Apocrine Carcinoma

Apocrine Carcinoma

Edi Brogi

Apocrine cells have abundant, densely eosinophilic cytoplasm and large round nuclei with prominent nucleoli. Apocrine lesions of the breast include apocrine metaplasia, an alteration that is part of FCCs, and atypical and frankly neoplastic apocrine epithelial proliferations. The relationship between the aforementioned lesions remains unclear. Except for apocrine metaplasia, the identification of “apocrine” lesions has somewhat limited reproducibility, and some authors regard “apocrine” morphology as a nonspecific alteration. In this chapter, the designation of “apocrine carcinoma” is used for carcinomas with predominantly apocrine morphology, as well as for carcinomas showing only apocrine features. Cells with apocrine morphology can also be found in some special subtypes of carcinomas.



The incidence of carcinomas having apocrine cytomorphology in at least 90% of the tumor is unknown. Carcinomas with apocrine features represent 1% (1) to 3% (2) of all breast carcinomas.

Age and Gender

Apocrine carcinomas can occur at any age, but most arise in postmenopausal women (1,2,3,4,5,6). The mean age of patients with invasive apocrine carcinoma in one series (2) was 58.5 years, significantly higher than the mean age of 54.4 years for women with invasive nonapocrine ductal carcinoma. Apocrine carcinomas are rare in men.

Genetic Predisposition

Breast lesions in patients with Cowden syndrome (germline PTEN mutation) often have apocrine morphology (7,8,9) but not exclusively. Apocrine carcinoma is not specifically linked to Cowden syndrome.

Presenting Symptoms and Imaging Studies

The findings are similar to those in patients with nonapocrine carcinomas. Bilateral apocrine carcinomas are uncommon (10). Apocrine ductal carcinoma in situ (DCIS) can be mass-forming. Apocrine DCIS often involves sclerosing lesions such as radial sclerosing lesion (RSL) and sclerosing adenosis (SA) (11), and can mimic invasive carcinoma clinically, radiologically, and microscopically. Calcifications are common in invasive apocrine carcinomas, in apocrine DCIS, and in atypical apocrine adenosis.


Apocrine Metaplasia

Apocrine metaplasia is a benign epithelial alteration that is part of fibrocystic changes (FCCs). It often involves benign cysts and has a papillary or micropapillary configuration (Fig. 15.1). In the absence of a true papilloma/papillary lesion, the qualification of “papillary” should not be used for apocrine metaplasia in the report of a needle core biopsy (NCB) specimen, as it might trigger an unnecessary excision. Calcium oxalate crystals with characteristic “broken glass” appearance are common in apocrine cysts (Fig. 15.1). Mammographically, they are detected as “milk of calcium,” and might be the target of NCB. Calcium oxalate crystals are almost invariably associated with benign apocrine metaplasia. Rarely, psammomatous calcifications can also occur in apocrine cysts (Fig. 15.1).

Atypical Apocrine Proliferations

Atypical apocrine proliferations that are not frankly neoplastic often occur in the context of sclerosing lesions, such as papilloma, RSL, and SA (Figs. 15.2 and 15.3), and can raise the differential diagnosis of apocrine DCIS. The atypical cells are cytologically similar to those of low-grade or even intermediate-grade apocrine DCIS, but the proliferation lacks the expansive growth, complex architecture, and/or necrosis and/or mitoses required for the diagnosis of apocrine DCIS (12). The term atypical apocrine adenosis (AAA) has been suggested for these lesions (13).

Size criteria to separate atypical apocrine proliferations from apocrine DCIS have been proposed. Some authors (14) used a 2-mm size cutoff. Another group (15) proposed a combination of cytologic and size criteria (<4 mm, 4-8 mm, and >8 mm). Severely atypical apocrine proliferations spanning at least 4 mm and less atypical lesions measuring at least 8 mm were classified as apocrine DCIS. Apocrine proliferations with modest apocrine atypia and size between 4 mm and 8 mm were referred to as “borderline.” Lesions with modest apocrine atypia and size smaller than 4 mm were classified as apocrine adenosis. Given the intrinsic difficulties in the interpretation
of atypical apocrine proliferations, a cautious diagnostic approach is recommended, particularly in the evaluation of NCB material. AAA is also discussed in Chapter 6.

FIGURE 15.1 Apocrine Metaplasia. Needle core biopsy specimens showing different lesions. A, B: Cystic papillary apocrine metaplasia is composed of cells with abundant eosinophilic cytoplasm, small round nuclei, and punctate nucleoli. The nuclei are regularly and evenly distributed with respect to the basement membrane. C: These glands are lined by a single layer of columnar cells with evenly spaced, basally oriented nuclei. The eosinophilia seen in A and B and the basophilia in C reflect different staining properties in apocrine lesions. D: Apocrine metaplasia with oxalate calcifications showing the characteristic “broken glass” appearance. E: Cystic apocrine metaplasia with psammomatous calcifications.

Apocrine DCIS

Apocrine DCIS has the same architectural patterns as non-apocrine DCIS (Figs. 15.4, 15.5, 15.6, 15.7). Involvement of lobules is common. Intermediate- to high-grade neoplastic apocrine cells have enlarged, hyperchromatic, and often pleomorphic nuclei, with prominent, and sometimes multiple and irregular, nucleoli. Binucleation and intranuclear inclusions are common. The nuclear chromatin is coarse and clumped, or deeply basophilic and smudged. Three-fold or greater variation of the nuclear diameter in adjacent neoplastic cells is common. High-grade apocrine DCIS often shows necrosis. It can have densely eosinophilic cytoplasm and resemble squamous DCIS, but it lacks keratin formation. Apocrine DCIS with intermediate nuclear grade usually shows obvious apocrine cytology. Low-grade apocrine DCIS is less frequent and more difficult to recognize. The nuclei are slightly larger than those of benign apocrine metaplastic cells, and the chromatin is denser; nucleoli are visible, but they are not conspicuous (Fig. 15.7). The cytoplasm of neoplastic apocrine cells is usually abundant and shows dense eosinophilia; it can also be granular. Focal cytoplasmic vacuolization or clearing may be present in atypical apocrine lesions,

but it is prominent in high-grade apocrine carcinomas. Foam cells are sometimes admixed with apocrine DCIS (Fig. 15.8).

FIGURE 15.2 Apocrine Metaplasia with Atypia. A: Two ducts are involved by an atypical apocrine proliferation. A detached papillary fragment lined by micropapillary apocrine epithelium is also present (arrow). B: The apocrine epithelium is arranged in micropapillae and focally shows incipient bridge formation. Focal “button-hole” arrangement is seen (arrow).

FIGURE 15.3 Apocrine Metaplasia with Atypia in a Radial Scar. A, B: A few sclerosed acini are minimally expanded by atypical apocrine cells. Calcifications are also present in A (arrows). The apocrine cytologic atypia is evident B, compared to the normal epithelium in an adjacent acinus.

FIGURE 15.4 Apocrine Ductal Carcinoma In Situ (DCIS), Intermediate-Grade, in a Radial Scar. A: This needle core biopsy material shows the periphery of a radial scar with focal DCIS. The elastotic center of the radial scar is on the right. B: The glands involved by apocrine DCIS are expanded and show cribriform architecture. Few small nests of carcinoma near the elastotic center of the radial scar simulate stromal invasion (arrows). C: The DCIS has intermediate nuclear grade. A mitotic figure is present (arrow). No evidence of invasive carcinoma was present in this case.

FIGURE 15.4 (continued)

FIGURE 15.5 Apocrine Ductal Carcinoma In Situ (DCIS), Intermediate-Grade, in a Sclerosing Lesion. A: This needle core biopsy material shows a sclerosing lesion with apocrine DCIS. B: An expanded duct is involved by apocrine DCIS with intermediate nuclear grade. Periductal fibrosis and inflammation are present. C: Intermediate-grade apocrine DCIS. A few cells have large nuclei with prominent nucleoli. A mitotic figure is present (arrow).

FIGURE 15.6 Apocrine Ductal Carcinoma In Situ (DCIS), Intermediate- and High-grade. A: Solid DCIS with necrosis. B: Cribriform DCIS with extension into lobular glands (on the left). C, D: Micropapillary and papillary foci of apocrine DCIS with pleomorphic, deeply basophilic nuclei. E: Flat micropapillary apocrine DCIS with high nuclear grade.

FIGURE 15.6 (continued)

FIGURE 15.7 Invasive and In Situ Apocrine Carcinoma, Low Nuclear Grade. A, B: This needle core biopsy sample from a breast mass in an 80-year-old woman shows invasive apocrine carcinoma with low nuclear grade. Solid and cribriform apocrine ductal carcinoma in situ of low nuclear grade is present in a few scattered ducts (arrows). Minimal stromal inflammation is noted.

FIGURE 15.8 Foam Cells Admixed with Apocrine Carcinoma. This needle core biopsy sample from a breast mass in a 56-year-old woman shows solid and cribriform ductal carcinoma in situ (DCIS) with low nuclear grade. Stromal inflammation is also present. Foam cells are present in ducts involved by apocrine DCIS.

The diagnosis of low-grade apocrine DCIS rests on the identification of expansive growth and/or complex and rigid architectural patterns characteristic of DCIS. The definitive diagnosis of low-grade apocrine DCIS can be very challenging, especially based on review of NCB material. The differential diagnosis includes apocrine atypia and apocrine metaplasia.

Apocrine DCIS often harbors calcifications, which are coarse, heterogenous, and associated with necrosis in high-grade DCIS, and punctate and small in low-grade DCIS. Periductal fibrosis and inflammation are common near ducts and lobules involved by apocrine DCIS or atypical apocrine epithelium. Foamy histiocytes in the stroma adjacent to apocrine DCIS may mimic invasive carcinoma with histiocytoid cells. Foam cells can be present in ducts involved by apocrine DCIS (Fig. 15.8).

Apocrine DCIS and AAA often arise within or near sclerosing lesions, such as RSL and SA (11). Papillary lesions often harbor apocrine metaplasia, and apocrine DCIS can be papillary and/or arise in a papillary lesion. When evaluating a papillary apocrine lesion, it is critical to determine whether the apocrine epithelial proliferation has cytologic and architectural atypia, and these parameters need to guide the diagnostic interpretation. The finding of very scant to absent myoepithelium around cytologically benign cystic and papillary apocrine lesions has been described (16,17,18). In the absence of cytologic and architectural atypia, the absence of myoepithelium does not justify a diagnosis of carcinoma, particularly of invasive carcinoma (Fig. 15.9). On the contrary, immunohistochemical stains for cytokeratin and myoepithelial markers are usually very useful for detecting minute invasive foci near apocrine DCIS and for ruling out invasion in cases of apocrine DCIS involving a sclerosing lesion.

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Nov 17, 2018 | Posted by in PATHOLOGY & LABORATORY MEDICINE | Comments Off on Apocrine Carcinoma
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