carcinoma in situ. (a, b) Tumour cells show marked nuclear pleomorphism, granular eosinophilic cytoplasm, and prominent nucleoli. Necrosis is seen in (b)
Apocrine ductal carcinoma in situ. (a) Low grade. (b) Intermediate grade. (c) High grade
Low-grade apocrine proliferation with focal cribriform architecture. Depending on its extent, this lesion can be classified as either a borderline lesion (atypical apocrine proliferation) or in situ ductal carcinoma
Apocrine ductal carcinoma in situ shows a cribriform architecture with several well-defined spaces and high nuclear grade features
Apocrine ductal carcinoma extending into adenosis and lobular units, distorting involved ducts and acini, making it difficult to separate in situ from invasive disease. Immunohistochemistry for myoepitheilial cells is helpful in distinguishing in situ from invasive components, with preserved myoepithelial cells in non-invasive elements
Clinical and Epidemiological Features
Clinical and epidemiological features are similar to those of non-apocrine DCIS.
There are no identifying imaging features specific to apocrine morphology. Similar to non-apocrine DCIS, apocrine DCIS may be associated with microcalcifications or may present as densities or masses.
Similar to non-apocrine DCIS, apocrine DCIS shows marked heterogeneity in terms of grading. In most cases, the diagnosis is not difficult because intermediate-grade or high-grade areas can be identified adjacent to low-grade apocrine lesions [18, 19]. The main diagnostic challenge is accurate categorisation of low-grade intraductal apocrine proliferations when they are identified on small biopsy specimens or when the low-grade apocrine proliferation is focal. Differentiating these lesions from complex benign proliferations can be challenging. Architectural complexity such as cribriforming, rigid arches, and bridges may serve as criteria to separate benign versus malignant intraductal proliferations of the breast in general, but benign intraductal apocrine proliferations can show similar complex architecture. Cytologic monotony is another feature that supports the atypical nature of an intraductal breast lesion, but cytologic monotony is a common finding in apocrine proliferations, even in benign apocrine metaplasia. In general, several features are used to distinguish apocrine DCIS from other intraductal apocrine proliferations: threefold variation in nuclear size, markedly enlarged nucleoli, necrosis, and mitotic activity (Fig. 7.20).
Apocrine DCIS. (a) Marked variation in nuclear size of apocrine DCIS cells (threefold increase in size as compared with nuclei of an adjacent, relatively unaffected duct, right field) is present, as well as mitoses (arrows) and distinct nucleoli. (b) Amorphous necrosis is present
The term “apocrine adenosis” has been used to describe a range of apocrine proliferations, including adenosis, sclerosing adenosis, radial scars, and complex sclerosing lesions with apocrine cytologic features (Fig. 7.21). Apocrine adenosis is typically a lobulocentric proliferation of small ducts and acini associated with architectural distortion secondary to stromal fibrosis (Fig. 7.22). The ducts and acini are lined by apocrine cells [20–25]. The term “atypical apocrine adenosis” is used to define cytologic atypia in these lesions. However, there is significant diagnostic difficulty in assessing cytologic atypia because even non-atypical apocrine cells have enlarged nuclei and prominent nucleoli, which may be regarded as morphologic evidence of “atypia”. Although there are clinically validated studies to categorise non-apocrine lesions as non-atypical versus atypical hyperplasia, these criteria are not directly applicable to apocrine lesions. An intraductal lesion with cytologic atypia characterised by a significant increase in nuclear size (three-time difference compared with the nuclei of non-neoplastic apocrine cells), enlarged nucleolus or multiple nucleoli, and necrosis is highly suggestive of DCIS (Figs. 7.23 and 7.24). Caution should be exercised when these features are present singularly or are focal. In general, atypical apocrine lesions with cytologic atypia are small (2–3 mm) and involve only single ductal lobular units, whereas DCIS is usually more extensive (>8 mm) [25, 26].
Sclerosing adenosis focally involved by apocrine proliferation with cribriform architecture (apocrine adenosis). Although the complex cribriform architecture is suggestive of low-grade apocrine DCIS, the lesion is classified as atypical apocrine adenosis because of its limited extent. Note the lobulocentric configuration on low magnification
Atypical apocrine adenosis. Apocrine change with focal cribriform architecture in a sclerosing lesion is shown
Apocrine DCIS, low nuclear grade. The nuclei vary slightly in size and shape and they are larger than those found in normal apocrine metaplasia. The lesion measured more than 1 cm on the slide
(a, b) Apocrine DCIS is composed of cells with large, hyperchromatic nuclei and prominent nucleoli. These abnormal cytoarchitectural changes were extensive
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Papillary Apocrine Change
Apocrine cells lining breast cysts may be arranged in papillary projections (Figs. 7.25 and 7.26). These changes may be associated with other ductal proliferative lesions of the breast such as florid usual ductal hyperplasia or atypical ductal hyperplasia. Additionally, papillary apocrine changes frequently coexist with columnar cell changes. When cystically dilated ducts are lined by multiple layers of apocrine epithelium with luminal infoldings, the term “papillary apocrine change” is used (Figs. 7.27 and 7.28) . This term should not be confused with papillary lesions (chapter 4) and some authors prefer to regard papillary apocrine change as part of the broader category of apocrine metaplasia. According to the architectural complexity of these papillary structures, these lesions are subclassified as complex or highly complex papillary apocrine change in a review by Page et al.  (Figs. 7.29 and 7.30). Complex lesions are characterised as papillary structures forming cribriform spaces and arches (Figs. 7.31 and 7.32). Highly complex papillary apocrine lesions are described as papillary lesions with arches extending into the central portion of the ductal lumen and crossing or touching each other. The authors indicated that papillary apocrine change was associated with a mild increase in breast cancer risk. However, biopsy specimens with highly complex papillary apocrine change had concurrent ductal epithelial proliferations, 20 % of which were atypical ductal hyperplasia and 80 % were other proliferative lesions such as usual ductal hyperplasia. They concluded that the increased risk of breast cancer was more related to ductal hyperplasia than to papillary apocrine change. Therefore, the presence of complex papillary apocrine lesions in a biopsy specimen may be considered a surrogate marker for significant proliferative change in the rest of the breast parenchyma. Pathologists should be alerted to search for high-risk lesions elsewhere in the specimen. When papillary apocrine change is complex, it may mimic apocrine DCIS. O’Malley and Bane  proposed the combination of cytologic and size criteria for distinguishing atypical apocrine lesions from apocrine DCIS. Apocrine DCIS should have nuclear enlargement in addition to cytologic atypia (defined as irregular nuclear membranes). Importantly, nuclear atypia should be extensive and not confined to only a few scattered cells. A few cytologically atypical cells may be observed even in benign apocrine metaplasia. Most experts use a minimum size of 4–8 mm, in conjunction with architectural atypia, as a requirement for establishing the diagnosis of low-grade apocrine DCIS. A borderline category has been proposed, consisting of proliferations with cytologic atypia that measure from 4 to 8 mm. Unfortunately, the clinical significance of such cases is unclear. Unless both cytologic and size criteria for in situ carcinoma are fully met, the lesion should not be classified as DCIS based on complex papillary architecture or cytologic atypia alone .
Papillary apocrine metaplasia. (a–d) Micropapillary growth can be seen. The nuclei are uniform and regular, and there is no pleomorphism
Papillary apocrine metaplasia. Papillary tufts of apocrine cells with snouts protrude into glandular lumens
Papillary apocrine metaplasia. Dilated terminal ductal lobular units show papillary fronds with architectural complexity
Papillary apocrine metaplasia. Intraluminal papillary projections formed by apocrine cells are seen, giving a complex architectural appearance
Proliferative papillary apocrine metaplasia. Cystically dilated ducts are lined by multiple layers of apocrine epithelium
Complex papillary apocrine metaplasia. (a–c) Architecturally complex papillary apocrine change shows arches extending into the central luminal space while crossing or touching each other. (d–f) Cytologic atypia (hyperchromasia and three-time size variation) can be focally present (arrow)