Description of Rare Diseases: Salivary Neoplasms
Salivary gland carcinomas (SGCs) are comprised of widely varied histopathologic subtypes and heterogeneous clinical behaviors. In the USA, approximately 2500 new cases are diagnosed each year and they constitute 5% of head and neck malignancies, 0.3% of all cancers (the mortality rate is approaching 20%). In general, salivary gland carcinomas afflict late- to middle-aged and elderly individuals with a mean age of 56 years. The annual incidence of salivary gland tumors in juveniles is 1 to 2 in 100,000 individuals and less than 10% of all juvenile head and neck tumors are located in the salivary glands. SGCs affecting children less than 10 years of age are very rare. In children, mucoepidermoid and acinic cell carcinomas are the most frequent salivary tumors, with 43% and 34% respectively. Recent SEERs data and surveys from the US and the UK indicate a rise in the incidence of SGCs, which was attributed to the prevalence of radiation exposure and/or to increasing use of fine-needle aspiration for diagnostic use, and greater access of elderly people to medical care. Little information is available on the racial distribution and incidence of SGCs.
The etiology of salivary gland tumors remains unknown. Of the risk factors investigated, exposure to radiation has been the only known factor associated with salivary gland tumors. Individual differences in intrinsic radio sensitivity have been implicated as an underlying cause for the development of these tumors. Recent data support a role for sensitivity to chromatin breaks and polymorphisms at certain repair genes in malignant salivary gland tumors.
Typically, the management of early resectable primary SGCs is complete surgical excision alone or with postoperative radiation therapy for tumors with close or microscopically positive margins and/or perineural involvement. Patients with locally advanced nonresectable, recurrent and metastatic SGCs have very limited therapeutic options. Few therapeutic trials using single or combined agents and targeted therapy have been performed, and the results are limited and disappointing due to the small size, inclusion of heterogeneous tumors and populations, loose pathologic categorization, and the lack of surrogate biomarkers. In contrast to other major malignancies, SGCs have no known precursor lesions, familial or genetic inheritance, and investigators have been hampered by difficulties in cultivating and/or developing cell lines and animal models.
Selection of Three Distinct Rare Salivary Malignancies for Study:
The SGCs targeted for study include mucoepidermoid carcinomas (MEC), adenoid cystic carcinoma (ACC) and adenocarcinoma salivary duct carcinoma (AC). Collectively, these three types comprise the most frequent malignancies, with incidence of 25-35%, 15-25%, and 6-10% for MEC, ACC and AC, respectively. They are also the most distinctive, aggressive and difficult-to-treat cancers. Because of their inter-tumoral unique phenotypic, cellular, hormonal, cytogenetic and molecular differences, they are considered distinctive entities for this purpose.
a) MECs are the most common malignant SGCs in both adults and children. MEC is believed to arise from the main duct and is comprised of pure neoplastic epithelial cells of variable morphology. Pathologically, they are graded into three grades dependent upon the structural and architectural histologies, and the extent of cytologic, abnormalities. Cytogenetic analyses of MECs have revealed a consistent specific translocation t(11;19) (q21;pl 3), either along with other nonspecific alterations or as the sole cytogenetic alteration. Cloning of this translocation has identified a fusion oncogene composed of exon 1 of the MECT1 (CRTC1/WAMTP) gene on chromosome 19pl3 and exons 2-5 of the MAML2 gene on chromosome 11q21. The MECTI domain included in the fusion binds the DNA binding protein CREB, and MAML2, providing a potent transcriptional activation domain that facilitates constitutive expression of CREB regulated genes. Studies of this fusion transcript in MECs have reported a correlation of tumor grade with occurrence restricted to the low-grade category. Fusion-negative MECs may evolve from a different evolutionary pathway and may represent a biologically distinctive category. The results also suggest that tumors lacking the fusion transcript behave more aggressively.
b) ACCs account for approximately 6% of all salivary tumors and comprise 30% of all salivary malignancies. Histopathologically, ACC manifests three distinctive forms that overlap with varying proportions in any given tumor. In contrast to MEC and adenocarcinomas, ACCs arise from the terminal duct segment and are composed of epithelial and myoepithelial neoplastic cells in tubular and/or cribriform patterns. The solid transformation of these forms is largely devoid of myoepithelial cells and is known for its aggressive clinical course. Cytogenetic studies of these tumors have reported frequent alterations at chromosomes 6p, 9p, and 17p, with the most consistent alteration is at 6q. This is supported by the high frequency loss of heterozygosity at 6q 23-25 region in these tumors in other studies. The involvement of the 6q region in several independent studies underscores the importance of this chromosomal region as a target for further investigations.
ACC is also characterized by a reciprocal translation between the long arm of chromosome 6 and the short arm of chromosome 9. This translocation generates a fusion gene called MYB-NFIB in approximately 30% of these tumors. Currently the fusion gene is associated with upregulation of the MYB gene.
c) ACs are comprised of purely malignant ductal epithelial cells that arise either de novo or in the setting of benign mixed tumors. They present in an older age group and not uncommonly at an advanced stage. In contrast to MEC and ACC, these tumors manifest a marked resemblance to high grade ductal carcinoma of the breast. Cytogenetic and molecular studies of these tumors are few and insufficient to draw any conclusions. Possibly, rearrangements of chromosome 8q12, alteration of chromosome 12q13-15 region, and amplification of both the HMG1C and MDM2 genes may be associated with these tumors. Several reports have indicated that translocations of chromosome 5(q22-23, q32-33) and t(10;12) (p15;q14-15) result in location of the entire HMG1C gene to chromosome 10.14 Alterations at 8q and/or 12q, and restricted alterations at chromosome 17p have also been observed. Studies have also reported homozygous deletion of p16, p53 alterations, and loss of heterozygosity at different loci on chromosome 6. We have recently characterized hormonal and growth factor receptors in a large number of these tumors. The differential expression of HER-2, EGFR, androgen, and estrogen may allow for their biological stratifications for therapy.