9.2.1 Introduction

MEC is one of the most common intraoral minor salivary gland malignancies. ¹⁰ Histologically, it is composed of three cell types (mucinous, intermediate, and epidermoid cells) and classified into low-„, intermediate-„, and high-grade MEC. ¹⁰

9.2.2 Epidemiology

The male-to-female ratio is 1:1.4; with an age range from 18 to 67 years (mean age of 60 years). ¹⁰ According to the WHO Classification of Head and Neck tumors, it is one of the most common salivary gland malignancies in young adults and children, and may be secondary to radiation exposure or prior treatment with chemotherapy (latency of 8 years). ¹⁰

9.2.3 Clinical Presentation

While presentation is dependent on site, size, and grade, ¹⁰ it often presents as an asymptomatic dome or swelling. The most common site is the palate, followed by lower lip or alveolar mucosa. ^{7 , 10} A potential pitfall is when MEC may clinically mimic an intraoral mucocele. ¹⁰

9.2.4 Diagnosis and Evaluation

MEC is characterized by three components, which include mucinous cells, intermediate-type cells, and epidermoid cells in variable proportions (▶ Fig. 9.1). The grading of these tumors accounts for solid versus cystic growth patterns, anaplasia, mitotic activity, necrosis, and invasiveness (i.e., perineural, lymphovascular, bone involvement, and/or metastasis).

Low-grade MECs are composed predominantly of a cystic component with a predominance of mucin, macrophages, and bland epithelioid cells. These lesions are usually well circumscribed.

Intermediate-grade MECs may show a mixture of solid and cystic components, without overt high-grade nuclear atypia, but are less well circumscribed. High-grade MECs are predominantly solid but must show at least focal intracellular mucin positivity to make the diagnosis. ¹⁰ According to the WHO classification, high-grade MECs should have at least one of the following: nuclear anaplasia, necrosis, increased mitotic rate, and perineural, lymphovascular, or bony invasion. The presence of keratinization is an unusual feature and may suggest squamous carcinoma/non-MEC tumor (e.g., necrotizing sialometaplasia, pleomorphic adenoma with squamous metaplasia, sclerosing polycystic adenosis, ¹⁰ or epithelial-myoepithelial carcinoma [EMC] with squamous differentiation).

Ancillary studies such as a mucicarmine or periodic acid-Schiff (PAS) with diastase can highlight the mucin within the cytoplasm of the malignant cells. A p40 or p63 immunohistochemistry may be helpful to highlight epithelioid/intermediate cell components, or Ki-67 for better assessment of high mitotic activity within a poorly differentiated MEC. If there is extensive squamous differentiation, the differential diagnosis may also include squamous cell carcinoma of the oral mucosa. In high-grade MEC, at least focal mucin is required and keratinization would not be present.

Some variants of MEC include unicystic, sclerosing, ciliated, Warthin-like, oncocytic, clear cell, spindle cell, goblet cell aggressive, psammomatous, and sebaceous type. ¹³ These rare variants have no prognostic implications. ¹⁴ While these subtypes are rare in minor salivary glands, a brief review of the more histologically challenging variants are described for accurate recognition.

• Sclerosing mucoepidermoid carcinoma (SMEC) is characterized histologically by dense, central hyalinizing sclerosis that lacks an inflammatory response and may obscure classic histomorphologic features of mucin, intermediate cells, or the epidermoid component. The periphery of the tumor may show a mixed infiltrate of plasma cells, eosinophils, or lymphocytes. This is a rare variant with reports predominating in major salivary glands, and very few reports in minor salivary glands. ¹³

• Ciliated MEC is defined by “macrocystic spaces punctuated by tubulopapillary proliferations of squamoid cells and ciliated columnar cells.” ¹⁵ While the ciliated component may suggest benignity, the proliferation of squamous cells can be noted and ancillary molecular testing may assist with a definitive diagnosis.

• The oncocytic variant (OMEC) is characterized by the presence of polyhedral cells with granular eosinophilic cytoplasm that may be arranged in a cystic, organoid, or alveolar pattern with interspersed mucous cells. Few and/or variable squamoid cells and intermediate cells may be present. Only rare cases have been reported in minor salivary glands, all low grade (n = 4). ¹⁴ Immunohistochemistry for p63 or p40 is helpful in distinguishing OMEC from oncocytoma or oncocytic carcinoma, with diffuse staining typically seen in the former, and only patchy, peripheral staining in the latter. ¹⁴

9.2.5 Molecular Testing

The gene fusions involving the MAML2 gene (CTRC1-MAML2 or CRTC3-MAML2) are found in the majority of MECs, of all grades (~75-80%). ¹⁵ This may be helpful in placing malignant cases into a definitive classification, when the histomorphologic diagnosis is elusive (i.e., poorly differentiated or variant MECs, etc.). Gene fusions involving MAML2 are no longer thought to be a contributor to prognosis; therefore, routine MAML2 testing for MEC is not required. ¹⁵