Emerging Biology of Malignant Salivary GlandTumors Offers New Insights into the Classification andTreatment of Mucoepidermoid Cancer

In this issue of Clinical Cancer Research , Okabe et al. (1) have analyzed 71 cases of mucoepidermoid cancer and 51 cases of non-mucoepidermoid cancer for the presence of the Mect1Maml2 fusion oncogene and have made a valuable observation. They confirmed that Mect1-Maml2 expression is specific for mucoepidermoid cancer and showed that fusion-positive tumors have histologic and prognostic features that are strikingly distinct from fusion-negative tumors. Although these data raise important points for both the diagnosis and management of these patients, it is helpful to first review the recent findings that have led to this retrospective clinical study. Malignant salivary gland tumors represent a heterogeneous collection of cancers, which, due to their low incidence in the population, have often been grouped together (2). Accordingly, there has been little progress in defining the prognosis and treatment for these distinct neoplastic diseases. For example, although mucoepidermoid cancer is the most common malignant salivary gland tumor, there had been few insights into the genetic or biological basis of this tumor in the 100 years since it was first described by Volkmann in 1895 (3). In 1945, Stewart et al. established the term ‘‘mucoepidermoid’’ and defined this neoplasm as a specific pathologic entity under the designation of ‘‘tumor’’ due to its often benign but unpredictable clinical behavior (4). Only in 1953 did Foote and Frazell establish the term mucoepidermoid carcinoma, considering them all as malignant lesions (5). It was also recognized at this time that a characteristic histologic feature of mucoepidermoid cancer was the presence of varying amounts of three different cell types designated as epidermoid cells, mucin-producing cells, and intermediate cells. The relative amounts of epidermoid and mucinproducing cells, as well as the degree of cyst formation and cell differentiation, subsequently allowed for a prognostic classification of mucoepidermoid cancer, which could be scored as grades 1 to 3 (6), or as low-grade, mid-grade, and high-grade tumors (7). Although Okabe et al. (1) used a semiquantitative grading system in the present study, which incorporates additional variables of tissue invasion, cell proliferation, and anaplasia (8), each of these classification systems have shown a limited ability to guide clinicians through the variable clinical course of individual cases or to help define the benefit versus morbidity of extensive surgical resection margins and adjuvant radiation therapy. A first clue toward understanding the etiologic basis for mucoepidermoid cancer was the identification of a recurrent t(11;19) chromosomal translocation in a subset of tumors. Importantly, this translocation was the sole abnormality in a few case reports (9), and the chromosomal rearrangement was detected in both salivary gland and bronchopulmonary mucoepidermoid cancers (10). This latter finding reinforced the observation that primary tumors with a mucoepidermoid cancer–like histologic pattern could arise from many different anatomic locations, which included the upper and lower aerodigestive tract, as well as rare cases from the thyroid, esophagus, pancreas, skin, and several other sites (see ref. 11 for citations). In fact, the initial mapping of the t(11;19) rearrangement and the cloning of the Mect1-Maml2 transcript arose fortuitously as part of a study of acquired mutations in young patients with lung cancer. An adenosquamous lung tumor sample, which was later reclassified as a case of pulmonary mucoepidermoid cancer, as well as the independently derived H292 (12) and H3118 mucoepidermoid cancer tumor cell lines, showed the t(11;19) rearrangement, which ultimately led to the identification of the identical novel fusion transcript in each case (13). Because the Mect1 gene on chromosome 19p only contributed 42 amino acids to the NH2 terminus of the chimeric gene product and had no known function at the time, initial efforts to define a functional role for the fusion oncogene focused on the Maml2 gene from chromosome 11q21, which contributed 981 amino acids to the transcript and was a new member of a Notch regulatory gene family called Mastermind (Fig. 1). In fact, the related Maml1 gene on chromosome 5 had been shown to be an essential coactivator for Notch signaling in vitro (14), which suggested that the t(11;19) translocation may have aberrantly deregulated Maml2/Notch signaling in these salivary gland tumor cells. Two observations supported this model. First, the ectopic expression of Mect1-Maml2 in vitro was shown to constitutively activate a prototypic Notch target gene Hes-1 in the absence of Notch ligand (13) and, second, a t(7;9) translocation that truncated the Notch1 receptor gene had previously been shown to underlie the genesis of some human T-cell leukemias, serving as a precedent for a connection between constitutive Notch signaling and cancer (15). A challenge to the model of Mect1-Maml2–mediated tumorigenesis, The Biology Behind