MAML2 Rearrangements in Variant Forms of Mucoepidermoid Carcinoma: Ancillary Diagnostic Testing for the Ciliated and Warthin-like Variants

Abstract

Mucoepidermoid carcinoma (MEC) is the most common salivary gland malignancy. Recent studies have shown that most MECs harbor gene fusions involving MAML2-an alteration that appears to be specific for MEC, a finding that could be diagnostically useful. While most cases of MEC are histologically straightforward, uncommon variants can cause considerable diagnostic difficulty. We present 2 variants of MEC for which MAML2 studies were crucial in establishing a diagnosis: a previously undescribed ciliated variant, and the recently described Warthin-like variant. All cases of ciliated and Warthin-like MEC were retrieved from the archives of The Johns Hopkins Hospital. Break-apart fluorescence in situ hybridization for MAML2 was performed on all cases. One ciliated MEC and 6 Warthin-like MECs were identified. The ciliated MEC presented as a 4.6 cm cystic lymph node metastasis originating from the tongue base in a 47-year-old woman. The Warthin-like MECs presented as parotid masses ranging in size from 1.2 to 3.3 (mean, 2.7 cm) in 4 women and 2 men. The ciliated MEC consisted of macrocystic spaces punctuated by tubulopapillary proliferations of squamoid cells and ciliated columnar cells. The Warthin-like MECs were comprised of cystic spaces lined by multilayered oncocytic to squamoid cells surrounded by a circumscribed cuff of lymphoid tissue with germinal centers. In these cases, the Warthin-like areas dominated the histologic picture. Conventional MEC, when present, represented a minor tumor component. MAML2 rearrangements were identified in all cases. Warthin-like MEC, and now a ciliated form of MEC, are newly described variants of a common salivary gland carcinoma. Unfamiliarity with these novel forms, unanticipated cellular features (eg, cilia), and morphologic overlap with mundane benign processes (eg, developmental ciliated cysts, Warthin tumor) or other carcinomas (eg, ciliated human papillomavirus-related carcinoma) may render these variants susceptible to misdiagnosis. These unusual variants appear to consistently harbor MAML2 fusions-a finding that establishes a clear link to conventional MEC and provides a valuable adjunct in establishing the diagnosis.

Figure 1

This ciliated mucoepidermoid carcinoma presented as a cystic metastasis to a lateral cervical lymph node (A). The cystic lining was comprised of variably proliferative papillae and glandular spaces (B). The tumor cells were predominantly intermediate cells with clear cytoplasm, admixed with squamoid and mucinous cells. The nuclei were very bland (C). Many of the tumor cells exhibited cilia (arrows) (D).

Figure 2

The ciliated mucoepidermoid carcinoma was positive for p16 by immunohistochemistry (A) but negative for high-risk HPV by RNA in situ hybridization (B). Break apart FISH for MAML2 was positive, with one intact gene and one rearranged.

Figure 3

The Warthin-like mucoepidermoid carcinomas closely resemble Warthin tumor at low power. There are composed of cystically dilated glands and surrounded by a well-circumscribed cuff of chronic inflammation with germinal centers (A). The squamoid epithelial lining may be multilayered and eosinophilic, resembling that of Warthin tumor (B). Most cases had at least rare foci of more proliferative epithelium recognizable as conventional mucoepidermoid carcinoma (C). Break apart FISH for MAML2 was positive throughout the tumor (D).

Figure 4

Comparison of the epithelial linings of Warthin-like mucoepidermoid carcinoma (A) and true Warthin tumor (B). The lining of Warthin-like mucoepidermoid carcinoma is more disorganized and less overtly oncocytic.