MAML2-Rearranged Primary Central Mucoepidermoid Carcinoma of the Mandible as an Incidental Finding: A Case Report and Review of the Literature of Molecularly Confirmed Cases

This report presents an extremely rare case of MAML2-rearranged primary central mucoepidermoid carcinoma (MEC) of the mandible that was discovered as an incidental finding. Our review of the literature identified 36 cases of MAML2-rearranged intraosseous lesions of the jaw (30 central MECs, 5 odontogenic cysts with mucous prosoplasia, and 1 glandular odontogenic cyst). Given the therapeutic indications for a diagnosis of MEC (a malignant neoplasm), MAML2 rearrangement should be confirmed in suspected cases of central MEC.

CMEC occurs more commonly in the mandible with the premolar-molar-angle region as the most common site of occurrence, and the majority of CMECs occur in the fifth to seventh decade of life with a predilection for females [1,2,19]. Common symptoms associated with CMEC are swelling and pain, with less common presentations including paraesthesia, tooth mobility, and trismus [1,19,20]. Radiographically, CMEC presents as a unilocular or multilocular radiolucency, exhibiting considerable radiographic overlap with odontogenic cysts and tumors [1,3,20,21]. However, glandular odontogenic cyst (GOC), a common radiographic and histomorphologic mimicker, has been shown to lack MAML2 rearrangement, discrediting the etiologic relationship between GOC and CMEC [12]. We report a rare case of primary CMEC of the mandible with MAML2 rearrangement in a 75-year-old female, adding to the few reports of documented MAML2 rearrangement in CMEC.

Case Report
A 75-year-old female patient was initially admitted to the Brooke Army Medical Center (BAMC) emergency room, San Antonio, for a motor vehicle accident when a neck lymphadenopathy was identified. Because of the lymphadenopathy and evaluation/extraction of non-restorable teeth #14 and #30, she was referred to the Oral & Maxillofacial Surgery Unit of BAMC from the general surgery unit of BAMC and a private dental office, respectively. The patient stated that the right neck swelling had progressively increased in size, prompting her to seek care with the general surgery unit. Extraoral examination was negative for facial asymmetry, erythema, and tenderness on palpation. An appreciable enlarged cervical lymph node of the neck was fixed and non-tender on palpation. Panoramic radiographic imaging revealed an asymptomatic ill-defined radiolucent lesion distal to tooth #31, without association with the apices, and no evidence of root resorption (Figure 1(a)). Intraorally, tooth #31 was not mobile, and the overlying tissue distal to tooth #31 was intact, normal in color, and without signs of infection, or purulence, but it was tender to palpation. A CT-scan of the skull and jaws showed the mandibular radiolucency measuring 23 mm in widest diameter, erosion of the lingual cortical plate, thinning of the buccal cortical plate, and absence of bucco-lingual bony expansion (Figures 1(b) and 1(c)).
An incisional biopsy of the lesion was performed, and histopathologic examination revealed an epithelial-lined cyst wall with infiltrating nest of an admixture of epidermoid and mucous cells with a predominant mucinous component (Figures 2(a), 2(b), and 2(c)). The following differential diagnoses were considered: CMEC, GOC, and primary intraosseous mucinous adenocarcinoma. To arrive at a definitive diagnosis, tissue was sent to the Mayo Clinic Genomics Laboratory in Rochester, MN, USA, for molecular testing. The MAML2 rearrangement was confirmed by fluorescence in-situ hybridization (Figure 2(d)), with 54% of examined cells translocated. A diagnosis of low-grade CMEC was rendered.
The patient underwent radical resection, including right partial mandibulectomy, partial resection of the adjacent floor of the mouth, and right selective neck dissection of levels 2 through 4. Gross evaluation of cut sections of the mandible revealed a cystic cavity filled with gelatinous material ( Figure 3). Final histopathologic examination was consistent with low-grade CMEC with soft tissue extension, perineural invasion, benign submandibular gland with chronic sialadenitis, and 2 of the 19 lymph nodes evaluated in right neck level 2 were positive for MEC. The patient's tumor was staged T3: N3b. The diagnosis of low-grade MEC was made based on the overwhelming cystic component, absence of necrosis, no to very low mitotic count per 10 high power field, and anaplasia absent.

Discussion
Primary CMEC is a rare salivary gland malignancy occurring in the jaws. The pathogenesis of CMEC within jaw bones is not fully understood, and several theories have been postulated [1,3,[22][23][24]. First, neoplastic transformation of entrapped mucous glands during the development of the jaw [24]. Second, neoplastic transformation of developmentally displaced ectopic salivary gland tissue in the jaw [23]. Third, neoplastic transformation of mucous cells in the pluripotent epithelial lining of pre-existing benign odontogenic cysts [1,3,22]. This latter theory is supported by the fact that Eversole et al. found approximately 50% of mandibular CMEC is associated with a dental cyst and/or impacted teeth, and Brookstone and Huvos reported similar findings in 32% of cases [1,3].
Our case was not associated with a dental cyst or an impacted tooth. The main symptoms associated with CMEC are swelling, pain, and paraesthesia [19,20]. The patient reported none of these symptoms in this case, as this was an incidental finding. Lack of associated symptoms may be credited to early detection, as the patient was under routine dental care.
In summary, we report an extremely rare case of MAML2-rearranged primary intraosseous MEC of the mandible that was discovered as an incidental radiographic finding. Our review of the literature identified 36 cases of MAML2-rearranged intraosseous lesions of the jaw (30 CMECs, 5 odontogenic cysts with mucous prosoplasia, and 1 GOC). Given the therapeutic indication for a diagnosis of MEC (a malignant neoplasm), MAML2 rearrangement should be confirmed in suspected cases of CMEC. However, a negative MAML2 rearrangement should not rule out a CMEC.

Data Availability
Data supporting this research article are available from the corresponding author or first author on reasonable request.

Conflicts of Interest
All authors declare that there are no financial conflicts associated with this study and that the funding source has no role in conceiving and performing the study.