Apocrine change in the breast is seen in a broad spectrum of lesions ranging from microscopic cysts to invasive apocrine carcinoma. Not only are some of these lesions difficult to categorise, but also there is controversy regarding their relative risk of subsequent carcinoma development. Fibrocystic change, fibroadenomas, hamartomas, papillomas, sclerosing adenosis and apocrine adenoma are all benign breast lesions that can show apocrine change as one of their histological features.
Apocrine lesions can be divided into simple and papillary apocrine changes, those of uncertain significance, those found in association with other lesions, apocrine ductal carcinoma in‐situ and invasive apocrine carcinoma. In addition to carcinomas with obvious apocrine differentiation, other carcinomas have some apocrine features and it may be that a significant number of breast tumours arise from apocrine epithelium or that a significant number can express some apocrine features.
Apocrine metaplasia in fibrocystic change
Fibrocystic change is an extremely common finding, which is evident in about 50% of women of reproductive age.6
Formation of cysts is one of the basic morphological criteria of this disease. These cysts can be microscopic or grossly visible. Miller et al
categorised cysts into two types based on their electrolyte content. Type I cysts have a high concentration of potassium and low concentrations of sodium and chloride (K:Na ratio >1.5). High concentrations of androgen and oestrogen conjugates and epidermal growth factor are also present in this type. Type II cysts have high concentrations of sodium and chloride and low concentrations of potassium (K:Na ratio <1.5). Lower concentrations of sex hormones and epidermal growth factor are also a feature of type II cysts. The cyst lining was found to be closely related to the content, where type I cysts are usually lined by apocrine cells and type II cysts are usually lined by flattened epithelium. There was initial evidence to suggest that type I cysts had a higher likelihood of recurrence than type II cysts,7,8
but this has not been reproduced in studies with larger numbers of patients and longer follow‐up.9
Women with palpable cysts who have undergone aspiration, have been reported to have a slightly increased risk of subsequent carcinoma development.10,11
However, two of the largest studies with long term follow‐up showed conflicting results. The current consensus is that gross cysts are not associated with any significant increased risk of subsequent carcinoma development, therefore these women do not require any further follow‐up than would be offered routinely.12,13
The study by Tsung et al14
revealed that apocrine cells were present in both type I and type II cysts and that cyst type could not predict the likelihood of subsequent carcinoma development.
The incidence of apocrine cysts found in normal breasts obtained from autopsies is said to be as high as 85%.15
This prompted Eusebi et al16
to conclude that apocrine features should be considered a normal change in breast epithelium rather than a true disease. Wellings and Alpers17
examined the frequency and age distribution of apocrine cysts in normal women versus women who developed cancer in the same or contralateral breast. They reported that apocrine cysts were more common in cancer‐associated breasts (83%) than in normal breasts (52%).
Also, the average number of foci with apocrine cysts was higher in cancer‐associated breasts. They concluded that apocrine metaplasia (APM) could be a manifestation of epithelial unrest. Their conclusion led Haagensen18
to suggest that APM of the breast is either a precursor of malignant transformation in itself or that the metaplasia is a reflection of an underlying stimulus that renders the breast more susceptible to neoplasia.
Microscopic cysts lined by a single layer of apocrine epithelium are non‐proliferative lesions that are not associated with any increased risk of subsequent carcinoma development.12,19
In 1996, Page et al20
stratified apocrine cysts lined by papillary apocrine epithelium into categories of increasing complexity using a combination of histological and cytological pattern rules. In this study, papillary apocrine change (PAC) was categorised into three forms: simple PAC, complex PAC and highly complex PAC (fig 3). Simple PAC can be identified when the epithelium lining an apocrine cyst is focally 3 or more cells thick, with the resulting mounds of cells showing no tendency to touch one another. These clumps of cells are broader at the base than at the tip.
Figure 3Increasing degrees of complexity of apocrine metaplasia. (A) Non‐papillary apocrine metaplasia. (B) Simple papillary apocrine metaplasia. (C) Complex papillary apocrine metaplasia. (D) Highly complex papillary apocrine metaplasia. (more ...)
In complex PAC, the papillae were taller, more attenuated and showed a tendency to touch each other within the lumen. Highly complex PACs were identified by the greatly elongated papillae, usually 2 or 3 cells in width, forming narrow arcades of apocrine cells intertwined with other papillations. This last category was quite uncommon, being only 1% of all reviewed biopsy specimens. The nuclear features were the same as those seen in unremarkable apocrine change. The authors reported that although there was a slight increased risk of subsequent carcinoma development in association with PAC, most of the increased risk was related to the presence of atypical hyperplasia of ductal (non‐apocrine) type (ADH). The relative risk was only 1.2 after women with ADH were excluded. Women with highly complex patterns of PAC without ADH did, however, experience a relative risk of 2.4, but due to the small number of cases, this did not achieve statistical significance. Apocrine cells do show a degree of nuclear variability, even in simple epithelium. This is partly a product of cross cutting of a large nucleus and partly an intrinsic property of apocrine epithelium. This phenomenon is recognised by most cytologists, especially in cyst fluids; even moderate degrees of nuclear variation and atypia are ignored unless there is necrosis or significant mitotic activity.
These lesions are extremely rare and the number of cases reported is not sufficient to determine the level of risk associated with these. They are unusual adenomas composed entirely of apocrine cells and are generally accepted to be benign. Pure breast adenomas with apocrine differentiation were described by Hertel et al
The criteria require the lesion to be homogenous throughout; to be sharply demarcated from the surrounding breast tissue; to have only epithelial proliferative elements; and to have a minimal, supportive stromal component.