Definition

Carcinoma ex pleomorphic adenoma is defined as a pleomorphic adenoma from which an epithelial malignancy is derived.

 ICD-O code 8941/3

Synonyms Carcinoma arising in a benign mixed tumour, carcinoma ex benign mixed tumour, carcinoma arising in a pleomorphic adenoma, malignant mixed tumour.

 Epidemiology

Many large series of carcinoma ex pleomorphic adenoma (Ca-ex-PA) have been reported and recently summarized: they comprise approximately 3.6% of all salivary tumours (range 0.9-14%), 12% of all salivary malignancies (range 2.8-42.4%), and 6.2% of all pleomorphic adenomas (range 1.9-23.3%) {898}. Ca-ex-PA usually presents in the 6th or 7th decades, approximately one decade later than patients with pleomorphic adenoma.

Etiology

 Many Ca-ex-PA probably result from the accumulation of genetic instabilities in long-standing pleomorphic adenomas.

Localization

 Ca-ex-PA most frequently arises in the parotid gland; but may also originate from the submandibular gland and minor salivary sites, most commonly the palate,occasionally with involvement of the nasopharynx {838}.

Clinical features

The typical history is that of a long-standing mass present much longer than 3 years with rapid growth over the previous few months; however, a significant proportion of patients present with a clinical history of less than three years {898,1533}. Patients frequently complain of a painless mass; but pain, facial nerve palsy, and skin fixation may also occur.

Macroscopy

 The average size of Ca-ex-PA is more than twice that of its benign counterpart, ranging from 1.5-25 cm in greatest diameter {786,2624}. Grossly, Ca-ex-PAs are usually poorly circumscribed and many are extensively infiltrative. Occasionally, tumours are well circumscribed, scar-like or appear completely encapsulated {252,2624}.

Histopathology

The proportion of benign versus malignant components can be quite variable. Occasionally, extensive sampling is necessary to find the benign component and in rare cases, a benign remnant might not be found. But if there is clinicopathologic documentation of a previously excised pleomorphic adenoma in the same site, then the malignancy can also be classified as a Ca-ex-PA. The malignant component is most frequently a poorly differentiated adenocarcinoma (salivary duct type or not otherwise specified) or an undifferentiated carcinoma; however, virtually any form of carcinoma may be found {898,1338, 1491}. An infiltrative, destructive growth pattern is the most reliable diagnostic criterion. Nuclear hyperchromasia and pleomorphism are frequent, although occasional tumours may demonstrate minimal atypia. This latter feature (tumour grade) directly correlates with prognosis. Necrosis is often present and mitoses are usually easy to find. Ca-ex-PAs should be subclassified into non invasive, minimally invasive (≤1.5 mm penetration of the malignant component into extra capsular tissue) and invasive (>1.5 mm of invasion from the tumour capsule into adjacent tissues), as the first two groups usually have an excellent prognosis while the latter has a more guarded prognosis. The distinction between noninvasive and invasive tumours is based on destructive invasion through the capsule into peritumoral tissues. Non-invasive Ca-ex-PAs are also referred to as carcinoma in-situ arising in a pleomorphic adenoma, intracapsular carcinoma ex pleomorphic adenoma or pleomorphic adenoma with severe dysplastic changes. Atypical changes within these tumours range from focal to diffuse often   with multifocal areas containing carcinoma, which frequently overgrows and replaces many of the benign elements. The earliest changes typically consist of tumour cells replacing the normal inner duct epithelial layer leaving the normal peripherally located myoepithelial layer intact.

Differential diagnosis

The most important differential diagnosis is between minimally invasive Ca-ex-PA and the more typical invasive Ca-ex-PA. This differential has prognostic significance, and affects decisions regarding the need for lymph node dissection and adjuvant radiotherapy. Also carcinomas may rarely arise in a histologically benign “adenoma” (“monomorphic” adenoma); they appear to have a more favourable prognosis {1576}.

Genetics

Cytogenetics Deletions of chromosome 5(q22-23, q32- 33) and t(10;12) (p15;q14-15) with 12q breakpoint at the 5’ of the HMGIC and translocation of the entire gene to the 10 marker chromosome followed by deletion/ amplification of the segment containing HMGIC and MDM2 genes have been reported {653,1220,2193}. Rearrangements of 8q12 are a frequent finding. Alterations at 12q13-15 with amplification of HMGIC and MDM2 genes have also been reported {2125}. Cytogenetic evidence of amplification (homogeneously stained region and double minute) was found in 40% of these tumours. Both genes may contribute to the malignant transformation of pleomorphic adenoma. Alterations at chromosomes 6q deletion and 8q rearrangements have been reported. Molecular genetics Microsatellite analysis of these tumours has shown LOH at chromosome 8q and 17p. Concurrent analysis of the benign and malignant components of these tumours showed 8q and/or 12q in both components and additional alterations in 17p only in the carcinoma {651}. In another study homozygous deletion of the p16 gene on chromosome 9p21 was found in carcinoma of one case and microsatellite instability was noted in both the adenoma and carcinoma components in two tumours {2510}. A single case report of a carcinosarcoma, in which the carcinoma and the sarcoma components were concurrently analyzed, showed lack of p53 alterations and concomitant LOH at different loci on chromosome 17 and 18 supporting monoclonality {932}.

 Prognosis and predictive factors

 In general, the recommended therapy is wide local excision with contiguous lymph node dissection. Adjuvant radiation therapy is recommended for widely invasive tumours. If the carcinomatous component is low-grade and/or minimally invasive and if the tumour is adequately excised, then adjuvant radiation therapy may not be necessary. Patients with non-invasive or minimally invasive Ca-ex-PA typically have an excellent prognosis, similar to benign pleomorphic adenoma. Metastatic spread is exceptional {726}. Invasive Ca-ex-PAs, as a group, are extremely aggressive malignancies with approximately 23-50% of patients developing one or more recurrences {786, 898,1491,1533}. The metastatic rate varies with each series; up to 70% of patients develop local or distant metastasis {877,898,1491}. Metastatic sites in order of frequency are lung, bone (especially spine), abdomen and central nervous system {786,2592}. Ca-ex-PA with capsular penetration of more than 1.5 mm is associated with a poor prognosis; survival rates at 5, 10, 15, and 20 years range from 25-65%, 18-50%, 10-35%, and 0-38%, respectively {786,877,1491, 1533,2592,2624}. Therefore, it is important to designate those Ca-ex-PA that are confined within the capsule and those invading through the capsule as noninvasive or invasive, respectively, and to differentiate within the latter group between widely invasive and minimally invasive tumours. One study showed that no patient with less than 8 mm invasion from the capsule died from the tumour, whereas all patients with invasion greater than 8 mm beyond the capsule ultimately died of disease {2624}. The local recurrence rate (LRR) in this latter series also correlated with extent of invasion; a LRR of 70.5% was found for tumours with invasion beyond 6 mm from the capsule, as compared to a LRR of 16.6% for tumours with invasion of less than 6 mm. In another study consisting of four patients with 5 mm of invasion beyond the tumour capsule, two died of disease and two were alive and well {1491}. The two patients with less than 5 mm of invasion (2 and 3 mm) were alive and well with no evidence of disease. Also, all four patients with intracapsular carcinoma were alive and well without evidence of disease progression. The improved prognosis for minimally invasive tumours has been confirmed by Brandwein et al who observed recurrence free for periods ranging from 1-4 years (mean 2.5 years) {252}. Tumour size and grade are also significant prognosticators in the more widely invasive Ca-ex-PAs. The five-year survival rates have been correlated with histologic subtype of the carcinoma component: there was a 30% survival rate for undifferentiated carcinomas, 50% for myoepithelial carcinomas, 62% for ductal carcinomas and 96% survival rate for terminal duct carcinomas {2624}. In addition, 63% of patients with high-grade carcinomatous components died of the disease, while patients with lower grade carcinomatous elements did not {1491}.