Pathology of Pleomorphic Adenoma 

Updated: Nov 05, 2015
  • Author: M Sherif Said, MD, PhD; Chief Editor: M Sherif Said, MD, PhD  more...
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Pleomorphic adenoma is a benign salivary gland tumor that exhibits wide cytomorphologic and architectural diversity. The tumor has the following 3 components:

  • An epithelial cell component

  • A myoepithelial cell component

  • A stromal (mesenchymal) component

Identification of these 3 components, which may vary quantitatively from one tumor to another, is essential to the recognition of pleomorphic adenoma. This tumor is also referred to as a benign mixed tumor.



Pleomorphic adenoma is the most common salivary gland tumor in both children and adults. In most series, it represents 45-75% of all salivary gland neoplasms [1, 2] ; the annual incidence is approximately 2-3.5 cases per 100,000 population. [3]

Pleomorphic adenoma occurs in individuals of all ages. However, it is most common in the third to sixth decades; the average age at presentation is between 43 and 46 years. [4] Pleomorphic adenoma is seen more often in females than in males (2:1 ratio).



Although the etiology of pleomorphic adenoma is unknown, the incidence of this tumor has been found to increase 15-20 years after exposure to radiation. [1] One study suggests that the simian virus (SV40) may play a causative role in the development of pleomorphic adenoma. [5]



Among the major salivary glands, the tail of the superficial lobe of the parotid salivary gland is the most common site of occurrence for pleomorphic adenoma (70-80% of cases), although this lesion can occur in any parotid location. [6] The tumor is less commonly seen in the submandibular salivary gland (10%) and is seldom encountered in the sublingual gland (1%). [7, 8]

With regard to the minor salivary glands (5-10% of cases), the palate (specifically, the junction of the soft and hard palates) and the lip are the most common sites for pleomorphic adenoma. Other sites of minor salivary gland involvement include the nose, the paranasal sinuses, and the larynx.

Rare or unusual sites of occurrence include ectopic salivary gland tissues (eg, in the mandible, neck lymph nodes, or axilla). A case has been reported of a pleomorphic adenoma presenting as a midline nodule in the isthmus of the thyroid in a 66-year-old man. [9]

Multiple tumors are unusual (1:40,000), but metachronous and synchronous tumors do occur. [10, 11, 12, 13] Synchronous occurrence of pleomorphic adenoma and Warthin tumor (the second most common benign salivary gland tumor) has been reported. [14, 15, 16, 17]


Clinical Features and Imaging

Pleomorphic adenoma usually presents as a slow-growing, painless mass, which may be present for many years. Symptoms and signs depend on the location. [8]

When the tumor occurs in the parotid gland, signs of facial nerve weakness are seldom encountered; however, if the tumor is large and has been neglected, facial nerve weakness is likely to arise as the result of malignant change. Pleomorphic adenoma in the deep lobe of the parotid gland may present as an oral retrotonsillar mass or parapharyngeal space tumor; indeed, tumors arising at this site are the source of the most common parapharyngeal space tumors. Rapid enlargement of a tumor nodule should raise concern about the development of malignant change.

Patients with minor salivary gland tumors may present with a variety of symptoms, depending on the site of the tumor; such symptoms include dysphagia, dyspnea, hoarseness, difficulty in chewing, and epistaxis.


Gross Findings

On gross examination, a pleomorphic adenoma is a single firm, mobile, well-circumscribed mass. Its color may vary from whitish-tan to gray to bluish, and its size may range from a few millimeters to quite large or even giant. [18, 19] Pleomorphic adenomas are irregularly shaped and have a bosselated surface.

Degenerative and cystic changes may be seen on sectioning. It is not unusual to observe evidence of focal or massive infarction. Recurrent tumors characteristically tend to present as multiple nodules of variable size.


Microscopic Findings

In the parotid gland, the tumor is usually surrounded by a fibrous capsule of variable thickness that may be focally deficient, especially in more mucoid tumors (see the image below). In minor salivary glands, no capsule is usually seen.

Capsule in pleomorphic adenoma. (A) Image shows pl Capsule in pleomorphic adenoma. (A) Image shows pleomorphic adenoma with thin fibrous capsule separating tumor from surrounding normal parotid gland tissue. (B) Image shows pleomorphic adenoma with less well developed focally absent capsule. Note small satellite tumor nodule (arrow) protruding outside major tumor mass.

Microscopic satellite tumor nodules, pseudopodia, and capsular penetration may be seen beyond the capsule (see the image below). This may be the cause of recurrence of pleomorphic adenomas in cases that were treated with simple enucleation or in cases in which surgical resection was performed with inadequate surgical margins. [20, 21, 22]

Recurrence of pleomorphic adenoma. Image shows rec Recurrence of pleomorphic adenoma. Image shows recurrent pleomorphic adenoma with 2 microscopically benign–appearing nodules. Multinodular tumor pattern is characteristic in recurrent pleomorphic adenomas.

The epithelial component consists of epithelial and myoepithelial cells with divergent growth patterns, including trabecular, tubular, solid, cystic, and papillary architecture.

Pure epithelial cells are mainly cuboidal. Cells that exhibit myoepithelial features [23, 24] may have plasmacytoid, epithelioid, spindle, oncocytic, or clear cell morphology.

In some studies, the most common myoepithelial cell type that was encountered displayed plasmacytoid cell morphology; the spindle cell type was the next most common type. [25] All cellular elements appear cytologically bland, with no significant mitotic activity.

The ducts and tubules seen in pleomorphic adenomas usually exhibit a lining comprising 2 cell types—that is, an inner cuboidal epithelial cell layer and an outer myoepithelial cell layer (or layers) tend to merge into the surrounding stromal component, which also contains dispersed or grouped modified myoepithelial cells (see the image below). The cuboidal epithelial cells occasionally have a clear cytoplasm; the myoepithelial cell cytoplasm ranges from deeply eosinophilic to clear.

Cells in pleomorphic adenoma. (A) Tubule/duct form Cells in pleomorphic adenoma. (A) Tubule/duct formations in pleomorphic adenoma. Well-defined inner epithelial lining, consisting of cuboidal cells with eosinophilic cytoplasm, which can focally be clear, is surrounded by collar of 1 or more layers of myoepithelial cells with mostly clear cytoplasm. Stroma in between contains dispersed spindled and epithelioid myoepithelial cells. (B) Similar tubular arrangement is seen, but collar of myoepithelial cells is not as well defined. Stroma in between shows dispersed spindled myoepithelial cells. In both A and B, note bland nature of cells and absence of atypia.

In a limited biopsy specimen or in fine-needle aspiration (FNA), the characteristics seen in the ductal or tubular elements may cause the pleomorphic adenoma to be confused with other salivary gland tumors that have a similar architecture, such as adenoid cystic carcinoma and epithelial-myoepithelial carcinoma. In some cases, the tubules or ducts have a less well-defined surrounding myoepithelial layer.

The stromal component is a product of the modified myoepithelial cells and may appear mucoid, myxoid, hyaline, chondroid, myxochondroid, or even osseous (see the image below). [26, 27] The stromal modified myoepithelial cell may undergo chondroid or osseous metaplasia. [28] Chondroid areas represent true cartilage formation (containing type II collagen and keratin sulfate); this finding tends to be specific to pleomorphic adenoma and thus helps differentiate pleomorphic adenoma from other suspected salivary gland tumors.

Different types of stroma in pleomorphic adenoma. Different types of stroma in pleomorphic adenoma. (A) Myxoid stroma. Note dispersed spindle myoepithelial cells in stroma, some of which have stellate morphology. (B) Chondroid stroma. (C) Stroma with cartilage formation. (D) Hyalinized stroma.

Some authors have found that a prominent hyalinized stroma is correlated with tumors that may have a propensity for malignant change. [29] It is important to note that exuberant hyalinization may also be observed in other salivary gland tumors, especially adenoid cystic carcinoma.

When the cellular elements predominate, the result is an epithelial cell–rich or myoepithelial cell–rich (ie, cellular) pleomorphic adenoma; when the mesenchymal/stromal component predominates, the result is a stroma-rich pleomorphic adenoma (see the image below). A pleomorphic adenoma with an equal proportion of the 2 components is often referred to as a classic or mixed-type tumor.

Cellularity in pleomorphic adenoma. Image shows tu Cellularity in pleomorphic adenoma. Image shows tumor with 2 contrasting regions. Visible in right upper part of image is cellular region with dense epithelial and myoepithelial cell component. In left lower part of image, dominant morphology is that of chondroid stroma, with only a few interspersed myoepithelial cells.

These differences in the cellular-stromal ratio do not appear to give rise to any clinical differences in tumor behavior. [1] In many cases, however, different regions in the same tumor show striking variations in morphology and cellularity.

Pleomorphic adenoma occasionally exhibits unusual components, including sebaceous cells, mucous cells, squamous cells, oncocytic cells, [30] serous acini, fibroadipose tissue, [31] and crystal formations such as tyrosine or oxalate crystals (see the image below).

Unusual findings in pleomorphic adenoma. (A) Tyros Unusual findings in pleomorphic adenoma. (A) Tyrosine crystals with characteristic rosette appearance. (B) Large cystic changes in pleomorphic adenoma that is rich in myoepithelial cells. Arrow indicates area of squamous cell metaplasia. (C) Foci of mature adipose tissue (fat) in the stroma. Note myoepithelial-rich stroma in background. (D) Areas of mucous signet–appearing cells (arrows) are present next to epithelial/myoepithelial formations.

The presence of mucous cells in pleomorphic adenoma, particularly in limited biopsy specimens, may prompt the examiner to consider entities such as mucoepidermoid carcinoma. [32, 33] However, the presence of other components (eg, stroma or myoepithelial cells) helps establish the correct interpretation.

Cystic changes are occasionally seen in pleomorphic adenoma. A large cyst may be present, or the tumor may be multicystic. However, such changes do not have an impact on the clinical course of the tumor.

Necrosis and increased mitosis are not commonly encountered in pleomorphic adenoma; when they do occur, a thorough search for evidence of malignant change is necessary. FNA or focal infarction may result in similar tumor changes, and this possibility should also be carefully considered. Other atypical findings, such as increased cellularity, focal atypia, pleomorphism, and capsular extension, should not be interpreted as indicating malignant change in the absence of other corroborating evidence.

The occasional presence of benign tumor fragments within vascular spaces in the tumor or in the immediate peritumoral vasculature is thought to result from perioperative manipulation of the tumor during surgical resection and should not be interpreted as indicating vascular invasion. [27]



In most instances, the diagnosis of pleomorphic adenoma is made through straightforward microscopic identification. However, immunohistochemistry (IHC) may be supportive and helpful in delineating the different cell types and components, as well as in differentiating pleomorphic adenoma from other tumors. [34, 35, 36, 37, 38, 39] The following IHC stains have proved helpful:

  • Keratin - Positive in luminal epithelial and abluminal basal/myoepithelial cells

  • Cam 5.2 and EMA - Positive in luminal epithelial cells

  • P-63 - Positive in abluminal basal and myoepithelial cells

  • Calponin, maspin, S-100 - Positive in myoepithelial cells

  • HHF-35 - Smooth-muscle myosin

  • Muscle-specific actin - Positive in myoepithelial cells

  • Glial fibrillary acidic protein - Positive in myoepithelial cells in myxoid areas

  • BMP - Positive in myoepithelial cells in myxoid and chondroid areas

  • BMP-6 - Positive in the cells in cartilage and in inner ductal cells

  • Aggrecan - Positive in myxochondroid matrix



Most cases of pleomorphic adenomas (70%) show cytogenetic aberrations. [2, 40, 41, 42, 43, 44, 45] These aberrations manifest themselves in the following 3 patterns:

  • Rearrangement of chromosome band 8q12 (the target gene is pleomorphic adenoma gene 1 [PLAG1]) - 39% of cases

  • Rearrangement of chromosome band 12q13-15 (the target gene is the high mobility group AT-hook 2 gene, HMGA2) - 8% of cases

  • Sporadic or clonal changes not involving the above 2 chromosomes - 23% of cases

Both PLAG1 [46] and HMGA2 gene translocations have been identified as tumor-specific in pleomorphic adenoma; their detection by means of real-time polymerase chain reaction (RT-PCR) or fluorescence in situ hybridization (FISH) aids in establishing the diagnosis.

One study has demonstrated the presence of the simian virus (SV40) sequence in human pleomorphic adenoma, suggesting an etiologic link. [5]

The mucin 1 gene (MUC1) has been found to be related to the recurrence of pleomorphic adenoma and to be associated with malignant transformation of this tumor, with carcinoma cells overexpressing MUC1. [47]


Prognosis and Predictive Factors

For most patients with benign, well-circumscribed tumors, the prognosis is excellent after surgical resection. However, recurrence can be a problem with pleomorphic adenomas, particularly those occurring in the parotid gland. [48] Recurrence has been related to many factors, including an incomplete capsule, extension of tumor nodules beyond the capsule, and intraoperative tumor rupture, [49] in which tumor contents spill into the operative field.

Recurrence usually occurs in a multinodular fashion. [50, 51] In some cases, it involves microscopic elements, which render operative control extremely difficult and increase the risk of multiple further recurrences, as well as the risk of future malignant transformation. Recurrences have been related to tumors with high mesenchymal content, particularly chondroid and myxoid stroma. In some series, recurrences seem to be more common in younger patients than in older ones. [52]

Malignant change occurs in 2-7% of cases and shows some association with multiple recurrences, deep lobe tumors, male gender, and older age.

A pleomorphic adenoma may undergo a malignant change that is not fully appreciated, because the malignant tumor is well differentiated and has a bland cellular morphology at a level indistinguishable from its benign counterpart, particularly with a small biopsy specimen or fine-needle aspiration (FNA). As a result, a malignant recurrence may be erroneously presumed to be benign.

An example of this mistaken presumption that is becoming increasingly recognized in the literature is a well-differentiated myoepithelial carcinoma ex pleomorphic adenoma with mild cytologic atypia that is presumed to be a cellular pleomorphic adenoma. [53] In these cases, the malignant change can be recognized only after careful assessment of the resected specimen and the discovery of evidence of malignancy (which is sometimes subtle). [54, 55, 56]