Myoepithelioma Pathology

Myoepithelioma is a benign salivary gland tumor that consists entirely of myoepithelial cells with variable cellular morphologies including spindle, epithelioid, plasmacytoid, or clear cells. It was recognized as a histologically distinct entity by the World Health Organization (WHO) in 1991.[1]

A myoepithelioma can be composed of one or a mixture of the above cell types, and a variable stromal component can be seen in these tumors. Among investigators, the level of "tolerance" for the presence of epithelial ductal elements in a myoepithelioma is variable and controversial (see Microscopic Findings). To date, a few hundred cases have been reported.

Myoepithelial cells are seen in many secretory organs including salivary glands, where they are usually encountered in the acini and intercalated ducts (see the image below). These cells express a dual epithelial and smooth muscle phenotype and are likely of ectodermal origin.[2, 3] Their neoplastic biologic behavior in many salivary gland tumors, unpredictable at times, has been and is still being characterized either as a major component of myoepithelial entities or as one of the components of many salivary gland tumors (eg, pleomorphic adenoma, adenoid cystic carcinomas).

Some authors believe that myoepitheliomas are a monomorphic, single-cell type variant of pleomorphic adenomas (in this case, myoepithelial cells).[3, 4] Other authors, very convincingly, describe a spectrum of salivary gland tumors with monomorphic adenomas (composed of pure epithelial cells; eg, canalicular adenoma) at one end, and myoepitheliomas (composed of myoepithelial cells only) at the other end—with pleomorphic adenomas offering a diverse range of mixture of cells and stroma in between.[2, 5, 6, 7]

In 1943, Sheldon was the first to identify myoepithelial tumors as a distinct salivary gland tumor entity.[8] Following Sheldon's reference, earlier series included those of Bauer and Fox as well as Bhaskar and Weinmann.[9, 10] The major myoepithelial neoplastic entities in which myoepithelial cells are the exclusive tumor component or a major neoplastic component include the following:

• Myoepithelioma

• Myoepithelial carcinoma (discussed in a separate article)

• Epithelial-myoepithelial carcinoma

• Myoepithelial-rich pleomorphic adenoma

Myoepitheliomas are also known as myoepithelial adenoma or benign myoepithelial tumors.

No clear etiologic factor has been identified for myoepitheliomas.

Myoepitheliomas are unusual and uncommon tumors that constitute only 1-1.5% of all salivary gland neoplasms.[4, 5, 11, 12, 13] Equal sex distribution is seen in most case series[4, 11, 14] ; however, analysis of 15 cases arising in the minor salivary glands of the palate showed a 2:1 female preponderance.[15] The average age of tumor incidence in affected individuals is 44 years, with a wide range from 9 to 85 years.[11, 16] Although myoepitheliomas have been reported in children, this tends to be a rare occurrence.[17]

Although myoepitheliomas have been reported in all major and most locations containing the minor salivary glands,[18, 19] the parotid gland is the primary site of occurrence of most reported tumors (40-50%),[5, 11] followed by the minor salivary glands as the second most preferred site (of which the palate is the most common location [21%]).[4, 11, 12, 14] The submandibular gland accounts for 10% of the tumors. A case of tongue-base involvement has been published,[20] as have rare cases of intraosseous tumors.[21, 22]

Myoepitheliomas present as a slowly growing, painless tumor mass. No cases in the parotid have been reported to be accompanied by facial nerve weakness, and those occurring in the palate rarely ulcerate.[23] As the tumor has been reported in variable head and neck locations, the symptoms will vary accordingly.

Gross findings

Myoepitheliomas are well-circumscribed, gray-white/tan/yellow, solid masses (average, 3-5 cm) with a smooth outline.[4, 14, 24] Degenerative changes are usually not a feature.

Microscopic findings

A myoepithelioma is composed exclusively of modified myoepithelial cells in which the normal phenotypic expression of the non-neoplastic myoepithelial cells has been altered (see the image below).[16]

Tumors arising in the parotid gland are usually encapsulated, in contrast to those arising in other major glands (submandibular and sublingual) or the minor salivary glands, which tend to lack a capsule or only have a partial capsule but are invariably well circumscribed.

Myoepithelial cell morphologies

Myoepithelial cells exhibit four main cell morphologies: spindle (most common), epithelioid, plasmacytoid, and clear cells (least common). A mixture of these subtypes may be present in one tumor. A relatively new variant exhibiting mucin containing cells has also been described.[25, 26]

Spindle cell myoepitheliomas have central fusiform/cigar-shaped nuclei, eosinophilic cytoplasm, and tapered ends, and they are usually arranged in interlacing fascicles (see the following image).

Epithelioid cell myoepitheliomas have large polygonal cells with central nuclei, and eosinophilic or amphophilic, sometimes focally clearing, cytoplasm. Although epithelioid cells can form pseudoacini/pseudoglandular structures, true glands or lumina are not seen (see the image below).[27]

Plasmacytoid cell myoepitheliomas have round to ovoid cells with abundant eosinophilic cytoplasm and eccentrically located nuclei (see the following image). The cells tend to be discohesive and occur mainly in aggregates in abundant mucoid stroma.

The plasmacytoid cell type is particularly encountered in palatal myoepitheliomas and has been the subject of some controversy that is largely due to its low level or complete absence of of expression of myogenic markers. Some authors have doubted their identification as myoepitheliomas,[28, 29] even suggesting that these tumors should be classified as adenomas or plasmacytoid adenocarcinomas. Other authors believe that the low expression of muscle tissue markers should still qualify them as myoepitheliomas[30] and that plasmacytoid cells may represent, with the other morphologic myoepithelial cell types, different stages of evolution in myoepitheliomas.[31]

Electron microscopic evidence suggests a myoepithelial origin for these cells (see the "Electron microscopy examination" section, below). Extracellular collagenous crystalloids can be seen in 10-20% of the plasmacytoid variant; these structures are approximately 50 to 100 µm in diameter and consist of radially arranged needle-shaped fibers composed of collagen types I and III, which stain red with the van Gieson method.[32]

Clear cell myoepitheliomas, the rarest type, have polygonal cells with clear cytoplasm (due to glycogen content) (see the following image). Sometimes the clear cells can exhibit a signet ringlike or lipoblastlike appearance.[27] Microcystic spaces containing amorphous material can be seen in clear cell myoepitheliomas, however, these features are also seen, albeit less frequently, with other cell types. When considering the diagnosis of clear cell myoepithelioma, it is important to remember that many salivary gland tumors and metastatic tumors to the salivary glands can exhibit clear cell morphology. A case of clear cell, giant myoepithelioma of a tongue base has been reported; histophathologic findings from a specimen obtained by coblator-assisted excision revealed cuboidal cell nests with abundant clear cyoplasm.[20] Immunohistochemistry was positive for p63.

Foci of oncocytic differentiation/metaplasia may also be seen in clear cell myoepitheliomas; on occasion, these features can predominate in the tumor.[33] Occasionally, the oncocytic nuclear pleomorphism, enlargement, and hyperchromasia can be concerning, but these have not been found to necessarily correlate with malignant change.

Gnepp encountered an unusual variant of benign and malignant myoepitheliomas containing intracellular mucin, or "mucinous myoepitheliomas," in three cases in 2013 and reviewed 17 previously reported literature cases; 13 arose in minor salivary glands (mostly the palate).[25] Four were classified as benign myoepitheliomas and 13 as malignant myoepitheliomas (usually showing low-grade malignancy). The tumors showed mucin containing cells with signet cell morphology (Alcian blue and mucicarmine positive) and variable positive staining for myoepithelial markers.[25] Skalova et al also reviewed this entity and defined it as a "myoepithelial tumor with foci of prominent cytoplasmic clearing frequently containing intracellular mucin material and having signet-ring morphology."[34]

Architectural patterns

Different architectural patterns including trabecular, nested, or solid may be seen. Dardick et al  described an unusual reticular pattern variant in which narrow, interconnected cords of tumor cells in a netlike fashion are surrounded by abundant mucoid stroma or loose vascularized stroma.[12, 35]

A myxoid (see the image below), mucoid, or hyalinized stroma may be seen among tumor cells that tends to be scant in hypercellular tumors. Although chondromyxoid stromas, typically seen in pleomorphic adenomas, are not usually observed in myoepitheliomas, chondroid metaplasia has been reported in some cases of myoepithelioma and myoepithelial carcinoma, in addition to squamous, adipocytic, and osseous metaplasia.[2, 16, 27, 30]

Cystic change has been reported in myoepitheliomas.[36, 37]

Myoepitheliomas versus pleomorphic adenomas

At times, the morphologic similarity between pleomorphic adenoma and myoepithelioma can make the differentiation between them difficult (eg, myoepithelial-rich pleomorphic adenoma versus myoepithelioma). The differentiation, however, is based on the total absence of ductal elements. Although some authors allow 5-10% of ductal differentiation within myoepitheliomas,[5, 14, 38] other investigators favor the total absence of ductal elements as a prerequisite for the diagnosis of myoepithelioma.[27, 39]

Many authors believe the behavior of myoepitheliomas and pleomorphic adenomas are similar,[5] although some authors contend that myoepitheliomas tend to exhibit a more aggressive growth pattern and a less predictable biologic behavior on long-term follow-up. Different cell types have not been found to relate to differences in a patient's age, biologic behavior, frequency of recurrence, or prognosis[4, 24, 38] ; however, other investigators argue that the clear cell variant may be more prognostically unpredictable than the other variants.[40]

It is important to point out that some myoepithelial carcinomas can present with a very bland cell morphology that may defy the clinical impression of malignancy and make identifying a myoepithelial carcinoma a difficult task histologically, particularly on limited biopsies. Observation of the infiltrative pattern, focal necrosis, and perineural invasion among other malignant indices may be the only clue to malignant change in a seemingly bland myoepithelioma,[41] a task that may only be possible on careful evaluation of the resected tumor.

Electron microscopy examination

Ultrastructurally, the myoepithelial cells contain abundant cytoplasmic filaments/fibrils, duplicity of basement membrane, perinuclear tonofilament bundles, attachment plaques on the cell membrane, and desmosome-type intercellular junctions.[4, 42, 43, 44, 45]

Interestingly, examination of the plasmacytoid cell types by electron microscopy in many studies showed the same fibrillar type as the spindle cell type; however, the fibrils in the plasmacytoid cell types were more disorganized[4] and did not exhibit focal densities as seen in spindle cells. In all other ways, however, there was homology of the ultrastructure of both cell types.

Cutaneous and soft-tissue myoepitheliomas rarely occur in the head and neck region[30, 39, 46] as well as in the lacrimal gland region[47] and should be differentiated from those of salivary gland origin. Soft-tissue myoepitheliomas are cytomorphologically similar by fine-needle aspiration biopsy to their salivary gland counterparts.[48]  Because soft-tissue myoepitheliomas can be misidentified mainly as extraskeletal myxoid chondrosarcoma, relatively broad immunohistochemical testing is needed for a specific diagnosis.[48]

In an series of 35 cases of cutaneous myoepitheliomas, Plaza et al found most had a noninfiltrative and nonencapsulated tumor solely in the dermis without subcutaneous involvement.[49] The majority of the tumors had a solid growth pattern (syncytial pattern), followed by a multindular growth pattern.

Myoepithelioma cells have been shown to be usually positive for the following markers:

• Cytokeratins (eg, AE1/AE3, CK 5/6, Cam 5.2, CK-7, and CK-14)

• Vimentin (reported to be positive in neoplastic myoepithelial cells and negative in normal myoepithelial cells)

As neoplastic transformation of myoepithelial cells can result in loss or modification of their smooth muscle phenotype,[16] variable positivity[28, 30, 50] for the following is seen:

• S-100 (usually positive in the neoplastic myoepithelial cells but not the normal salivary gland myoepithelial cells)

• Calponin (the most sensitive myogenic marker[51, 52] )

• Smooth muscle actin (SMA)

• Muscle-specific actin (MSA)

• Smooth muscle myosin

• P63 protein

• Glial fibrillary acidic protein (GFAP)

• Myoepithelioma shows frequent expression of SOX10 (80%), although SOX10 positivity is seen in only a third of myoepithelial carcinomas.[53]

Myoepithelial cells are typically negative for carcinoembryonic antigen (CEA), signifying no tubular differentiation. E-cadherin expression has also been detected in myoepitheliomas.[54]

Many investigators have found that cells with spindle cell morphology have the strongest immunoreactivity to smooth muscle markers, followed by the epithelioid cells, with the plasmacytoid and clear cells showing lesser if not absent activity on occasions.[39, 55] Neoplastic myoepithelium has been well established to not always retain actin expression.[38, 56]

Fortunately, many such confirmations can be resolved by using a combination of these markers. Usually, a combination of a keratin in conjunction with the detection of S-100, vimentin, and/or a myogenic marker is required for confirmation of the diagnosis of a myoepithelioma.

Plaza et al noted the following positive immunohistochemical findings in their series of 35 cases of cutaneous myoepitheliomas[49] :

• S100: 88% of cases
• Epithelial membrane antigen (EMA): 59% of cases
• AE1/AE3: 44% of cases
• GFAP: 36% of cases
• Calponin: 22% of cases
• p63: 17% of cases
• CAM 5.2: 16% of cases

An additional five cases showed only S100 expression.[49]

Note that some differences have been found in the expression of some markers in salivary gland myoepitheliomas in contrast to soft-tissue myoepitheliomas.[39]

El-Naggar et al reported findings from their cytogenetic analysis of a parotid myoepithelioma in which there were alterations in chromosomes 1, 9, 12, and 13.[57] The investigators also showed that myoepitheliomas and pleomorphic adenomas share the chromosome 12q alteration reported in a subset of pleomorphic adenomas.[57]

Hungermann et al noted the paucity of genetic alterations in 12 myoepithelioma cases, in which only 3 cases showed chromosomal loss; these alterations preferentially involved chromosomes 2, 4, and 8.[58]

Weber et al detected mutations in p53 in 3 of 12 myoepitheliomas examined, with no mutations in p63 or p73 in the examined cases.[59] Vekony et al demonstrated that deregulation of the p16INK4a senescence pathway is involved in the development of myoepithelial tumors and that additional inactivation of p53 is seen in benign recurrences.[60]

Skalova et al examined the presence of the EWSR1 rearrangement in a variety of clear cell salivary gland carcinomas with myoepithelial differentiation.[61] The study described for the first time EWSR1 gene rearrangement in a subset of myoepithelial carcinomas arising in minor and major salivary glands. The EWSR1-rearranged clear cell myoepithelial carcinomas de novo (CCMC) represents a distinctive aggressive variant composed predominantly of clear cells with frequent necrosis. Most EWSR1-rearranged CCMCs of salivary glands are characterized by poor clinical outcomes.[61]

Yun et al published the case of a 36-year-old woman with an intraosseous myoepithelioma arising from the fourth metatarsal bone; next-generation cytogenetic sequencing identified a rare EWSR1-PBX3 fusion.[21]  EWSR1-PBX3 fusion by massively parallel next-generation RNA sequencing has also been described in a cutaneous syncytial myoepithelioma arising in a 44-year-old woman.[62]

According to Scibba and Brannon, when compared with pleomorphic adenomas, myoepitheliomas are less prone to recurrence after complete surgical resection[4] with only 1 recurrence in 16 cases observed over a period of 1 month to 7 years. However, other investigators have found higher recurrence rates.[14] Nayak et al found that of 42 previously reported myoepithelial tumors, 93% of them eventually followed a benign course, whereas only 7% eventually pursued a malignant course.[40]