Benign and Atypical Apocrine Lesions
Apocrine metaplasia: This is a change of native breast ductal epithelial cells into cells showing eosinophilic granular cytoplasm, a large open nucleus with a single nucleolus, and decapitation secretion. Apocrine metaplasia can be subtyped into simple, papillary, and complex depending on architectural complexity. Apocrine metaplasia can coexist with columnar cell change, sometimes even involving the same duct spaces.
Apocrine adenosis: This is apocrine change in sclerosing adenosis. Some authors use a different definition, as a haphazard proliferation of bland glands with apocrine differentiation and use this term as synonymous with adenomyoepithelial adenosis.
Atypical apocrine change within sclerosing adenosis (atypical apocrine adenosis): Generally seen in postmenopausal women, these cases are defined as having a 3× variation in nuclear size. They have no necrosis and few mitoses.
Atypical apocrine hyperplasia: This is a rare lesion within ducts which shows complex bridging and a 3× variation in nuclear size but which does not have the periductal inflammation, periductal fibrosis, and mitotic activity associated with apocrine ductal carcinoma in situ. There is not a universal agreement on the upper size cutoff to differentiate this lesion from apocrine DCIS.
Incidence: Microscopic apocrine change is frequent in the female breast after the age of 30, is uncommonly observed in women younger than 19, and increases with age, persisting postmenopausally.
Atypical apocrine lesions are uncommon, and the precise incidence is unknown.
Site: Breast parenchyma, no specific localizations
Treatment: Benign apocrine changes and apocrine cell metaplasia: Apocrine metaplasia is quite common within the breast, is not premalignant and hence does not require surgical intervention.
Atypical apocrine change within sclerosing adenosis (atypical apocrine adenosis): Insufficient cases have been studied to determine if surgical excision is warranted or not (in view of the clinical concern of concurrent apocrine DCIS or invasive apocrine carcinoma).
Atypical apocrine hyperplasia: Complete surgical excision recommended.
Atypical apocrine change in a papilloma: Complete surgical excision recommended.
Outcome: Benign apocrine lesions pose no long-term risk to the patient.
Regarding atypical apocrine lesions, Fuehrer et al. (2012) showed that the rate of breast cancer diagnosis in follow-up of patients diagnosed with atypical apocrine change within sclerosing adenosis (8.1%) was not appreciably different from that of the cohort overall (7.8%). Calhoun and Booth (2014) showed that out of seven patients diagnosed with atypical apocrine change within sclerosing adenosis, none of these diagnoses were upgraded to ductal carcinoma in situ or invasive carcinoma following surgical excision; hence it remains unclear whether a diagnosis of atypical apocrine change within sclerosing adenosis in isolation requires surgical excision or not.
Apocrine lesions of the breast can present as cystic or solid breast lesions, which may be associated with microcalcification (calcium phosphate or calcium oxalate/Weddellite microcalcifications). They can form macroscopically visible cystic spaces. Juvenile papillomatosis shows a “Swiss cheese”-like appearance due to the formation of multiple cysts.
Apocrine cells often form the lining of type 1 cysts. Type 1 cysts have a high concentration of potassium relative to sodium and chloride concentration (K/Na ratio greater than 1.5). They also contain high concentrations of androgens, estrogen conjugates, and epidermal growth factor. Conversely, type 2 cysts have high concentrations of sodium and chloride relative to potassium concentration (K/Na ratio less than 1.5). Type 2 cysts also have lower concentrations of sex hormones and epidermal growth receptor factor.
As type 1 cysts have been shown to contain androgens and, given their nuclear androgen receptors (AR), they may be subject to continuous stimulation leading to proliferation. This may lead to papillary proliferation unless the cyst becomes extremely tense when the lining becomes attenuated. Apocrine metaplasia is a major component of fibrocystic change (“Fibrocystic Changes”) and is a diagnostic feature of this condition.
Metaplastic change within many organs is related to the development of cancer, for example, in the lung and cervix, but is not a sine qua non. Apocrine metaplasia is quite common within the breast and usually is not premalignant. There are, however, some examples where apocrine change may well form the precursor of certain types of carcinoma. The common benign apocrine lesions will be described below.
Apocrine Cells in Other Lesions
Apocrine cells can also be seen associated with sclerosing adenosis (“Sclerosing Adenosis”) and also in other lesions such as complex fibroadenomas (“Fibroadenoma”), hamartomas (“Hamartoma”), and papillomas (“Papillary Lesions”) and are the major constituent of other lesions such as apocrine adenoma. They are not a constituent of phyllodes tumors as these appear to be monoclonal lesions unless in extremely rare examples; the phyllodes tumor (“Phyllodes Tumor”) may have developed within a complex fibroadenoma.
Fibroadenoma and Hamartoma with Apocrine Change
Of note, some benign fibroepithelial lesions may occasionally show apocrine cysts and apocrine metaplasia with attenuated or absent myoepithelial cells (Cserni 2008). In these rare cases, further immunohistochemistry as well as careful assessment for other accompanying features of malignancy (significant cytological atypia, desmoplastic stromal response, mitotic activity, loss of the normal lobular architecture) is essential in order to avoid overcalling a benign lesion.
Papilloma with Apocrine Change
Apocrine Change within Sclerosing Adenosis
This is an unusual apocrine proliferation, which resembles a tubular adenoma but composed entirely of apocrine cells. These lesions are extremely rare and are not thought to have an increased risk of subsequent carcinoma; however too few are reported to quantify the absolute risk.
Atypical Apocrine Lesions
Atypia in apocrine cells is difficult to quantify as apocrine cells have large nuclei, and in standard 3–5 μm sections the nuclear size can appear quite variable due to the plane of the section of each nucleus. However, benign apocrine cells can often appear quite pleomorphic even in cytological preparations where the actual nuclear size can be more readily appreciated. Currently the accepted definition of atypia in apocrine proliferations is a variation in nuclear size of greater than three times. Atypical apocrine lesions are rare but fall mainly into two types: atypical apocrine change within sclerosing adenosis (atypical apocrine adenosis) and atypical apocrine hyperplasia.
Atypical Apocrine Change Within Sclerosing Adenosis (Atypical Apocrine Adenosis)
This was investigated by Seidman et al. (1996) who discovered a 5.5× increased relative risk of subsequent breast cancer in postmenopausal women. These cases are defined as having a 3× variation in nuclear size. They have no necrosis and few mitoses. If necrosis is present or mitotic activity is prominent, the possibility of cancerization of lobules by high-grade apocrine ductal carcinoma in situ (“DCIS”) should be considered. Some of these lesions appear to arise in the context of a complex sclerosing lesion (“Complex Sclerosing Lesion”), and occasional cases have an association with established apocrine ductal carcinoma in situ.
Atypical Apocrine Hyperplasia
This is a rare lesion within ducts, which shows complex bridging and a 3× variation in nuclear size but which does not have the periductal inflammation, periductal fibrosis, and mitotic activity associated with apocrine ductal carcinoma in situ. Necrosis, if present, indicates that the lesion is apocrine ductal carcinoma in situ. Size cutoffs for defining a lesion as apocrine ductal carcinoma in situ rather than atypical apocrine hyperplasia have been suggested at 2 mm or 4 mm, but there is not a universal agreement on this.
Apocrine Change in Core Biopsies
Benign apocrine metaplasia: Apocrine cells contain AR and a number of proteins designated as gross cystic disease fluid proteins (GCDFP) such as GCDFP 15, GCDFP 24, and GCDFP 44. They are positive for cytokeratin (CK) 8/18 and negative for CK 5 and hence represent fully differentiated epithelial cells. Although normal apocrine cells are AR positive and estrogen (ER) and progesterone receptor (PR) negative, because in the breast they are metaplastic, some cells may be seen which are intermediate between columnar cells and fully differentiated apocrine cells. In this case they may have both ER and PR. HER2 staining can be a little controversial in that occasionally some otherwise normal apocrine cells lining cysts may show membrane staining on the basal and lateral aspects of the cell but not on the luminal surface. The significance and function of this are unknown.
Atypical apocrine lesions: Apocrine carcinomas are interesting in that they carry AR but may also be positive for ER and PR and are often HER2 positive. Some, however, may be triple negative. Atypical apocrine lesions also have this variability in that they may lose functional markers of apocrine differentiation such as GCDFP 15, 24, and 44. The use of p53 and Ki-67 immunohistochemistry has been suggested to help differentiate between benign and malignant apocrine lesions (Collins et al. 2011).
Gromov et al. (2015) and Celis et al. (2007) propose that carcinomas with apocrine features arise from atypical and benign precursors. It has been demonstrated that malignant lesions acquire mutations as they become more aggressive. Celis et al. studied cases of sclerosing adenosis with apocrine metaplasia and identified non-obligate putative apocrine precancerous lesions as defined by the expression of p53 and/or MPR14 (S100A9) which is a marker highly overexpressed in pure invasive apocrine carcinomas.
Selim et al. (2002) showed that cases of apocrine cell metaplasia showed loss of heterozygosity (LOH)/allelic instability (AI), most frequently involving 11q (INT2), 1p (MYCL1), and 13q (D13S267). In their study, one case of apocrine metaplasia was associated with DCIS. In this case, one area of DCIS showed allelic alterations at 11q (INT2) and 17p (TP53), as did the area of apocrine metaplasia in the same case. This area also showed LOH at 17q (D17S250). The other focus of DCIS, however, also showed allelic loss at 16q.
A proportion of atypical apocrine lesions show intermediate overexpression of HER2 (2+) but no amplification of the gene. A possible scenario is that continued stimulation by androgen may lead to the development of established neoplasia in these cases, and continued stimulation of the overexpressed receptor may lead to amplification of the gene and hence uncontrolled proliferation.
References and Further Reading
- Celis, J. E., Moreira, J. M. A., Gromova, I., Cabezón, T., Gromov, P., Shen, T., Timmermans, V., & Rank, F. (2007). Characterization of breast precancerous lesions and myoepithelial hyperplasia in sclerosing adenosis with apocrine metaplasia. Molecular Oncology, 1, 97–119.CrossRefPubMedPubMedCentralGoogle Scholar