Myoepithelial
Lesions/Neoplasms Myoepithelial
Lesions/Neoplasms
Contents
15.1 Background . . . 410
15.2 Immunoprofile . . . 410
15.3 Myoepithelial Cell Hypertrophy . . . 410
15.3.1 Definition . . . 410
15.3.2 Microscopic Features . . . 410
15.3.3 Additional Comments . . . 410
15.4 Myoepitheliosis (Myoepithelial Hyperplasia) . . . 410
15.4.1 Definition . . . 410
15.4.2 Macroscopy . . . 410
15.4.3 Microscopic Features . . . 410
15.4.4 Additional Comments . . . 411
15.5 Adenomyoepithelioma . . . 411
15.5.1 Definition . . . 411
15.5.2 Macroscopy . . . 411
15.5.3 Microscopic Features . . . 411
15.5.4 Additional Comments . . . 411
15.5.5 Further Reading . . . 411
15.6 Sarcomatoid Carcinoma with Myoepithelial Differentiation (Myoepithelial Carcinoma, Malignant Myoepithelioma) . . . 412
15.6.1 Definition . . . 412
15.6.2 Macroscopy . . . 412
15.6.3 Microscopic Features . . . 412
15.6.4 Additional Comments . . . 413
15.6.5 Further Reading . . . 413
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15.1 Background
The appearance of myoepithelial cells varies significantly from a bipolar “naked” nuclei with very scant cytoplasm to cells with rounded nuclei with abundant eosinophilic or clear cytoplasm.
Several benign and malignant neoplasms in the breast are main- ly or partly related to myoepithelial cells. Myoepithelial lesions such as hypertrophy or hyperplasia, adenomyoepithelioma, car- cinoma arising in the background of adenomyoepithelioma, and carcinoma with MEC differentiation (myoepithelial carcinoma) are the subjects of this chapter. Adenoid cystic carcinoma, which is also related to myoepithelial cells, is discussed else- where (breast carcinomas, special types).
15.2 Immunoprofile
It is important to keep in mind that myoepithelial cells can be positive for some of the “myoepithelial markers” but completely negative for others. The immunoreactivity of myoepithelial cells is often a matter of differentiation and function of the cells and, therefore, can vary significantly, even within the same lesion.
Currently, no single specific myoepithelial marker is available.
But a number of myoepithelial markers can be used reliably, particularly in combination and in association with the mor- phology.
Myoepithelial cells are commonly positive for smooth muscle (SM) actin, calponin, SM myosin (heavy chain), S100 protein, CD10, and p63. Recent markers include 14-3-3 sigma, CD29, and nerve growth factor receptor (NGFR/p75) [18, 20, 22, 24, 25].
Normal and neoplastic myoepithelial cells are very often pos- itive for SM actin, S100 protein, CD10, and p63. In difficult cases, at least two of these markers should be used in combination. The immunoreaction for these markers can be diffuse and intense or focal. Basal-type cytokeratins such as CK5/6, CK14, and CK17 are usually positive in MEC, and they can also be positive in some lu- minal epithelial cells. These cytokeratins should not be used alone as reliable markers for myoepithelial cells. Estrogen recep- tor (ER), progesterone receptor (PR), and androgen receptor (AR) are characteristically negative in normal and neoplastic myoepithelial cells. Desmin is also negative.
15.3 Myoepithelial Cell Hypertrophy
15.3.1 Definition
Prominent presence of a myoepithelial cell layer characterized by enlargement of cells with abundant cytoplasm.
15.3.2 Microscopic Features (Fig. 98)
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Even at low magnification, a distinct cell population of basally located cells surrounding luminal epithelial cells of ducts and lobules is present.
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At higher magnification, one cell layer of enlarged myoepithe- lial cells with abundant clear or eosinophilic cytoplasm is evident.
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Sometimes a plasmacytoid appearance of myoepithelial cells with eccentric nuclear position can be observed. A hobnail pattern of myoepithelial cells can rarely be found.
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Myoepithelial cells may show a myoid look, with spindle- shaped cells with deep eosinophilic, fibrillar cytoplasm (also called as myoid differentiation).
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Association with adenosis, epithelial hyperplasia, and papillo- ma is not infrequent.
15.3.3 Additional Comments
By definition, hypertrophy should be distinguished from hyper- plasia of myoepithelial cells; whereas in hypertrophy there is only one layer of enlarged myoepithelial cells, myoepithelial cell hyperplasia or myoepitheliosis is characterized by a numerical increase of myoepithelial cells with or without enlargement of such individual cells.
In rare cases, myoepithelial cell hypertrophy may be associ- ated with some degree of nuclear atypia. The significance of atypia in that setting is not clear.
15.4 Myoepitheliosis (Myoepithelial Hyperplasia)
15.4.1 Definition
Hyperplasia of myoepithelial cells growing into and/or around small ducts and lobules. Often a microscopic, multifocal finding.
15.4.2 Macroscopy
Either normal or firm irregular area of the cut surface.
15.4.3 Microscopic Features
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Usually, there is a multifocal proliferation of myoepithelial
cells in the peripheral duct system (terminal duct/lobular
units).
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Spindle, round, or cuboidal myoepithelial cells are evident, with eosinophilic or clear cytoplasm.
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Rarely, a plasmacytoid appearance is seen.
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The cuboidal cells may show longitudinal nuclear grooves mimicking transitional cells.
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Mitotic activity and nuclear atypia may rarely be present.
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Association with (sclerosing) adenosis and peripheral intra- ductal papilloma can occur.
15.4.4 Additional Comments
The presence of significant nuclear atypia in myoepitheliosis warrants a designation of atypical myoepitheliosis. The clinical significance of atypia in that setting is, however, not investigated.
In some cases of adenosis, prominent myoepithelial hypertro- phy and hyperplasia may occur; these cases have been designat- ed adenomyoepithelial adenosis. The distinction between ade- nomyoepithelial adenosis and small adenomyoepithelioma, however, is subjective and not well defined.
15.5 Adenomyoepithelioma
15.5.1 Definition
A solitary and often centrally located tumor composed of prolif- erating myoepithelial cells around small epithelial-lined spaces.
15.5.2 Macroscopy
Sharply delineated, round to multilobulated tumor with firm to rubbery consistency and greyish-white, yellow, or pink cut sur- face. Some cases may show irregular and infiltrating margins. In large tumors, cystic areas and necrosis may occur.
15.5.3 Microscopic Features (Fig. 99)
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Most adenomyoepitheliomas are circumscribed, showing aggregates of nodules.
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Layers or aggregates of myoepithelial cells around epithelial lined spaces are evident.
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The tumor often shows a lobulated growth pattern. Prominent spindle cells or a tubular pattern may also be present.
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The lobulated type (variant) of adenomyoepithelioma dis- plays solid nests of myoepithelial cells with eosinophilic or clear cytoplasm proliferating around compressed epithelial cells.
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Rounded aggregates of tumor cells may infiltrate into the sur- rounding normal breast tissue.
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Focal or multifocal necrosis may be seen.
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Neoplastic myoepithelial cells with a plasmacytoid appear- ance showing abundant eosinophilic cytoplasm and eccen- trally located nuclei may be present.
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The tubular variant often has ill-defined margins and displays rounded tubules lined by easily identifiable luminal epithelial and basally located myoepithelial cells.
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Sometimes spindle cells are the predominant cell component, with few epithelial-lined spaces.
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Many tumors have one or more nodules in which there is a focal papillary growth pattern.
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Up to three mitotic figures per 10 hpf may be seen in myo- epithelial cells.
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Apocrine and mucinous metaplasia can be present. Apocrine metaplastic cells may show some degree of nuclear variation and atypia.
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Central hyalinization, particularly in the lobulated variant, is a common finding.
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Satellite nodules adjacent to the lobulated variant can be seen in some cases.
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Intraductal papillary configurations extending into ducts out- side the gross tumorous lesion may be observed.
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Rarely, areas of squamous metaplasia or sebaceous differenti- ation are present.
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Rarely, chondroid metaplasia and a pattern closely similar to salivary gland pleomorphic adenoma may occur.
Caution
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An adenomyoepithelioma with combined atypical features including high-grade nuclear atypia, increased mitotic activi- ty (more than three mitosis per 10 hpf ), and focally infiltrative margins should be interpreted very cautiously; these features would strongly favor a carcinoma arising in the background of adenomyoepithelioma. If there is no clear-cut invasive car- cinoma, wide local excision of the atypical adenomyoepithe- lioma with close clinical follow-up is recommended.
15.5.4 Additional Comments
Some investigators regard most adenomyoepitheliomas as a variant of intraductal papillomas that are associated with promi- nent myoepithelial hyperplasia. On the other hand, it has been suggested that some adenomyoepitheliomas may represent a variant of nodular adenosis (adenosis tumor) with significant myoepithelial hypertrophy and hyperplasia (adenomyoepithelial adenosis) [11, 12].
The group of tumors sometimes referred to as mixed tumors or pleomorphic adenomas of the breast are mostly variants of adenomyoepithelioma.
The majority of adenomyoepitheliomas are benign. Tumors with infiltrating margins or those with high mitotic activity have a potential for recurrence and/or distant (lung) metastases [2, 4, 8, 15, 17, 25, 26].
15.5.5 Further Reading
1. Ahmed A. The myoepithelium in the human breast carcinoma.
J Pathol 1974;112:121–135.
2. 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;124:632–636.
3. Azzopardi JG. Problems in breast pathology. WB Saunders, Philadel- phia, 1979, pp. 339–340.
4. Bult P, Verwiel JM, Wobbes T, et al. Malignant adenomyoepithelioma of the breast with metastasis in the thyroid gland 12 years after ex- cision of the primary tumor. Case report and review of the litera- ture. Virchows Arch 2000;436:158–166.
5. Chen PC, Chen CK, Nicastri AD, Wait RB. Myoepithelial carcinoma of the breast with distant metastasis and accompanied by adeno- myoepitheliomas. Histopathology 1994;24:543–548.
6. Flinner RL, Hammond EH. The myoepithelial cell in lesions of the breast: a review. Pathol Annu 1993;28 (Pt 2):145–169.
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7. Foschini MP, Eusebi V. Carcinomas of the breast showing myo- epithelial cell differentiation. A review of the literature. Virchows Arch (A) 1998;432:303–310.
8. Foschini MP, Pizzicannella G, Peterse JL, et al. Adenomyoepithe- lioma of the breast associated with low grade adenosquamous and sarcomatoid carcinomas. Virchows Arch 1995;427:243–250.
9. Guelstein VI, Tchpysheva TA, Ermilova VD, et al. Myoepithelial and basement membrane antigens in benign and malignant human breast tumors. Int J Cancer 1993;53:269–277.
10. Jabi M, Dardick I, Cardigos N. Adenomyoepithelioma of the breast.
Arch Pathol Lab Med 1988;112:73–76.
11. Kiaer H. Adenomyoepithelial adenosis. Am J Surg Pathol 1987;11:
235.
12. Kiaer H, Nielsen B, Paulsen S, et al. Adenomyoepithelial adenosis and low-grade malignant adenomyoepithelioma of the breast. Vir- chows Arch A Pathol Anat Histopathol 1984;405:55–76.
13. Lakhani SR, O’Hare MJ, Monaghan P, et al. Malignant myoepithe- lioma (myoepithelial carcinoma) of the breast: a detailed cytoker- atin study. Clin Pathol 1995;48:164–167.
14. Livasy CA, Karaca G, Nanda R, et al. Phenotypic evaluation of basal- like subtype of invasive breast carcinoma. Mod Pathol 2006;19:
264–271.
15. Loose JH, Patchefsky AS, Hollander IJ, et al. Adenomyoepithelioma of the breast: a spectrum of biologic behavior. Am J Surg Pathol 1992;16:868–876.
16. Maiorano E, Ricco R,Virgintino D, et al. Infiltrating myoepithelioma of the breast. Appl Immunohistochem 1994;2:130–136.
17. McLaren BK, Smith J, Schuyler PA, et al. Adenomyoepithelioma:
clinical, histologic, and immunohistologic evaluation of a series of related lesions. Am J Surg Pathol 2005;29:1294–1299.
18. Nakajima T, Shimooka H, Weixa P, et al. Immunohistochemical demonstration of 14-3-3 sigma protein in normal human tissues and lung cancers, and the preponderance of its strong expression in epithelial cells of squamous cell lineage. Pathol Int 2003;53:353–360.
19. Pia-Foschini M, Reis-Filho JS, Eusebi V, Lakhani SR. Salivary gland- like tumours of the breast: surgical and molecular pathology. J Clin Pathol 2003;56:497–506.
20. Popnikolov NK, Cavone SM, Schultz PM, Garcia FU. Diagnostic util- ity of p75 neurotrophin receptor as a marker of breast myoepithelial cells. Mod Pathol 2005;18:1535–1541.
21. Rasbridge Sa, Millis RR. Adenomyoepithelioma of the breast with malignant features. Virchows Arch (A) 1998;432(2):123–130.
22. Reis-Filho JS, Steele D, Di Palma S, et al. Distribution and signifi- cance of nerve growth factor receptor (NGFR/p75(NTR)) in nor- mal, benign and malignant breast tissue. Mod Pathol 2006;19:
307–319.
23. Seifert G. Are adenomyoepithelioma of the breast and epithelial- myoepithelial carcinoma of the salivary glands identical tumors?
Virchows Arch 1998;433:285–288.
24. Simpson PT, Gale T, Reis-Filho JS, et al. Distribution and signifi- cance of 14-3-3 sigma, a novel myoepithelial marker, in normal, be- nign, and malignant breast tissue. J Pathol 2004;202:274–285.
25. Simpson RH, Cope N, Skalova A, et al. Malignant adenomyoepithe- lioma of the breast with mixed osteogenic, spindle cell, and carcino- matous differentiation. Am J Surg Pathol 1998;22:631–636.
26. Tavassoli FA. Myoepithelial lesions of the breast. Myoepitheliosis, adenomyoepithelioma, and myoepithelial carcinoma. Am J Surg Pathol 1991;15:554–568.
27. Weidner N, Levine JD. Spindle-cell adenomyoepithelioma of the breast. A microscopic, ultrastructural, and immunohistochemical study. Cancer 1988;62:1561–1567.
28. Zarbo RJ, Oberman HA. Cellular adenomyoepithelioma of the breast. Am J Surg Pathol 1983;7:863–870.
15.6 Sarcomatoid Carcinoma with Myoepithelial Differentiation (Myoepithelial Carcinoma, Malignant Myoepithelioma)
15.6.1 Definition
A malignant epithelial spindle cell tumor with immunoprofile of myoepithelial cells (myoepithelial differentiation).
15.6.2 Macroscopy
A solitary firm to rubbery greyish-white tumor, often with irreg- ular and infiltrating margins.
15.6.3 Microscopic Features (Figs. 69–73)
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The tumor is composed almost entirely of interlacing spin- dled cells without a glandular component. The hallmark of the tumor is a sarcomatoid appearance.
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A storiform pattern is often present.
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Significant nuclear atypia and numerous mitotic figures are often readily present .
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Rarely, the tumor cells appear very bland (low-grade carcino- ma).
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Giant tumor cells with bizarre hyperchromatic nuclei may be present.
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Infiltration of the surrounding normal breast tissue is com- mon.
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Aggregates of collagen and prominent central hyalinization may be present.
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Refer also to the section on metaplastic carcinoma.
Caution
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The differential diagnosis includes sarcomatous overgrowth in a phylloides tumor; mammary sarcoma, NOS type; spindle cell variant of squamous cell (metaplastic) carcinoma; fibro- matosis; and myofibroblastic neoplasms.
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Carcinoma with myoepithelial differentiation can easily be mistaken for sarcoma. Primary mammary sarcoma without association with high-grade phylloides tumors are, however, extremely rare and should be diagnosed very cautiously;
immunohistochemistry for a variety of cytokeratins and myoepithelial markers is often necessary to identify or ex- clude a carcinoma with myoepithelial differentiation.
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Occasionally, spindle cell carcinomas with myoepithelial cell differentiation reveal very bland-looking nuclei and no increased mitotic activity. These features can easily be misin- terpreted as reactive stromal changes.
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Carcinoma with myoepithelial differentiation (myoepithelial carcinoma) usually show at least a focal positive immunoreac- tivity for basal-type cytokeratins such as CK5/6, CK34BE12, CK14, or CK17 (carcinoma with basal-like differentiation). A myoepithelial differentiation can be recognized after per- formance of immunohistochemistry for SM actin, p63, CD10, or CD29. Two more recently introduced myoepithelial mark- ers include 14-3-3 sigma and p75 neurotrophin receptor (nerve growth factor receptor, NGFR/p75), which are fre- quently positive in tumors with myoepithelial differentiation.
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15.6.4 Additional Comments
Sarcomatoid carcinoma of the breast with myoepithelial differ- entiation has also been designated myoepithelial carcinoma or malignant myoepithelioma. Based on the morphology, immuno- histochemistry, and ultrastructural features, a myoepithelial ori- gin of the tumorous spindle cells has been suggested. While a myoepithelial differentiation can be observed in the vast majori- ty of such cases, a myoepithelial origin of tumor cells cannot be proved in most cases and currently remains a matter of specula- tion [6]. The designation of sarcomatoid carcinoma with myo- epithelial differentiation therefore seems -more appropriate.
Spindle cell squamous (metaplastic) breast carcinoma typi- cally shows a positive immunoreaction for basal-type cytoker- atins and p63 but is negative for actin and CD10 [1, 2, 5, 6, 7a, 8–10].
Like other myoepithelial markers, 14-3-3 sigma protein is not specific for myoepithelial cells [7b]. In normal human tissues, the strongest immunoreactivity for 14-3-3 sigma protein is ob- served in squamous epithelial cells at various sites, followed by basal and myoepithelial cells of various glands.
15.6.5 Further Reading
1. Adem C, Reynolds C, Adlakha H, et al. Wide spectrum screening keratin as a marker of metaplastic spindle cell carcinoma of the breast: an immunohistochemical study of 24 patients. Histopathol- ogy 2002;40:556–562.
2. Carter MR, Hornick JL, Lester S, Fletcher CDM. Spindle cell (sarco- matoid) carcinoma of the breast. A clinicopathologic and immuno- histochemical analysis of 29 cases. Am J Surg Pathol 2006;30:
300–309.
3. Dunne B, Lee AH, Pinder SE, et al. An immunohistochemical study of metaplastic spindle cell carcinoma, phyllodes tumor and fibro- matosis of the breast. Hum Pathol 2003;34:1009–1015.
4. Khan HN, Wyld L, Dunne B, et al. Spindle cell carcinoma of the breast: a case series of a rare histological subtypes. Eur J Surg Oncol.
2003;29:600–603.
5. Kurian KM, Al-Nafussi A. Sarcomatoid/metaplastic carcinoma of the breast: a clinicopathological study of 12 cases. Histopathology 2002;40:58–64.
6. Leibl S, Gogg-Kamerer M, Sommersacher A, et al. Metaplastic breast carcinomas: are they of myoepithelial differentiation? Immunohis- tochemical profile of the sarcomatoid subtype using novel myo- epithelial markers. Am J Surg Pathol 2005;29:347–353.
7a. Leibl S, Moinfar F. Mammary NOS-type sarcoma with CD10 expres- sion: a rare entity with features of myoepithelial differentiation. Am J Surg Pathol 2006;30:450–456.
7b. Mhawech P, Greloz V, Assaly M, Hermann F. Immunohistochemical expression of 14-3-3 sigma protein in human urological and gyne- cological tumors using a multi-tumor microarray analysis. Pathol Int 2005;55:77–82.
8. Popnikolov NK, Cavone SM, Schultz PM, Garcia FU. Diagnostic util- ity of p75 neurotrophin receptor (p75NTR) as a marker of breast myoepithelial cells. Mod Pathol 2005;18:1535–1541.
9. Reis-Filho JS, Milanezi F, Paredes J, et al. Novel and classic myoep- ithelial/stem cell markers in metaplastic carcinomas of the breast.
Appl Immunohistochem Mol Morphol 2003;11:1.8.
10. Reis-Filho JS, Steele D, Di Palma S, et al. Distribution and signifi- cance of nerve growth factor receptor (NGFR/p75NTR) in normal, benign and malignant breast tissue. Mod Pathol 2006;19:307–319.
11. Sneige N, Yaziji H, Mandavilli SR, et al. Low-grade (fibromatosis- like) spindle cell carcinoma of the breast. Am J Surg Pathol 2001;25:
1009–1016.
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Fig. 98: Myoepithelial cell alterations including hypertrophy, myoid hypertrophy, and atypia Figs. 98.1, 98.2, and 98.3: Lobules with myoepithe- lial cell hypertrophy showing a prominent myo- epithelial cell layer characterized by enlargement of cells with abundant cytoplasm. Even at low magni- fication, a distinct cell population of basally located cells is present surrounding luminal epithelial cells.
Figs. 98.4, and 98.5: Sometimes myoepithelial cells may show a myoid look; spindle shaped cells with deep eosinophilic, fibrillar cytoplasm (myoid differ- entiation).
Figs. 98.6, 98.7, and 98.8: In rare cases, myoepithe- lial cell hypertrophy may be associated with signifi- cant cytologic atypia characterized by enlarged hy- perchromatic nuclei, irregular nuclear membrane, and prominent nucleoli. However, the significance of myoepithelial cell atypia is unclear.
Fig. 98: Final remarks
●
By definition, hypertrophy should be distin-
guished from hyperplasia of myoepithelial
cells. In hypertrophy, there is only one layer of
enlarged myoepithelial cells with abundant
cytoplasm. Myoepithelial hyperplasia or myo-
epitheliosis is characterized by a numerical
increase of myoepithelial cells with or without
enlargement of such individual cells.
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Fig. 99: Adenomyoepithelioma.
Case history: A 66-year-old woman presented with a solitary and centrally located firm tumor in her right breast. The excisional biopsy showed a well- delineated, multilobulated, greyish-white tumor with firm to rubbery consistency. The tumor meas- ured 2.9 cm in greatest diameter.
Figs. 99.1 and 99.2: The tumor is predominantly sharply delineated, revealing a lobulated growth pattern.
Figs. 99.3 and 99.4: Focally, the tumor shows an infiltrative growth pattern with irregular nests of tumor cells with clear cytoplasm.
Fig. 99.5: In addition to solid nests of tumor cells, several areas of the tumor display a tubular growth pattern with easily identifiable luminal epithelial and basally located myoepithelial cells. Note the clear cell change of the myoepithelial cells.
Fig. 99.6: Areas of the tumor showing elongated tubules and aggregates of myoepithelial cells with abundant clear cytoplasm. There is no cytologic atypia or increased mitotic activity.
Fig. 99.7: Immunohistochemistry for smooth mus- cle actin demonstrates a prominent myoepithelial cell component of this tumor. Note the lobulated growth pattern of the tumor.
Fig. 99.8: Higher magnification of immunoreac- tion for smooth muscle actin shows positive my- oepithelial cells and negative luminal epithelial cells. Several other myoepithelial markers such as smooth muscle myosin (heavy-chain), calponin, p63, and CD10 were also positive in this tumor (not shown).
Fig. 99: Final remarks
●
The focal presence of infiltrative growth pat-
tern in an adenomyoepithelioma in the ab-
sence of significant cytologic atypia and/or
increased mitotic activity (more than three mi-
toses per 10 hpf ) can be ignored and should
not lead to the diagnosis of atypical adeno-
myoepithelioma or adenomyoepithelial carci-
noma.
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Myoepithelial Lesions/Neoplasms
