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Apocrine Ductal Carcinoma In Situ Involving a Sclerosing Lesion With Adenosis

Report of a Case
Daniel W. Visscher, MD

metaplasia is a ubiquitous of the N Apocrinefibrocystic change spectrum.component mostly mammary Although associated with cysts, apocrine metaplasia can also present as a proliferative lesion, rarely with cytologic atypism. Apocrine atypia is characterized by 3-fold nuclear enlargement, multiple nucleoli, and hyperchromatism and generally arises in florid adenosis or radial sclerosing lesions. Dramatic apocrine atypia may be very difficult to distinguish from apocrine ductal carcinoma in situ. The latter is distinguished from apocrine atypia by greater extent of the lesion (.0.4 cm) and the presence of greater nuclear pleomorphism with nuclear membrane irregularity. The clinical significance of apocrine atypia is poorly understood and reflects the lack of published outcome studies. Herein, I report a case in which apocrine ductal carcinoma in situ presented as atypical apocrine adenosis in a needle core breast biopsy. It illustrates the problem of assessing apocrine atypia and apocrine ductal carcinoma in situ in small samples. (Arch Pathol Lab Med. 2009;133:18171821)

characterized by extensive adenosis with apocrine atypia and stromal fibrosis (Figure 2, a through d). This case, an example of apocrine DCIS presenting as atypical apocrine adenosis in a core biopsy, will be used to discuss and illustrate some unresolved controversies involving apocrine metaplasia and its relationship to breast carcinoma. COMMENT The pathologic spectrum of apocrine breast lesions, summarized in Table 1, is quite diverse. Apocrine metaplasia is such a ubiquitous finding in benign breast biopsies that it is often overlooked when examining histologic sections during the course of everyday practice. Apocrine metaplasia is so common that some authors1 have gone so far as to suggest that apocrine phenotype is a variant of normal mammary differentiation. Necropsybased surveys, however, report 50% prevalence in normal breast tissue.2 The mechanism underlying apocrine metaplasia is unclear; the cells are characterized by expression of androgen (but not estrogen) receptor and GCDFP-15 (prolactin inducible protein). The familiar cytoplasmic appearance reflects the presence of abundant coarse granules. Apocrine metaplasia is the cellular component in the hallmark lesion of fibrocystic mastopathy type-1 cysts, the fluid of which is rich in potassium and sex steroid conjugates. Lumens of apocrine cysts often contain microcalcifications of the conventional type. They may also harbor oxalate crystals; these do not stain but are refractile and birefringent. Biopsies with missing microcalcifications should be carefully examined for presence of these crystals. They are often associated with mononuclear inflammation in adjacent stroma. Is Apocrine Metaplasia in Cysts Associated With Increased Breast Cancer Risk? There is broad consensus that biopsies showing simple cysts, lined by a single layer of apocrine cells, do not convey increased risk for subsequent breast carcinoma (ie, in the absence of proliferative lesions such as duct hyperplasia). However, cysts are sometimes lined by multiple layers of apocrine epithelium, termed papillary apocrine change (PAC) (Figure 3, a). Page et al3 are the only authors who have systematically studied PAC. They identified PAC in 27% (1611 of 5966) of benign breast biopsy specimens; PAC was architecturally complex or
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CASE HISTORY The patient is a 35-year-old woman who presented with a palpable breast lump. On the mammogram, suspicious calcifications were present in the corresponding area. An ultrasound-guided core biopsy from the abnormality demonstrated atypical apocrine metaplasia (Figure 1, a and b). This interpretation prompted an open excision which, on gross examination, showed poorly demarcated, rubbery, tan-white cut surfaces containing multiple smooth-walled cysts. Although the tissue was abnormally firm, no distinct nodules were present. Histologic sections from the excision showed apocrine ductal carcinoma in situ (DCIS) arising in a complex sclerosing lesion
Accepted for publication June 22, 2009. From the Department of Pathology, University of Michigan, Ann Arbor. The author has no relevant financial interest in the products or companies described in this article. Presented at New Frontiers in Pathology: An Update for Practicing Pathologists, University of Michigan, Ann Arbor, September 18, 2008. Reprints: Daniel W. Visscher, MD, Department of Pathology, University of Michigan, 1500 E Medical Center Dr, Room 2G332, Ann Arbor, MI 48109 (e-mail: danielvi@umich.edu). Arch Pathol Lab MedVol 133, November 2009

Figure 1. Photomicrographs from needle core biopsy. a, Needle core breast biopsy specimen at intermediate magnification shows sclerosing lesion with adenosis and apocrine populations. b, High magnification of atypical apocrine cells in the core biopsy specimen shows hyperchromasia, irregular nuclear membranes, and a mitotic figure (hematoxylin-eosin, original magnifications 3100 [a] and 3600 [b]). Figure 2. Photomicrographs from the excisional biopsy. a, Low-magnification photomicrograph of the excision specimen shows a very cellular proliferation with cystic, sclerosing, and microglandular elements. b, One of the ducts in the excision specimen shows apocrine ductal carcinoma in situ characterized by a cribriform proliferation of cells. It is immediately adjacent to an area of adenosis involved by the lesion. c, High magnification of a nearby duct shows malignant apocrine cells characterized by pleomorphic nuclei, multiple nucleoli, nuclear membrane irregularity, mitotic activity, and individual cell necrosis. d, Area of adenosis in excision specimen at high magnification shows cytologically abnormal apocrine cells (hematoxylin-eosin, original magnifications 340 [a], 3200 [b], and 3600 [c and d]).

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Apocrine Lesions of the Breast


Simple and complex cysts PAC including apocrine atypia Juvenile papillomatosis APM involving radial sclerosing lesion, adenosis or papilloma, including atypical apocrine adenosis Apocrine DCIS (low and high grade) Apocrine carcinoma, invasive Abbreviations: APM, apocrine metaplasia; DCIS, ductal carcinoma in situ; PAC, papillary apocrine change.

highly complex in only 6.5% and 1.0% of specimens, respectively. Highly complex PAC was described as arches extending far into the central space and tending to cross or touch each other at least twice. Papillary apocrine change was associated with an increase in breast cancer risk (1.433.13) compared to that in the population overall. However, the increased risk was largely eliminated after correction for concurrent atypical ductal hyperplasia, which was present in 20% of biopsy specimens with highly complex PAC. Further, 50/60 biopsy specimens with highly complex PAC had other proliferative lesions such as usual ductal hyperplasia. Hence, the presence of florid PAC in a biopsy may be

considered a surrogate marker for significant proliferative mastopathy. As such, it should prompt a search for highrisk index lesions elsewhere in the biopsy. In the study by Page et al,3 papillary apocrine change lesions were confined to those cases that lacked nuclear atypism. These lesions may be architecturally quite complex; however, they were uniformly characterized by nuclear cytological pattern(s) as seen in usual apocrine change. On occasion, as the authors note, the degree of architectural complexity in PAC can be rather worrisome and associated with nuclear atypism. This fact may raise the differential diagnosis of apocrine atypia or even DCIS. What Is Apocrine Atypia: Does It Have Clinical Significance? Apocrine atypia is generally seen in association with mass-forming, cellular sclerosing lesions that often contain papillomas and florid adenosis. Because both benign and atypical apocrine populations can involve simple microglandular units but can also form worrisome intraductal papillary and cribriform structures, the concept of apocrine atypia is essentially cytologic. Further, because even normal apocrine cell populations are

Figure 3. Apocrine proliferations of the breast. a, Papillary apocrine change. Note enlarged nuclei. b, Apocrine ductal carcinoma in situ with angular, hyperchromatic nuclei. c, Atypical apocrine adenosis with enlarged nuclei. Chromatin is dispersed and nuclear membrane abnormalities are lacking. d, Apocrine atypia involving a duct. The cells are growing in a cribriform manner and the nuclei are hyperchromatic with inconspicuous nucleoli (hematoxylin-eosin, original magnifications 3600). Arch Pathol Lab MedVol 133, November 2009 Apocrine DCIS Involving Sclerosing LesionVisscher 1819

significantly larger than ductal cells, it must be emphasized that criteria for apocrine atypia are derived and applied within the reference frame of apocrine cells. For example, most authors emphasize that apocrine atypia is characterized by significant (33) nuclear enlargement, but the assessment is made relative to normal apocrine cells. To further confuse the matter, a partial morphologic overlap nearly always exists between normal and atypical apocrine populations within individual lesions. Even clearly benign lesions may contain an occasional enlarged cell with an atypical nucleus. Major problems have limited the clinical value of assessing apocrine atypia in daily practice. Perhaps most disturbing, from a diagnostic point of view, is the fact that atypical apocrine lesions form a histologic spectrum, such that there is partial microscopic overlap between atypical apocrine proliferations and low-grade apocrine DCIS. Second, use of the term apocrine atypia is, at the present time, descriptive; its clinical significance has yet to be unequivocally established (ie, in the sense of atypical ductal or lobular hyperplasia). Finally, because borderline apocrine atypias are relatively uncommon, it is harder to develop experience and confidence with their evaluation. OMalley et al45 have attempted to define criteria for distinguishing benign, atypical, and low-grade malignant apocrine lesions. Apocrine atypia is cytologically characterized by (1) 3-fold nuclear enlargement (ie, compared to normal apocrine cells), (2) nucleolar enlargement or multiple nucleoli, (3) slightly irregular nuclear membranes, and (4) fine (versus coarse) nuclear chromatin (Figure 3, c and d). Necrosis is absent, although focal apoptosis may be identified. Importantly, the lesion is usually of limited extent (ie, ,4 mm). Low-grade apocrine DCIS, in contrast, more noticeably demonstrates irregular nuclear membranes and coarse chromatin in addition to nuclear enlargement (Figure 3, b). Importantly, nuclear atypism is more widespread among the cell population in apocrine DCIS (.25% of cells). Finally, in low-grade apocrine DCIS, the lesion should exceed 4 mm and involve more than 2 lobular units with intervening ducts. Apoptosis may be observed, although necrosis is not present (as would be seen in high-grade lesions). A truly cribriform architecture is more characteristic of low-grade apocrine DCIS than of apocrine atypia. Fortunately, from a diagnostic perspective, apocrine DCIS is more frequently a high-grade lesion, in which case malignant features such as comedo necrosis, tumefactive growth, and overtly atypical cytologic features are readily appreciated. As noted by OMalley et al,4,5 the cytologic and size criteria for distinguishing apocrine atypia from low-grade DCIS are yet to be tested in a long-term follow-up study. In fact, even the clinical behavior of low-grade apocrine DCIS remains similarly undefined, especially for smaller lesions. But, as noted above, atypical apocrine lesions form a relatively broad morphologic continuum, and quite a generous degree of heterogeneity exists even within individual cases. Although the criteria enumerated above are no doubt useful, some features may not be present or a mixture of atypical and malignant cytologic findings may be present. For this reason, an indeterminate or borderline category has been proposed, consisting of proliferations with worrisome cytologic features that extend 4 to 8 mm; unfortunately, the clinical significance
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of such cases, which comprised the truly problematic diagnoses, is also unclear. Is Apocrine Adenosis a High-Risk or a Precancerous Lesion? The size and cytologic criteria proposed by OMalley et al4,5 do not distinguish intraductal apocrine proliferations from those arising in/ associated with sclerosing adenosis. This has the advantage of providing a unifying approach but does not address whether or not apocrine atypia in adenosis lesions (ie, as in our case) represent a special entity. As noted above, apocrine metaplasia may involve or arise in papillomas, radial scars, and sclerosing adenosis. (Clear distinction between these entities can be problematic at times owing to their frequent admixture in sclerosing lesions.) Even when not atypical, apocrine adenosis involving sclerosing lesions can impart a very busy and cellular morphologic profile that, when accompanied by stromal fibrosis and architectural distortion, can resemble a malignant lesion on casual inspection. The benign nature of these problematic biopsy specimens, however, is readily appreciated by demonstrating the abundance of myoepithelium with special stains (actin, p63, calponinwhichever you happen to prefer). There is some evidence that atypical apocrine adenosis lesions are associated with increased breast cancer risk. First, similar to PAC, the frequency of atypical ductal hyperplasia is increased in biopsies that have prominent apocrine adenosis.6 Second, Seidman et al7 reported that patients with atypical apocrine adenosis had an increased relative risk (5.53) for subsequent breast carcinoma development. This study, however, did not adjust for the effect of concurrent atypical ductal hyperplasia. It also included a relatively large number of biopsy specimens from older women. This fact raises the question of whether some of their cases may have represented partially sampled examples of apocrine DCIS. (Note the analogy to our case, in which atypical apocrine cells from DCIS apparently colonized adenosis in a core biopsy sample.) A smaller study by Carter and Rosen8 found no elevated risk of breast cancer, although their cohort included only 47 patients with short-term follow-up (median, 35 months). Hence, as with apocrine ductal lesions with atypia, the association of atypical apocrine adenosis with breast cancer risk is questionable at this time. CONCLUSIONS The major lesson from this case is that the presence of apocrine atypia involving/arising in adenosis can be a problem in core biopsies because it may represent unsampled apocrine DCIS. This problem is analogous to that observed for atypical ductal hyperplasia in core biopsies that show DCIS upon open excision. Apocrine atypia in a core biopsy should be evaluated with particular attention to the cytologic features, including chromatin density, nucleoli, and nuclear membranes. Subtle cytologic features, unfortunately, may potentially be overlooked because the constellation of cellularity and sclerosis with distortion can mimic malignancy and draw attention to the necessity of performing myoepithelial staining to rule out invasion. In my opinion, open biopsy should be considered to rule out malignancy if significant apocrine atypia is present in a core biopsy.9 In addition, open biopsies with apocrine atypia should be subjected to generous sampling to rule out apocrine DCIS.
Apocrine DCIS Involving Sclerosing LesionVisscher

Diagnostically problematic apocrine lesions, fortunately, are uncommon and the most common pitfall is overdiagnoses of malignancy, as noted above. Criteria for distinguishing apocrine atypia from low-grade apocrine DCIS are different from those applied to conventional ductal lesions; they involve a different threshold for lesion extent and are weighted to cytologic (versus architectural) features. The clinical significance of apocrine atypia in otherwise benign biopsies is not known, but there is evidence that it may convey increased breast cancer risk, possibly via an association with other highrisk index lesions.
References
1. Eusebi V, Damiami S, Losi L, et al. Apocrine differentiation of breast epithelium. Adv Anat Pathol. 1997;4:139155.

2. Wellings S, Alpers C. Apocrine cystic metaplasia: subgross pathology and prevalence in cancer-associated versus random autopsy breasts. Hum Pathol. 1987:18(4):381386. 3. Page DL, Dupont WD, Jensen RA. Papillary apocrine change of the breast: associations with atypical hyperplasia and risk of breast cancer. Cancer Epidemiol Biomarkers Prev. 1996;5(1):2932. 4. OMalley FP, Page DL, Nelson EH, et al. Ductal carcinoma in situ of the breast with apocrine cytology: definition of a borderline category. Hum Pathol. 1994;25(2):164168. 5. OMalley FP, Bane AL. The spectrum of apocrine lesions of the breast. Adv Anat Pathol. 2004;11(1):19. 6. Simpson JF, Page DL, Dupont WD. Apocrine adenosisa mimic of mammary carcinoma. Surg Pathol. 1990;3:289299. 7. Seidman JD, Ashton M, Lefkowitz M. Atypical apocrine adenosis of the breast: a clinicopathologic study of 37 patients with 8.7-year follow up. Cancer. 1996;77(12):25292537. 8. Carter DJ, Rosen PP. Atypical apocrine metaplasia in sclerosing lesions of the breast: a study of 51 patients. Mod Pathol. 1991;4(1):15. 9. Wells CA, El-Ayat GA. Non-operative breast pathology: apocrine lesions. J Clin Pathol. 2007;60(12):13131320.

Prepare Now for the CAP 10 Abstract Program


Plan now to submit abstracts and case studies for the College of American Pathologists (CAP) 2010 meeting, which will be held September 26th through the 29th in Chicago, Illinois. Submissions for the CAP 10 Abstract Program will be accepted from: Monday, February 1, 2010, through Monday, April 5, 2010. Accepted submissions will appear in the September 2010 issue of the Archives of Pathology & Laboratory Medicine. Visit the ARCHIVES Web site at http://arpa.allenpress.com and also the CAP Web site at www.cap.org for additional abstract program information.

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