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
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.
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
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
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
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
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 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
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.
- Dixon, J. M., Lumsden, A. B., and Miller, W. R. The relationship of cyst type to risk factors for
breast cancer and the subsequent development of breast cancer in patients with breast cystic disease.
Eur.J.Cancer Clin.Oncol, 21: 1047-1050, 1985.
- Bruzzi, P., Dogliotti, L., Naldoni, C., Bucchi, L., Costantini, M., Cicognani, A., Torta, M., Buzzi,
G. F., and Angeli, A. Cohort study of association of risk of breast cancer with cyst type in women with
gross cystic disease of the breast. BMJ., 314: 925-928, 1997.
- Dixon, J. M., McDonald, C., and Miller, W. R. Risk of breast cancer in women with palpable breast
cysts: a prospective study. Lancet, 353: 1742-1745, 1999.
- Devitt, J. E., To, T., and Miller, A. B. Risk of breast cancer in women with breast cysts. CMAJ.,
147: 45-49, 1992.
- Jones, B. M. and Bradbeer, J. W. The presentation and progress of macroscopic breast cysts.
Br.J.Surg., 67: 669-671, 1980.
- Haagensen CD. Diseases of the Breast.Philadelphia: W. B. Saunders, 1981.
- Roberts, M. M., Jones, V., Elton, R. A., Fortt, R. W., Williams, S., and Gravelle, I. H. Risk of
breast cancer in women with history of benign disease of the breast. Br.Med.J.(Clin.Res Ed.), 288: 275-278, 1984.
- Bundred, N. J., West, R. R., Dowd, J. O., Mansel, R. E., and Hughes, L. E. Is there an increased risk
of breast cancer in women who have had a breast cyst aspirated? Br.J.Cancer, 64: 953-955, 1991.
- Haagensen CD, Bodian, C. A., and Haagensen, D. E. Jr. Breast Cancer Risk and Detection.Philadelphia:
W. B. Saunders, 1981.
- Dupont, W. D. and Page, D. L. Risk factors for breast cancer in women with proliferative breast
disease. N.Engl.J Med., 312: 146-151, 1985.
- Fitzgibbons, P. L., Henson, D. E., and Hutter, R. V. Benign breast changes and the risk for
subsequent breast cancer: an update of the 1985 consensus statement. Cancer Committee of the College of
American Pathologists.see comments Arch.Pathol Lab.Med.,
122: 1053-1055, 1998.
- Izuo, M., Okagaki, T., Richart, R. M., and Lattes, R. DNA content in "apocrine metaplasia" of
fibrocystic disease of the breast. Cancer, 27: 643-650, 1971.
- Page, D. L., Dupont, W. D., and Jensen, R. A. Papillary apocrine change of the breast: associations
with atypical hyperplasia and risk of breast cancer. Cancer Epidemiol.Biomarkers.Prev., 5: 29-32, 1996.
- Eusebi, V., Casadei, G. P., Bussolati, G., and Azzopardi, J. G. Adenomyoepithelioma of the breast
with a distinctive type of apocrine adenosis. Histopathology, 11: 305-315,
- Page, D. L. and Simpson, J. F. What is apocrine adenosis, anyway? Histopathology
2001.Oct.;39.(4.):433.-4., 39 : 433-434.
- Carter, D. J. and Rosen, P. P. Atypical apocrine metaplasia in sclerosing lesions of the breast: a
study of 51 patients. Mod.Pathol., 4: 1-5, 1991.
- Wells, C. A., McGregor, G. I., Makunura, C. N., Yeomans, P., and Davies, J. D. Apocrine adenosis: a
precursor of aggressive breast cancer. J Clin Pathol, 48: 737-742, 1995.
- Raju, U., Zarbo, R. J., Kubus, J., and Schultz, D. S. The histologic spectrum of apocrine brest
proliferations: A comparative study of morphology and DNA content by image analysis. Hum Pathol, 24: 173-181, 1993.
- Seidman, J. D., Ashton, M., and Lefkowitz, M. Atypical apocrine adenosis of the breast: a
clinicopathologic study of 37 patients with 8.7-year follow-up. Cancer, 77:
- Simpson, J. F., Page, D. L., and Dupont, W. D. Apocrine adenosis-a mimic of mammary carcinoma.
Surgical Pathology, 3: 289-299, 1990.
- Jin, Z., Tamura, G., Satoh, M., Meguro, T., Miura, T., Hayashi, M., Osakabe, M., Ohmura, K., Ogata,
S., Endoh, Y., and Motoyama, T. Absence of BAT-26 instability in gastric intestinal metaplasia. Pathol
Int.2001.Jun.;51.(6.):473.-5., 51: 473-475.
- Selim, A. G., El-Ayat, G., and Wells, C. A. c-erbB2 oncoprotein expression, gene amplification, and
chromosome 17 aneusomy in apocrine adenosis of the breast. J.Pathol 2000 Jun.;191.(2.):138.-42., 191: 138-142.
- Moriya, T., Sakamoto, K., Sasano, H., Kawanaka, M., Sonoo, H., Manabe, T., and Ito, J.
Immunohistochemical analysis of Ki-67, p53, p21, and p27 in benign and malignant apocrine lesions of the
breast: its correlation to histologic findings in 43 cases. Mod.Pathol 2000 Jan.;13.(1.):13.-8., 13: 13-18.
- Selim, A. G., El-Ayat, G., and Wells, C. A. Expression of c-erbB2, p53, Bcl-2, Bax, c-myc and Ki-67
in apocrine metaplasia and apocrine change within sclerosing adenosis of the breast. Virchows
Arch.2002.Nov.;441.(5.):449.-55., 441: 449-455.
- O'Malley, F. P., Page, D. L., Nelson, E. H., and Dupont, W. D. Ductal carcinoma in situ of the breast
with apocrine cytology: definition of a borderline category. Hum.Pathol, 25: 164-168, 1994.
- Tavassoli, F. A. and Norris, H. J. Intraductal apocrine carcinoma: a clinicopathologic study of 37
cases. Mod.Pathol, 7: 813-818, 1994.
- Page, D. L. and Rogers, L. W. Combined histologic and cytologic criteria for the diagnosis of mammary
atypical ductal hyperplasia. Hum.Pathol, 23: 1095-1097, 1992.
- Durham, J. R. and Fechner, R. E. The histologic spectrum of apocrine lesions of the breast.
Am.J.Clin.Pathol 2000 May.;113.(5.Suppl.1.):S3.-18., 113: S3-18.
- Murphy, L. C., Tsuyuki, D., Myal, Y., and Shiu, R. P. C. Isolation and sequencing of a cDNA clone for
a prolactin-inducible protein (PIP). J Biol Chem, 262: 15236-15241, 1987.
- Kapucuoglu, N., Losi, L., and Eusebi, V. Immunohistochemical localization of Bcl-2 and Bax proteins
in in situ and invasive duct breast carcinomas. Virchows Arch., 430:
- Mazoujian, G., Pinkus, G. S., Davis, S., and Haagensen, D. E., Jr. Immunohistochemistry of a gross
cystic disease fluid protein (GCDFP-15) of the breast. A marker of apocrine epithelium and breast
carcinomas with apocrine features. Am.J.Pathol., 110: 105-112, 1983.
- Tavassoli, F. A., Purcell, C. A., Bratthauer, G. L., and Man, Y. G. Androgen receptor expression
along with loss of bcl-2, ER and PR expression in benign and malignant apocrine lesions of the breast:
implications for therapy. The Breast Journal, 2: 261-269, 1996.
- Selim, A. G. and Wells, C. A. Immunohistochemical localisation of androgen receptor in apocrine
metaplasia and apocrine adenosis of the breast: relation to oestrogen and progesterone receptors. J
Clin Pathol, 52: 838-841, 1999.
- Gatalica, Z. Immunohistochemical analysis of apocrine breast lesions. Consistent over-expression of
androgen receptor accompanied by the loss of estrogen and progesterone receptors in apocrine metaplasia
and apocrine carcinoma in situ. Pathol Res Pract., 193: 753-758, 1997.
- Leal, C., Henrique, R., Monteiro, P., Lopes, C., Bento, M. J., De Sousa, C. P., Lopes, P., Olson, S.,
Silva, M. D., and Page, D. L. Apocrine ductal carcinoma in situ of the breast: histologic classification
and expression of biologic markers. Hum.Pathol 2001.May.;32.(5.):487.-93.,
- Eusebi, V., Damiani, S., Losi, L., and Millis, R. R. Apocrine differentiation in breast epithelium.
Adv.Anat.Pathol, 4: 139-155, 1997.
- Lakhani, S. R., Slack, D. N., Hamoudi, R., Collins, N., Stratton, M. R., and Sloane, J. P. Detection
of allelic imbalance indicates that a proportion of mammary hyperplasia of usual type are clonal,
neoplastic proliferations. Lab Invest, 74: 129-135, 1996.
- Lininger, R. A., Zhuang, Z., Man, Y., Park, W. S., Emmert-Buck, M., and Tavassoli, F. A. Loss of
heterozygosity is detected at chromosomes 1p35-36 (NB), 3p25 (VHL), 16p13 (TSC2/PKD1), and 17p13 (TP53)
in microdissected apocrine carcinomas of the breast. Mod.Pathol., 12:
- Jones, C., Damiani, S., Wells, D., Chaggar, R., Lakhani, S. R., and Eusebi, V. Molecular cytogenetic
comparison of apocrine hyperplasia and apocrine carcinoma of the breast. Am.J.Pathol
2001.Jan.;158.(1.):207.-14., 158: 207-214.
- Washington, C., Dalbegue, F., Abreo, F., Taubenberger, J. K., and Lichy, J. H. Loss of heterozygosity
in fibrocystic change of the breast: genetic relationship between benign proliferative lesions and
associated carcinomas. Am.J.Pathol 2000 Jul.;157.(1.):323.-9., 157:
- Scott, M. A., Lagios, M. D., Axelsson, K., Rogers, L. W., Anderson, T. J., and Page, D. L. Ductal
carcinoma in situ of the breast: reproducibility of histological subtype analysis.see comments Hum.Pathol, 28: 967-973,
- Consensus Conference on the classification of ductal carcinoma in situ. The Consensus Conference
Committee. Cancer, 80: 1798-1802, 1997.