Human Pathology (2014) 45, 2130–2135
www.elsevier.com/locate/humpath
Original contribution
Atypical apocrine adenosis diagnosed on breast core biopsy: implications for management☆ Benjamin C. Calhoun MD, PhD ⁎, Christine N. Booth MD Department of Pathology, Robert J. Tomsich Pathology and Laboratory Medicine Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195 Received 12 May 2014; revised 6 June 2014; accepted 11 June 2014
Keywords: Breast; Core Biopsy; Atypia; Screening; Diagnosis
Summary Apocrine adenosis (AA) and atypical apocrine adenosis (AAA) are uncommon findings in breast biopsies that may be misinterpreted as carcinoma. The data from long-term follow up studies of open biopsies suggest that AAA is not a high-risk or precursor lesion. The clinical significance and risk implications of AAA diagnosed on core biopsy are not well established. The goal of this study was to determine the frequency of carcinoma in excision specimens after a core biopsy diagnosis of AA or AAA. We identified 34 core biopsies of AA (22) and AAA (12) performed between 1996 and 2014. The mean age at diagnosis was 60 years. The most common indications for core biopsy were calcifications (11), a mass or density (18), and a mass or density with calcifications (3). Two cases were detected on magnetic resonance imaging (MRI) studies. Available pathology reports and slides were reviewed, and surgical excision findings were correlated with core biopsy diagnoses. Of the core biopsies with AA or AAA, 7 also contained atypical ductal or lobular hyperplasia (AH) and 4 contained ductal carcinoma in situ or invasive carcinoma. In the absence of coexisting AH or carcinoma in the initial core biopsy specimen, none of the surgical excision specimens after a diagnosis of AA (2) or AAA (7) contained ductal carcinoma in situ or invasive carcinoma. AAA by itself is an uncommon core biopsy diagnosis that may not require surgical excision. © 2014 Elsevier Inc. All rights reserved.
1. Introduction In early descriptions of apocrine change and sclerosing adenosis (SA) of the breast, these histologic findings were regarded as benign and unlikely to be related to the development of carcinoma [1]. Subsequent long-term follow-up studies of patients with open biopsies established the cancer risk implications of many histologic types of benign breast disease (BBD) [2,3]. Among BBD categories, proliferative disease with ☆
There was no specific external funding for this study, and the authors have no relevant financial disclosures. ⁎ Corresponding author. Cleveland Clinic, Department of Pathology, 9500 Euclid Avenue, Mail Code L25, Cleveland, OH 44195. E-mail address: [email protected] (B. C. Calhoun). http://dx.doi.org/10.1016/j.humpath.2014.06.010 0046-8177/© 2014 Elsevier Inc. All rights reserved.
atypia, or atypical hyperplasia (AH), was associated with the highest breast cancer risk [4–6]. By itself, apocrine change was associated with a relative risk (RR) of 1.2 for invasive carcinoma [7], and SA was associated with an RR of 1.7 [8]. Comparatively little is known about the risk associated with the presence of benign or atypical apocrine change in SA, often referred to as apocrine adenosis (AA) or atypical apocrine adenosis (AAA). In the Nashville cohort, AA showed an association with AH [9], but the cancer risk independent of coexisting AH is not well established. In a recent report from the Mayo BBD cohort, 2.7% (1/37) of patients with AAA alone developed invasive carcinoma, suggesting that AAA may not be a high-risk or precursor lesion [10]. AAA is part of the spectrum of apocrine lesions in the breast, ranging from benign apocrine change to apocrine ductal
Atypical apocrine adenosis on breast core biopsy carcinoma in situ (DCIS) and invasive carcinoma. AA and AAA are of particular interest to pathologists because they can mimic patterns of DCIS and invasive carcinoma, potentially leading to the overdiagnosis of malignancy [9,11,12]. The diagnostic criteria applied to atypical apocrine proliferations are variable and not well validated in studies with clinical outcomes [13]. Features suggested to distinguish atypical or borderline apocrine lesions from apocrine DCIS include a threefold variation in nuclear size, prominent nucleoli, the absence of necrosis or architectural atypia, and limited extent [14–16]. Many of the same criteria have been applied to the diagnosis of AAA. In addition, studies reporting the highest RR of cancer for AAA may have included cases with cancerization of SA by apocrine DCIS [13,16]. With the widespread use of percutaneous core biopsy of the breast, attention has been focused on the risk of finding a carcinoma in an excision specimen after a core biopsy diagnosis of atypia. Several studies correlating core biopsy diagnoses of atypical ductal hyperplasia (ADH), atypical lobular hyperplasia, and flat epithelial atypia (FEA) with the frequency of carcinoma on excision have been published. However, no core biopsy series of AA or AAA have been reported. The objective of this study was to determine the frequency of carcinoma in excision specimens after a core biopsy diagnosis of AA or AAA. After almost any core biopsy diagnosis containing the term “atypical,” most patients will be offered surgery to exclude the possibility of a more worrisome process. The data from this series may help distinguish patients who require surgery from those who may be offered clinical and radiologic follow-up as an alternative.
2. Materials and methods This study was approved by the Cleveland Clinic Institutional Review Board. Breast core biopsies with a diagnosis of AA or AAA from January 1, 1996, to February 11, 2014, were retrieved from the Anatomic Pathology information system CoPathPlus (Cerner Corporation, Kansas City, Missouri) using the search terms “apocrine,” “adenosis,” and “breast.” The initial search results included 34 core biopsies with AA or AAA from 31 patients from 1996 to 2014. The indications for core biopsy and patient age at core biopsy were recorded for all cases. For all core biopsies, the presence and type of coexisting (in the same core) or concurrent (in a concurrent ipsilateral core biopsy) atypia or carcinoma were recorded. Cases with coexisting atypia or carcinoma and cases without a subsequent surgical excision pathology report in CoPath were excluded from further study. Cases with another pattern of atypia, carcinoma in situ, or invasive carcinoma in ipsilateral core biopsies performed concurrently or within 4 months of the core biopsy with AA or AAA were also excluded. For the remaining patients, core biopsy findings were correlated with the histologic findings in surgical excision specimens.
2131 AA cases showed a whorled lobulocentric pattern of sclerosis and a cell population with granular eosinophilic cytoplasm typical of apocrine change. Biopsies with AAA showed similar overall architecture with cytologic atypia that tended to be variable (Fig. 1). Nuclear enlargement and prominent nucleoli were evident in foci with atypia. None of the cases contained necrosis or an architectural pattern that would meet criteria for ADH or DCIS. All available surgical pathology reports and slides for excision specimens after a core biopsy diagnosis of AA or AAA alone were reviewed. The presence and location of calcifications were included in the pathology reports for the core biopsies and the excision specimens. The submitted sections for all of the excision specimens included biopsy sites. One patient had 2 sites with AA on core biopsy, and 1 patient had 3 sites with AAA on core biopsy. Each core biopsy site was individually correlated with a corresponding excision specimen when possible. Excision specimens containing AA or AAA and another pattern of atypia were classified based on the coexisting pattern of atypia.
3. Results A total of 34 core biopsies from 31 patients were initially identified, 22 with AA and 12 with AAA (Table). The mean and median ages for all patients were 60 and 58 years, respectively. Two core biopsies were magnetic resonance imaging (MRI)–guided, 13 were stereotactic, and 19 were ultrasound guided. The indication for biopsy was calcifications in 11, a mass or mammographic density in 21 (3 of which were associated with calcifications), and an enhancing lesion on MRI in 2 cases. One patient with AA had a history of invasive carcinoma in the ipsilateral breast, and 1 patient with AA had a history of DCIS in the ipsilateral breast. Six patients, 3 with AA and 3 with AAA, had a history of invasive carcinoma in the contralateral breast. One patient with AAA had a history of AH in the ipsilateral breast. Of the 22 core biopsies with AA (Fig. 2), 18 were excluded from further study. Eleven did not have an available pathology report for an excision, and 7 had a more advanced lesion in the same core or a concurrent ipsilateral core biopsy. In the 7 core biopsies with AA and coexisting or concurrent atypia or carcinoma, 5 had AH, 1 had DCIS, and 1 had invasive carcinoma (Table). Of the 4 core biopsies with AA alone and a subsequent surgical excision, 2 of the excision specimens contained AA and FEA. Two of the core biopsies with AA alone were from 1 patient who also had a core biopsy with AAA several years later, and that core biopsy was immediately followed by surgery as discussed below. Neither of the surgical specimens after a core biopsy diagnosis of AA alone contained DCIS or invasive carcinoma. Of the 12 core biopsies with AAA (Fig. 3), 5 had a more advanced lesion in the same core or a concurrent ipsilateral
2132
B. C. Calhoun, C. N. Booth
Fig. 1 Apocrine adenosis without atypia showing a lobulocentric whorled pattern (A and B) (×10, hematoxylin and eosin). AAA with marked variation in nuclear size and prominent nucleoli (C and D) (×40, hematoxylin and eosin).
core biopsy, and 2 of these cases also lacked a pathology report for an excision. In the 5 core biopsies with AAA and coexisting or concurrent atypia or carcinoma, 2 had AH, 3 had DCIS, and none had invasive carcinoma (Table). The 7 excision specimens corresponding to core biopsies with AAA alone contained AAA (5) and AA (1) and AH (1). One of the patients with AAA on excision had 3 ipsilateral core biopsies over an 8-year period with AA in the first 2 biopsies and AAA in a third core biopsy that was immediately followed by surgery. None of the surgical specimens following a core biopsy diagnosis of AAA alone contained DCIS or invasive carcinoma.
4. Discussion In a search of the Cleveland Clinic files from 1990 through early 2014, we identified only 34 cases of AA and AAA diagnosed on core biopsy. A wide variety of proliferative and nonproliferative sclerosing lesions have been included in prior studies of AA and AAA ([9, 11, 13]). This series was almost entirely confined to cases with a pattern of SA involved by an apocrine or atypical apocrine epithelial cell population, possibly further limiting our sample size. The expected frequency of AA and AAA on core biopsies specifically is not well established. In longterm follow-up studies of open biopsies, less than 1% of patients had AAA [10] and approximately 3% had AA [9]. In a series of approximately 5000 consultation cases, 1.2% of
biopsies contained AAA [11]. These lesions are uncommon and may be misinterpreted by pathologists as invasive ductal (apocrine) carcinoma or DCIS involving SA. Immunohistochemical staining should demonstrate the presence of a myoepithelial cell layer, although it may be patchy and attenuated in these sclerosing lesions. In the context of apocrine cytology and a sclerosing lesion, a diagnosis of DCIS should not be made in the absence of an epithelial proliferation with the architectural features of DCIS and/or necrosis. The results of this study are in agreement with key findings in prior studies of AA and AAA. The average at the time of biopsy was 60, very similar to the average ages of 59 and 58 reported by Fuehrer et al [10] and Carter and Rosen [11]. An association with AH was seen in cases of AA from the Nashville cohort [9], and 7 (20.6%) of the core biopsies in this series were associated with coexisting or concurrent ipsilateral AH. Many of the biopsies in the Nashville cohort also contained a papilloma or a complex sclerosing lesion [9], and 2 of the cases in this series were associated with a papilloma and a complex sclerosing lesion. In this series of AA and AAA diagnosed on core biopsy, none of the 7 cases with follow-up excisions contained carcinoma when core biopsies that also contained AH were excluded. None of the 51 patients with AAA reported by Carter and Rosen developed carcinoma after an average of 35 months of follow-up [11]. When cases with AH were excluded, 5.4% (2/37) of patients with AAA in the Mayo cohort developed carcinoma (1 case of carcinoma in situ and 1 of invasive carcinoma) [10]. In a series of 37 cases with an
Atypical apocrine adenosis on breast core biopsy Table
2133
Apocrine adenosis and atypical apocrine adenosis on breast core biopsy
Core
Diagnosis
Age
Indication
Type
Atypia/carcinoma
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34
AA AA AA AAA AA AA AA AAA AA AA AAA AA AA AAA AA AA AAA AA AA AA AA AAA AA AAA AA AAA AA AAA AA AAA AAA AA AAA AA
67 49 48 83 57 57 50 62 46 54 67 79 54 57 78 65 58 52 70 50 53 68 41 71 57 57 64 66 56 58 64 39 63 62
Calcifications Asymmetric density Calcifications Asymmetric density Mass Mass Mass Asymmetric density + calcifications Mass Calcifications Calcifications Mass + calcifications Calcifications Calcifications Mass + calcifications Mass Calcifications Calcifications Calcifications Calcifications Mass Mass Mass Mass Mass Enhancing asymmetry on MRI Mass Calcifications Mass Mass Enhancing mass on MRI Mass Mass Mass
Stereotactic Ultrasound Stereotactic Ultrasound Ultrasound Ultrasound Ultrasound Stereotactic Ultrasound Stereotactic Stereotactic Ultrasound Stereotactic Stereotactic Stereotactic Ultrasound Stereotactic Stereotactic Stereotactic Stereotactic Ultrasound Ultrasound Ultrasound Ultrasound Ultrasound MRI Ultrasound Stereotactic Ultrasound Ultrasound MRI Ultrasound Ultrasound Ultrasound
IDC
DCIS
DCIS
ADH
ADH DCIS ADH
ADH
ALH DCIS
ADH ADH
NOTE. Core biopsy diagnosis, age, indication for biopsy, and presence of atypia or carcinoma in the same core biopsy, a concurrent core biopsy, or a core biopsy within 4 months of the diagnosis of AA or AAA are listed. Abbreviations: IDC, invasive ductal carcinoma; DCIS, ductal carcinoma in situ; ADH, atypical ductal hyperplasia; ALH, atypical lobular hyperplasia; AA, apocrine adenosis; AAA, atypical apocrine adenosis; MRI, magnetic resonance imaging.
AA (22)
Excluded (18)
Included (4)
Excisions (2)
AA (2)
Other* (2)
FEA^ (1)
Fig. 2 There were 22 cases of AA on core biopsy. A total of 18 cases were excluded from further analysis: 11 cases without an available excision pathology report and 7 cases with concurrent or coexisting atypia or carcinoma. Of the 4 core biopsies with corresponding excisions, 1 contained AA, 1 contained AA and FEA (^), and 2 were from a patient with a subsequent core biopsy diagnosis of AAA that immediately preceded excision (Other*).
2134
B. C. Calhoun, C. N. Booth AAA (12)
Excluded (5)
Included (7)
Excisions (7)
AA (1)
AAA (5)
AH (1)
Fig. 3 There were 12 cases of AAA on core biopsy. The 5 cases excluded from further analysis had concurrent or coexisting atypia or carcinoma. Of the 7 cases with corresponding excisions, 5 contained AAA, 1 contained AA, and 1 contained AH.
average of 8.7 years of follow-up, Seidman et al [16] reported an RR of 5.5 for the development of invasive carcinoma, but cases with cancerization of SA by apocrine DCIS may have been included in this study [13]. Risk stratification and risk reduction are important goals in the clinical management of patients with epithelial atypia of the breast. Two distinct but presumably related categories of risk require consideration. In the largest case-control studies of open biopsies, the risk associated with AH was defined as the RR (or odds ratio) of the patient developing a subsequent carcinoma (in either breast), usually 10 to 15 years after an open biopsy [4–6]. In the current context of routine percutaneous breast core biopsy, the risk of finding a carcinoma on excision has become a more immediate concern. Our series lacks the long-term clinical follow-up data to address the likelihood of the subsequent development of carcinoma. The goal of this study was to establish the rate of upgrade to DCIS or invasive carcinoma after a core biopsy diagnosis of AA or AAA. Patients with a core biopsy diagnosis of AAA were probably offered surgery based on concerns about limited sampling of a more worrisome lesion and/or the (undefined) risk of finding carcinoma in adjacent tissue. For clarification, pathologists could consider a comment in the pathology report indicating that much less is known about the breast cancer risk associated with AAA as compared to other atypical breast lesions (eg, ADH and atypical lobular hyperplasia). Correlation with clinical and imaging findings and determination of the extent of the abnormality remaining after core biopsy could be recommended. Direct communication with members of the multidisciplinary care team may be required to make sure patients are not given a 5-year and lifetime risk of developing carcinoma based on risk models (eg, Gail model) that do not incorporate data on AAA. In this series of 34 breast core biopsies, 7 cases with pure AA or AAA had surgical excision follow-up, and none was upgraded to carcinoma on excision. The detection of AH
in one of the cases of AAA and coexisting FEA in one of the cases of AA could have implications for risk stratification. The number of cases of these relatively uncommon entities limits our ability to draw firm conclusions. However, our findings raise the possibility that patients diagnosed with AAA on core biopsy may not be required to undergo surgical excision of the affected area. In the absence of coexisting AH, case by case evaluation with careful correlation of radiologic and histologic findings may be a reasonable approach. Additional investigation of more cases, perhaps in a multi-institutional study, would undoubtedly be helpful in defining the best management for this group of patients. Surgery should always be considered for patients with discordant imaging studies or limited sampling of the radiographic abnormality on core biopsy.
References [1] Foote FW, Stewart FW. Comparative studies of cancerous versus noncancerous breasts. Ann Surg 1945;121:6-53. [2] Dupont WD, Page DL. Risk factors for breast cancer in women with proliferative breast disease. N Engl J Med 1985;312:146-51. [3] Hartmann LC, Sellers TA, Frost MH, et al. Benign breast disease and the risk of breast cancer. N Engl J Med 2005;353:229-37. [4] Collins LC, Baer HJ, Tamimi RM, Connolly JL, Colditz GA, Schnitt SJ. Magnitude and laterality of breast cancer risk according to histologic type of atypical hyperplasia: results from the Nurses' Health Study. Cancer 2007;109:180-7. [5] Page DL, Dupont WD, Rogers LW, Rados MS. Atypical hyperplastic lesions of the female breast. A long-term follow-up study. Cancer 1985;55:2698-708. [6] Degnim AC, Visscher DW, Berman HK, et al. Stratification of breast cancer risk in women with atypia: a Mayo cohort study. J Clin Oncol 2007;25:2671-7. [7] 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;5:29-32. [8] Jensen RA, Page DL, Dupont WD, Rogers LW. Invasive breast cancer risk in women with sclerosing adenosis. Cancer 1989;64:1977-83.
Atypical apocrine adenosis on breast core biopsy [9] Simpson JF, Page DL, Dupont WD. Apocrine adenosis—a mimic of mammary carcinoma. Surg Pathol 1990;3:289-99. [10] Fuehrer N, Hartmann L, Degnim A, et al. Atypical apocrine adenosis of the breast: long-term follow-up in 37 patients. Arch Pathol Lab Med 2012;136:179-82. [11] Carter DJ, Rosen PP. Atypical apocrine metaplasia in sclerosing lesions of the breast: a study of 51 patients. Mod Pathol 1991;4:1-5. [12] Bianchi S, Palli D, Galli M, et al. Reproducibility of histological diagnoses and diagnostic accuracy of non palpable breast lesions. Pathol Res Pract 1994;190:69-76.
2135 [13] O'Malley FP, Bane A. An update on apocrine lesions of the breast. Histopathology 2008;52:3-10. [14] Tavassoli FA, Norris HJ. Intraductal apocrine carcinoma: a clinicopathologic study of 37 cases. Mod Pathol 1994;7:813-8. [15] O'Malley FP, Page DL, Nelson EH, Dupont WD. Ductal carcinoma in situ of the breast with apocrine cytology: definition of a borderline category. HUM PATHOL 1994;25:164-8. [16] 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;77:2529-37.
www.elsevier.com/locate/humpath
Original contribution
Atypical apocrine adenosis diagnosed on breast core biopsy: implications for management☆ Benjamin C. Calhoun MD, PhD ⁎, Christine N. Booth MD Department of Pathology, Robert J. Tomsich Pathology and Laboratory Medicine Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195 Received 12 May 2014; revised 6 June 2014; accepted 11 June 2014
Keywords: Breast; Core Biopsy; Atypia; Screening; Diagnosis
Summary Apocrine adenosis (AA) and atypical apocrine adenosis (AAA) are uncommon findings in breast biopsies that may be misinterpreted as carcinoma. The data from long-term follow up studies of open biopsies suggest that AAA is not a high-risk or precursor lesion. The clinical significance and risk implications of AAA diagnosed on core biopsy are not well established. The goal of this study was to determine the frequency of carcinoma in excision specimens after a core biopsy diagnosis of AA or AAA. We identified 34 core biopsies of AA (22) and AAA (12) performed between 1996 and 2014. The mean age at diagnosis was 60 years. The most common indications for core biopsy were calcifications (11), a mass or density (18), and a mass or density with calcifications (3). Two cases were detected on magnetic resonance imaging (MRI) studies. Available pathology reports and slides were reviewed, and surgical excision findings were correlated with core biopsy diagnoses. Of the core biopsies with AA or AAA, 7 also contained atypical ductal or lobular hyperplasia (AH) and 4 contained ductal carcinoma in situ or invasive carcinoma. In the absence of coexisting AH or carcinoma in the initial core biopsy specimen, none of the surgical excision specimens after a diagnosis of AA (2) or AAA (7) contained ductal carcinoma in situ or invasive carcinoma. AAA by itself is an uncommon core biopsy diagnosis that may not require surgical excision. © 2014 Elsevier Inc. All rights reserved.
1. Introduction In early descriptions of apocrine change and sclerosing adenosis (SA) of the breast, these histologic findings were regarded as benign and unlikely to be related to the development of carcinoma [1]. Subsequent long-term follow-up studies of patients with open biopsies established the cancer risk implications of many histologic types of benign breast disease (BBD) [2,3]. Among BBD categories, proliferative disease with ☆
There was no specific external funding for this study, and the authors have no relevant financial disclosures. ⁎ Corresponding author. Cleveland Clinic, Department of Pathology, 9500 Euclid Avenue, Mail Code L25, Cleveland, OH 44195. E-mail address: [email protected] (B. C. Calhoun). http://dx.doi.org/10.1016/j.humpath.2014.06.010 0046-8177/© 2014 Elsevier Inc. All rights reserved.
atypia, or atypical hyperplasia (AH), was associated with the highest breast cancer risk [4–6]. By itself, apocrine change was associated with a relative risk (RR) of 1.2 for invasive carcinoma [7], and SA was associated with an RR of 1.7 [8]. Comparatively little is known about the risk associated with the presence of benign or atypical apocrine change in SA, often referred to as apocrine adenosis (AA) or atypical apocrine adenosis (AAA). In the Nashville cohort, AA showed an association with AH [9], but the cancer risk independent of coexisting AH is not well established. In a recent report from the Mayo BBD cohort, 2.7% (1/37) of patients with AAA alone developed invasive carcinoma, suggesting that AAA may not be a high-risk or precursor lesion [10]. AAA is part of the spectrum of apocrine lesions in the breast, ranging from benign apocrine change to apocrine ductal
Atypical apocrine adenosis on breast core biopsy carcinoma in situ (DCIS) and invasive carcinoma. AA and AAA are of particular interest to pathologists because they can mimic patterns of DCIS and invasive carcinoma, potentially leading to the overdiagnosis of malignancy [9,11,12]. The diagnostic criteria applied to atypical apocrine proliferations are variable and not well validated in studies with clinical outcomes [13]. Features suggested to distinguish atypical or borderline apocrine lesions from apocrine DCIS include a threefold variation in nuclear size, prominent nucleoli, the absence of necrosis or architectural atypia, and limited extent [14–16]. Many of the same criteria have been applied to the diagnosis of AAA. In addition, studies reporting the highest RR of cancer for AAA may have included cases with cancerization of SA by apocrine DCIS [13,16]. With the widespread use of percutaneous core biopsy of the breast, attention has been focused on the risk of finding a carcinoma in an excision specimen after a core biopsy diagnosis of atypia. Several studies correlating core biopsy diagnoses of atypical ductal hyperplasia (ADH), atypical lobular hyperplasia, and flat epithelial atypia (FEA) with the frequency of carcinoma on excision have been published. However, no core biopsy series of AA or AAA have been reported. The objective of this study was to determine the frequency of carcinoma in excision specimens after a core biopsy diagnosis of AA or AAA. After almost any core biopsy diagnosis containing the term “atypical,” most patients will be offered surgery to exclude the possibility of a more worrisome process. The data from this series may help distinguish patients who require surgery from those who may be offered clinical and radiologic follow-up as an alternative.
2. Materials and methods This study was approved by the Cleveland Clinic Institutional Review Board. Breast core biopsies with a diagnosis of AA or AAA from January 1, 1996, to February 11, 2014, were retrieved from the Anatomic Pathology information system CoPathPlus (Cerner Corporation, Kansas City, Missouri) using the search terms “apocrine,” “adenosis,” and “breast.” The initial search results included 34 core biopsies with AA or AAA from 31 patients from 1996 to 2014. The indications for core biopsy and patient age at core biopsy were recorded for all cases. For all core biopsies, the presence and type of coexisting (in the same core) or concurrent (in a concurrent ipsilateral core biopsy) atypia or carcinoma were recorded. Cases with coexisting atypia or carcinoma and cases without a subsequent surgical excision pathology report in CoPath were excluded from further study. Cases with another pattern of atypia, carcinoma in situ, or invasive carcinoma in ipsilateral core biopsies performed concurrently or within 4 months of the core biopsy with AA or AAA were also excluded. For the remaining patients, core biopsy findings were correlated with the histologic findings in surgical excision specimens.
2131 AA cases showed a whorled lobulocentric pattern of sclerosis and a cell population with granular eosinophilic cytoplasm typical of apocrine change. Biopsies with AAA showed similar overall architecture with cytologic atypia that tended to be variable (Fig. 1). Nuclear enlargement and prominent nucleoli were evident in foci with atypia. None of the cases contained necrosis or an architectural pattern that would meet criteria for ADH or DCIS. All available surgical pathology reports and slides for excision specimens after a core biopsy diagnosis of AA or AAA alone were reviewed. The presence and location of calcifications were included in the pathology reports for the core biopsies and the excision specimens. The submitted sections for all of the excision specimens included biopsy sites. One patient had 2 sites with AA on core biopsy, and 1 patient had 3 sites with AAA on core biopsy. Each core biopsy site was individually correlated with a corresponding excision specimen when possible. Excision specimens containing AA or AAA and another pattern of atypia were classified based on the coexisting pattern of atypia.
3. Results A total of 34 core biopsies from 31 patients were initially identified, 22 with AA and 12 with AAA (Table). The mean and median ages for all patients were 60 and 58 years, respectively. Two core biopsies were magnetic resonance imaging (MRI)–guided, 13 were stereotactic, and 19 were ultrasound guided. The indication for biopsy was calcifications in 11, a mass or mammographic density in 21 (3 of which were associated with calcifications), and an enhancing lesion on MRI in 2 cases. One patient with AA had a history of invasive carcinoma in the ipsilateral breast, and 1 patient with AA had a history of DCIS in the ipsilateral breast. Six patients, 3 with AA and 3 with AAA, had a history of invasive carcinoma in the contralateral breast. One patient with AAA had a history of AH in the ipsilateral breast. Of the 22 core biopsies with AA (Fig. 2), 18 were excluded from further study. Eleven did not have an available pathology report for an excision, and 7 had a more advanced lesion in the same core or a concurrent ipsilateral core biopsy. In the 7 core biopsies with AA and coexisting or concurrent atypia or carcinoma, 5 had AH, 1 had DCIS, and 1 had invasive carcinoma (Table). Of the 4 core biopsies with AA alone and a subsequent surgical excision, 2 of the excision specimens contained AA and FEA. Two of the core biopsies with AA alone were from 1 patient who also had a core biopsy with AAA several years later, and that core biopsy was immediately followed by surgery as discussed below. Neither of the surgical specimens after a core biopsy diagnosis of AA alone contained DCIS or invasive carcinoma. Of the 12 core biopsies with AAA (Fig. 3), 5 had a more advanced lesion in the same core or a concurrent ipsilateral
2132
B. C. Calhoun, C. N. Booth
Fig. 1 Apocrine adenosis without atypia showing a lobulocentric whorled pattern (A and B) (×10, hematoxylin and eosin). AAA with marked variation in nuclear size and prominent nucleoli (C and D) (×40, hematoxylin and eosin).
core biopsy, and 2 of these cases also lacked a pathology report for an excision. In the 5 core biopsies with AAA and coexisting or concurrent atypia or carcinoma, 2 had AH, 3 had DCIS, and none had invasive carcinoma (Table). The 7 excision specimens corresponding to core biopsies with AAA alone contained AAA (5) and AA (1) and AH (1). One of the patients with AAA on excision had 3 ipsilateral core biopsies over an 8-year period with AA in the first 2 biopsies and AAA in a third core biopsy that was immediately followed by surgery. None of the surgical specimens following a core biopsy diagnosis of AAA alone contained DCIS or invasive carcinoma.
4. Discussion In a search of the Cleveland Clinic files from 1990 through early 2014, we identified only 34 cases of AA and AAA diagnosed on core biopsy. A wide variety of proliferative and nonproliferative sclerosing lesions have been included in prior studies of AA and AAA ([9, 11, 13]). This series was almost entirely confined to cases with a pattern of SA involved by an apocrine or atypical apocrine epithelial cell population, possibly further limiting our sample size. The expected frequency of AA and AAA on core biopsies specifically is not well established. In longterm follow-up studies of open biopsies, less than 1% of patients had AAA [10] and approximately 3% had AA [9]. In a series of approximately 5000 consultation cases, 1.2% of
biopsies contained AAA [11]. These lesions are uncommon and may be misinterpreted by pathologists as invasive ductal (apocrine) carcinoma or DCIS involving SA. Immunohistochemical staining should demonstrate the presence of a myoepithelial cell layer, although it may be patchy and attenuated in these sclerosing lesions. In the context of apocrine cytology and a sclerosing lesion, a diagnosis of DCIS should not be made in the absence of an epithelial proliferation with the architectural features of DCIS and/or necrosis. The results of this study are in agreement with key findings in prior studies of AA and AAA. The average at the time of biopsy was 60, very similar to the average ages of 59 and 58 reported by Fuehrer et al [10] and Carter and Rosen [11]. An association with AH was seen in cases of AA from the Nashville cohort [9], and 7 (20.6%) of the core biopsies in this series were associated with coexisting or concurrent ipsilateral AH. Many of the biopsies in the Nashville cohort also contained a papilloma or a complex sclerosing lesion [9], and 2 of the cases in this series were associated with a papilloma and a complex sclerosing lesion. In this series of AA and AAA diagnosed on core biopsy, none of the 7 cases with follow-up excisions contained carcinoma when core biopsies that also contained AH were excluded. None of the 51 patients with AAA reported by Carter and Rosen developed carcinoma after an average of 35 months of follow-up [11]. When cases with AH were excluded, 5.4% (2/37) of patients with AAA in the Mayo cohort developed carcinoma (1 case of carcinoma in situ and 1 of invasive carcinoma) [10]. In a series of 37 cases with an
Atypical apocrine adenosis on breast core biopsy Table
2133
Apocrine adenosis and atypical apocrine adenosis on breast core biopsy
Core
Diagnosis
Age
Indication
Type
Atypia/carcinoma
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34
AA AA AA AAA AA AA AA AAA AA AA AAA AA AA AAA AA AA AAA AA AA AA AA AAA AA AAA AA AAA AA AAA AA AAA AAA AA AAA AA
67 49 48 83 57 57 50 62 46 54 67 79 54 57 78 65 58 52 70 50 53 68 41 71 57 57 64 66 56 58 64 39 63 62
Calcifications Asymmetric density Calcifications Asymmetric density Mass Mass Mass Asymmetric density + calcifications Mass Calcifications Calcifications Mass + calcifications Calcifications Calcifications Mass + calcifications Mass Calcifications Calcifications Calcifications Calcifications Mass Mass Mass Mass Mass Enhancing asymmetry on MRI Mass Calcifications Mass Mass Enhancing mass on MRI Mass Mass Mass
Stereotactic Ultrasound Stereotactic Ultrasound Ultrasound Ultrasound Ultrasound Stereotactic Ultrasound Stereotactic Stereotactic Ultrasound Stereotactic Stereotactic Stereotactic Ultrasound Stereotactic Stereotactic Stereotactic Stereotactic Ultrasound Ultrasound Ultrasound Ultrasound Ultrasound MRI Ultrasound Stereotactic Ultrasound Ultrasound MRI Ultrasound Ultrasound Ultrasound
IDC
DCIS
DCIS
ADH
ADH DCIS ADH
ADH
ALH DCIS
ADH ADH
NOTE. Core biopsy diagnosis, age, indication for biopsy, and presence of atypia or carcinoma in the same core biopsy, a concurrent core biopsy, or a core biopsy within 4 months of the diagnosis of AA or AAA are listed. Abbreviations: IDC, invasive ductal carcinoma; DCIS, ductal carcinoma in situ; ADH, atypical ductal hyperplasia; ALH, atypical lobular hyperplasia; AA, apocrine adenosis; AAA, atypical apocrine adenosis; MRI, magnetic resonance imaging.
AA (22)
Excluded (18)
Included (4)
Excisions (2)
AA (2)
Other* (2)
FEA^ (1)
Fig. 2 There were 22 cases of AA on core biopsy. A total of 18 cases were excluded from further analysis: 11 cases without an available excision pathology report and 7 cases with concurrent or coexisting atypia or carcinoma. Of the 4 core biopsies with corresponding excisions, 1 contained AA, 1 contained AA and FEA (^), and 2 were from a patient with a subsequent core biopsy diagnosis of AAA that immediately preceded excision (Other*).
2134
B. C. Calhoun, C. N. Booth AAA (12)
Excluded (5)
Included (7)
Excisions (7)
AA (1)
AAA (5)
AH (1)
Fig. 3 There were 12 cases of AAA on core biopsy. The 5 cases excluded from further analysis had concurrent or coexisting atypia or carcinoma. Of the 7 cases with corresponding excisions, 5 contained AAA, 1 contained AA, and 1 contained AH.
average of 8.7 years of follow-up, Seidman et al [16] reported an RR of 5.5 for the development of invasive carcinoma, but cases with cancerization of SA by apocrine DCIS may have been included in this study [13]. Risk stratification and risk reduction are important goals in the clinical management of patients with epithelial atypia of the breast. Two distinct but presumably related categories of risk require consideration. In the largest case-control studies of open biopsies, the risk associated with AH was defined as the RR (or odds ratio) of the patient developing a subsequent carcinoma (in either breast), usually 10 to 15 years after an open biopsy [4–6]. In the current context of routine percutaneous breast core biopsy, the risk of finding a carcinoma on excision has become a more immediate concern. Our series lacks the long-term clinical follow-up data to address the likelihood of the subsequent development of carcinoma. The goal of this study was to establish the rate of upgrade to DCIS or invasive carcinoma after a core biopsy diagnosis of AA or AAA. Patients with a core biopsy diagnosis of AAA were probably offered surgery based on concerns about limited sampling of a more worrisome lesion and/or the (undefined) risk of finding carcinoma in adjacent tissue. For clarification, pathologists could consider a comment in the pathology report indicating that much less is known about the breast cancer risk associated with AAA as compared to other atypical breast lesions (eg, ADH and atypical lobular hyperplasia). Correlation with clinical and imaging findings and determination of the extent of the abnormality remaining after core biopsy could be recommended. Direct communication with members of the multidisciplinary care team may be required to make sure patients are not given a 5-year and lifetime risk of developing carcinoma based on risk models (eg, Gail model) that do not incorporate data on AAA. In this series of 34 breast core biopsies, 7 cases with pure AA or AAA had surgical excision follow-up, and none was upgraded to carcinoma on excision. The detection of AH
in one of the cases of AAA and coexisting FEA in one of the cases of AA could have implications for risk stratification. The number of cases of these relatively uncommon entities limits our ability to draw firm conclusions. However, our findings raise the possibility that patients diagnosed with AAA on core biopsy may not be required to undergo surgical excision of the affected area. In the absence of coexisting AH, case by case evaluation with careful correlation of radiologic and histologic findings may be a reasonable approach. Additional investigation of more cases, perhaps in a multi-institutional study, would undoubtedly be helpful in defining the best management for this group of patients. Surgery should always be considered for patients with discordant imaging studies or limited sampling of the radiographic abnormality on core biopsy.
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