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Keywords:

  • apocrine cysts;
  • apocrine ductal carcinoma in situ;
  • breast;
  • cDNA expression arrays;
  • molecular studies

Abstract

  1. Top of page
  2. Abstract
  3. Apocrine cysts
  4. Papillary apocrine change
  5. Non-atypical apocrine proliferations
  6. Atypical apocrine proliferations
  7. Apocrine DCIS
  8. Invasive apocrine carcinoma
  9. Immunohistochemical studies
  10. Molecular studies
  11. Proteomics
  12. Summary
  13. References

Apocrine change occurs in a spectrum of benign lesions in the female breast and is also demonstrated in a subgroup of in situ and invasive carcinomas. Recent research has focused on the molecular phenotype of both benign and malignant apocrine lesions. This review will briefly summarize the morphological characteristics and risk associations of the spectrum of apocrine proliferations, but will focus on the updated molecular studies of both in situ and invasive apocrine carcinomas.


Abbreviations:
15PDGH

15-hydroxyprostaglandin dehydrogenase

AR

androgen receptor

CGH

comparative genomic hybridization

DCIS

ductal carcinoma in situ

ER

oestrogen receptor

GCDFP

gross cystic disease fluid protein

HMG-CoA reductase

hydroxymethylglutaryl coenzyme A reductase

LOH

loss of heterozygosity

PAC

papillary apocrine change

PR

progesterone receptor

Apocrine cysts

  1. Top of page
  2. Abstract
  3. Apocrine cysts
  4. Papillary apocrine change
  5. Non-atypical apocrine proliferations
  6. Atypical apocrine proliferations
  7. Apocrine DCIS
  8. Invasive apocrine carcinoma
  9. Immunohistochemical studies
  10. Molecular studies
  11. Proteomics
  12. Summary
  13. References

Apocrine cysts can be divided into gross or palpable cysts and microscopic cysts. Both are common, particularly in premenopausal women. Although there has been controversy regarding the level of risk associated with gross (palpable) cysts,1–8 the current consensus is that both gross (palpable) cysts and microscopic cysts lined by a single layer of apocrine epithelium are non-proliferative lesions that are not associated with any increased risk of subsequent development of carcinoma.8,9 Thus, women with these changes do not require any further follow-up than would be offered routinely.9

Papillary apocrine change

  1. Top of page
  2. Abstract
  3. Apocrine cysts
  4. Papillary apocrine change
  5. Non-atypical apocrine proliferations
  6. Atypical apocrine proliferations
  7. Apocrine DCIS
  8. Invasive apocrine carcinoma
  9. Immunohistochemical studies
  10. Molecular studies
  11. Proteomics
  12. Summary
  13. References

Microscopic cysts may be lined by apocrine epithelium arranged in papillary formations which protrude into the cyst lumen (Figure 1A,B). One study has categorized papillary formations into three groups—simple, complex and highly complex—based on the length of the papillations and the tendency to form arches.10 This study reported that, although 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).10 Thus, the finding of highly complex PAC should prompt a thorough search for the presence of concurrent atypical hyperplasia. However, it should also be noted that PAC in the absence of atypical hyperplasia in adjacent breast tissue is not associated with any subsequent risk of carcinoma.10

image

Figure 1. A, Highly complex papillary apocrine change. The papillae are elongated and form complex architectural patterns. B, High power shows the classic features of benign apocrine cells with enlarged nuclei, prominent, but uniform, nucleoli and abundant eosinophilic granular cytoplasm. C, Apocrine ductal carcinoma in situ (DCIS). Papillary formations project into the lumen and are somewhat reminiscent of the architecture in (A), but note the intraluminal necrosis characteristic of apocrine DCIS. D, High power of apocrine DCIS. This photomicrograph is at the same magnification as (B). Note the markedly enlarged nuclei, the multiple, irregular nucleoli, coarse chromatin and irregular nuclear membranes, which contrast with the appearance of the benign apocrine cells in (B).

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Non-atypical apocrine proliferations

  1. Top of page
  2. Abstract
  3. Apocrine cysts
  4. Papillary apocrine change
  5. Non-atypical apocrine proliferations
  6. Atypical apocrine proliferations
  7. Apocrine DCIS
  8. Invasive apocrine carcinoma
  9. Immunohistochemical studies
  10. Molecular studies
  11. Proteomics
  12. Summary
  13. References

The term ‘apocrine adenosis’ has been applied to a range of apocrine proliferations.11–15 Simpson and Page have used this term to describe apocrine change in deformed lobular units, sclerosing adenosis, radial scars and complex sclerosing lesions and, indeed, the term is commonly applied to these lesions in current practice.12

Several studies have attempted to define the immunophenotypical profile of apocrine adenosis. However, these studies are difficult to interpret as it is unclear which apocrine lesions they have investigated.16–18 Given the spectrum of non-proliferative and proliferative apocrine lesions designated as apocrine adenosis, we discourage its use and prefer to describe the specific underlying entity in which apocrine change is present, as has been proposed by Eusebi et al.19 Future studies, using a more precise categorization of proliferative apocrine lesions, may elucidate the conflicting results that have so far been reported for the many lesions described as apocrine adenosis.

Atypical apocrine proliferations

  1. Top of page
  2. Abstract
  3. Apocrine cysts
  4. Papillary apocrine change
  5. Non-atypical apocrine proliferations
  6. Atypical apocrine proliferations
  7. Apocrine DCIS
  8. Invasive apocrine carcinoma
  9. Immunohistochemical studies
  10. Molecular studies
  11. Proteomics
  12. Summary
  13. References

There is controversy regarding the criteria used to define cytological atypia and the clinical significance of atypia in apocrine epithelium. This applies particularly to apocrine change within sclerosing lesions. Much of this difficulty is related to the fact that normal apocrine cells are large and have prominent nucleoli. Few studies have assessed the clinical significance of atypia in apocrine proliferations. One study defined atypia as the presence of ‘prominent pleomorphic nucleoli’ and an increased nuclear–cytoplasmic ratio. None of the women in the study using this definition of atypia developed breast carcinoma, with an average follow-up period of 35 months.13 In contrast, others14 have reported a significant increased risk of subsequent carcinoma development in women with atypical apocrine proliferations defined as a threefold nuclear enlargement of the apocrine cells with enlarged nucleoli. Although the relative risks were high in this study (5.5 overall, 14 in women > 60 years old), it is likely that some of these cases represented cancerization of sclerosing adenosis by ductal carcinoma in situ (DCIS); thus the relative risks are likely to be an overestimate of the risk associated with these atypical apocrine proliferations.

The term ‘borderline’ has been used to recognize a group of atypical apocrine lesions that have some, but not all, of the features of DCIS. Although there are clinically validated criteria described for non-apocrine lesions that can be used to differentiate between cases of atypical ductal hyperplasia and low-grade DCIS,8,20 these criteria are not readily applicable to apocrine lesions. Few studies have attempted to define criteria to separate atypical apocrine lesions from minimal examples of apocrine DCIS.21 The presence of nuclear atypia has been emphasized by all studies, and has been defined as a threefold nuclear enlargement with nucleolar enlargement by some groups. Others have defined atypia as the presence of multiple small nucleoli in apocrine cells showing variability in nuclear size, but lacking coarse chromatin or irregular nuclear membranes. In addition to nuclear atypia, some groups have emphasized the extent of the atypical apocrine proliferation in separating atypical proliferation from a minimal example of in situ carcinoma;22 others have used architectural features and the presence of necrosis in making this distinction.23 The major limitations of these studies, however, are the lack of long-term clinical follow-up data.21

Given that the criteria proposed to separate atypical apocrine proliferations from apocrine DCIS are arbitrary and not clinically validated, a pragmatic approach to their management is recommended. When an atypical apocrine proliferation is encountered in a lumpectomy specimen and is completely excised, a conservative approach, including routine follow-up, is suggested, but when an atypical apocrine lesion is identified in a core biopsy specimen, local excision may be considered to exclude the presence of apocrine DCIS.

Apocrine DCIS

  1. Top of page
  2. Abstract
  3. Apocrine cysts
  4. Papillary apocrine change
  5. Non-atypical apocrine proliferations
  6. Atypical apocrine proliferations
  7. Apocrine DCIS
  8. Invasive apocrine carcinoma
  9. Immunohistochemical studies
  10. Molecular studies
  11. Proteomics
  12. Summary
  13. References

Apocrine DCIS is often characterized by a proliferation of apocrine cells showing marked nuclear pleomorphism with enlarged nuclei, multiple prominent nucleoli and irregular nuclear membranes; comedo necrosis is invariably present in such cases. When these features are seen, a diagnosis of apocrine DCIS is not difficult to make (Figure 1C,D; Figure 2).

image

Figure 2.  Apocrine ductal carcinoma in situ (DCIS). A, Cancerization of lobules is noted, which is a typical pattern seen in apocrine DCIS. B, High power shows the malignant apocrine cells with nuclear pleomorphism, coarse chromatin and a high nuclear–cytoplasmic ratio.

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Although 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.24 Some consider the vast majority of apocrine DCIS lesions to be at least intermediate grade,23 whereas others have attempted to stratify these lesions further on the basis of a three-tier grading system.25 A striking heterogeneity of these apocrine DCIS lesions has been reported;25 this is our experience also.

Invasive apocrine carcinoma

  1. Top of page
  2. Abstract
  3. Apocrine cysts
  4. Papillary apocrine change
  5. Non-atypical apocrine proliferations
  6. Atypical apocrine proliferations
  7. Apocrine DCIS
  8. Invasive apocrine carcinoma
  9. Immunohistochemical studies
  10. Molecular studies
  11. Proteomics
  12. Summary
  13. References

Invasive apocrine carcinoma has generally been regarded as a morphological variant of invasive ductal carcinoma, no special type, rather than a distinct subtype, as studies have shown that they are indistinguishable clinically from this group of mammary carcinomas.26–28 However, this assumption has recently been brought into question.29

Microscopically, apocrine carcinomas demonstrate the same architectural growth pattern as invasive ductal carcinomas of no special type, differing only in their cytological appearance (Figure 3). The cells are characterized by the typical apocrine features of abundant eosinophilic granular cytoplasm and prominent, and often multiple, nucleoli. The incidence of pure apocrine carcinoma varies from < 1% to 4%.30–32 Such variability in incidence is likely to be a result of the lack of well-defined diagnostic criteria. Rosen has stipulated that the term should be reserved for ‘neoplasms in which all or nearly all the epithelium has apocrine cytologic features’.33 Focal apocrine differentiation insufficient to meet the criteria outlined above has been reported in 12–57% of invasive ductal carcinomas of no special type.32,34 Areas of apocrine differentiation have also been reported in special-type cancers, particularly lobular carcinomas.35 The apocrine phenotype can be further corroborated by additional studies, including the presence of periodic acid–Schiff-positive cytoplasmic granules, immunoexpression of the 15-kDa glycoprotein of cystic breast disease (GCDFP) and the demonstration of empty vesicles and osmiophilic membrane-bound granules at the ultrastructural level.32,36,37

image

Figure 3. A, Apocrine ductal carcinoma in situ forming a cribriform pattern. There is associated invasive apocrine carcinoma present in the upper portion of the photomicrograph. B, High power view of the invasive apocrine carcinoma.

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Although the microscopic appearance of these tumours is striking, we do not currently recognize these tumours as special-type carcinomas. However, given the characteristic immunohistochemical and molecular phenotype that these tumours exhibit, and the possible difference in their clinical behaviour,29 it is possible that further research may lead to their recognition as a distinct subgroup.

Immunohistochemical studies

  1. Top of page
  2. Abstract
  3. Apocrine cysts
  4. Papillary apocrine change
  5. Non-atypical apocrine proliferations
  6. Atypical apocrine proliferations
  7. Apocrine DCIS
  8. Invasive apocrine carcinoma
  9. Immunohistochemical studies
  10. Molecular studies
  11. Proteomics
  12. Summary
  13. References

Apocrine lesions have long been reported to have an altered expression profile for hormone receptors compared with their non-apocrine counterparts. Benign apocrine metaplastic lesions have been shown to be androgen receptor (AR) positive and negative for oestrogen receptor (ER) and progesterone receptor (PR) expression.17,38–40 This unique receptor profile is largely retained in apocrine DCIS,25,39 but is more variable in invasive apocrine carcinomas39,41,42 (see Table 1). The differences in reported positivity between different studies could be accounted for by the small number of invasive apocrine carcinomas in these series, as well as differences in the diagnostic criteria used to define apocrine carcinoma. Use of different antibody clones and different cut-off levels to dichotomize results could also account for some of the variability. Nevertheless, the presence of high rates of AR positivity in these invasive tumours could perhaps expand the therapeutic options for these women in the future.

Table 1.   Immunohistochemical profile of apocrine lesions
 Benign apocrine proliferationsApocrine DCISInvasive apocrine carcinoma
  1. DCIS, Ductal carcinoma in situ.

  2. *These cases did not show HER2 gene amplification.

Oestrogen receptor0% positive17,390–6% positive25,393.8–60% positive39,41
Progesterone receptor0% positive17,390–3% positive25,395.8–40% positive39,41
Proliferation index (Ki67)0–14.5 16,46 Mean 2.7%180.4–28.725 Mean 14.7%186.9–23.7 18 Mean 15.3%18
Androgen receptor100% positive 17,3997% positive2556–100% positive39,41,42
BCL20% positive39,460–3% positive25,3950% positive39
p530–30% positive16,39,4662–67% positive25,3946–50% positive18,39
c-myc100% positive46–48Not knownNot known
HER2 protein overexpression10–57% positive*16,4647% positive2550% positive42

BCL2 is an anti-apoptotic gene which functions to inhibit mitochondria-mediated caspase activation. High levels of BCL2 expression have been observed in 75–80% of invasive carcinomas.43–45 The expression of BCL2 is highly correlated with ER and PR expression; thus it is hardly surprising that this ER-regulated gene is absent from benign apocrine lesions.39,46 Low levels of BCL2 positivity have been observed in apocrine DCIS39, but higher rates have been reported in invasive apocrine carcinoma39 (Table 1).

p53, a tumour suppressor gene located on chromosome 17p13, has been reported in 0–30% of benign apocrine lesions 16,39,46, up to 67% of apocrine DCIS cases 25,39 and approximately 50% of invasive apocrine carcinomas, (Table 1). Neither its association with underlying mutations nor the clinical significance of p53 alterations has been explored specifically in apocrine lesions.

A number of authors have demonstrated elevated expression of c-myc oncoprotein in benign apocrine metaplastic lesions.46–48 This increased protein expression has not been reported to be accompanied by c-myc gene amplification, and its significance, if any, is unclear.

The proliferation index, as measured by Ki67, has been reported as generally low in benign apocrine lesions.16,18,46 The median proliferation index for apocrine DCIS was 5.2 in one study,25 but there was a wide variation (0.4–28.7), with the highest proliferation indices associated with high-grade apocrine DCIS.25 One study has reported a mean proliferation index of 15.3 for invasive apocrine carcinoma with a range of 6.9–23.7.18

HER2/neu overexpression and/or gene amplification

HER2/neu protein overexpression has been reported in both benign and malignant apocrine lesions.16,25,42,46 The overall HER2/neu positivity rate in apocrine DCIS in one study was 47%, but the rate was significantly associated with grade (71% in high-grade apocrine DCIS versus 20% in low-grade apocrine DCIS). Few invasive apocrine carcinomas have been studied for HER2/neu expression; one study has reported a positivity rate of 50% in a small series of cases42 (Table 1). HER2/neu gene amplification studies have not, for the most part, been conducted in tandem with HER2/neu protein overexpression studies.

Molecular studies

  1. Top of page
  2. Abstract
  3. Apocrine cysts
  4. Papillary apocrine change
  5. Non-atypical apocrine proliferations
  6. Atypical apocrine proliferations
  7. Apocrine DCIS
  8. Invasive apocrine carcinoma
  9. Immunohistochemical studies
  10. Molecular studies
  11. Proteomics
  12. Summary
  13. References

Loss of heterozygosity

Loss of heterozygosity (LOH) studies are used as a surrogate marker for the presence of tumour suppressor genes which may be causally involved in the development of neoplastic conditions. LOH has been detected at 1p, 3p, 11q, 13q, 16q and 17q in benign apocrine proliferations.49,50 In a series of matched apocrine metaplastic lesions and adjacent invasive carcinomas, the authors have demonstrated that seven of 14 specimens shared LOH of one or more loci in common.51

Comparative genomic hybridization

Comparative genomic hybridization (CGH) allows for the detection of genomic regions of gain and loss in tumours in regions that may harbour oncogenes or tumour suppressor genes, respectively. Jones and colleagues52 performed conventional CGH on a series of apocrine breast lesions including 10 cases of PAC, 10 cases of apocrine DCIS and four cases of invasive apocrine carcinoma. They made some notable findings; the average copy number changes increased with increasing lesion complexity, a finding thought to reflect the stochastic accumulation of genetic alterations over time, necessary for the acquisition of the fully malignant phenotype. Second, there were shared regions of loss and/or gain between PAC and DCIS, and between DCIS and invasive apocrine carcinoma, reinforcing the concept that these lesions are related. Third, they identified recurrent regions of loss and gain, suggesting that the process is non-random and likely to be related to molecular pathways of evolution and/or a specific cell of origin.53–56 The common regions of loss and gain that these authors identified are summarized in Table 2. Indeed, these results have led some of the authors of this paper to speculate in a second publication that apocrine hyperplastic lesions may be the precursor lesions of some cases of intermediate and high-grade DCIS.57 More extensive studies, with larger sample sizes and higher resolution techniques, are needed to support this hypothesis.

Table 2.   Comparative genomic hybridization study of benign and malignant apocrine lesions of the breast52
 Benign apocrine proliferationsApocrine DCISInvasive apocrine carcinoma
  1. DCIS, Ductal carcinoma in situ.

Average copy number changes4.110.414.8
Common losses1p, 2p, 10q, 16q, 17q, 22q1p, 2p, 2q, 8q, 9q, 12q, 16q, 17q, 22q1p, 2p, 2q, 5q(2), 8q, 9q, 11q, 12q, 16q, 17q
Common gains1p, 2q, 13q1p, 1q, 2q, 3q, 4q, 5q, 7q1p, 1q, 2q, 3q, 3p, 13q

cDNA expression arrays

Substantial insights into the molecular pathways and cell of origin of breast cancers have been facilitated by their molecular subtyping using cDNA expression arrays. This work has been pioneered in large part by the Stanford group, who have identified five genetically distinct subgroups of invasive breast cancers: two ER+ groups (Luminal A and Luminal B); and three ER− groups (Basal-like, HER2 and Normal Breast-like).53–55,58 These subgroups have been found to broadly reflect biological behaviour,56 but not specific morphological tumour types.

A recent cDNA expression array study59 has discovered a group of tumours with a molecular signature driven in large part by the expression of the AR. All of the tumours in this group were ER− and were non-basal tumours, but overlapped significantly with the HER2 group as defined by the intrinsic gene set in the Stanford array studies.53–55 Pathological review of these tumours has shown that they demonstrate marked apocrine features. The genes that discriminated this group comprised what the authors referred to as an ‘apocrine molecular signature’, which was found to contain an abundance of genes with a role in metabolism, as determined by the Gene Ontology database. The authors speculated that the ‘apocrine molecular signature’ group is enriched in HER2+ tumours, suggesting a link between HER2 signalling and the molecular apocrine phenotype.59 Further studies are required to confirm these findings.

Proteomics

  1. Top of page
  2. Abstract
  3. Apocrine cysts
  4. Papillary apocrine change
  5. Non-atypical apocrine proliferations
  6. Atypical apocrine proliferations
  7. Apocrine DCIS
  8. Invasive apocrine carcinoma
  9. Immunohistochemical studies
  10. Molecular studies
  11. Proteomics
  12. Summary
  13. References

Celis and colleagues undertook a novel proteomics approach using two-dimensional polyacrylamide gel electrophoresis and mass spectrometry, to investigate the constituent proteins of benign apocrine cyst fluid to identify apocrine-specific markers.60 They identified a number of proteins preferentially expressed in cyst fluid, including those regulated by hormones, particularly androgen, and those involved in metabolic pathways such as lipid biosynthesis. These proteins included GCDFP-15, apo D, 15-hydroxyprostaglandin dehydrogenase (15PDGH), hydroxymethylglutaryl coenzyme A reductase (HMG-CoA reductase) and cathepsin D. GCDFP-15, in particular, has been extensively studied in apocrine lesions.36,37 Among the more novel protein discoveries, the authors have validated 15PDGH and HMG-CoA reductase as being specific markers of apocrine cells. Moreover, they have demonstrated that 15PDGH was expressed in five of six pure invasive apocrine carcinomas, but was not present in any of the non-apocrine invasive carcinoma controls. This led the authors to hypothesize a direct precursor relationship between benign apocrine proliferations and invasive apocrine carcinoma. In a subsequent study, the authors have suggested that a panel of five histochemical markers (15PGDH, HMG-CoA reductase, p53 and two markers shown by others to be specific for malignant apocrine cells: S100A7 and S100A9) could provide a protein expression signature specific for apocrine cells.61 Validation of these findings has not yet been performed.

Summary

  1. Top of page
  2. Abstract
  3. Apocrine cysts
  4. Papillary apocrine change
  5. Non-atypical apocrine proliferations
  6. Atypical apocrine proliferations
  7. Apocrine DCIS
  8. Invasive apocrine carcinoma
  9. Immunohistochemical studies
  10. Molecular studies
  11. Proteomics
  12. Summary
  13. References

Epidemiological studies have shown no increased risk of development of carcinoma associated with the majority of benign apocrine lesions of the breast. However, the genetic similarities between some benign and malignant apocrine lesions suggest that at least a subset of these benign lesions may behave in a non-obligate precursor fashion. This possible relationship requires further investigation.

Recent molecular studies have indicated that invasive apocrine carcinomas may represent a distinct subgroup of breast cancers characterized by overexpression of the AR and metabolism-related genes. These findings may have potential therapeutic implications for women with invasive apocrine carcinomas.

References

  1. Top of page
  2. Abstract
  3. Apocrine cysts
  4. Papillary apocrine change
  5. Non-atypical apocrine proliferations
  6. Atypical apocrine proliferations
  7. Apocrine DCIS
  8. Invasive apocrine carcinoma
  9. Immunohistochemical studies
  10. Molecular studies
  11. Proteomics
  12. Summary
  13. References
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