Mucoepidermoid Resembling Squamous Cell Carcinoma in the Premaxilla: A Diagnostic Challenge

Salivary gland malignancy represents a rare yet diverse entity that covers a heterogenous spectrum of neoplasm of various clinical behavior, ranging from protracted, indolent to aggressive, life-threatening manner. Accurate histopathological diagnosis is imperative in terms of prognostication and further management planning. Herein, we report a case of an intermediate grade mucoepidermoid carcinoma of premaxilla masquerading as squamous cell carcinoma. Despite repeated biopsies, histological examinations failed to establish an accurate diagnosis. The patient eventually underwent wide surgical excision of the primary lesion with simultaneous bilateral supra - omohyoid neck dissection. Diagnosis dilemma encountered along with subsequent management are further discussed.


INTRODUCTION
Salivary gland malignancy is a rare entity which contributes around 5% of all head and neck tumours (1). Mucoepidermoid carcinoma (MEC) is the most common malignant neoplasm arising from salivary glands (1). It constitutes about 30% of all salivary gland tumours (2). Histologically, MEC can be categorized into mild, intermediate and high grade (1,(3)(4)(5). Histological findings in high-grade MEC includes solid islands of intermediate and epidermoid cells, which resembles the histological finding in squamous cell carcinoma (SCC), attributing to the its diagnostic dilemma (1). Meticulous evaluation ought to be undertaken to avoid diagnosis inaccuracy.

CASE REPORT
A sixty-eight-year-old lady with no known comorbid presented with painless swelling over the alveolus for the past three months. The mass has progressively increased in size which eventually prompted her for the clinic visit. There were neither history of betel nut chewing nor alcoholic consumption. She also denied family history of head and neck malignancy or any prior radiation exposure. Clinical examination revealed an irregular mass measuring 3 cm x 3 cm located over the premaxilla region ( Figure 1). The mass was non-tender, hard in consistency with irregular surface and border. Examination of other subunits of the oral cavity were otherwise unremarkable.
There was no palpable neck node. Contrast-enhanced computed tomography (CT) performed, demonstrated asymmetrical thickened mucosa over the premaxilla region, with intact underlying cortical bone. No regional and distant metastasis was noted.
An incisional biopsy under local anesthesia was performed. Histopathological examination (Hpe) revealed presence of small islands of stratified squamous epithelium, dyskeratotic cells with keratin pearl formation as well as microcystic formation ( Figure 2). The Hpe was suggestive of MEC and SCC. Hence, a repeated incisional biopsy was performed, given the uncertainty in diagnosis.
The repeated sample showed presence of para-keratinised stratified squamous epithelium tumour composed of island, clusters, nests and strains of blandlooking neoplastic epithelial cells. They exhibited features of nuclear pleomorphism, hyperchromatic nuclei and microcystic formation. (Figure 3). No definite conclusion could be drawn from the second biopsy. The patient was counselled and underwent wide local excision of the primary lesion with bilateral supra-omohyoid neck dissection. Intraoperative frozen section analysis of the excised tumour demonstrated clear surgical margin. Final diagnosis confirmed intermediate grade MEC. She recovered well post-operatively and has been on active clinical surveillance with no evidence of recurrence till date ( Figure 4).

DISCUSSION
First described by Massao and Berger back in 1924, the mucoepidermoid tumour was regarded as a benign lesion which composed of distinct group of neoplasm of salivary gland (2)(3)(4). It is reported to have slight female predominance with a ratio of 3:2 (2). MEC is more prevalent in the fifth and sixth decades of life (2). Approximately two-thirds of MEC arise within the parotid gland (1). The hard palate represents the most frequent site of a minor salivary gland MEC, followed by retromolar region, floor the of mouth, the buccal mucosa and the lower lip (2). Regardless of its location, the most typical clinical manifestation of a minor salivary gland MEC is an asymptomatic swelling that insidiously increases in size (5). Other presentations include pain, ulcer, regional nodal disease and resorption of the underlying bone, which often indicate disease advancement.
MEC is composed of three histological types of cells, namely (1)  The overlapping histological morphologies impose a significant challenge to differentiate between a moderate and high-grade MEC from SCC (1)(4)(6). Differentiating these two entities is deemed necessary as to prognosticate the survival outcome and to outlay the possible treatment plan. The usage of Period acid-sniff (PAS) and mucicarmine stains were reported to be satisfactory in differentiating the two pathologies (6). This however, may not be applicable when squamous cell carcinoma invades the salivary gland structure, which may be easily mistaken as a MEC. Necrotic areas, which are weakly mucicarminepositive, may also contribute to the diagnosis error. In our case overlapping features of keratin pearls with occasional microcystic formation led to the diagnosis of SCC.
Immunohistochemistry staining with various cytokeratins (CKs) can also help to differentiate the two entities due to their difference of tumour origin. SCC originates from epidermis and is positive for CK10, whereas MEC originates from the excretory duct of salivary gland and is CK13 positive (6). The other distinctive feature observed by Aroujo et al. is that SCC is strikingly positive for CK14 (6). Intraoperative frozen section provides insight into the adequacy of margin and to determine the involvement of perineural or lymph vascular involvement. Additionally, it has a respectable accuracy in differentiating benign lesions from malignancies, thereby avoiding under or overtreatment (7). Nevertheless, the employment of a frozen section in differentiating a high-grade MEC from squamous cell carcinoma may be of limited value due to the overlapping of histological morphology.
Radiological modalities such as CT and Magnetic Resonance Imaging (MRI) are invaluable in delineating the extent of the pathology. Evidence of bony invasion is best seen with CT (2). MRI plays role in evaluating the soft tissues involvement of the surrounding oral cavity. Low-grade MEC behaves indolently with radiological features of lobulated or cystic lesion with underlying intact periosteum. Intermediate grade tumour may exhibit features of bony erosion, whereas high-grade MEC may show extensive cortical bony destruction and regional or distant metastasis (2).
The rationale of performing a selective neck dissection in a node-negative MEC remains contentious. Darling R et al. reported an overall rate of nodal disease as high as 40% in patients with high-grade MEC, whereas no regional metastasis was found in low-grade MEC (8). Sood S at el reported a 40 % incidence of lymph node metastasis in intermediate and high-grade tumours (9). An ipsilateral elective neck dissection is best performed when primary lesions are of a higher grade owing to their predilection of nodal metastasis.
The typical extent of the neck dissection was a supra-omohyoid neck dissection as in our case, with completion of a full modified radical neck dissection if frozen sections denote evidence of disease. The alternative management will be elective radiotherapy if surgery is contraindicated.
Neck treatment for early-stage (T1 or T2) node-negative SCC of the oral cavity has also sparked some controversies. The National Comprehensive Cancer Network (NCCN) guideline proposed two modalities for the management of SCC of the oral cavity in early-stage, namely surgery and radiotherapy (9). Surgical treatment includes resection of the primary lesion with or without simultaneous neck dissection (10). However, there was no elaboration on the benefits of simultaneous neck dissection (11). The proponents for selective neck dissection argued that early-stage SCC harbours strong evidence of occult metastasis, ranging from 8.2 % -46.3 % (12). A different school of taught supported observational policy to avoid overtreatment in those without occult metastasis. Liu X et al. demonstrated a similar five years overall survival rate and diseasespecific survival in both groups. This led to the conclusion that observational policy may be an available option for T1/T2N0 SCC as close active surveillance is mandatory in all SCC patients despite different management (12). In our presenting case, the initial histopathological specimens failed to confirm the diagnosis. By correlating with the clinical presentation of a rapid growing midline lesion, bilateral supra-omohyoid neck dissection was justified. Post-operative surveillance after one year showed no evidence of recurrence.

CONCLUSION
MEC of the hard palate represents the most common salivary gland malignancy and should be treated like any other head and neck cancers. Histochemical staining with CK helps to differentiate MEC and SCC. Wide local excision with or without neck dissection remains the treatment modality of both early-stage highgrade MEC and SCC. In case whereby surgical intervention is contraindicated, radiotherapy is advocated.