Malignant mixed tumors of the salivary gland: a study of loss of heterozygosity in tumor suppressor genes

Abstract

Carcinosarcomas and carcinoma ex pleomorphic adenoma of the salivary glands are rare tumors that fit into the broader category of malignant mixed tumors. Although most evidence has suggested that the different morphologic components arise from a common clonal origin, there are very few studies that have provided molecular evidence for this clonality. In this study, we examined a set of seven carcinosarcomas and four carcinomas ex pleomorphic adenoma for tumor suppressor gene loss of heterozygosity, in order to assess the clonal patterns in the varying components. Microdissection was performed to obtain each morphological component and tumor suppressor gene loci on 3p, 5q, 9p, 17p, 17q, and 18q were analyzed. The fractional allelic loss (FAL) was calculated for each area, and the different targets were compared for their molecular profile. The overall mean FAL of the malignant targets was 42%. In carcinosarcomas, the sarcomatous targets had a higher mean FAL than the carcinomatous targets (68 vs 46%, respectively) and in carcinomas ex pleomorphic adenoma, the mean FAL in the benign component was 11 vs 46% seen in the carcinomatous component. The most frequently lost genetic loci were p53 (17p13, 73%), nm23-H1 (17q21, 55%), and DCC (18q21, 50%). Loss of heterozygosity of 17q21 and 9p21 only occurred in carcinosarcomas and not in carcinomas ex pleomorphic adenoma. Within the carcinosarcomas, the mutational profiles were conserved between epithelial and sarcomatous areas. In carcinomas ex pleomorphic adenoma, loss of heterozygosity was uncommon in the benign component, but the mutations were conserved in the corresponding malignant areas. These results support the hypothesis that the carcinomatous and sarcomatous components of carcinosarcomas are clonally related. Furthermore, these data support prior studies that suggest a common clonal origin for the benign and malignant components of carcinomas ex pleomorphic adenoma. Keywords: carcinosarcoma; pleomorphic adenoma; carcinoma ex pleomorphic adenoma; loss of heterozygosity Malignant mixed tumors of the salivary gland are diverse and include three different subcategories of lesions: carcinosarcomas, carcinoma ex pleomorphic adenoma, and metastasizing pleomorphic adenomas. Both types of frankly malignant tumors behave aggressively, with poor 5-year survival.

Carcinoma Ex Pleomorphic Adenoma: Case Report and Options for Systemic Therapy

“…Studies have suggested that cxpa follows a multistep model of carcinogenesis, with progressive loss of heterozygosity at chromosomal arm 8q, and then arms 12q and 17p 15 . Alterations in PLAG1 and MYC, coded on chromosome 8, have been associated with cxpa [16][17][18] .…”

Assessment of TP53 mutations in benign and malignant salivary gland neoplasms

“…Weber and co-workers analyzed TP53 mutations by direct sequencing of exons 4-9 and detected mutations in 4/42 PA and 3/12 myoepitheliomas [14]. Despite the evidence that TP53 might be altered in SGN [10,13,14,16,17,18], we sequenced all of our samples and found only four missense mutations, one nonsense TP53 mutation and a very low frequency of LOH at the 17p 13.1 region in our subset of salivary tumor samples.…”

“…These previous papers relied on different techniques (SSCP, for example, which misses mutations when compared to direct sequencing), and in some of them, sequencing was only performed on a few samples. In salivary gland neoplasms, LOH at the TP53 locus has also been reported, mainly in malignant salivary neoplasms or based on visual comparison of the intensity of the alleles [15,16,17,18]. It is important to note that some TP53 mutations do not result in positive immunostaining.…”

Carcinosarcoma ex Non-Recurrent Pleomorphic Adenoma Composed of TTF-1 Positive Large Cell Neuroendocrine Carcinoma and Myofibrosarcoma: Apropos a Rare Case

“…There is ample molecular evidence for a clonal relation in CSs arising in the uterine corpus and this pattern has increasingly been demonstrated in CS of other organs [30,31]. The literature on this topic regarding CS of salivary glands is scarce, but there is mounting evidence that a clonal relation between the carcinomatous and sarcomatous components also hold true in the salivary glands [32][33][34][35]. Speculatively, but in line with current thinking regarding tumorigenesis, the difference between the two categories of CS would then be that the malignant transformation in (1) occurs in a neoplastic, albeit benign, cell in contrast to an uncommitted stem cell in (2), which then through ''genetic instability'' gives rise to two or more lines of differentiation.…”

“…A few points of interest are: (1) Frequent loss of 17p (where TP53 is located) has been reported [34] and (2) both overexpression of p53 and TP53 mutations have been reported [27,39]. However, the relation between immunohistochemically detected p53 and the presence of mutation is not simple.…”