Encyclopedia of Pathology

Living Edition
| Editors: J.H.J.M. van Krieken

Benign and Atypical Apocrine Lesions

  • Reena KhiroyaEmail author
  • Clive Wells
Living reference work entry
DOI: https://doi.org/10.1007/978-3-319-28845-1_4739-1

Synonyms

Definition

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.

Clinical Features

  • 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.

  • Age: 19–90

  • Sex: Female

  • 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.

Macroscopy

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.

Microscopy

Apocrine cells are a normal constituent of the sweat glands around the nipple and in the axilla, but when found in the ducts and lobules within the breast, these appear to be a consequence of metaplasia, possibly related to columnar cell change and hormonal stress. Apocrine cells have eosinophilic granular cytoplasm due to secretory vacuoles, a large open nucleus with a single nucleolus, and decapitation secretion. Apocrine cells carry androgen receptor, as do some examples of columnar cell change and therefore this may be a response to androgenic stimulation. Although some authors believe that apocrine cells are a normal constituent of the breast, they can sometimes be seen as partial metaplasia within a duct, the rest of the lining of which is columnar cell change (Fig. 1 (H&E)).
Fig. 1

Columnar cell change and apocrine metaplasia occurring within same duct spaces, with associated microcalcifications

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 Cysts

Grossly palpable cysts lined by apocrine epithelium usually contain cyst fluid with a high K+/Na+ ratio, which is characteristic of the type 1 cyst. Apocrine cells form the lining of type 1 cysts (Fig. 2 (H&E)) and may be seen as a flattened lining if the cyst is extremely tense precluding the development of papillary apocrine metaplasia. It is often, however, seen as papillary apocrine metaplasia, which has been classified by Page (Page et al. 1996) into simple (Fig. 3 (H&E)), complex (Figs. 4 and 5 (H&E)), and highly complex. In his study of premalignant conditions, the simple and complex forms were not related to subsequent malignancy. There were too few of the highly complex variety as defined in the study to comment on the possible premalignant connotation of these.
Fig. 2

Apocrine metaplasia and apocrine cysts

Fig. 3

Simple apocrine metaplasia

Fig. 4

Papillary apocrine metaplasia

Fig. 5

Complex apocrine metaplasia

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

Dupont and Page (1994) identified a group of fibroadenomas (“Fibroadenoma”) with features leading to a slightly increased risk of subsequent carcinoma of 2.17×. These lesions had either apocrine metaplasia (Fig. 6 (H&E)), sclerosing adenosis (“Sclerosing Adenosis”), or epithelial hyperplasia (“Epithelial Hyperplasia”). It is unclear which of these components would be responsible for greater risk, and also nowadays some of these so-called complex fibroadenomas may better be classified as hamartomas (“Hamartoma”), especially those formerly called pericanalicular where there is little lobular stromal proliferation. Much of this distinction is semantic as fibroadenomas in general appear to be a special type of hamartoma rather than a clonal lesion.
Fig. 6

Apocrine metaplasia within a fibroadenoma

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

Most large duct papillomas have a simple columnar lining around a papillary core, which may be associated with regular hyperplasia. Some, however, may develop apocrine change (Fig. 7 (H&E)), and this may appear rather solid in some cases. Atypical apocrine change (Fig. 8 (H&E)) can be seen in papillomas and is discussed below. Encapsulated papillary carcinomas (“Encapsulated Papillary Carcinoma”) do not have apocrine elements within them. Apocrine change within papillary lesions is generally regarded as a sign of benignity, but atypical apocrine proliferation within a papilloma may cause difficulty in distinguishing these atypical papillomas from apocrine ductal carcinoma in situ developing in the papilloma.
Fig. 7

Apocrine change within a benign papilloma

Fig. 8

Atypical apocrine change within a papilloma

Apocrine Change within Sclerosing Adenosis

This is a relatively uncommon lesion where apocrine cells form the majority of the epithelial component in a background of sclerosing adenosis (Fig. 9 (H&E)). It has also been called apocrine adenosis, but this term has also been used for an unusual change in adenomyoepitheliomas (“Adenomyoepithelioma”). Unless there is clear atypia within this, the consequences are unclear. However, there are some worrying features of cases of apocrine atypia within sclerosing adenosis which demand further investigation (see below).
Fig. 9

Apocrine change within sclerosing adenosis

Apocrine Adenoma

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

Apocrine metaplasia may be responsible for microcalcification on mammography as it may contain Weddellite calcification. This is a reflection of fibrocystic change. If no other lesion is present and there is no atypia, the patient can be reassured and discharged from the clinic. Similarly patients with apocrine change within fibroadenomas or hamartomas can also be reassured. Papillomas with apocrine change are currently recommended to require excision, which may be performed by vacuum excision biopsy unless clear atypia is identified on the core biopsy. Apocrine change within sclerosing adenosis is controversial. If there is no apocrine atypia within this, some pathologists would regard this as a benign (B2) lesion. As the relative risk of these lesions is still controversial, some pathologists would still call these atypical (B3) even without cytological atypia of the apocrine cells. Clearly atypical apocrine change should be subject to further intervention and given a B3 designation. Many of these cases will, however, be associated with sclerosing lesions which will qualify for a B3 designation in their own right. Atypical apocrine hyperplasia (Fig. 10 (H&E)) should always raise the possibility of associated apocrine ductal carcinoma in situ and excision undertaken.
Fig. 10

Atypical apocrine hyperplasia in a core biopsy

Juvenile Papillomatosis

Juvenile papillomatosis is a term given to a localized area of fibrocystic change which generally occurs in young women but which can also be seen in patients up to 60 years old. The lesion usually presents as a single discrete mass although multifocal and bilateral lesions have been described. The lesion is composed of multiple cysts, hence its alternative name of “Swiss cheese disease.” The lining of the cysts is usually apocrine metaplasia with a marked papillary component. The original description (Rosen et al. 1985) also cited regular hyperplasia, sclerosing adenosis, and abundant foamy macrophages as associated features (Fig. 11 (H&E)). The risk of subsequent carcinoma is not dissimilar to that of the general population at approximately one in ten women although cases with bilateral disease or a positive family history are stated to be at increased risk. In essence, therefore, this lesion can be thought of as a localized area of fibrocystic change and it should not be confused with true papillary proliferations such as papillary hyperplasia of young adults (Rosen 1985) or multiple papilloma syndrome (Papotti et al. 1984), the latter having an increased propensity for the development of in situ carcinoma. The proliferation is not papillary in the sense of the two above conditions and is not exclusively in juveniles. This terminology appears to have led to confusion between the three conditions, and the authors would prefer that this lesion is referred to as localized fibrocystic change (“Swiss cheese disease”) rather than given the designation of a “papillary” lesion. It is therefore included in this chapter instead of being linked with true papillary lesions.
Fig. 11

Juvenile papillomatosis showing multiple cyst formation

Immunophenotype

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).

A proportion of atypical apocrine lesions show intermediate overexpression of HER2 (2+) (Fig. 12 (IHC)) but no amplification of the gene. Immunostaining for HER2 can help in the assessment of atypical apocrine lesions as, if there is strong positivity for HER2 and amplification, it is likely that one is dealing with cancerization of lobules by apocrine ductal carcinoma in situ, and further sections should be taken to try to identify more typical in situ carcinoma.
Fig. 12

Atypical apocrine change within a papilloma showing intermediate expression of HER2 protein

Molecular Features

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.

Differential Diagnosis

Atypical apocrine change within sclerosing adenosis (“Sclerosing Adenosis”) (atypical apocrine adenosis) can be misdiagnosed as invasive apocrine carcinoma. Atypical apocrine hyperplasia could also potentially be diagnosed as DCIS (“DCIS”) if the size or extent of the lesion is overestimated.

References and Further Reading

  1. Calhoun, B. C., & Booth, C. N. (2014). Atypical apocrine adenosis diagnosed on breast core biopsy: Implications for management. Human Pathology, 45, 2130–2135.CrossRefPubMedGoogle Scholar
  2. 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
  3. Collins, L. C., Cole, K. S., Marotti, J. D., Hu, R., Schnitt, S. J., & Tamimi, R. M. (2011). Androgen receptor expression in breast cancer in relation to molecular phenotype: Results from the Nurses’ Health Study. Modern Pathology, 14, 924–931.CrossRefGoogle Scholar
  4. Cserni, G. (2008). Lack of myoepithelium in apocrine glands of the breast does not necessarily imply malignancy. Histopathology, 52, 253–255.CrossRefPubMedGoogle Scholar
  5. Fuehrer, N., Hartmann, L., Degnim, A., Allers, T., Vierkant, R., Frost, M., & Visscher, D. (2012). Atypical apocrine adenosis of the breast: Long-term follow-up in 37 patients. Archives of Pathology and Laboratory Medicine, 136, 179–182.CrossRefPubMedGoogle Scholar
  6. Gromov, P., Espinoza, J. A., & Gromova, I. (2015). Molecular and diagnostic features of apocrine breast lesions. Expert Review of Molecular Diagnostics, 15, 1011–1022.CrossRefPubMedGoogle Scholar
  7. Page, D. L., Dupont, W. D., & Jensen, R. A. (1996). Papillary apocrine change of the breast: Associations with atypical hyperplasia and risk of breast cancer. Cancer Epidemiology, Biomarkers and Prevention, 5, 29–32.PubMedGoogle Scholar
  8. Papotti, M., Gugliotta, P., Ghiringhello, B., & Bussolati, G. (1984). Association of breast carcinoma and multiple intraductal papillomas: An histological and immunohistochemical investigation. Histopathology, 8, 963–975.CrossRefPubMedGoogle Scholar
  9. Rosen, P. P. (1985). Papillary duct hyperplasia of the breast in children and young adults. Cancer, 56, 1611–1617.CrossRefPubMedGoogle Scholar
  10. Rosen, P. P., Holmes, G., Lesser, M. L., Kinne, D. W., & Beattie, E. J. (1985). Juvenile papillomatosis and breast carcinoma. Cancer, 55, 1345–1352.CrossRefPubMedGoogle Scholar
  11. Seidman, J. D., Ashton, M., & Lefkowitz, M. (1996). Atypical apocrine adenosis of the breast: A clinicopathologic study of 37 patients with 8.7-year follow-up. Cancer, 77, 2529–2537.CrossRefPubMedGoogle Scholar
  12. Selim, A. G. A., Ryan, A., El-Ayat, G., & Wells, C. A. (2002). Loss of heterozygosity and allelic imbalance in apocrine metaplasia of the breast: Microdissection microsatellite analysis. The Journal of Pathology, 196, 287–291.CrossRefPubMedGoogle Scholar

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© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.University College London HospitalLondonUK