Background

Mucoepidermoid carcinoma (MEC) is the most common malignant salivary gland tumor (D'Antonio et al., 2015). MEC consists of squamoid cells, intermediate cells, and mucous cells in varying proportions (Liao et al., 2016). MEC may occasionally show presence of other cell types including clear cells and oncocytes. The diagnosis becomes challenging when these cells predominate (Luna, 2006; Coca-Pelaz et al., 2015; Gill et al., 2017). Oncocytic mucoepidermoid carcinoma (OMEC) has a predominance of oncocytes with no well-defined percentage (Weinreb et al., 2009). OMEC is a rare variant. Only a few cases have been reported involving mostly the parotid gland. Submandibular gland is a rare site for OMEC with only four cases reported in the English literature (Corcione et al., 2007; Krishnanand et al., 2007; **g et al., 2012; Avila et al., 2019). Table 1 summarizes them. Mastermind-like 2 (MAML2) translocation is detected in about 66% MEC and many oncocytic MEC (Seethala et al., 2010; García et al., 2011). Skalova et al. found only MAML2 rearranged OMEC with no MAML2 negative OMEC in their study (Skálová et al., 2020). However, Garcia et al. found 4 out of 14 OMEC that were MAML2 negative. All 14 of their cases were parotid tumors (García et al., 2011). We report a rare case of MAML2 negative oncocytic MEC of the submandibular gland. To the best of our knowledge MAML2 negative OMEC has not been reported in the submandibular gland.

Table 1 Cases of submandibular OMEC reported in English literature
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Case presentation

We present a rare case of MAML2 negative OMEC of the submandibular gland in a 73-year-old female with an 11-month history of a left neck mass. CT revealed a large centrally necrotic left submandibular gland mass with a thick enhancing soft tissue rim. Fine-needle aspiration cytology confirmed malignancy. Left submandibular gland resection with marginal mandibulectomy and ipsilateral neck dissection was performed.

Grossly, a circumscribed, solid-cystic tumor measuring 13.5 × 11 × 4.5 cm, arising from the submandibular gland was identified. Microscopic examination revealed an un-encapsulated and infiltrative proliferation of oncocytes forming cords, nests, and sheets. The oncocytes were polygonal in shape and revealed abundant eosinophilic and granular cytoplasm with centrally located nuclei having prominent nucleoli (Fig. 1A, B & C). Tubulocystic areas with rare vacuolated cells and foci of squamoid and intermediate cells were present (Fig. 1D, E & F). A diagnosis of mucoepidermoid carcinoma, intermediate grade, with features of pure oncocytic variant was made. No perineural invasion was identified. Two ipsilateral cervical lymph nodes and mandible were involved. Mucicarmine and alcian blue special stains demonstrate rare intraluminal and intracytoplasmic mucin (Fig. 2A & B). Immunohistochemical (IHC) stains demonstrated immunoreactivity for p63 (diffuse; Fig. 3A), p40 (Fig. 3B), CK5/6 (diffuse, Fig. 3C), and weak and rare immunoreactivity for GATA 3 and GCDFP-15. No immunoreactivity was seen for CK7, calponin, S-100, TTF-1, and thyroglobulin, supporting our diagnosis and ruling out salivary duct carcinoma, mammary analog secretory carcinoma, plasmacytoid myoepithelioma, and metastatic thyroid neoplasm. Table 2 shows specifications of IHC antibodies used. No rearrangement of the MAML2 gene on fluorescent in-situ hybridization testing was identified, when tested at two independent centers. Rearrangements of the MAML2 gene on 11q21 were evaluated using MAML2 break-apart FISH probes (Empire Genomics, Buffalo, NY) on formalin-fixed and paraffin-embedded (FFPE) tissue slides.

Fig. 1
figure 1

Morphology on hematoxylin & eosin staining. A, B & C A solid-cystic infiltrative proliferation of oncocytes forming nests, cords, and trabeculae (H&E; 40X, 100X & 200X). D Tubulocystic area showing cysts lined by oncocytes and rare vacuolated cells (H&E; 200X). E Focus of squamoid cells (H&E; 200X). F Focus of intermediate cells (H&E; 200X)

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Fig. 2
figure 2

Special stains. A Mucicarmine highlighting intracellular mucin (400X). B & C Alcian blue highlighting intraluminal and intracellular mucin (400X & 200X)

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Fig. 3
figure 3

Immunohistochemical stains. A Diffuse nuclear p63 immunostain highlighting squamoid (IHC; 100X). B Diffuse nuclear immunostain highlighting squamoid cells (IHC; 100X). C Diffuse cytoplasmic and membranous CK5/6 immunostain highlighting squamoid cells (IHC; 100X)

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Table 2 IHC antibody specifications
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The patient also had co-morbidities including HCV infection, cirrhosis, coronary artery disease with stent placement and hypertension. She presented 10 days after discharge with left femoral neck fracture and underwent left hip hemiarthroplasty. The pathologic examination revealed signs of fracture without any pathology in the bone. A month later she had right femoral neck fracture which was surgically repaired. Patient tolerated the procedure well and was admitted to the floor. Five days later patient clinically declined and found to be in septic shock secondary to C. difficile colitis. Total abdominal colectomy was performed. However, patient continued to clinically decline and expired the next day.

Discussion and conclusion

MEC is composed of squamoid, intermediate and mucous cells in varying proportions. Other cell types that could be found are clear cells, columnar cells, goblet cells, and oncocytes (Qayoom et al., 2021). Occasionally, clear cells and oncocytes predominate with rare mucinous cells which are the only clue to the diagnosis of MEC. Such cases pose a diagnostic challenge for pathologists. OMEC presents in the age range of 20 to 80 years with a male predilection (Kwon et al., 2010). Most are cystic and have a favourable prognosis (Weinreb et al., 2009). OMEC can be mimicked by many benign and malignant neoplasms, including oncocytoma, oncocytic variant of cystadenoma, oncocytic carcinoma, myoepithelioma, oncocytic pleomorphic adenoma, metaplastic Warthin’s tumor, salivary duct carcinoma, and metastatic renal cell carcinoma. Distinguishing these from OMEC is imperative due to prognostic differences. P63 is considered a potential marker that could differentiate between these entities. The epidermoid/squamoid cells of OMEC are immunoreactive for p63. Oncocytomas and oncocytic carcinoma are also p63, however, the staining pattern is predominantly peripheral/basal (McHugh et al., 2007). Metastatic renal cell carcinoma is p63 negative (McHugh et al., 2007). Myoepithelioma and squamous cell carcinoma stain diffusely with p63 but both lack mucin-producing cells. Myoepithelioma also stains for other myoepithelial markers, such as calponin and actin. Warthin’s tumors typically don’t have mucous cells or intercellular bridges in the oncocytic cells and are non-infiltrative (Weinreb et al., 2009). Pleomorphic adenomas have chondro-myxoid stroma and are generally non-infiltrative (Skálová et al., 1999). The Table 3 summarises the differential diagnosis of OMEC.

Table 3 Differential diagnoses of OMEC
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Rearrangement in MAML2 gene, a component of the Notch signaling pathway, has been promising in diagnosing MEC and its variants accurately. MAML2 translocation by FISH is detected in approximately 66% typical MEC cases and about 71% of oncocytic MEC (Liao et al., 2016; García et al., 2011). In contrast, most of the imitators of MEC are negative for MAML2 translocation. Thus, Liao et al. suggested that MAML2 translocation can be used as a diagnostic tool to detect OMEC. However, our case of MAML2 negative OMEC introduces an important consideration that MAML2 negative OMEC do exist, and the diagnosis should not be solely based on the presence of MAML2 translocation.

Previous studies considered MAML2 to confer a favourable prognosis (Seethala et al., 2010). However, recently the prognostic significance of MAML2 rearrangement has been challenged (Skálová et al., 2020). Our case, which was MAML2 negative, had an aggressive course with spread to mandible bone and regional lymph nodes.

In summary, we present a rare case of MAML2 negative OMEC of the submandibular gland composed primarily of oncocytes with only rare mucous cells, epidermoid cells and intermediate cells. Further studies are required to understand the pathogenesis of MEC and the prognostic significance of MAML2 rearrangement in its pathogenesis. An awareness that MAML2 negative OMEC exists will prevent misdiagnosis and incorrect treatment as many of the differential diagnoses of OMEC are benign.