Myoepithelial cells in pathology

Abstract

Myoepithelial cells are a normal constituent of the salivary acini and ducts and are found between the epithelial cells and the basement membrane. Microscopically myoepithelial cells are thin and spindle-shaped and ultrastructurally they possess a number of Cytoplasmic processes that extend between and over the acinar and ductal-lining cells, and they show features of both smooth muscle and epithelium. They play a vital role during expulsion of saliva and regulates the electrolytic exchange. They also perform as tumor suppressors and are considered to play a very important role in differentiation of various salivary gland tumors and help in the diagnosis of tumors. Neoplastic myoepithelial cells in both benign and malignant tumors can take numerous forms including epithelioid, plasmacytoid, spindle and clear cell variant, and this variability largely accounts for difficulties in histopathological diagnosis.

Myoepithelial cells are usually found in glandular epithelium as a thin layer above the basement membrane but normally beneath the luminal cells. They are present in the sweat glands, mammary glands, lacrimal glands and in salivary glands. Myoepithelial cells are stellate-shaped and also known as basket cells. Every cell consists of a cell body from which four to eight processes branch out and embrace the secretory unit.[1]

Myoepithelial cells have been described in the salivary glands, lacrimal glands, mammary glands, prostate gland and in the sweat glands.[2]

The term myoepithelial cell was first used by Renault in 1897 in the parotid gland, myoepithelial cells were first described by Zimmermann in 1898.[3]

Myoepithelial cells are flat cells with 4–8 processes that embrace the glandular end pieces and ducts.[4]

Role of Myoepithelial Cells

During embryonic development, they are involved in branching morphogenesis of developing salivary gland and promotion of epithelial cell differentiation. Myoepithelial cells are responsible for extracellular matrix synthesis, chiefly basement membrane materials. It contracts when the gland is stimulated to secrete, compressing the underlying parenchymal cells, thus aiding in the expulsion of saliva and preventing damage to the other cells. Intermediary location between luminal and stroma cells plays an essential role and regulates electrolyte exchange.[5]

Recent studies show that myoepithelial cells have a tumor suppressor role as they exert a paracrine anti-invasive role by promoting epithelial differentiation, synthesis of basement membrane secreting proteinase inhibitors, and inhibiting angiogenesis.[5,6]

Definition

The cells, which have the appearance of smooth muscle cells, but are developed from ectoderm, are called “myoepithelial cells.” Thus they may be recognized by the presence of myofilament proteins that are related to those of smooth muscle, desmosomal attachments are dark bodies, in conjugation with intermediate filaments that contain cytokeratin which express their affinity with epithelia.[7]

Functions of Myoepithelial Cells

• Give support for the secretory cell

• Prevent over distention, as secretory products accumulate within the cytoplasm of secretory unit

• Contract and expand the diameter of the intercalated ducts, thus reflects the outflow

• Help in the rupture of acinar cells packed with mucous secretion

• Their contraction expresses the secretion and helping to propel it along the glandular ducts

• By good value of their position, sandwiched between the glandular epithelial cells and Stroma containing the blood vessels, they may have a role in the transport process and or control of glandular metabolism

• They also produce a lot of the basement membrane material

• They synthesize a growth factor that maintains glandular epithelium health and supports its growth, according to Garrett and Emerlin

• Help salivary flow to overcome the increase in peripheral resistance.[8]

Its contractile function helps to expel secretions from the Lumina of the secretory units and ducts.

Supporting functions are:

• The structure of myoepithelial cell is similar to that of smooth muscle

• Immunofluorescent studies indicate the presence of actin, myosin and related proteins in myoepithelial cells

• Measurements of ductal pressure after appropriate stimulation suggest a contractile process.[8]

Ultrastructure of Myoepithelial Cells

Electron microscopically myoepithelial cells shows processes filled with longitudinally oriented fine filaments about 4–6 nm thick. A small, dense body, which forms a cytoskeleton network in association with 10 nm diameter filaments, is present between the filaments. Cytoplasmic organelles are perinuclear, and the plasma membrane is parallel to the basement membrane of parenchymal cells. Micropinocytic vesicles are present on the surface facing secretory cells.[1]

Various Forms of Myoepithelial Cells

Myoepithelial cells (ME) cell can differentiate and form different morphological cell types.

• Angulate/basaloid cells: Small hyperchromatic nuclei with faint eosinophilic cytoplasm

• Epitheloid cells: Polygonal cell with vesicular nuclei and ample cytoplasm

• Clear cells: Contains clear cytoplasm due to glycogen

• Spindle cells: Elongated, fusiform with pale cytoplasm

• Plasmacytoid (hyaline cells): Bright eosinophilic cytoplasm with eccentric nuclei.

These various forms are helpful in diagnosing salivary gland tumors. A single salivary gland tumor can have different forms of myoepithelial cells. The cell types can undergo metaplasia such as chondroid, squamous or oncocytic.[5,6,9]

Identification of Myoepithelial Cells

Myoepithelial cell identification and detection is an important connection with the study of salivary gland tumors. Myoepithelial cells can be recognized by light microscopy through enzyme histochemistry and special stains and immunohistochemistry for their myofibrils.

Stains used for ME cell identification:[10,11]

• H and E stain (only nucleus is visible)

• Phosphotungstic acid hematoxylin

• Iron hematoxylin

• Levanol fast cyanine (Coomassie Blue)

• Silver impregnation method

• Immunoperoxidase stain.

Markers for Myoepithelial Cells

Because of their varied growth pattern of salivary glands pathologies can often be misdiagnosed and result in misinterpretation. To avoid this situation, it requires not only knowledge with the spectrum of histopathology but also interest to the diagnostic criteria for various salivary gland pathologies.[12] Biologic markers of malignant disease play a growing role in cancer diagnosis and treatment.[13]

S-100 protein

Toto. et al. First identified as a neurogenic cell-associated protein, but it also has been found in myoepithelial cells of normal salivary glands and pleomorphic adenoma, possibly in relation to the filamentous component in the myoepithelial cells.[14,15]

Keratin

The recognition of keratin in the myoepitheliomas is consistent with an ectodermal origin and its stronger localization in the perinuclear area and in the cell membrane area appears consistent with the distribution of tonofilaments and desmosomes. Cytokeratin 4–6 and cytokeratin 14 identify myoepithelium in the normal gland.[12]

Prekeratin and vimentin

Seifort reported the presence of both prekeratin and vimentin in the spindle cells of pleomorphic adenoma. Vimentin, an intermediate filament is found in cells of mesenchymal origin and neuroectodermal origin. It is closely related to the myofilaments and cell adhesions. This suggests that myoepithelial cells in pleomorphic adenoma and myoepitheliomas may be capable of expressing both ectodermal and mesenchymal cytoskeletal filaments during neoplastic transformation.

Fibronectin and laminin

Two types of glycoprotein are identified in the extracellular matrix in the epithelial cells. They are also found in the cytoplasm and the cell membranes of the myoepithelial cells in the myoepitheliomas. Fibronectin is also present in the myxoid and microcystic areas of the myoepitheliomas.

Elastin

Appears globular as well as diffusely spread in the myoepitheliomas especially between the plasmacytoid cells and in myxoid cells.

Muscle-specific Actin and Myosin, Glial Fibrillary Acidic Protein

Muscle-specific actin, cytokeratin 14, vimentin and glial fibrillary acidic protein are diagnostic markers of neoplastic myoepithelial cells.[15]

p63

p63 is essential for epithelial cell survival and may function as an oncogene. In normal salivary glands, p63 was expressed in the nuclei of myoepithelial and basal duct cells.[16]

Myoepithelial Cells in Salivary Gland Tumors

Non neoplastic myoepithelial cell proliferation

Much research on salivary gland myoepithelial proliferations is focused on neoplasms, and very little is subsequently known of myoepithelial participation in neoplastic conditions. Emmelin et al. found architectural changes disturbing myoepithelial cells of the parotid and submandibular glands of cats after ductal ligation. Processes of myoepithelial cells protruded into the interstitial places, giving rise to bizarre appearances.[17,18]

Neoplastic myoepithelial cell proliferation

Basal cell adenoma

Basal cell adenoma was first described by Kleisasser and Klein in 1967. This tumor is considered as monomorphic due to lack of myxochondroid component. It can be differentiated from pleomorphic adenoma by lack of myoepithelial differentiation. Presence of hyalinized matrix in basal cell adenoma gives an evidence of myoepithelial cell contribution.[17,19]

Pleomorphic adenoma

Myoepithelial cells are primary proliferating cells in Pleomorphic adenoma. The myoepithelial cell differentiation is major in these tumors and responsible for various “mesenchymal” components and their morphological variety.[18,19]

Adenoid cystic carcinoma

Epithelial and myoepithelial differentiation in adenoid cystic carcinoma is evident in three patterns: Solid, cribriform and tubular. Myoepithelial cells are present as small basaloid/angulate cells in periductal location or in cribriform structures. Solid variant display scattered or peripheral basaloid myoepithelial cells in small nests/sheets.[20]

Epithelial myoepithelial carcinoma

Clear myoepithelial cells cuffed the epithelial tubules. Biomorphic epithelial myoepithelial carcinomas are similar to ACC in their staining of outer clear cells with myoepithelial markers in conjunction with vimentin/cytokeratins.[21]

Mucoepidermoid carcinoma

Dardick et al. reported that the myoepithelial cell has an ordered pattern connecting luminal epithelial cells surrounded by intermediate cells that are considered to be modified myoepithelial cells. Some researchers believe that this neoplasm originates from the reserve duct cell either excretory or intercalated duct. Fewer others believe that myoepithelial cells have a role in the histogenesis.[18,21,22]

Polymorphous low-grade adenocarcinoma

Immunohistochemical and ultrastructural studies in favors or against myoepithelial contribution have been reported. Focal staining with smooth muscle markers has been detected in this lesion. There is said to be significant myoepithelial differentiation denoted by the presence of analogous histological pattern as in the myoepitheliomatous zone of pleomorphic adenoma and adenoid cystic carcinoma.[18,21,23]

Conclusions

The neoplastic myoepithelial cells are considered to be a key cellular participant in the morphogenetic process responsible for different histological appearances of salivary gland tumors. It has a key role in the genesis of these tumors, being capable of dedifferentiation, metaplasia and transdifferentiation. Understanding the myoepithelial cells has thus important implications for helpful diagnostic problems and improving the classification of salivary gland tumors.