Update of Common Salivary Tumors
Moderators: Dr. John Eveson and Dr. Silloo Kapadia
Section 2 -
Carcinoma Ex Pleomorphic Adenoma
Jean E. Lewis
Carcinoma ex pleomorphic adenoma (CXPA) represents the most common form of malignant mixed
tumor. The term malignant mixed tumor is used in a general sense to denote the various malignancies
which may be associated with pleomorphic adenoma. The current WHO classification separates these into
CXPA, carcinosarcoma, and metastasizing pleomorphic adenoma. Carcinosarcoma ("true malignant mixed
tumor") and metastasizing pleomorphic adenoma are exceedingly rare neoplasms.
CXPA implies the development of an epithelial malignancy concurrent or subsequent to a
pleomorphic adenoma (PA). When metastases develop, they are composed of carcinomatous elements alone.
CXPA represents approximately 3-5% of all salivary gland tumors and 10-15% of salivary gland
CXPA occurs over a fairly wide age range, with the majority of cases in the
6th-8th decade. The mean age is 50-60 years, approximately 10 years later than
that of a PA. Most series report a slight female predominance. The "classic" presentation is that of a
longstanding mass (presumably the benign component) which undergoes sudden rapid enlargement. It has
been suggested that the risk of malignancy progressively increases with the duration of the PA, and
Thackray estimated that approximately 25% of untreated PAs would eventually develop carcinoma.
Alternatively, carcinoma may develop after multiple recurrences of PA. In many patients, however, a
rapidly growing mass is reported without prior history of salivary gland tumor. Signs or symptoms of
malignancy, such as pain, palsy, or fixation may be noted. The parotid gland is involved in about
three-fourths of cases, followed by minor salivary glands (especially the palate) and the submandibular
Grossly, CXPA tends to be larger than conventional PA. In addition to features of PA, zones of
necrosis and hemorrhage may be noted. Lack of circumscription or areas of gross invasion are important
clues to its malignant nature.
The proportion of carcinoma to benign PA varies greatly from case to case, although the malignant
component usually predominates. Typically the carcinoma is represented by a high grade malignancy;
adenocarcinoma not otherwise specified and salivary duct carcinoma are the histologic subtypes most
frequently encountered. Other histologies reported include undifferentiated carcinoma, squamous cell
carcinoma, mucoepidermoid carcinoma, adenoid cystic carcinoma, myoepithelial carcinoma, and polymorphous
low grade adenocarcinoma. Extensive sampling may be required to detect the benign component. The
residual PA is often largely hyalinized and/or calcified.
In the majority of cases, the diagnosis of CXPA poses no difficulty. The poorly differentiated
nature of the carcinomatous component is easily appreciated, as it exhibits extensive infiltration,
perineural invasion, necrosis, high mitotic rate, etc. Differential diagnosis includes a wide range of
other salivary carcinomas, when misinterpretation results from the under-recognition of preexistent PA.
A poorly differentiated salivary carcinoma which is difficult to classify should raise the suspicion of
CXPA and also provoke a search for a possible preexistent PA. At the other end of the spectrum, early
carcinomatous transformation of a PA may prove a diagnostic challenge. Uncommon cases showing frankly
malignant features but without extracapsular extension have been designated as noninvasive carcinoma or
intracapsular carcinoma. However, follow-up of these patients has revealed an excellent prognosis
similar to that of conventional PA. In addition, patients with minimal invasion beyond the capsule
appear to have a better prognosis than those with widely invasive carcinoma. The WHO now subclassifies
CXPA into non-invasive, minimally invasive (defined as < 1.5 mm penetration of the malignant
component into extra-capsular tissue) and invasive ( > 1.5 mm of invasion beyond the capsule). The
interpretation of lesser degrees of cytologic atypia, increased mitotic activity, or lack of
encapsulation in an otherwise benign PA is more problematic. Focal atypia, especially involving the
myoepithelial component, may occasionally be observed in PA and is probably not of clinical
significance. Necrosis, squamous metaplasia, and epithelial atypia may be observed following FNA of a
benign mixed tumor. Focal vascular invasion has been rarely described in an otherwise benign PA. In
some series, mitoses or apparent infiltration of adjacent tissues by the PA has been associated with
increased risk of recurrence or metastases of a cytological benign PA (see below). A study of 65
atypical PAs by Auclair and Ellis found that malignant transformation of PA was correlated with the
histologic features of prominent hyalinization and at least moderate mitotic activity.
Recurrent chromosomal abnormalities reported in both benign PA and CXPA are found at 8q and 12q.
Loss of heterozygosity studies show similar genetic abnormalities in the benign and malignant components
of a given tumor, with additional aberrations typically found in the carcinoma, frequently involving
17p. Several studies have suggested that pleomorphic adenomas with abnormalities at 12q may be at
increased risk of malignant transformation. The carcinomatous component may show overexpression of
Her-2/neu or p53, and an increase in the proliferation index by MIB1, features which may help identify
early malignant change in a PA.
Treatment of CXPA is wide surgical excision. Total or radical parotidectomy and neck dissection is
appropriate for parotid gland tumors. Adjunct radiation therapy may be recommended for extensive local
and /or regional disease. These are aggressive tumors, with a 5-year determinate survival of
approximately 50%. Regional and distant metastases are frequent. Distant metastases favor lung and
bone, especially the spinal column. Prognostic factors include stage, tumor size, grade, and extent of
Carcinosarcoma, or true malignant mixed tumor, is composed of both carcinomatous and sarcomatous
elements, and each component is capable of metastasis. These neoplasms may arise de novo or in association with a benign PA (CXPA). The histologic subtypes of
carcinoma cover a similar spectrum to that seen in CXPA. The sarcomatous component is usually the
dominant feature, and is often represented by chondrosarcoma. Examples of osteosarcoma, fibrosarcoma,
and malignant fibrous histiocytoma have been reported. Several cases of carcinosarcoma have exhibited a
prominent population of osteoclast-like giant cells. Recent investigations have reported the presence of
epithelial markers in the spindle cell component, similar p53 profiles between the carcinomatous and
sarcomatous areas, as well as preserved mutational profiles between the two components in loss of
heterozyosity studies. These lines of evidence support the monoclonal origin of carcinosarcoma (i.e.
Carcinosarcomas are extremely uncommon tumors which comprise well less than 1% of salivary gland
neoplasms. Reported cases have occurred in adults with a mean age in the 6th decade.
Carcinosarcoma has proven lethal in more than half of the literature cases with follow-up. The lung is
the favored metastatic site.
Differential diagnosis of carcinosarcoma includes other biphasic tumors of the head and neck, i.e.
synovial sarcoma and spindle cell squamous carcinoma, primary salivary sarcomas and CXPA. In synovial
sarcoma, both the epithelial and mesenchymal elements are less pleomorphic than those seen in
carcinosarcoma. The glandular structures are relatively simple and the stroma is composed of densely
cellular, uniform spindle cells. Spindle cell squamous carcinoma arises from the mucosal surface and may
be a diagnostic consideration in minor salivary gland sites. The epithelial component of spindle cell
carcinoma is always epidermoid, rather than glandular, and dysplasia may be appreciated in the overlying
mucosa. Any presumed primary sarcoma of salivary origin should be well sampled to detect a minor
carcinomatous component. The most common histologic subtypes of primary salivary sarcoma are malignant
peripheral nerve sheath tumor and fibrosarcoma. Rarely, CXPA can show myxochondroid type stromal
induction. However, frankly sarcomatous elements should be recognized to substantiate a diagnosis of
Metastasizing pleomorphic adenoma denotes the development of metastasis from an otherwise
unremarkable benign tumor. Both cytologically benign epithelial and stromal components are present in
the metastatic tumor. Histologic features of the primary tumor which may consistently predict the
development of metastases have not been identified. Increased mitotic activity and infiltrative growth
pattern have been suggested as possible hallmarks of metastatic potential. However, in Wenig's report of
11 cases, neither histologic parameters or flow cytometric analysis were predictive of the development of
metastases. It appears that prior surgical manipulation may be a prerequisite to metastatic spread.
Metastasizing PA has occurred in patients with a broad age range and a mean of approximately 30 years
at original presentation. The parotid is the most frequent primary site. There is a wide interval from
the time of original excision to the detection of metastasis, and many patients suffer repeated local
recurrence prior to metastasis. Sites of metastasis include bone, lung, and regional lymph nodes. These
are generally indolent tumors, and patients may survive for extended periods with metastatic disease.
Recommended therapy is wide local excision for both primary and metastatic tumors.
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