Pleomorphic Adenoma

 Pleomorphic Adenoma:

Definition:

"Benign neoplasm characterized by dual cell type differentiation and melting of the outer basal/myoepithelial cells into a stroma showing chondromyxoid features.The coexistence of epithelial and mesenchymal elements gives rise to the synonym mixed tumor, but pleomorphic adenoma is now widely accepted as a monoclonal epithelial tumor with divergent differentiation"

                -Fletcher

"Mixed tumor is a benign, epithelial-derived tumor composed of cells that demonstrate both epithelial and mesenchymal differentiation. The epithelial differentiation manifests as well-formed ductal structures with closely associated nonductal cells that frequently include spindle, round, stellate, plasmacytoid, polygonal, and clear forms. The nonductal element demonstrates varying degrees of myxoid, hyaline, cartilaginous,or osseous differentiation. In the major salivary glands the tumors are usually encapsulated but in the minor glands they usually are not. The terms mixed tumor and pleomorphic adenoma are used synonymously; the former emphasizes the “mixture” of epithelial and mesenchymal elements while the latter denotes the considerable morphologic diversity that these adenomas exhibit."

            -Ellis

Pleomorphic adenoma is the commonest salivary gland tumor.Cytologic and histologic variations are innumerable.The only constant feature is the coordinated proliferation of luminal and non luminal cells (basal/myoepithelial cells)  and the tendency for the latter to predominate over the former.Neoplastic abluminal cells are described as "swarm of bees" enclosing the ductal structures.The connective tissue stroma is highly variable.

The term pleomorphic adenoma was suggested by Willis owing to the unusual histologic pattern of the lesion.

It constitutes 53-77%,44-68% and 33-43% of salivary gland tumors of parotid gland,submandibular gland and sublingual gland respectively

Synonyms:Mixed tumor,enclavoma,branchioma,endothelioma,endochondroma

Histogenesis:Myoepithelial cells and intercalated ductal reserve cells are believed to be responsible .

    Hubner and associates:Myoepithelial cells are responsible for morphologic diversity

    Regezi and Batsaki:Intercalated duct reserve cells differentiate into ductal and myoepithelial cells and later can undergo metaplasia 

    Batsaki:Role of myoepithelial cells is uncertain and that it may have either an active or passive participant histogenetically.

    Dardick and associates:Questioned the role of both ductal reserve and myoepithelial cells.They stated that neoplastically altered epithelial cell with potential for multidirectional differentiation might be responsible for pleomorphic adenoma

Clinical Features:

    Painless slow growing firm mass

    Can occur in any age but the mostly affects young and middle aged adults (30-60 years)

    Most common primary salivary gland tumor to develop during childhood

    Slight female predilection with F:M -6:4

    In parotid ,mostly affects the superficial lobe which presents as a swelling overlying the ramus infront of the ear

    Facial palsy and pain rare

    Initially,the tumor mass is mobile.As it progresses,it becomes less mobile.If neglected,it grows in grostheque proportion

    In 10% of the case,deep lobe is affected beneath the facial nerve

    Rarely,it can occur bilaterally growing in synchoronous or metachoronous way

    Amongst the minor salivary gland,palate is most frequently affected

Pathological Features

Macroscopic features:Irregular to ovoid mass with well defined border.; Either incomplete fibrous capsule or completely unencapsulated

    Cut surface:Rubbery,fleshy,mucoid ,glistening with homogenous tan/white color.Areas of hemorrhage and infarction are also seen

Microscopic features:   

Growth Pattern. Pleomorphic adenoma is thinly encapsulated . A few small, smooth-contoured buds (protuberances) may protrude through the fibrous capsule. Occasionally, tumor islands may appear outside the capsule at a short distance from the main tumor mass , but serial sectioning usually demonstrates that such satellites are in fact outgrowths continuous with the main tumor mass and should not be regarded as invasion. Pleomorphic adenoma can grow entirely within a dilated duct. Vascular invasion can be found in 1% to 3% of cases, but this is not associated with adverse outcome. Perineural invasion can also rarely occur, but its significance is currently unclear.Pleomorphic adenoma is characterized by highly variable growth patterns in different areas of the same tumor.

Basic Cellular Organization. The prototypic histologic appearance consists of tubular structures enveloped by myoepithelial mantles submerging in a chondromyxoid stroma. The interface between the tumor islands and the stroma is usually poorly demarcated. The myoepithelial mantle radiates centrifugally, forming sheets, clusters, lattices, and isolated cells, where they appear to melt into the sea of stroma they produce . While the melting phenomenon is characteristic, it can be focal, and some areas of the tumor can be composed of tubules or trabeculae well delineated from the stroma .

Foote and Frazell have categorized the neoplasm into

    1.Prinicipally myxoid

    2.Myxoid and cellular components present in equal proportion

    3.Predominantly cellular

    4.Extremely cellular

Luminal Cell Component. The luminal cell component takes the form of anastomosing tubules, cysts, ribbons, and solid sheets . The cells are columnar, cuboidal, or flat. The duct lumens may be empty or contain eosinophilic colloid-like material, which is PAS-positive diastase resistant and variably mucicarmine positive . Rarely, metaplastic change to squamous, sebaceous, oncocytic, or clear cells can occur . Very occasionally, the epithelium may form goblet or mucous cells, which in association with squamous epithelium

Myoepithelial Component.:Myoepithelial or modified myoepithelial cells appear as cuboidal, spindle, stellate, plasmacytoid hyaline, nondescript epithelioid, or hydropic clear cells . The spindle or cuboidal cells surround the ducts in a single layer, thick mantle, or radiating corona . They can form nondescript sheets, trabeculae, and even cribriform structures.

Plasmacytoid hyaline cells represent the most distinctive form of modified myoepithelial cells; they are oval shaped, with homogeneous eosinophilic hyaline cytoplasm . The nucleus is round and eccentrically located, with a tendency for peripheral margination of the dense chromatin. Plasmacytoid hyaline cells are so named because of their superficial resemblance to plasma cells, but they are larger, show less coarse clumping of the chromatin, lack a perinuclear Golgi zone, and possess eosinophilic rather than amphophilic cytoplasm. They are usually arranged in aggregates or sheets, often with focal areas of noncohesive growth . Since their occurrence is restricted to pleomorphic adenoma and myoepithelioma, their identification is of great diagnostic value, especially in small biopsies. There can be cells with morphologic features intermediate between plasmacytoid hyaline cells and other types of myoepithelial cells.Stellate or spindled myoepithelial cells occur singly or form anastomosing strands, suspended in an abundant myxoid matrix . Uncommonly, myoepithelial cells may merge into squamous nests or cystic squamous-lined structures filled with keratin, suggesting an ability to differentiate directly toward the squamous lineage . In occasional cases, myoepithelial cells dominate the tumor.

Stroma. Extracellular stroma is one of the defining components of pleomorphic adenoma, although its quantity can range from scanty to abundant. It is composed mostly of acidic mucosubstances produced by the modified myoepithelial cells, and is positive for Alcian blue but variably positive for PAS. The stroma takes the form of a mixture of chondroid (hyaline cartilage), myxoid, chondromyxoid, hyaline, and very rarely, osseous and adipose tissues . Of interest, adipocytic cell differentiation is uncommon except in cutaneous sites. Isolated or groups of stellate, oval or polygonal cells are suspended in the matrix. The presence of chondromyxoid stroma in a salivary gland tumor is practically pathognomonic of pleomorphic adenoma .Vacuolar degeneration of myoepithelial cells is responsible for cartilaginous appearance.  In tumors in which chondromyxoid matrix predominates, the sparse ductal structures are often confined to the subcapsular zone. Tumors with very scanty or no extracellular stroma are often called cellular pleomorphic adenomas ; they can be recognized by the focal melting of the myoepithelial mantles. It has been suggested that recurrence is more frequent for stroma-rich tumors, which have a higher chance of spillage of mucoid stroma during operation. Highly cellular tumors, on the other hand, may be more prone to malignant change.

Homogenous, fibrillary, or radiating hyaline material can be interspersed among the epithelial or myoepithelial cells . Crystalloids composed of collagenous substance, tyrosine, and oxalate are sometimes found between the cellular or stromal components. Tyrosine crystals often appear as daisy-heads in the myxoid stroma. Elastic fibers are present in variable amounts in most pleomorphic adenomas, and they are particularly abundant in longstanding lesions. They show up as globular masses or irregular bands with fluffy outlines on histochemical staining . These thick elastic fibers are diagnostically helpful because they are very uncommon in other salivary gland tumors.

Fine-Needle Aspiration–Associated Changes

    Fine-needle aspiration commonly results in hemorrhagic tracts and micronecrosis, accompanied by variable reparative changes 

     Complete or incomplete infarction can also occur 

     There can be florid reactive proliferation of the myoepithelium, which can protrude into the fibrous capsule or show nodular bulging beneath the endothelium of veins. 

    Atypical squamous metaplasia is also common

Genetic changes:

    t(3;8) or t(5;8) involving PLAG1(8q21)-Common

    t(3;12) involving HMGA2(12q14)-Uncommon

Immunohistochemistry:

Glandular component:EMA, CEA, or c-kit

Myoepithelial  component:CK14, p40/p63, and various myoid markers (such as actin, myosin, and calponin,S100,GFAP.

Differential Diagnosis:

1.Basal cell adenoma:

2.Myoepithelioma

3.Adenoid cystic carcinoma

4.Mucoepidermoid carcinoma

Treatment:

Parotidectomy preserving facial nerve