In 2012, Rotellini et al. proposed WT with myxoid and squamous metaplasia. In the same year, Mohapatra and Satyanarayana reported MEC with numerous eosinophilic epithelia lacking typical epidermal, mesenchymal, and mucous cells and with extensive lymphocytic infiltration, which was considered WT MEC for diagnostic purposes. The term WT MEC was first formally proposed in the diagnosis of salivary gland tumors by Ishibashi et al in 2015. Recently, several cases of mutant MEC, consisting of multilayered cuboidal eosinophils and abundant lymphoid tissue with germinal centers similar to the WT form, have been reported[5–6]. In salivary gland pathology, WT MEC is a rare tumor, and many tumors have been misdiagnosed as MT in the past due to the significant histologic similarities that exist between WT MEC and WT.
WT and MEC are neoplasms of salivary gland origin and can be characterized as two distinct neoplasms with different histologic diagnostic criteria and clinical features: WT is a clearly demarcated parotid tumor with a cystic structure and variable papillary shape histologically composed of (i) prominent lymphoid stroma and oncocytic epithelial elements; (ii) oncocytic epithelium consists of two layers of outer cuboidal basal cells with nuclei at the base and luminal epithelial cells with nuclei predominantly on the luminal side[8, 9]. On the other hand, MEC, the most common salivary gland malignancy, especially in young adults, typically aggregates epidermal cells, intermediate cells, and mucous cells, forming a solid or cystic pattern[8, 10]. When analyzed histologically, WT MECs observed under low power show a cystic structure of oncocytic epithelial cells with lymphoid interstitium, and their cellular arrangement and characteristics are strongly reminiscent of WT. The most important finding is that WT MECs lack the well-arranged, bilayered oncocytic epithelial tissue characteristic of WT. In rare cases, perineural invasion and necrosis are also observed.Only 26 cases of WT MEC have been reported in the literature, including this case, since the first report by Ishibashi et al. in 2015[7, 11, 13]. The most common and predominant complaint is a painless mass, and all cases preferentially affect women and originate in the parotid gland. It is generally believed that this tumor appears in adults, but it can also occur in teenagers, as the broad age range is 13–60 years[11, 13]. The main pathologic differential diagnoses of MT MEC were WT with squamous and mucous epithelium metaplasia and malignant transformation of benign Warthin's tumor to MEC (MEC ex-WT).
In WT, the formation of squamous and mucous epithelium metaplasia may occur; transformation of WT is usually localized, with an increase in the epithelial layer and the formation of cystic structures covered with mucous and nonkeratinized squamous epithelial cells. However, WT MECs exhibit atypical cells and infiltrative growth and lack the well-arranged bilayered oncocytic epithelial tissue characteristic of WT. The presence of double oncocytic epithelium (mucous and squamous epithelium metaplasia) is one of the most reliable histologic findings that distinguish metaplastic WT from WT MEC In addition, while the transformation of WT to the squamous epithelium is 7.5%, the presence of both mucous and squamous epithelium metaplasia in WT is extremely rare (0.2%). In addition, since MEC is more common in adults or teenage females but WT is more common in males in their 50s to 60s who are smokers, a differential diagnosis may be possible based on these clinical features. The most important finding is that WT, which has both mucous and squamous epithelium metaplasia, lacks the MAML2 rearrangement that is often present in WT MEC and conventional MEC. The present case lacked bilayers of oncocytic epithelial tissue, and the epithelium was multilayered and contained single scattered mucous cells. In addition, there were small foci of tumor cells infiltrating and proliferating into the surrounding lymphoid stroma. Thus, based on this pathologic morphology, this case was diagnosed as WT MEC, but not as WT with mucous and squamous epithelium.
The most common malignant transformation from the epithelial component of WT may result in squamous cell carcinoma. Other malignant metastatic tumors from WT include oncocytic carcinoma, adenocarcinoma, and MEC. Nevertheless, it is important to note that they can occur simultaneously in the salivary glands as collision tumors. To support the diagnosis of MEC ex-WT, Seifert et al. proposed four criteria: (i) the presence of a WT background, (ii) a transition zone between the epithelial components of WT and MEC, MEC ex-WT, (iii) invasive growth into surrounding tissues (iv) exclusion of metastasis of the extra salivary primary tumor to lymphatic stromal components. It is noteworthy that this can also occur in MAML2. In addition, WT generally occurs more frequently in older males; therefore, it is highly unlikely that MEC ex-WT occurs in children or teenagers. Rarely the epithelial portion of WT tumors can become malignant, but the cause of this is not yet fully understood. Stimulation by chronic local inflammation, hypoxia, and ischemia is thought to play an important role in the transformation from benign epithelium to atypical hyperplasia. In the present case, there was no WT background or no transition zone between the epithelial components of WT and MEC. Therefore, we conclude that the final diagnosis in this case is WT MEC, not MEC ex-WT.
The most important diagnostic clue for WT MEC is MAML2 rearrangement by FISH analysis, which is specific for MEC and correlates with low- and intermediate-grade histology and improved prognosis. Cytogenetic studies by Citak EC et al., which characterize both MECs, have identified a specific chromosomal translocation: t(11;19) (q21;p13), resulting in a new fusion oncogene, CRTC1-MAML2. Most recent studies have not reported MAML2 rearrangements in WT; in the study of Bieńkowski et al., MAML2 rearrangements were not observed in 114 WT cases, including WT with squamous and mucous epithelium metaplasia. Although it is unfortunate that FISH analysis of MAML2 was not performed in this case, the diagnosis of WT MEC was possible based on typical histological features.
Current guidelines state that the treatment strategy for MEC is often to perform a total parotidectomy with some degree of neck dissection. In cases of high-grade tissue or positive resection margins, adjuvant radiation therapy should be considered. To date, few cases have been reported with follow-up, but with regard to WT MEC in a 17-year-old female, there is one case of recurrence as a normal MEC 4 years later. However, like low-grade normal MEC, WT MEC appears to have a slow biological behavior, and no metastasis of WT MEC has been reported to date. In addition, most cases with WT MEC have been successfully treated with complete local excision. In the present clinical report, since the resection margins and lymph node metastasis were negative, postoperative adjuvant therapy was not performed, and no recurrence or metastasis was observed at 1-year follow-up.