Different patterns of malignant change occur in pleomorphic adenoma, of which carcinoma ex pleomorphic adenoma is one form; the other 2 forms are true malignant mixed tumor (carcinosarcoma) and metastasizing pleomorphic adenoma.
In addition to the 3 forms listed above, in 2007, an extremely rare case of adenoma characterized by pure sarcomatous change with no epithelial carcinomatous component was reported from the MD Anderson Cancer Center and was named high-grade sarcoma ex pleomorphic adenoma. 
Among these types of adenoma, carcinoma ex pleomorphic adenoma is the most commonly encountered; it was first described by Beahrs et al in 1957.  It is defined as a carcinoma that arises in the epithelial and/or myoepithelial component of a pleomorphic adenoma. In most instances (75%), the luminal epithelial cells undergo malignant change. In 19% of cases, a dual epithelial/myoepithelial differentiated carcinoma is seen. Pure myoepithelial malignant change is seen in only 6% of cases.
Carcinoma ex pleomorphic adenoma constitutes 99% of all cases of malignant mixed tumors; it develops in 6% of all pleomorphic adenomas. It constitutes 3.6-4% of all salivary gland tumors and 12% of all malignant salivary gland tumors. [3, 4, 5, 6]
Carcinoma ex pleomorphic adenoma is seen in patients in the sixth to seventh decades of life. [2, 7] Gender preference has been variably reported in different series. [8, 7, 2] Carcinoma ex pleomorphic adenoma is rarely encountered in patients younger than 30 years and is rarely seen in children. [9, 10] The average median age at onset is 61 to 67 years; this median age at onset is 10 to 20 years older than the median age of patients with pleomorphic adenoma, lending support to the view that longstanding tumors are more prone to malignant change. [2, 11]
Malignant transformation may occur up to 50 years after a pleomorphic adenoma is first diagnosed; the average period before malignant transformation is 20 years. The exact etiologic factors associated with malignant transformation are largely ill defined; however, exposure to radiation is thought to be a factor. It is also thought that malignant change may result from the development and accumulation of genetic instabilities within the tumor. 
A study by Hu et al suggests that promoter methylation of the p16 gene may be linked with the malignant evolution of pleomorphic adenoma to carcinoma ex pleomorphic adenoma. The increased expression in the cytoplasm of p16 protein combined with the decreased expression in the nucleus of this same protein may lead to this transformation. 
Interestingly, the rate of occurrence seems to increase with increases in the period during which pleomorphic adenoma is left untreated.  According to some investigators, the rate of malignant change is 1.5% in the first year in which the adenoma goes untreated; it increases to 9.5% after 15 years.
Carcinoma ex pleomorphic adenoma more commonly occurs in the major salivary glands than in the minor salivary glands.
Carcinoma ex pleomorphic adenoma is most frequently seen in the parotid gland (67%); the submandibular gland is less frequently involved (15%). The sublingual gland is involved in only 1% of cases. [3, 4]
Fine-needle aspiration is generally one of the first steps taken in diagnosing a salivary gland mass. It is interesting to note that carcinoma ex pleomorphic adenoma tends to occur in the deep lobe of the parotid, in contrast to most pleomorphic adenomas, which tend to occur in the superficial lobe.  This fact may account for the low preoperative diagnostic accuracy and sensitivity of fine-needle aspiration in diagnosing carcinoma ex pleomorphic adenoma.
Clinical Features and Imaging
The patient usually presents with a history of a slowly growing, painless mass [19, 20] that suddenly or over a short period enlarges rapidly. Patients usually present with symptoms and signs suggesting malignancy (eg, fixation to surrounding structures,  occasional pain, skin infiltration, trismus,  facial nerve weakness, or palsy  ). Facial nerve weakness or palsy has been detected in approximately 23-40% of cases. [22, 23, 24]
Some patients with carcinoma ex pleomorphic adenoma have a history of multiple previous surgeries for pleomorphic adenoma  ; such a history might suggest the possibility of malignant transformation. This is relevant, considering the fact that some cases of very well-differentiated epithelial malignancy (eg, myoepithelial carcinoma ex pleomorphic adenoma) are sometimes not fully appreciated. Careful observation of the resected tumor may reveal malignancy. 
Carcinoma ex pleomorphic adenomas vary considerably in size; sizes may range from 1 cm to greater than 20 cm. Macroscopic features that suggest malignant transformation in pleomorphic adenoma include poorly defined and/or infiltrative tumor margins,  the presence of foci of hemorrhage, and necrosis. However, some malignant tumors are well circumscribed [19, 26] (eg, noninvasive or minimally invasive varieties).
The most common malignant epithelial subtype seen in carcinoma ex pleomorphic adenoma is poorly differentiated adenocarcinoma not otherwise specified (NOS). Almost all other malignant varieties of salivary gland tumors have been described (eg, undifferentiated carcinoma, squamous cell carcinoma, mucoepidermoid carcinoma, salivary duct carcinoma, adenoid cystic carcinoma, myoepithelial carcinoma, and epithelial myoepithelial carcinoma). [27, 3, 19, 21, 11, 27, 28, 29] The percentage of the malignant component varies widely; in some instances, the locations of the original benign pleomorphic adenoma are difficult to ascertain (see Media files 1-4). 
Although in most instances, the features of malignant transformation are evident, some very well-differentiated cancers (eg, myoepithelial carcinoma) or cancers that exhibit morphologically limited nuclear atypia may be somewhat challenging to evaluate for the presence of malignancy. 
Clinical experience has engendered an appreciation of the evolution of carcinoma ex pleomorphic adenoma over time. Presentations vary and may include the following: carcinoma in situ, in which atypical nuclei replace the ductal luminal layer while the not atypical myoepithelial layer is retained focally or multifocally [31, 32, 33] ; carcinoma that breaks from the confines of the myoepithelial layer to invade the surrounding stroma while remaining intracapsular; and frankly invasive cancer that extends beyond the capsule of the pleomorphic adenoma. [19, 34]
Tumors that invade beyond the capsule into the surrounding tissue by less than 1.5 cm are considered minimally invasive; overall, patients with this form of disease have an excellent prognosis. Those tumors that invade beyond 1.5 cm are considered invasive; with such tumors, prognoses vary in accordance with tumor stage and grade.  Tumors should be carefully evaluated with regard to the degree of invasion of tumor, because treatment will vary accordingly.
The grade of the cells seen in the cancerous epithelial component varies from well differentiated to poorly differentiated to anaplastic, depending on the cancerous subtype.  Most carcinomas are high grade, but some are low grade. However, the histologic grades of the tumor should be judged according to how the carcinomatous category is usually graded in an individual tumor. For example, a mucoepidermoid carcinoma ex pleomorphic adenoma is histologically categorized as being of low, intermediate, or high grade histologically, as is done in the case of a mucoepidermoid carcinoma occurring as an individual tumor.
Perineural invasion  and angiovascular invasion are commonly encountered in the invasive types; necrosis is prominent in the high-grade types.
Determining the different types of cells in the tumor by use of immunohistochemistry may aid in establishing an accurate diagnosis Tumor markers are described in the Medscape Reference article Pathology of Pleomorphic Adenoma. However, specific additional markers have occasionally proven useful in cases of carcinoma ex pleomorphic adenoma. Immunoreactivity for p53 was observed by some authors to be a useful tool in differentiating pleomorphic adenoma from carcinoma ex pleomorphic adenoma. Indeed, some authors have reported that p53 may be used as a means of early detection of malignant change in pleomorphic adenoma [36, 37, 38, 31, 39] ; other authors, however, have disputed this claim.
Immunoreactivity (overexpression) for HER2 (c-erbB-2) has been used by some investigators to differentiate carcinoma ex pleomorphic adenoma from atypical pleomorphic adenoma [39, 40, 41, 42] ; others have found no significant correlation. Immunoreactivity for cyclin A and its increased expression have also been noted by some investigators to correlate with the development of carcinoma ex pleomorphic adenoma. [43, 44]
Recently, expression of X-linked inhibitor of apoptosis protein (XIAP) (a protein that is associated with aggressive behavior in tumors) was studied in both pleomorphic adenoma and carcinoma ex pleomorphic adenoma.  The results indicated an increase in the expression of XIAP from pleomorphic adenoma to cellular pleomorphic adenoma to carcinoma ex pleomorphic adenoma, or even atypical areas within pleomorphic adenoma. Such findings suggest that XIAP expression may be an additional marker to aid in the evaluation of malignant change in pleomorphic adenoma.
Deletions of chromosome 5 have been reported, as have alterations in chromosome 17q and 6q deletion.
Tumor Spread and Staging
The American Joint Committee on Cancer (AJCC)  staging system for malignant tumors of the major salivary glands (ie, the parotid, submandibular, sublingual glands) is as follows:
Table. TNM classification (Open Table in a new window)
|Tx||Primary tumor cannot be assessed|
|T0||No evidence of primary tumor|
|T1||Tumor 2 cm or less in greatest dimension without extraparenchymal extension|
|T2||Tumor more than 2 cm but not more than 4 cm in greatest dimension without extraparenchymal extension|
|T3||Tumor more than 4 cm and/or tumor having extraparenchymal extension|
|T4a||Tumor invades skin, mandible, ear canal, and/or facial nerve|
|T4b||Tumor invades skull base and/or pterygoid plates and/or carotid artery|
|N-||Regional lymph nodes|
|NX||Regional lymph nodes cannot be assessed|
|N0||No regional lymph node metastasis|
|N1||Metastasis into a single ipsilateral lymph node, 3 cm or less in greatest dimension|
|N2||Metastasis into a single ipsilateral lymph node, greater than 3 cm in greatest dimension but not greater than 6 cm in greatest dimension, or in multiple ipsilateral lymph nodes, none greater than 6 cm in greatest dimension, or in bilateral or contralateral lymph nodes, none greater than 6 cm in greatest dimension|
|N3||Metastasis in a lymph node greater than 6 cm in greatest dimension|
|MX||Distant metastasis cannot be assessed|
|M0||No distant metastasis|
Table. Stage grouping (Open Table in a new window)
|Stage I||T1 N0 M0|
|Stage II||T2 N0 M0|
|Stage III||T3 N0 M0|
|T1 N1 M0|
|T2 N1 M0|
|T3 N1 M0|
|Stage IVA||T4a N0 M0|
|T4a N1 M0|
|T1 N2 M0|
|T2 N2 M0|
|T3 N2 M0|
|T4a N2 M0|
|Stage IVB||T4b Any N M0|
|Any T N3 M0|
|Stage IVC||Any T Any N M1|
Tumor spread can occur by direct extension and lymphovascular or perineural invasion. As mentioned above, the tumor can be histologically divided on the basis of temporal evolution into the following:
Carcinoma in situ
Minimally invasive (1.5 cm or less extension beyond the capsule)
Invasive/widely invasive (greater than 1.5 cm extension beyond the capsule)
For carcinoma ex pleomorphic adenoma arising in the minor salivary glands, staging is determined in accordance with the system of the region of occurrence.
Prognosis and Predictive Factors
Patients with noninvasive and minimally invasive tumors have an excellent prognosis; for these tumors, the metastatic potential is very low. [50, 34] Tumors in the invasive category tend to behave in a more aggressive fashion; up to 25-50% of patients experience recurrence, [3, 7, 19] and up to 60-70% of patients develop local or distant metastasis.  Metastatic sites include lymph nodes, bone (especially vertebral bodies), and the brain.
The stage of the disease plays an important role in prognosis. Patients with stage I disease generally have an excellent prognosis, whereas the survival rate for patients with stage IV disease is extremely poor. A recent study of 22 patients with CXPA confirmed this general tendency.  In that study, both the 5-year disease-specific and overall survival rates were 60%; the recurrence-free survival rate after 5 years was 85%. Interestingly, in this series, the incidence of higher-stage disease correlated with older age (the average age of patients with stage IV disease was 67 years), whereas lower-stage disease correlated with younger age (the average age of patients with stage I or II disease was 53 years).
The survival rate has been correlated with the size, type, and histologic grade of cancer, particularly with regard to the widely invasive types. Patients with undifferentiated carcinoma have the worst survival rate (30%); those with polymorphous low-grade adenocarcinoma have the highest survival rate (96%).