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Adenomyoepithelioma of the breast: a brief diagnostic review.

Myoepithelial cells are present in the normal mammary duct system and are often prominent in benign lesions, such as usual ductal hyperplasia, sclerosing adenosis, and intraductal papilloma. (1) Tumors largely or entirely composed of myoepithelial cells have also been reported. (2)

Adenomyoepithelioma (AME), a biphasic neoplastic proliferation of luminal and myoepithelial cells, was first described by Hamperl (1) in 1970. As Hamperl noted, this tumor may display a heterogeneous pattern because of the variable proliferation of epithelial and myoepithelial cells. Papillary architecture is seen in most tumors, and therefore, AME is considered to be a variant of intraductal papilloma. (3) Striking morphologic heterogeneity, such as papillary configuration or multinodularity, especially in a limited biopsy sample, (4-6) may not be appreciated, which may lead to erroneous diagnoses of carcinoma. (3) So far, other than case reports, only 4 comprehensive series studies (2,3,6,7) have been reported. Although most AMEs have been benign, sporadic malignant AMEs with distant metastases have also been reported. (2,7-9) Recognition of this entity, accurate diagnosis, and knowledge of the expected behavior are important in guiding the most appropriate patient management.

CLINICAL FEATURES

Patient age ranged from 22 to 92 years (mean age, 59 years) in one series of study. (6) Nearly all of the affected patients have been women, although rare cases have been reported in men. (10) Patients usually present with a solitary, palpable nodule, (6) and the duration of symptoms varies from several weeks to several months. (2) The tumors are usually located in a peripheral portion of the breast, (3) although the lesions have been found centrally or near the areola. (2,11) Tenderness and serous nipple discharge have been found infrequently. (2) On mammography, AME appears as a round or lobulated, dense, mostly circumscribed mass, sometimes with partially indistinct margins. (12) Calcifications and cystic appearance are not typical findings. (13)

GROSS PATHOLOGIC FEATURES

The size of AME ranges from 0.3 cm to 7 cm, with an average size of 2.5 cm. (2,6) The tumors have been described as round to lobulated, well circumscribed or discrete, and firm. (2,3) Multinodular or papillary configurations and focal cystic changes have also been described. (6,14,15) The recurrent tumors had irregular borders and ranged from 2 cm to 6 cm. (7) The cut surface reveals pink-white to gray-tan tissue with focal to diffuse translucency. (2,7) Hemorrhage and focal necrosis have also been reported. (3,5,16)

MICROSCOPIC PATHOLOGY AND IMMUNOHISTOCHEMISTRY

The AME tumor has a biphasic nature, composed of cuboidal to columnar, epithelial-lined tubules surrounded by myoepithelial cells. (6) A spectrum of histologic patterns, however, has been observed among various examples of these tumors and even in different areas of individual tumors. (3) These variations were based on the distribution of proliferating glandular and myoepithelial cells, the extent of spindle or polygonal configuration of myoepithelial cells, the prominence of papillary component, and the degree of fibrosis. (3)

Three variants of AMEs were described by Tavassoli. (2) The first variant is the tubular pattern, which is characterized by a balanced proliferation of rounded tubules, as well as unusually prominent and hyperplastic myoepithelial cells. The second variant is the spindle cell type, which is composed of a predominantly spindled myoepithelial cell proliferation admixed with a few columnar, epithelial-lined tubules. Finally, the third variant exhibits a lobular pattern composed of solid nests of myoepithelial cells proliferating around compressed tubules; the solid nests of tumor are then surrounded by fibrous connective tissue septa of varying thicknesses. (2)

Most AMEs have papillary configuration and, therefore, have been considered a variant of intraductal papilloma by some authors or a morphologic evolution from intraductal papilloma (Figure 1, A). (3,7,17) Myoepithelial cells forming nests or sheets frequently display a spindle to myoid appearance at places with clear cytoplasm. This solid proliferation may displace, compress, or obliterate the epithelial gland, resulting in a zone nearly devoid of glands (Figure 1, B and C). (2,3,6) These areas, if pronounced, may lead to a differential diagnosis of myoepithelioma. The myoid areas may exhibit myoepithelial cells with pink to amphophilic cytoplasm or a plasmacytoid appearance with dense, hyaline-like, glassy eosinophilic cytoplasm and eccentric nuclei (Figure 1, D). (2,12,17) Myxochondroid matrices produced by the myoepithelial cells may also be noted, as seen in pleomorphic adenomas (Figure 1, E). (6,12) Dense, collagenous, hyaline-like matrix materials can be seen in thick basement membranes. (18) Epithelial cells tend to have hyperchromatic nuclei and dense eosinophilic to amphophilic cytoplasm, when compared with myoepithelial cells. (17) Apocrine metaplasia of epithelial cell component, as well as squamous and sebaceous metaplasia may be variably present. (2,17,19) Atypical features, including increased mitotic activity, cytologic atypia with nuclear pleomorphism, prominent nucleoli, hyperchromasia, and necrosis, if observed, are usually associated with cases that either recurred or had a malignant clinical outcome (Figure 1, F). (2,7,9)

The interplay between epithelial and myoepithelial cell elements is highlighted by immunohistochemical staining with antibodies specific for these 2 components. The cytoplasm of epithelial cells uniformly reacts with antibodies to cytokeratins, such as cytokeratin AE1/3 (Figure 2, A and B), CAM 5.2, or CK7. (6,7) The luminal surfaces of the glandular cells are positive for the epithelial membrane antigen. (17) Polygonal and spindle myoepithelial cells are not reactive to epithelial membrane antigen and are often only subtly reactive or weakly reactive to cytokeratin AE1/3. (6,7) The myoepithelial component is highlighted by p63, smooth muscle myosin heavy chains, CK5, CD10, calponin, actin, and S100. (6,7,17,20) McLaren et al (6) reported that p63 produced the best results with consistent, intense nuclear staining (Figure 2, C), whereas some studies have reported discontinuous staining patterns. (20) The distribution and intensity of staining for anti-actin antibodies is heterogeneous, more conspicuous in spindle cells than in clear polygonal cells. However, no reactivity to actin is seen in epithelial cells. (17)

Smooth muscle myosin-heavy chain is the most sensitive marker, which is easier to interpret than smooth muscle actin and muscle-specific actin because of its low cross-reactivity with myofibroblasts. (17,20,21) Calponin is also highly sensitive for detecting myoepithelial cells with cytoplasmic staining (Figure 2, D), but [calponin.sup.+] myofibroblasts can be detected in up to 74% of breast proliferations by light, patchy staining patterns. (20) S100 was expressed in virtually all of the myoepithelial cells, with variable intensity and uniformity of reactivity. (7,17,20) Most of the luminal epithelial cells are S100-, but some reports have noted strong expression in the luminal epithelial cells. In these cases, its diagnostic utility as a myoepithelial marker may be limited. (17,22-24) The myoepithelial-specific antibodies display various cross-reactivity patterns and variable protein expression, especially in the neoplastic myoepithelial cells compared with their normal counterparts. (17,20) Therefore, a panel-based approach of 2 or more markers should be used to minimize the chance of failure in detecting the myoepithelial cells. (17,20)

Proliferative indices of Ki-67 immunostaining are present in both compartments of the tumor but may be higher in the myoepithelial cells than it is in the ductal cells. (25) Immunostain for estrogen is either negative or weakly positive in a patchy pattern. (12) Progesterone receptor and ERBB2 (formerly Her2/neu) have, however, been consistently reported to be negative in all the published studies. (3,12)

DIFFERENTIAL DIAGNOSIS

Most AMEs appear to represent variants of intraductal papilloma. (3) The differentiation of papilloma with prominent myoepithelial cells from AMEs can be made based on architecture, pattern, and degree of myoepithelial proliferation. (6) Those cases with only myoepithelial cells lining the papillae and forming the basal layer below the epithelial elements and without nests, nodules, or an increased proportion of myoepithelial cells are categorized as papillomas with prominent myoepithelial cells. (6) Myoepithelial cell markers highlight the presence of prominent myoepithelial cells within the papillae and at the periphery. (20) When the stroma associated with papillary lesions are sclerotic or exuberant, nuclear stains, such as p63 and maspin, should be included in a myoepithelial marker panel to avoid cross-reactivity with myofibroblasts within the sclerotic stroma. (20) A diagnosis of AME is favored if myoepithelial proliferation is extensive and involves the lesion diffusely. (12) Nipple adenoma may mimic AME, but the presence of florid ductal hyperplasia and the pseudoinfiltrative pattern of stromal sclerosis entrapping glandular epithelium without an entrapped fibrous tissue or supporting fibrovascular cores are useful features to help differentiate the former. (6) Clear cell carcinoma may also mimic AMEs, but that may be differentiated by the presence of both epithelial and myoepithelial cell types, and confirmed with immunohistochemical stains, if necessary. (6) Metaplastic tumors associated with papilloma are also included in the differential diagnoses. (26) The rarest adenosis variant of AME has an infiltrative growth pattern that resembles microglandular adenosis. Microglandular adenosis is characterized by an absence of myoepithelial layer and S100 positivity. (17)

When the tumor predominantly displays a spindle cell component, it may morphologically be mistaken for a myoid hamartoma or leiomyoma. (2) Strong reactivity for S100 and p63, and minimal staining for actin and cytokeratin in AME are helpful in differentiating the 2 lesions. (2,17) Myoid hamartomas also strongly express CD34, unlike AME, which is negative. Lesions composed exclusively of benign myoepithelial cells suggest a diagnosis of myoepithelioma. (1,2,17) Thorough sampling of the tumor to identify the luminal epithelial component would help separate AMEs from myoepithelioma.

Some areas of an AME may resemble adenoid cystic carcinoma of the breast, but that has infiltrative borders and a characteristic cribriform architecture in most cases. The myoepithelial cells of an adenoid cystic carcinoma tend to be smaller, more hyperchromatic, and basaloid appearing and have much less cytoplasm than do those of an AME. (12) In addition, adenoid cystic carcinoma may be excluded by the absence of the 2 types of mucins and the presence of apocrine epithelia. (6) Pleomorphic adenomas have features that overlap with AMEs, but a hyaline matrix with chondroid areas and distinct encapsulation are more prominent in pleomorphic adenoma. (6,12,17)

The diagnosis of AME on a needle core biopsy can be challenging because of morphologic heterogeneity. In limited biopsy material, the sampled tissue may even be mistaken for invasive carcinoma, especially in tumors that have compact glandular structures with clear cell epithelioid myoepithelial proliferation. (3-5,17) The presence of regularly spaced, rounded or ovoid glands; unidirectional streaming of the glands; and prominent clear cell or spindle cell myoepithelium are some morphologic clues to the diagnosis of AME. (4) Immunostains for myoepithelial markers, especially p63, are useful for highlighting the abundant myoepithelial components. (4) Atypical features, such as pronounced nuclear pleomorphism, mitotic activity, necrosis, invasive growth, and the overgrowth of 1 of the 2 components of the lesion may not be evident in the needle core biopsy. Therefore, excisional biopsy is recommended to rule out a carcinoma arising in an AME. (4)

BIOLOGIC BEHAVIOR AND TREATMENT

Most AMEs can be treated by local excision, but local recurrences have occurred 8 months to 5 years after initial excision. (2,7,27) In the Tavossoli (2) study, most tumors with recurrence were of the tubular type of lesions, extending into, and blending with, the adjacent normal ducts. The recurrent lesions lacked an aggressive morphologic appearance or noticeable mitotic activity. (2) The recurrent tumor with a lobulated variant displayed only cytologic atypia and had an increased mitotic activity with 8/10 high-power fields (as compared with 3/10 high-power fields in the original tumor). (2) Cytologic atypia and mitotic rates were found to be variable in other studies. (7) Peripheral intraductal extension, incomplete excision, and variable cytologic atypia may be linked to local recurrence. (2,3,7)

Although most AMEs are benign, malignant transformations of tumors have been reported in the literature. (2,7-9,13,28) Because of the biphasic nature of the tumor, carcinomas may arise from ductal epithelial cells, myoepithelial cells, or both. (9,29,30) A myoepithelial carcinoma arising in an adenomyoepithelioma with a high Ki-67 labeling index in myoepithelial cells has been reported. (30) Distant metastases to lung, brain, and liver have also been reported. (7,8,13,28) Loose et al (7) suggested using the term Malignant AME to identify tumors with metastatic potential for the lesions associated with more-aggressive histologic features that include high mitotic activity and marked cytologic atypia. Axillary lymph node metastasis was reported in the Tavassoli (2) study, but the possibility of the direct extension of the tumor to the lymph node was taken into consideration because of the proximity of the node with the primary lesion. (2)

Complete excision with appropriate margins is recommended to prevent local recurrence. (2,7,17) If the lesion recurs, a wider excision would be required. (2) Mastectomy or breast-conserving surgery with radiation and axillary dissection are not necessary for benign AMEs but may be indicated for carcinoma arising from AMEs. (2,17)

SUMMARY

The AME of the breast is a relatively rare, benign tumor that has a spectrum of disordered epithelial-myoepithelial proliferations. Because of the morphologic heterogeneity of this tumor, misinterpretation on a needle biopsy may occur. (4,6) Recognition of biphasic cellular elements and the overall architecture of the tumor in combination with immunohistochemistry are important when diagnosing AMEs. Although most tumors have been benign, local recurrences, malignant transformations, and metastases have been reported. Cases with significant cytologic atypia, necrosis, and brisk mitotic rates raise the likelihood that the lesion is malignant AME and carries the potential risk of metastasis. (7,8) Therefore, atypical features should be noted in the pathology report, and complete excision with adequate margins is recommended to decrease the potential for recurrence and metastasis.

References

(1.) Hamperl H. The myothelia (myoepithelial cells): normal state; regressive changes; hyperplasia; tumors. Curr Top Pathol. 1970;53:161-220.

(2.) Tavassoli FA. Myoepithelial lesions of the breast: myoepitheliosis, adenomyoepithelioma, and myoepithelial carcinoma. Am J Surg Pathol. 1991; 15(6):554-568.

(3.) Rosen PP. Adenomyoepithelioma of the breast. Hum Pathol. 1987;18(12): 1232-1237.

(4.) Hoda SA, Rosen PP. Observations on the pathologic diagnosis of selected unusual lesions in needle core biopsies of breast. Breast J. 2004;10(6):522-527.

(5.) Zhang C, Quddus MR, Sung CJ. Atypical adenomyoepithelioma of the breast: diagnostic problems and practical approaches in core needle biopsy. Breast J. 2004;10(2):154-155.

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(7.) Loose JH, Patchefsky AS, Hollander IJ, et al. Adenomyoepithelioma of the breast: a spectrum of biologic behavior. Am J Surg Pathol. 1992;16(9):868-876.

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(10.) Tamura G, Monma N, Suzuki Y, Satodate R, Abe H. Adenomyoepithelioma (myoepithelioma) of the breast in a male. Hum Pathol. 1993;24(6):678-681.

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(12.) Hayes MM. Adenomyoepithelioma of the breast: a review stressing its propensity for malignant transformation. J Clin Pathol. 2011;64(6):477-484.

(13.) Trojani M, Guiu M, Trouette H, De Mascarel I, Cocquet M. Malignant adenomyoepithelioma of the breast: an immunohistochemical, cytophotometric, and ultrastructural study of a case with lung metastases. Am J Clin Pathol. 1992; 98(6):598-602.

(14.) Papaevangelou A, Pougouras I, Liapi G, et al. Cystic adenomyoepithelioma of the breast. Breast. 2004;13(4):356-358.

(15.) Laforga JB, Aranda FI, Sevilla F. Adenomyoepithelioma of the breast: report of two cases with prominent cystic changes and intranuclear inclusions. Diagn Cytopathol. 1998;19(1):55-58.

(16.) Zarbo RJ, Oberman HA. Cellular adenomyoepithelioma of the breast. Am J Surg Pathol. 1983;7(8):863-870.

(17.) Rosen PP. Myoepithelial neoplasms. In: Rosen's Breast Pathology. 3rd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2009:137-160.

(18.) Fukuoka K, Kanahara T, Tamura M, et al. Basement membrane substance in adenomyoepithelioma of the breast. Acta Cytol. 2001;45(2):282-283.

(19.) Cai R, Tan P. Adenomyoepithelioma of the breast with squamous and sebaceous metaplasia. Pathology. 2005;37(6):557-559.

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(22.) GillettCE, Bobrow LG, Millis RR. S100 protein in human mammary tissue-immunoreactivity in breast carcinoma, including Paget's disease of the nipple, and value as a marker of myoepithelial cells. J Pathol. 1990;160(1):19-24.

(23.) Dwarakanath S, Lee AK, Delellis RA, et al. S-100 protein positivity in breast carcinomas: a potential pitfall in diagnostic immunohistochemistry. Hum Pathol. 1987;18(11):1144-1148.

(24.) Nayar R, Breland C, Bedrossian U, et al. Immunoreactivity of ductal cells with putative myoepithelial markers: a potential pitfall in breast carcinoma. Ann Diagn Pathol. 1999;3(3):165-173.

(25.) Koyama M, Kurotaki H, Yagihashi N, et al. Immunohistochemical assessment of proliferative activity in mammary adenomyoepithelioma. Histopathology. 1997;31(2):134-139.

(26.) Gobbi H, Simpson JF, Jensen RA, Olson SJ, Page DL. Metaplastic spindle cell breast tumors arising within papillomas, complex sclerosing lesions, and nipple adenomas. Mod Pathol. 2003;16(9):893-901.

(27.) Young RH, Clement PB. Adenomyoepithelioma of the breast: a report of three cases and review of the literature. Am J Clin Pathol. 1988;89(3):308-314.

(28.) Jones C, Tooze R, Lakhani SR. Malignant adenomyoepithelioma of the breast metastasizing to the liver. Virchows Arch. 2003;442(5):504-506.

(29.) Han JS, Peng Y. Multicentric adenomyoepithelioma of the breast with atypia and associated ductal carcinoma in situ. Breast J. 2010;16(5):547-549.

(30.) Han B, Mori I, Nakamura M, et al. Myoepithelial carcinoma arising in an adenomyoepithelioma of the breast: case report with immunohistochemical and mutational analysis. Pathol Int. 2006;56(4):211-216.

Ji Yoon Yoon, MD; Dhananjay Chitale, MD

Accepted for publication June 20, 2012.

From the Department of Pathology and Laboratory Medicine, Henry Ford Hospital, Detroit, Michigan.

The authors have no relevant financial interest in the products or companies described in this article.

Reprints: Ji Yoon Yoon, MD, Department of Pathology and Laboratory Medicine, Henry Ford Hospital, 2799 W Grand Blvd, Detroit, MI 48202 (e-mail: jyoon1@hfhs.org).

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Author:Yoon, Ji Yoon; Chitale, Dhananjay
Publication:Archives of Pathology & Laboratory Medicine
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Date:May 1, 2013
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