SHORT COMMUNICATION
Malignant Adenomyoepithelioma of the Breast: A Review Nasrollah Ahmadi, PhD,* Shahrzad Negahban, MD,† Azita Aledavood, MD,† Khosrow Daneshbod, MD, FCAP,† and Yahya Daneshbod, MD† *Department of Pathobiology, School of Veterinary Medicine, Shiraz University, Shiraz, Iran; † Department of Pathology, Dr. Daneshbod Pathology Laboratory, Shiraz, Iran
n Abstract: Malignant adenomyoepithelioma (MAME) of the breast is a rare lesion characterized by dual population of epithelial and myoepithelial cells which one or both components show malignant features. We report a case of MAME of the breast in a 46-year-old woman diagnosed by fine-needle aspiration with extensive review of the literature. Classification, clinical presentation, cyto-pathologic, and immunohistochemical features are described. This lesion showed both malignant components of epithelial and myoepithelial cells in cytology and histology. The malignancy was convincingly supported by high mitotic figures, pleomorphism, and invasion in tissue sections. This review of MAMEs showed that cyto-histologic diagnosis is difficult and should be supported by immunohistochemical study. n Key Words: cytology, fine-needle aspiration, histopathology, immunohistochemistry, literature review, malignant adenomyoepithelioma
A
denomyoepitheliomas (AMEs) are a rare tumor of the breast consisted of proliferation of outer myoepithelial cells, either pure or admixed with the inner epithelial cells (1–3). In the classification of the myoepithelial lesions by Tavassoli (4), AMEs has been subdivided into three variants, arranged in spindle cell type, tubules, and lobules. Malignant transformation of one of the two cellular components or both may occur in this lesion with distant metastases (1–10). However, malignant adenomyoepithelioma (MAME) in which both cellular components undergo malignant transformation is exceptionally uncommon (3). We herein describe a MAME in a 46-year-old woman with extensive literature review. PATIENT AND METHODS History The patient is a 46-year-old woman with left breast mass. On ultrasonography, the lesion was identified as
Address correspondence and reprint requests to: Yahya Daneshbod, MD, Department of Pathology, Dr. Daneshbod Pathology Laboratory, Shiraz, 7134777118, Iran, or e-mail: [email protected] This paper is presented partly in the 38th European Congress of Cytology 2014, September 27–30, 2014 – Geneva, Switzerland. DOI: 10.1111/tbj.12390 © 2015 Wiley Periodicals, Inc., 1075-122X/15 The Breast Journal, Volume 21 Number 3, 2015 291–296
a lobulated circumscribed and homogenous solid hypo-echoic mass about 1.9 9 1 cm (Fig. 1a). A mammography study was in favor of fibroadenoma (Fig. 1b). Fine-needle aspiration (FNA) biopsy and excisional biopsy was undertaken. Cytology, Histology, and Immunohistochemistry (IHC) By ultrasound guided FNA biopsy, 0.3 mL bloody material is yielded and slides were stained by Wright and Papanicolaou methods. Cell block is also prepared and processed according to histology. The tumor specimen was fixed in 10% neutral buffered formalin, routinely dehydrated, embedded in paraffin, and cut into 4-lm-thick sections for H and E staining and light microscopy. An immunohistochemical study was carried out using bond polymer refine detection system. 3-30 diaminobenzidine and Harris hematoxylin were used as the chromogen and the counterstaining materials, respectively. RESULTS Cytology The cytologic examination of the FNA revealed many large sheets of neoplastic ductal epithelial cells with foci of acinar pattern. Aggregates showed
292 • ahmadi et al.
(b)
(a)
Figure 1. (a) Ultrasound showing lobulated circumscribed and homogenous solid hypo-echoic mass. (b) A mammography showing a density in the left breast with ill-defined superior border and associated architectural distortion at 10 o’clock position.
crowding and irregular large round nuclei with poor polarity. The cells showed evenly distributed granular and fine chromatin pattern and conspicuous small nucleoli with ample gray blue dense cytoplasm (Fig. 2a–d). Also, there are atypical naked myoepithelial cells with abnormal mitotic figures in background (Fig. 3a–c). Cell block showed ductal elements surrounded by multiple myopeithelial layers (Fig. 3d).
(Fig. 5b), smooth muscle actin, cytokeratin 5, weak positivity for pancytokeratin (Fig. 5c), and about 70% proliferative activity by Ki-67 (Fig. 5d). Both estrogen and progesterone receptors were negative. The final diagnosis of MAME was made and mastectomy was performed. The tumor had neither recurred locally nor metastasized 2 years after surgery. Literature Review
Histopathology Grossly, the tissue specimen consisted of a soft irregular tissue measuring 6 9 5 9 2 cm which cut section showed a 2.5 9 2 9 1.5 cm mass. Histopathologic examination showed a well demarcated and lobulated tumor arranged as multiple, glandular, or acinar structures with dual cell population and a pushing border in the periphery (Fig. 4a and b). It consisted of a central location of glandular epithelial cells with a hyperchromatic nuclei and dense eosinophilic cytoplasm surrounded by prominent layers of myoepithelial cells with predominantly clear or eosinophilic abundant cytoplasm (Fig. 4c). Also, there were prominent features of malignancy such as increased mitotic figures in 10 high power field (HPF), hyperchromatic enlarged vesicular nuclei containing prominent nucleoli and marked nuclear atypia or cellular pleomorphism (Fig. 4d). Immunohistochemistry The tumor cells revealed myoepithelial proliferation with p63 (Fig. 5a), high molecular weight keratins
So far, 30 papers which described 64 cases of MAME of the breast have been reported in the medical literature (Table 1). The age range of these MAMEs was from 33 to 93 (mean, 63.6 years). Tumor size ranged from 1 to 17 cm with mean size of 3.48 cm. They often involve the right side more than the left side. This literature review revealed that up to 50% of MAMEs had tissue invasion or infiltrating margins and the rate of mitotic figures varied from one to 62 per 10 HPF. Seventeen of these 64 MAME cases have metastasized to lymph nodes (11,12,14), lung (1,2,5,8,9,13–16), brain (1,6,9), bone (11,14), thyroid (7), liver (17), kidney (16), skin (14), soft tissue (9), and thoracic wall (12). The histopathologic features of these metastatic tumors were similar to those of the primary MAMEs in the breast. Local recurrence also occurred in 10 cases. The malignancy features such as pleomorphism and necrosis was reported in 40/64 and 31/64, respectively. Malignant features arose from either myoepithelial (25/64), epithelial (15/64), or both cell components
Malignant Adenomyoepithelioma of the Breast • 293
Figure 2. (a–d) Fine-needle aspiration cytology showing many large sheets of neoplastic ductal epithelial cells with foci of acinar and trabecular pattern. The cells showed evenly distributed granular and fine chromatin pattern and conspicuous small nucleoli with ample gray blue dense cytoplasm (Papanicolaou, Wright stain, 9100).
Figure 3. (a–c) Fine-needle aspiration cytology showing atypical naked myoepithelial cells with abnormal mitotic figures in background (arrow; Papanicolaou stain, 9200). (d) Cell block showed ductal elements surrounded by multiple myoepithelial layers (H&E, 9100).
(a)
(b)
(c)
(d)
(a)
(b)
(c)
(d)
(24/64). These MAMEs were classified as biphasic MAME or epithelial-myoepithelail carcinoma (1,3,6– 10,13,14,16,18–22), matrix-producing biphasic MAME (2,12), myoepithelial carcinoma or malignant myoepithelioma arising in AME (9–11,15,17,23–29), epithelial carcinoma or adenocarcinoma, invasive ductal carcinoma or undifferentiated carcinoma arising in AME (5,6,9,30,31). FNA cytology was done in ten cases and only five had malignant features (5/ 10).
DISCUSSION The main histologic criteria for predicting malignancy of AMEs include cellular and nuclear pleomorphism, high mitotic figures in 10 HPF, surrounding tissue invasion and necrosis (1–10). Frequently, local recurrent lesions occur due to incomplete excision or persistent intraductal foci (13). Loose et al. (1), believed that local recurrence alone is not justification for all AMEs to be considered malignant. According to Hayes (9), MAME has greater potential to local
294 • ahmadi et al.
(a)
(b)
(c)
(d)
(a)
(b)
(c)
(d)
recurrence and significant metastatic potential and these metastases typically occur in patients with high grade malignant transformation. According to Tavassoli (4), as long as the biphasic proliferation of both myoepithelial and epithelial cell components are present in the tumor, the term “AME” is used. Either the epithelial, myoepithelial, or both components of an AMEs may give rise to a carcinoma (5,6). True biphasic “MAME” is a tumor with malignant features in both epithelial and myoepithelial cell components that also is named epithelial-
Figure 4. (a and b) Low and high power photomicrograph of the neoplastic mass showing a well demarcated and lobulated tumor arranged as multiple, glandular, or acinar structures with dual cell population. (c) A central location of glandular epithelial cells with a hyperchromatic nuclei and dense eosinophilic cytoplasm surrounded by prominent layers of myoepithelial cells with predominantly clear or eosinophilic abundant cytoplasm (d) Features of malignancy such as increased mitotic figures, hyperchromatic enlarged vesicular nuclei containing prominent nucleoli, and marked nuclear atypia (H&E, 9100, 9200, 9300, 9400).
Figure 5. Immunohistochemistry showing myoepithelial cells by p63 (a), high molecular weight keratins (b), weak positivity for pancytokeratin (c). About 70% of the neoplastic cell nuclei were positive for Ki-67 (d) (Immunoperoxidase, 9200).
myoepithelial carcinoma in the new nomenclatures. The term “myoepithelial carcinoma” is also used to designate malignant myoepithelioma, which is the pure proliferation of atypical spindle myoepithelial cells without an epithelial component (13). Otherwise, malignancy occurring in either epithelial or myoepithelial cell components are more accurately designated as “carcinoma arising within an AME” (6). In fine needle aspirates, the presence or absence of ductal structures and/or apocrine cells, dual cell population (biphasic nature), stromal elements, prominent
Malignant Adenomyoepithelioma of the Breast • 295
Table 1. Clinicopathological Features of MAME in the Literature Cytology Author(s) Trojani et al. (1992) Loose et al. (1992)
Age(y)/sex
Side
51/F 48/F 42/F 49/F 54/F 58/F 64/F 43/F 76/F 72/F 39/F 81/F 76/F 50/F 60/F 52/F 71/F 86/F 82/F 41/F
L Rt L NR Rt Rt Rt L L Rt L Rt NR L Rt L Rt L L Rt
Kurashina (2002)
73/F
Jones et al. (2003) Howlett et al. (2003) Harigopal et al. (2004) Hungermann et al. (2005)
Size (cm)
MC
Result
2 1.7 6 4.5 17 3.5 3 4 1.7 4.5 1.3 3 15 4 9 1.6 1 4 13 1.3
ME ME ME ME M E ME E ME ME ME E ME ME ME ME ME ME E E
L
2.2
ME
Suspicious
71/F 74/F 75/F 45-93/F (No. =14)
Rt Rt L NR
3 NR 4.5 NR
€l et al. (2006) Noe Han et al. (2006) Fan et al. (2007) Oka et al. (2007) Choi et al. (2009) Honda & Iyama (2009) Hegyi et al. (2009) Zizi-Sermpetzoglou et al. (2009) Leung et al. (2010) Hayes (2011)
67/F 69/F 56/F 77/F 68/F 53/F 41/F 80/F 65/F 33-93/NR (No. 13 cases)
L Rt Rt L Rt Rt Rt L Rt NR
1.1 2.5 2 3.8 15 5 6 4 1.6 1–14
Marian et al. (2013)
56/F 41/F 60/F 49/F 46/F
Rt Rt Rt Rt L
1.2 1.9 2 8 6
M M ME M (13) ME (1) M M M ME E ME M ME M E(9) M(1) ME(3) M M ME M ME
Pauwels & De Potter (1994) Chen et al. (1994) Nomura et al. (1996) Rasbridge & Millis (1998)
Simpson et al. (1998) Takahashi et al. (1999) Bult et al. (2000) Ahmed & Heller (2000) Kihara et al. (2001) Ng (2002)
Petrozza et al. (2013) Robinson et al. (2014) Current case (2014)
ND ND
Findings – –
ND ND Positive ND
– – Carcinoma –
ND ND ND ND Positive Negative
Positive Positive Positive ND
– – – – Malignant cells & sarcoma Apocrine & spindle cells, naked nuclei & foamy macrophages Spindle myoepithelial epithelial cells, admixed with a few epithelial cells, and atypical cells Carcinoma Malignant Malignant Hemangiopericytoma –
Negative ND ND ND ND ND ND Positive ND ND
Benign epithelial cells – – – – – – NR – –
ND ND Negative Positive
– – Intracystic papillary lesion Ductal myoepithelial cells with marked atypia & mitosis
y, year; Rt, right; L, left; MC, malignant component; E, epithelial; M, myoepithelial; NR, not reported; ND, Not done; PA, Pleomorphic adenoma.
squamous metaplasia, and tubular or cribriform structures may act as a pitfall for erroneous diagnosis of AMEs. In FNA cytology, AMEs may be misdiagnosed with myoepithelial/stromal cell-rich lesions such as phyllodes tumor, biphasic adenoid cystic carcinoma, malignant myoepithelioma, myofibroblastoma, metaplastic carcinoma, apocrine carcinoma, low grade adenosquamus carcinoma, AME adenosis, ductal adenoma (sclerosed intraductal papilloma), and pleomorphic adenoma of the breast (30,32,33). However,
the cytologic appearance of ductal epithelial and spindle myoepithelial cell duality with atypical features such as pleomorphism and high mitotic activity in combination with cell block and IHC analysis can lead to definitive diagnosis of MAMEs. Based on this review, immunostains for estrogen and progesterone receptors (ER and PgR) was either negative or weakly positive in AME. In conclusion, it seems that the aggressive appearance, clinical outcomes and probability for metastasis
296 • ahmadi et al.
could not be precisely predicted. Consequently, these problems may give rise to the difficulties in staging, grading and estimation of the prognosis and the treatment of MAMEs. Acknowledgment We like to thanks Farid Moinfar MD for reviewing this case. CONFLICTS OF INTEREST None. REFERENCES 1. Loose JH, Patchefsky AS, Hollander IJ, et al. Adenomyoepithelioma of the breast. A spectrum of biologic behavior. Am J Surg Pathol 1992;16:868–76. 2. Simpson RH, Cope N, Skalova A, et al. Malignant adenomyoepithelioma of the breast with mixed osteogenic, spindle cell, and carcinomatous differentiation. Am J Surg Pathol 1998;22:631– 6. 3. Ahmed AA, Heller DS. Malignant adenomyoepithelioma of the breast with malignant proliferation of epithelial and myoepithelial elements: a case report and review of the literature. Arch Pathol Lab Med 2000;124:632–6. 4. Tavassoli FA. Myoepithelial lesions of the breast. Myoepitheliosis, adenomyoepithelioma, and myoepithelial carcinoma. Am J Surg Pathol 1991;15:554–68. 5. Michal M, Baumruk L, Burger J, et al. Adenomyoepithelioma of the breast with undifferentiated carcinoma component. Histopathology 1994;2:274–6. 6. Rasbridge SA, Millis RR. Adenomyoepithelioma of the breast with malignant features. Virchows Arch 1998;432:123–30. 7. Bult P, Verwiel JMM, Wobbes T, et al. Malignant adenomyoepithelioma of the breast with metastasis in the thyroid gland 12 years after excision of the primary tumor: a case report and review of the literature. Virchows Arch 2000;436:158–66. 8. Kihara M, Yokomise H, Irie A, et al. Malignant adenomyoepithelioma of the breast with lung metastases: report of a case. Surg Today 2001;31:899–903. 9. Hayes MM. Adenomyoepithelioma of the breast: a review stressing its propensity for malignant transformation. J Clin Pathol 2011;64:477–84. 10. Hungermann D, Buerger H, Oehlschlegel C, et al. Adenomyoepithelial tumors and myoepithelial carcinomas of the breast- a spectrum of monophasic and biphasic tumors dominated by immature myoepithelial cells. BMC Cancer 2005;5:92. 11. Chen PC, Chen CK, Nicastri AD, et al. Myoepithelial carcinoma of the breast with distant metastasis and accompanied by adenomyoepitheliomas. Histopathology 1994;24:543–8. 12. Oka K, Sando N, Moriya T, et al. Malignant adenomyoepithelioma of the breast with matrix production may be compatible with one variant form of matrix-producing carcinoma: a case report. Pathol Res Pract 2007;203:599–604. 13. Trojani M, Guiu M, Trouette H, et al. Malignant adenomyoepithelioma of the breast. An immunohistochemical, cytophotometric, and ultrastructural study of a case with lung metastases. Am J Clin Pathol 1992;98:598–602.
14. Takahashi II, Tashiro H, Wakasugi K, et al. Malignant adenomyoepithelioma of the breast: a case with distant metastases. Breast Cancer 1999;6:73–7. 15. No€el JC, Simon P, Aguilar SF. Malignant myoepithelioma arising in cystic adenomyoepithelioma. Breast J 2006;12:386. 16. Honda Y, Iyama K. Malignant adenomyoepithelioma of the breast combined with invasive lobular carcinoma. Pathol Int 2009;59:179–84. 17. Jones C, Tooze R, Lakhani SR. Malignant adenomyoepithelioma of the breast metastasizing to the liver. Virchows Arch 2003;442:504–6. 18. Pauwels C, De Potter C. Adenomyoepithelioma of the breast with features of malignancy. Histopathology 1994;24:94–6. 19. Harigopal M, Park K, Chen X, et al. Pathologic quiz case: a rapidly increasing breast mass in a postmenopausal woman. Malignant adenomyoepithelioma. Arch Pathol Lab Med 2004; 128:235–6. 20. Kurashina M. Fine needle aspiration cytology of benign and malignant adenomyoepithelioma: report of two cases. Diagn Cytopathol 2002;26:29–34. 21. Zizi-Sermpetzoglou A, Vasilakaki T, Grammatoglou X, et al. Malignant adenomyoepithelioma of the breast-case report. Eur J Gynaecol Oncol 2009;30:234–6. 22. Petrozza V, Pasciuti G, Pacchiarotti A, et al. Breast adenomyoepithelioma: a case report with malignant proliferation of epithelial and myoepithelial elements. World J Surg Oncol 2013;11:285. 23. Hegyi L, Thway K, Newton R, et al. Malignant myoepithelioma arising in adenomyoepithelioma of the breast and coincident multiple gastrointestinal stromal tumors in a patient with neurofibromatosis type 1. J Clin Pathol 2009;62:653–5. 24. Fan F, Smith W, Wang X, et al. Myoepithelial carcinoma of the breast arising in an adenomyoepithelioma: mammographic, ultrasound and histologic features. Breast J 2007;13:203–4. 25. Leung TK, Chu JS, Huang PJ, et al. Breast MRI for monitoring images of an “adenomyoepithelioma with malignant features”, before, during, and after chemotherapy. Breast J 2010;16:652–3. 26. Marian C, Boila A, Soanca D, et al. Malignant transformation of adenomyoepithelioma of the breast by a monophasic population: a report of two cases and review of literature. APMIS 2013;121:272–9. 27. Robinson A, Mayne J, Boroumand N, et al. Malignant adenomyoepithelioma: a rare entity. Breast J 2014;20:94–6. 28. 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;56:211–6. 29. Howlett DC, Mason CH, Biswas S, et al. Adenomyoepithelioma of the breast: spectrum of disease with associated imaging and pathology. Am J Roentgenol 2003;180:799–803. 30. Ng WK. Adenomyoepithelioma of the breast. A review of three cases with reappraisal of the fine needle aspiration biopsy findings. Acta Cytol 2002;46:317–24. 31. Choi SY, Kim JS, Kim SJ, et al. Malignant adenomyoepithelioma of the breast presenting as a large mass that grew slowly without metastasis. J Breast Cancer 2009;12:219–22. 32. Diaz NM, McDivitt RW, Wick MR. Pleomorphic adenoma of the breast: a clinicopathologic and immunohistochemical study of 10 cases. Hum Pathol 1991;22:1206–14. 33. Gusterson BA, Sloane JP, Middwood C, et al. Ductal adenoma of the breast: a lesion exhibiting a myoepithelial/epithelial phenotype. Histopathology 1987;11:103–10.
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Malignant Adenomyoepithelioma of the Breast: A Review Nasrollah Ahmadi, PhD,* Shahrzad Negahban, MD,† Azita Aledavood, MD,† Khosrow Daneshbod, MD, FCAP,† and Yahya Daneshbod, MD† *Department of Pathobiology, School of Veterinary Medicine, Shiraz University, Shiraz, Iran; † Department of Pathology, Dr. Daneshbod Pathology Laboratory, Shiraz, Iran
n Abstract: Malignant adenomyoepithelioma (MAME) of the breast is a rare lesion characterized by dual population of epithelial and myoepithelial cells which one or both components show malignant features. We report a case of MAME of the breast in a 46-year-old woman diagnosed by fine-needle aspiration with extensive review of the literature. Classification, clinical presentation, cyto-pathologic, and immunohistochemical features are described. This lesion showed both malignant components of epithelial and myoepithelial cells in cytology and histology. The malignancy was convincingly supported by high mitotic figures, pleomorphism, and invasion in tissue sections. This review of MAMEs showed that cyto-histologic diagnosis is difficult and should be supported by immunohistochemical study. n Key Words: cytology, fine-needle aspiration, histopathology, immunohistochemistry, literature review, malignant adenomyoepithelioma
A
denomyoepitheliomas (AMEs) are a rare tumor of the breast consisted of proliferation of outer myoepithelial cells, either pure or admixed with the inner epithelial cells (1–3). In the classification of the myoepithelial lesions by Tavassoli (4), AMEs has been subdivided into three variants, arranged in spindle cell type, tubules, and lobules. Malignant transformation of one of the two cellular components or both may occur in this lesion with distant metastases (1–10). However, malignant adenomyoepithelioma (MAME) in which both cellular components undergo malignant transformation is exceptionally uncommon (3). We herein describe a MAME in a 46-year-old woman with extensive literature review. PATIENT AND METHODS History The patient is a 46-year-old woman with left breast mass. On ultrasonography, the lesion was identified as
Address correspondence and reprint requests to: Yahya Daneshbod, MD, Department of Pathology, Dr. Daneshbod Pathology Laboratory, Shiraz, 7134777118, Iran, or e-mail: [email protected] This paper is presented partly in the 38th European Congress of Cytology 2014, September 27–30, 2014 – Geneva, Switzerland. DOI: 10.1111/tbj.12390 © 2015 Wiley Periodicals, Inc., 1075-122X/15 The Breast Journal, Volume 21 Number 3, 2015 291–296
a lobulated circumscribed and homogenous solid hypo-echoic mass about 1.9 9 1 cm (Fig. 1a). A mammography study was in favor of fibroadenoma (Fig. 1b). Fine-needle aspiration (FNA) biopsy and excisional biopsy was undertaken. Cytology, Histology, and Immunohistochemistry (IHC) By ultrasound guided FNA biopsy, 0.3 mL bloody material is yielded and slides were stained by Wright and Papanicolaou methods. Cell block is also prepared and processed according to histology. The tumor specimen was fixed in 10% neutral buffered formalin, routinely dehydrated, embedded in paraffin, and cut into 4-lm-thick sections for H and E staining and light microscopy. An immunohistochemical study was carried out using bond polymer refine detection system. 3-30 diaminobenzidine and Harris hematoxylin were used as the chromogen and the counterstaining materials, respectively. RESULTS Cytology The cytologic examination of the FNA revealed many large sheets of neoplastic ductal epithelial cells with foci of acinar pattern. Aggregates showed
292 • ahmadi et al.
(b)
(a)
Figure 1. (a) Ultrasound showing lobulated circumscribed and homogenous solid hypo-echoic mass. (b) A mammography showing a density in the left breast with ill-defined superior border and associated architectural distortion at 10 o’clock position.
crowding and irregular large round nuclei with poor polarity. The cells showed evenly distributed granular and fine chromatin pattern and conspicuous small nucleoli with ample gray blue dense cytoplasm (Fig. 2a–d). Also, there are atypical naked myoepithelial cells with abnormal mitotic figures in background (Fig. 3a–c). Cell block showed ductal elements surrounded by multiple myopeithelial layers (Fig. 3d).
(Fig. 5b), smooth muscle actin, cytokeratin 5, weak positivity for pancytokeratin (Fig. 5c), and about 70% proliferative activity by Ki-67 (Fig. 5d). Both estrogen and progesterone receptors were negative. The final diagnosis of MAME was made and mastectomy was performed. The tumor had neither recurred locally nor metastasized 2 years after surgery. Literature Review
Histopathology Grossly, the tissue specimen consisted of a soft irregular tissue measuring 6 9 5 9 2 cm which cut section showed a 2.5 9 2 9 1.5 cm mass. Histopathologic examination showed a well demarcated and lobulated tumor arranged as multiple, glandular, or acinar structures with dual cell population and a pushing border in the periphery (Fig. 4a and b). It consisted of a central location of glandular epithelial cells with a hyperchromatic nuclei and dense eosinophilic cytoplasm surrounded by prominent layers of myoepithelial cells with predominantly clear or eosinophilic abundant cytoplasm (Fig. 4c). Also, there were prominent features of malignancy such as increased mitotic figures in 10 high power field (HPF), hyperchromatic enlarged vesicular nuclei containing prominent nucleoli and marked nuclear atypia or cellular pleomorphism (Fig. 4d). Immunohistochemistry The tumor cells revealed myoepithelial proliferation with p63 (Fig. 5a), high molecular weight keratins
So far, 30 papers which described 64 cases of MAME of the breast have been reported in the medical literature (Table 1). The age range of these MAMEs was from 33 to 93 (mean, 63.6 years). Tumor size ranged from 1 to 17 cm with mean size of 3.48 cm. They often involve the right side more than the left side. This literature review revealed that up to 50% of MAMEs had tissue invasion or infiltrating margins and the rate of mitotic figures varied from one to 62 per 10 HPF. Seventeen of these 64 MAME cases have metastasized to lymph nodes (11,12,14), lung (1,2,5,8,9,13–16), brain (1,6,9), bone (11,14), thyroid (7), liver (17), kidney (16), skin (14), soft tissue (9), and thoracic wall (12). The histopathologic features of these metastatic tumors were similar to those of the primary MAMEs in the breast. Local recurrence also occurred in 10 cases. The malignancy features such as pleomorphism and necrosis was reported in 40/64 and 31/64, respectively. Malignant features arose from either myoepithelial (25/64), epithelial (15/64), or both cell components
Malignant Adenomyoepithelioma of the Breast • 293
Figure 2. (a–d) Fine-needle aspiration cytology showing many large sheets of neoplastic ductal epithelial cells with foci of acinar and trabecular pattern. The cells showed evenly distributed granular and fine chromatin pattern and conspicuous small nucleoli with ample gray blue dense cytoplasm (Papanicolaou, Wright stain, 9100).
Figure 3. (a–c) Fine-needle aspiration cytology showing atypical naked myoepithelial cells with abnormal mitotic figures in background (arrow; Papanicolaou stain, 9200). (d) Cell block showed ductal elements surrounded by multiple myoepithelial layers (H&E, 9100).
(a)
(b)
(c)
(d)
(a)
(b)
(c)
(d)
(24/64). These MAMEs were classified as biphasic MAME or epithelial-myoepithelail carcinoma (1,3,6– 10,13,14,16,18–22), matrix-producing biphasic MAME (2,12), myoepithelial carcinoma or malignant myoepithelioma arising in AME (9–11,15,17,23–29), epithelial carcinoma or adenocarcinoma, invasive ductal carcinoma or undifferentiated carcinoma arising in AME (5,6,9,30,31). FNA cytology was done in ten cases and only five had malignant features (5/ 10).
DISCUSSION The main histologic criteria for predicting malignancy of AMEs include cellular and nuclear pleomorphism, high mitotic figures in 10 HPF, surrounding tissue invasion and necrosis (1–10). Frequently, local recurrent lesions occur due to incomplete excision or persistent intraductal foci (13). Loose et al. (1), believed that local recurrence alone is not justification for all AMEs to be considered malignant. According to Hayes (9), MAME has greater potential to local
294 • ahmadi et al.
(a)
(b)
(c)
(d)
(a)
(b)
(c)
(d)
recurrence and significant metastatic potential and these metastases typically occur in patients with high grade malignant transformation. According to Tavassoli (4), as long as the biphasic proliferation of both myoepithelial and epithelial cell components are present in the tumor, the term “AME” is used. Either the epithelial, myoepithelial, or both components of an AMEs may give rise to a carcinoma (5,6). True biphasic “MAME” is a tumor with malignant features in both epithelial and myoepithelial cell components that also is named epithelial-
Figure 4. (a and b) Low and high power photomicrograph of the neoplastic mass showing a well demarcated and lobulated tumor arranged as multiple, glandular, or acinar structures with dual cell population. (c) A central location of glandular epithelial cells with a hyperchromatic nuclei and dense eosinophilic cytoplasm surrounded by prominent layers of myoepithelial cells with predominantly clear or eosinophilic abundant cytoplasm (d) Features of malignancy such as increased mitotic figures, hyperchromatic enlarged vesicular nuclei containing prominent nucleoli, and marked nuclear atypia (H&E, 9100, 9200, 9300, 9400).
Figure 5. Immunohistochemistry showing myoepithelial cells by p63 (a), high molecular weight keratins (b), weak positivity for pancytokeratin (c). About 70% of the neoplastic cell nuclei were positive for Ki-67 (d) (Immunoperoxidase, 9200).
myoepithelial carcinoma in the new nomenclatures. The term “myoepithelial carcinoma” is also used to designate malignant myoepithelioma, which is the pure proliferation of atypical spindle myoepithelial cells without an epithelial component (13). Otherwise, malignancy occurring in either epithelial or myoepithelial cell components are more accurately designated as “carcinoma arising within an AME” (6). In fine needle aspirates, the presence or absence of ductal structures and/or apocrine cells, dual cell population (biphasic nature), stromal elements, prominent
Malignant Adenomyoepithelioma of the Breast • 295
Table 1. Clinicopathological Features of MAME in the Literature Cytology Author(s) Trojani et al. (1992) Loose et al. (1992)
Age(y)/sex
Side
51/F 48/F 42/F 49/F 54/F 58/F 64/F 43/F 76/F 72/F 39/F 81/F 76/F 50/F 60/F 52/F 71/F 86/F 82/F 41/F
L Rt L NR Rt Rt Rt L L Rt L Rt NR L Rt L Rt L L Rt
Kurashina (2002)
73/F
Jones et al. (2003) Howlett et al. (2003) Harigopal et al. (2004) Hungermann et al. (2005)
Size (cm)
MC
Result
2 1.7 6 4.5 17 3.5 3 4 1.7 4.5 1.3 3 15 4 9 1.6 1 4 13 1.3
ME ME ME ME M E ME E ME ME ME E ME ME ME ME ME ME E E
L
2.2
ME
Suspicious
71/F 74/F 75/F 45-93/F (No. =14)
Rt Rt L NR
3 NR 4.5 NR
€l et al. (2006) Noe Han et al. (2006) Fan et al. (2007) Oka et al. (2007) Choi et al. (2009) Honda & Iyama (2009) Hegyi et al. (2009) Zizi-Sermpetzoglou et al. (2009) Leung et al. (2010) Hayes (2011)
67/F 69/F 56/F 77/F 68/F 53/F 41/F 80/F 65/F 33-93/NR (No. 13 cases)
L Rt Rt L Rt Rt Rt L Rt NR
1.1 2.5 2 3.8 15 5 6 4 1.6 1–14
Marian et al. (2013)
56/F 41/F 60/F 49/F 46/F
Rt Rt Rt Rt L
1.2 1.9 2 8 6
M M ME M (13) ME (1) M M M ME E ME M ME M E(9) M(1) ME(3) M M ME M ME
Pauwels & De Potter (1994) Chen et al. (1994) Nomura et al. (1996) Rasbridge & Millis (1998)
Simpson et al. (1998) Takahashi et al. (1999) Bult et al. (2000) Ahmed & Heller (2000) Kihara et al. (2001) Ng (2002)
Petrozza et al. (2013) Robinson et al. (2014) Current case (2014)
ND ND
Findings – –
ND ND Positive ND
– – Carcinoma –
ND ND ND ND Positive Negative
Positive Positive Positive ND
– – – – Malignant cells & sarcoma Apocrine & spindle cells, naked nuclei & foamy macrophages Spindle myoepithelial epithelial cells, admixed with a few epithelial cells, and atypical cells Carcinoma Malignant Malignant Hemangiopericytoma –
Negative ND ND ND ND ND ND Positive ND ND
Benign epithelial cells – – – – – – NR – –
ND ND Negative Positive
– – Intracystic papillary lesion Ductal myoepithelial cells with marked atypia & mitosis
y, year; Rt, right; L, left; MC, malignant component; E, epithelial; M, myoepithelial; NR, not reported; ND, Not done; PA, Pleomorphic adenoma.
squamous metaplasia, and tubular or cribriform structures may act as a pitfall for erroneous diagnosis of AMEs. In FNA cytology, AMEs may be misdiagnosed with myoepithelial/stromal cell-rich lesions such as phyllodes tumor, biphasic adenoid cystic carcinoma, malignant myoepithelioma, myofibroblastoma, metaplastic carcinoma, apocrine carcinoma, low grade adenosquamus carcinoma, AME adenosis, ductal adenoma (sclerosed intraductal papilloma), and pleomorphic adenoma of the breast (30,32,33). However,
the cytologic appearance of ductal epithelial and spindle myoepithelial cell duality with atypical features such as pleomorphism and high mitotic activity in combination with cell block and IHC analysis can lead to definitive diagnosis of MAMEs. Based on this review, immunostains for estrogen and progesterone receptors (ER and PgR) was either negative or weakly positive in AME. In conclusion, it seems that the aggressive appearance, clinical outcomes and probability for metastasis
296 • ahmadi et al.
could not be precisely predicted. Consequently, these problems may give rise to the difficulties in staging, grading and estimation of the prognosis and the treatment of MAMEs. Acknowledgment We like to thanks Farid Moinfar MD for reviewing this case. CONFLICTS OF INTEREST None. REFERENCES 1. Loose JH, Patchefsky AS, Hollander IJ, et al. Adenomyoepithelioma of the breast. A spectrum of biologic behavior. Am J Surg Pathol 1992;16:868–76. 2. Simpson RH, Cope N, Skalova A, et al. Malignant adenomyoepithelioma of the breast with mixed osteogenic, spindle cell, and carcinomatous differentiation. Am J Surg Pathol 1998;22:631– 6. 3. Ahmed AA, Heller DS. Malignant adenomyoepithelioma of the breast with malignant proliferation of epithelial and myoepithelial elements: a case report and review of the literature. Arch Pathol Lab Med 2000;124:632–6. 4. Tavassoli FA. Myoepithelial lesions of the breast. Myoepitheliosis, adenomyoepithelioma, and myoepithelial carcinoma. Am J Surg Pathol 1991;15:554–68. 5. Michal M, Baumruk L, Burger J, et al. Adenomyoepithelioma of the breast with undifferentiated carcinoma component. Histopathology 1994;2:274–6. 6. Rasbridge SA, Millis RR. Adenomyoepithelioma of the breast with malignant features. Virchows Arch 1998;432:123–30. 7. Bult P, Verwiel JMM, Wobbes T, et al. Malignant adenomyoepithelioma of the breast with metastasis in the thyroid gland 12 years after excision of the primary tumor: a case report and review of the literature. Virchows Arch 2000;436:158–66. 8. Kihara M, Yokomise H, Irie A, et al. Malignant adenomyoepithelioma of the breast with lung metastases: report of a case. Surg Today 2001;31:899–903. 9. Hayes MM. Adenomyoepithelioma of the breast: a review stressing its propensity for malignant transformation. J Clin Pathol 2011;64:477–84. 10. Hungermann D, Buerger H, Oehlschlegel C, et al. Adenomyoepithelial tumors and myoepithelial carcinomas of the breast- a spectrum of monophasic and biphasic tumors dominated by immature myoepithelial cells. BMC Cancer 2005;5:92. 11. Chen PC, Chen CK, Nicastri AD, et al. Myoepithelial carcinoma of the breast with distant metastasis and accompanied by adenomyoepitheliomas. Histopathology 1994;24:543–8. 12. Oka K, Sando N, Moriya T, et al. Malignant adenomyoepithelioma of the breast with matrix production may be compatible with one variant form of matrix-producing carcinoma: a case report. Pathol Res Pract 2007;203:599–604. 13. Trojani M, Guiu M, Trouette H, et al. Malignant adenomyoepithelioma of the breast. An immunohistochemical, cytophotometric, and ultrastructural study of a case with lung metastases. Am J Clin Pathol 1992;98:598–602.
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