Central mucoepidermoid carcinoma arising directly from a glandular odontogenic cyst of the mandible: a case report

Background Central mucoepidermoid carcinoma (MEC) is a rare salivary gland tumor that affects the jawbone. Glandular odontogenic cyst (GOC) is also a rare odontogenic developmental cyst with glandular differentiation. GOC shares some histological features with central MEC, and a pre-existing GOC can develop into central MEC. Here, we present a rare case of central MEC developed directly from a pre-existing GOC of the mandible. Case presentation A 67-year-old Japanese man presented with a cystic lesion in the right third molar region. Histologically, the biopsy specimen demonstrated both typical findings of a GOC component lined with non-keratinized squamous epithelium and a recognizable component of central MEC consisting of polycystic nests with mucous cells, intermediate cells, and epidermoid cells in the cyst wall. The results from the immunohistochemistry for cytokeratin (CK) profiling demonstrated that, while both central MEC and GOC expressed CKs 7, 14, 18, and 19, CK13 was interestingly exclusively expressed in GOC. Fluorescence in-situ hybridization (FISH) revealed the rearrangement of the Mastermind like (MAML)-2 gene in both the MEC and GOC components. Conclusions Our case suggests that central MEC and GOC may be in the same spectrum of diseases caused by the rearrangement of the MAML-2 gene. However, given that the expression profile of CK13 was completely different between central MEC and GOC, they can be considered as separate tumors. Overall, we demonstrated a rare case in which central MEC may have originated directly from the GOC.


Background
The most common type of salivary gland tumor arising from the jaw is central mucoepidermoid carcinoma (MEC) 1 . With regard to the developmental origin, 50% of the central MECs are associated with an odontogenic cyst or unerupted tooth 1 . Glandular odontogenic cyst (GOC) is an uncommon developmental cyst and numerous histopathological features of GOC, such as eosinophilic surface cuboidal cells, intraepithelial microcysts, and mucous cells have been described 2 . GOC shares some histopathological features with central MEC, including a cystic space lined by an epithelium consisting of mucous cells and squamous cells; consequently, it may be confused with central MEC 3 . However, there is only one report of GOC transforming to central MEC 4 . Therefore, GOC is the most important entity in the differential diagnosis of central MEC; however, the morphological similarities make diagnosis di cult. Although immunohistochemistry for the cytokeratin (CK) pro le and analysis of the Mastermind like (MAML)-2 gene rearrangement are reportedly useful for distinguishing GOC from central MEC, only a limited numbers of the cases have been described 3, 5-10 . The aims of this case study were to analyze the immunohistochemical expression of CKs and MAML-2 gene rearrangement in a case of central MEC arising from a GOC, and to compare the ndings between GOC and central MEC.

Case Presentation
Clinical history A 67-year-old Japanese man gave a history of being diagnosed with a cystic lesion in the right third molar region of the mandible by X-rays 11 years earlier. Subsequently, a tooth extraction had been performed.
However, cyst enucleation and histopathological examination had not been carried out at that time. Eight years after the tooth extraction, he noticed a gingival swelling which lasted for three years. The medical history was negative, with the exception of prostatic hypertrophy. On examination, a slight swelling was palpable in the gingiva of the right third molar region of the mandible. There was no stula but a part of the bone had a defect. A panoramic radiograph revealed a radiolucent cystic lesion, measuring 10 x 12 mm in the same area (Fig.1a, yellow arrows). A computed tomography (CT) showed an unilocular radiolucent lesion along with cortical bone resorption of the mandible on the lingual side (Fig. 1b). On the basis of clinical and radiological ndings, a presumptive diagnosis of an odontogenic cyst was made and a biopsy was performed. The incisional biopsy resulted in a diagnosis of central MEC arising from a GOC as described below. Chest and abdominal CT ndings were within normal limits. A magnetic resonance imaging (MRI) revealed a contrast defect in the same area (Fig. 1c). Cervical lymph node metastasis was absent on MRI. Due to the malignant nature of the tumor as well as a history of previous surgeries, a partial mandiblectomy was performed to remove the lesion with a su cient surgical margin and the tumor was surgically excised under general anesthesia. Following a nal diagnosis of central MEC, the patient made an uneventful recovery and demonstrated no clinical evidence of recurrence in the two years following the surgery.

Pathological ndings
Microscopic examination of the biopsy material showed an enlarged unilocular cyst (Fig. 2a). The cystic lumen was lined by epithelial cells and was surrounded by thick brous connective tissue. Additionally, a solid polycystic lesion was also seen on one side (Fig. 2a, black arrows). Numerous microcysts and mucous goblet cells were observed in the lining epithelium (Fig. 2b). The intraepithelial mucin in the mucous goblet cells was positive for mucicarmin staining (Fig. 2c). Eosinophilic cuboidal cells (Fig. 2d) and ciliated cells (Fig. 2e) were scattered within the non-keratinized squamous epithelial cells. These histopathological ndings were suggestive of a GOC. In addition to the cyst wall consisting of brous connective tissue and the above-mentioned non-keratinized squamous epithelium coating the brous stroma (Fig. 2a, black square and 2f), the proliferation of many cystic nests containing mucous materials was observed in another part of the cyst wall (Fig.2a, yellow square and 2g). The lining epithelium inside several cysts consisted of a mixture of epidermoid, mucous, and intermediate cells (Fig. 2g). These ndings served to con rm the diagnosis of central MEC arising from a GOC.
We evaluated the cytokeratin (CK) pro le by immunostaining to compare the CK expression patterns between central MEC and GOC in the biopsy specimen. The lining epithelium comprising non-keratinized squamous cells in the GOC part (Fig. 2f) showed immunopositivity for CK 7 (Fig. 3a), CK13 (Fig. 3c), CK14 (Fig. 3e), CK18 (Fig. 3g), and CK19 (Fig. 3i). On the other hand, the central MEC part was positively stained for CK7 (Fig. 3b), CK14 (Fig. 3f), CK18 (Fig. 3h), and CK19 (Fig. 3j), whereas immunoreactivity for CK13 was not detected (Fig. 3d). In the nal surgical specimen obtained after mandibular partial resection, the tumor with several cystic spaces could be seen to expand into the submucosal area under the gingival mucosa from the mandibular bone in the cut surface (Fig. 4a). The resected specimen contained only central MEC (Fig. 4b). The keratin immunohistochemical pro les of CKs were similar to the previous results of central MEC in the biopsy specimen, which was not positive for CK13 (Fig. 4c) but was positive for CK18 (Fig. 4d). The histopathological examination of the nal surgical specimen con rmed the presence of central MEC arising from a previous GOC after consideration of the histopathological ndings of the biopsy specimen.
We sought to clarify the relationship of GOC to central MEC by performing MAML-2 molecular analysis of the lesion. Break-apart uorescence in situ hybridization (FISH) for MAML-2 was performed. The component of central MEC in the biopsy specimen exhibited the MAML-2 rearrangement by break apart FISH (Fig. 5a). In cystic areas of the GOC, the MAML-2-split was also present (Fig.5b). Additionally, MAML-2 rearrangement was also detected in central MEC of the nal surgical specimen (Fig. 5c).

Discussion And Conclusions
We described a rare case of central MEC arising from a GOC of the mandible. The GOC is an uncommon cyst accounting for 0.012 to 1.3% of all cysts located in the facial part of the skull 4 . Central MEC is also very rare, representing only 2 to 4 % of all MECs 5 . Several cases formerly diagnosed as central MEC may have been cases of GOC and some central MECs could have originated from GOCs 4, 6 . There are previously reported cases in which the rst biopsy was diagnosed as GOC, but the recurrent lesion was central MEC 4, 6 . To our knowledge, this is the rst case report describing a case where central MEC occurred directly from GOC. In other words, our case showed a cystic lesion with pathological ndings typical of a GOC, but there was also a recognizable component of central MEC at the same time in the cyst wall.
Regarding the strong histopathological similarities between GOC and central MEC, previous reports have suggested that the differences in the expression pattern of CKs in GOC and central MEC may be helpful for diagnosis 5-8 . Our results demonstrated that while both central MEC and GOC expressed CKs 7, 14, 18, and 19, CK13 was only expressed in GOC. Therefore, the immunohistochemical pro le of CK13 may be useful for differential diagnosis of central MEC and GOC. Pires  previously reported that the reciprocal immunohistochemical expression pattern of CK17 and CK13 in the oral mucosal epithelia correspons to the grades of malignancy in the oral squamous cell malignancies, and that their immunohistochemical pro les were evaluated by referring to the presence or absence of positivities as follows: the CK17+/CK13− pattern indicated carcinoma in situ or squamous cell carcinoma, while the CK17−/CK13+ pattern meant normal and dysplastic epithelia 11, 12 . CK13 positivity can be a hallmark of squamous epithelium within the normal keratinization processes 11, 12 . Rearrangements of MAML-2 have recently been detected in up to 75 % of MECs of the salivary glands, and are very speci c for this tumor type 3 . Bishop et al. reported MAML-2 rearrangements in central MECs; however, the MAML-2 status of GOCs is not known 3 . In our present case, MAML-2 rearrangements by break apart FISH were present not only in the central MEC in the biopsy specimen as well as the nal surgical specimen but also in the cystic area of the GOC. Reddy et al. reported that rearrangements of MAML-2 are not always reliable for differentiating central MEC from GOC, as a lesion diagnosed as a cyst of unknown origin with features slightly suggestive of GOC was also positive for MAML-2 rearrangement 9 . In a study by Greer et al., MAML-2 rearrangements were detected in one case out of 11 previously diagnosed GOCs, and it was suggested that recurrent biologically aggressive GOCs with MAML-2 rearrangements were a precursor of central MEC 10 . GOC is similar in histological features to central MEC, and the MAML-2 rearrangements detected by break apart FISH are the same as central MEC, suggesting that GOC may be the same entity as central MEC.
Notably, odontogenic cysts are usually rather innocuous lesions that do not recur after curettage. Nevertheless, intraosseous carcinoma, including central MEC is associated with these cysts in 75% cases 1 . Therefore, when a cystic lesion caused by an impacted tooth is extracted, the cyst wall needs to be properly removed surgically and it is important to request a histopathological examination to con rm the diagnosis.