—  INTERNATIONAL SOCIETY OF BREAST PATHOLOGY   —

Apocrine Lesions of the Breast


Frances P. O'Malley
Mt. Sinai Hospital
Toronto, ON, Canada


Despite much study, the relationship between apocrine proliferations and breast cancer risk remains controversial. Apocrine cells occur in a spectrum of benign and malignant lesions, many of which are discussed below.

APOCRINE CYSTIC FORMATION
Gross cystic change, a common occurrence in premenopausal women, generally presents as a single cyst. The electrolyte content of the cyst fluid is closely related to the nature of the cyst lining: Cysts with a Na+/K+ ratio < 3 are usually lined by apocrine cells (type I cysts), while those with a Na+/K+ >3 are lined by flattened epithelium (type II cysts). There was initial evidence to suggest that type I cysts had a higher likelihood of recurrence than cysts lined by flattened epithelium.1,2 , but this has not been reproduced in studies with larger numbers of patients and longer follow-up. 3

There have been several studies investigating a possible association between cystic change and subsequent carcinoma development. 2-10 Two of the largest studies with long term follow-up showed conflicting results. Haagensen9 demonstrated a 3 fold increased relative risk, which was further elevated in the presence of a positive family history. Dupont and Page, in contrast, found that women with gross cysts who did not have a family history of breast cancer, had a relative risk of only 1.5, and women with microscopic cysts were not at any increased risk compared to a reference population.10 A more recent study by Dixon3 reported follow-up data on over 1300 women who had palpable cysts aspirated between 1981 and 1987. They found a slightly increased risk of breast cancer regardless of cyst type and the risk was highest for those women < 45 years.

Simple apocrine metaplasia is not associated with any increased risk of subsequent carcinoma development.11 While apocrine cells lining microscopic cysts are usually arranged in a single layer, papillary arrangements that protrude into the cyst lumen are not uncommon. Apocrine cells in such papillary formations tend to demonstrate a higher percentage of tetraploidy than apocrine cells in simple cystic formations.12 One study subcategorised apocrine papillary formations into three groups - simple, complex and highly complex – based on the length of the papillations and the tendency to form arches. This study reported that, while there was a slightly increased risk of subsequent carcinoma overall, most of the elevated risk was due to the presence of atypical hyperplasia in cases showing highly complex papillary apocrine change (PAC). Only 1% of almost 3,000 reviewed biopsies showed highly complex PAC, yet, atypical hyperplasia was present in 20% of these cases.13

APOCRINE ADENOSIS
The term "apocrine adenosis" was first used by Eusebi et al to describe apocrine change in a glandular proliferation associated with two cases of adenomyoepithelioma 14 . However, it is more commonly used in the literature to describe apocrine change in sclerosing adenosis. 15-20 Apocrine adenosis was seen in 18.3% of consultation cases and in 3% of a consecutive series of benign breast biopsies in one study. The authors reported a statistically significant increased association with atypical hyperplasia in this study, with foci of atypical hyperplasia being twice as common in cases with "apocrine adenosis" than in those without. 20

Apocrine adenosis has been suggested by some to represent a neoplastic process.21 This conclusion was based on the finding of monoclonality in a single case which presented clinically as a palpable mass and measured 4.3 cm in maximum dimension. Thus it was clearly different from the lesions described as "apocrine adenosis" by others.15,16,19

Several studies have investigated the presence of molecular markers in apocrine adenosis.17,22,23 HER2/neu protein overexpression was reported in 10/18 (55.6%) of such cases by one group,22 but the authors reported lack of HER2/neu amplification in all of these cases, calling into question the immunohistochemical results22 . A higher proliferation index has been consistently demonstrated in apocrine adenosis than in apocrine metaplasia.17,23,24

ATYPICAL APOCRINE ADENOSIS
The clinical significance of cytologic atypia in apocrine metaplasia, particularly when present in sclerosing lesions, is controversial. Carter et al 16 reported follow-up data on 51 patients with atypical apocrine metaplasia within sclerosing lesions. With an average follow-up of 35 months, none of the women developed breast carcinoma. In contrast, Seidman et al 19 reported an increased risk of subsequent carcinoma development in atypical apocrine proliferative lesions. They defined cytologic atypia in this setting as a three fold nuclear enlargement of the apocrine cells with enlarged nucleoli and coined the term "atypical apocrine adenosis" for such lesions. The reported relative risks were high; 5.5 overall, (95% confidence interval, 1.9 to 16). In women older than 60 years of age the relative risk was 14 (95% confidence interval 4.1 to 48). The authors state, though, that they made no attempt to separate out a group of non-invasive apocrine carcinomas beyond the designation of the presence/absence of atypia as defined above. Also cases with a co-occurrence of atypical ductal hyperplasia were not excluded. For these reasons the relative risks are most likely an overestimate of the risk associated with so called atypical apocrine adenosis.

APOCRINE "BORDERLINE" LESIONS
An attempt to define criteria to separate atypical apocrine lesions from minimal examples of apocrine DCIS has been made 25,26. Pattern, cytology and extent criteria have been established to separate cases of low grade DCIS from atypical ductal hyperplasia. 10,27 These criteria, however, are not readily applicable to apocrine lesions. To help foster a more uniform categorization of proliferative apocrine lesions that do not easily fall into the unequivocally benign or malignant categories, we used cytologic characteristics (usual apocrine, borderline features, or "as in DCIS") and extent criteria (<4mm, 4-8mm and >8mm).25 We called a lesion with usual apocrine cytology that measured < 8mm benign. Lesions > 4mm with cytologic features as in DCIS (irregular nuclear membrane, coarse chromatin, multiple, prominent nucleoli) were diagnosed as apocrine DCIS. Lesions that measured < 4mm, but demonstrated the same nuclear features were classified as limited apocrine DCIS, with the expectation that such lesions are highly unlikely to behave in a precursor fashion. A "borderline" category was defined primarily by the cytologic features of nuclear enlargement, the presence of slightly irregular nuclear membranes and multiple, small nucleoli. Follow-up studies are needed to determine the clinical utility of this approach to classification.

Tavassoli26 used cytologic atypia (defined as at least 3-fold nuclear enlargement) and nuclear stratification or papillary tufting to describe atypical apocrine lesions. Cases were classified as atypical apocrine hyperplasia when they exhibited both cytologic atypia as defined above and stratification with papillary formations, while atypical apocrine metaplasia showed cytologic atypia only. The extent criterion of 2 mm was used to separate proliferative apocrine lesions showing cytologic atypia and a cribriform architecture from apocrine DCIS. This study included some follow-up information, although the majority of patients were treated by mastectomy, so the natural history of these atypical apocrine proliferations remains unclear.

Tavassoli et al found the presence of necrosis particularly useful in distinguishing benign apocrine lesions from apocrine DCIS.26 Indeed, they recommend caution in the diagnosis of apocrine DCIS in the absence of necrosis. We25 concur with others28 that necrosis is not a prerequisite for a diagnosis of apocrine DCIS, but when necrosis is present, the nuclear grade tends to be high and the diagnosis of DCIS in this setting is not difficult.25

In summary, the studies that have attempted to define criteria for borderline apocrine lesions are limited by the lack of long term clinical follow-up data. Follow-up data is required to further our understanding of the biologic potential of these "borderline" apocrine lesions.

IMMUNOPHENOTYPE OF APOCRINE LESIONS
Gross cystic disease protein (GCDFP-15) is a glycoprotein that can be utilized to identify apocrine function. The gene has been localized to chromosome 7 and is identical to prolactin inducible protein.29 It is present in benign apocrine lesions as well as invasive carcinoma with apocrine features. Thus it has no utility in differentiating benign proliferative apocrine lesions from apocrine lesions that have malignant potential.

Apocrine epithelium, both benign and malignant, appears to exhibit a distinct immunoprofile compared to non-apocrine cells. They are frequently negative for estrogen and progesterone receptors, but commonly show androgen receptor immunopositivity, in contrast to benign non-apocrine breast epithelium.30-36

MOLECULAR STUDIES OF APOCRINE LESIONS
There is little molecular data available on proliferative apocrine lesions. Two studies investigating loss of heterozygosity at loci associated with invasive carcinoma failed to demonstrate allelic imbalances at these loci in apocrine hyperplasias. However, a limited number of loci were investigated in these studies.37,38

A study utilizing comparative genomic hybridization in a series of papillary apocrine hyperplasias, apocrine ductal carcinoma in-situ and invasive apocrine carcinomas showed

molecular alterations in all three groups of lesions. While the number of alterations was lower in the papillary apocrine hyperplasias compared to the in-situ and invasive apocrine lesions, there was overlap in the pattern of genetic alterations between the benign and malignant apocrine lesions.39 These findings, supported by others 40, suggest that at least some apocrine proliferations may be clonal in nature.

APOCRINE DCIS
Apocrine DCIS that presents the least diagnostic difficulty is characterized by an extensive proliferation of apocrine cells showing marked nuclear pleomorphism with enlarged nuclei, multiple prominent nucleoli and irregular nuclear membranes. This diagnosis is facilitated by the presence of comedo-type necrosis.

While apocrine DCIS can also be diagnosed in cases with lesser degrees of nuclear pleomorphism, the diagnostic challenge in such cases is the accurate categorization of the nuclear grade.41 While the participants of The Consensus Conference on the Classification of Ductal Carcinoma in-situ 42 recognized apocrine DCIS as a special variant, they did not make recommendations on the subclassification of apocrine DCIS. Some consider the vast majority of apocrine DCIS lesions to be at least intermediate grade.26 More recently, attempts have been made to define criteria for low grade apocrine DCIS.35 Follow-up studies are required to further clarify this issue.

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