Primary mucoepidermoid carcinoma of the external auditory canal with a CRTC1::MAML2 fusion: A case report and a review of literature

Mucoepidermoid carcinoma is a malignant neoplasm of exocrine glands that arises predominantly in salivary glands. It is seldom encountered as a primary cutaneous neoplasm, and in those patients, it often involves the external auditory canal. Given their rarity, they can pose a diagnostic challenge and prompt extensive workup. In salivary glands, mucoepidermoid carcinomas commonly harbor CRTC1/3::MAML2 fusions; however, genetic alterations of primary cutaneous neoplasms are less characterized, with previous studies reporting CRTC1 rearrangements in the absence of MAML2 aberrations. Herein, we report a case of a primary cutaneous mucoepidermoid carcinoma of the external auditory canal with a CRTC1::MAML2 rearrangement. We also review the clinical, morphologic, and molecular features of this neoplasm and compare them to those reported in the literature and to histopathologic mimics.


| INTRODUCTION
Mucoepidermoid carcinoma (MEC) is a malignant neoplasm of exocrine glands that arises predominantly in salivary glands.Cutaneous involvement may result from the direct extension of a primary salivary gland tumor, metastasis from a distant site, or more rarely the result of a primary cutaneous neoplasm.Primary cutaneous MEC (cMEC) may arise de novo or in a preexisting nevus sebaceus. 1A subset of de novo cases is encountered in the external auditory canal.There, they may prompt consideration of primary or metastatic adenocarcinoma and adenosquamous carcinoma among others.While salivary gland mucoepidermoid carcinomas usually harbor chromosomal rearrangements of MAML2 with CRTC1/3, 2,3 genetic alterations of cMECs are less characterized, with previous studies reporting CRTC1 rearrangements in the absence of MAML2 aberrations. 4Careful utilization of ancillary testing could help confirm the diagnosis and ensure proper management.

| DISCUSSION
Mucoepidermoid carcinoma is a well-characterized malignancy of the major salivary glands with infrequent presentation in the sinonasal tract, lacrimal passages, bronchi, esophagus, thymus, breast, pancreas, prostate, and skin. 6Although the etiopathology of cMEC is unclear, it has been postulated to arise from sweat glands or ectopic salivary glands.Its proposed origin from sweat glands is based on the shared ectodermal derivation of sweat glands and salivary glands and the identification of mucin in normal and tumoral sweat glands tissue. 7][10][11] cMECs are more prevalent in white individuals (80%) with a mean age of diagnosis of 63.4 years (range 23-94 years).They are typically low-grade neoplasms (75.5%) that present as asymptomatic or ulcerated nodules in the face (84.3%), followed by the trunk and the extremities.
Overall, cMECs have a 5-year overall survival (OS) and diseasespecific survival (DSS) of 68.2% and 76%, respectively. 12Fatalities are more prevalent in high-grade neoplasms. 12,13In this regard, predictors of survival include older age (shorter OS and DSS), highgrade lesion (shorter OS), face as lesion site (longer OS and DSS), and surgical resection as a treatment modality (longer OS and DSS). 12cMEC arising particularly in the external auditory canal is even more rare.[11]14 A recent study reported only four cases in a cohort of 135 individuals with ceruminous carcinomas of the external auditory canal. 15One patient died as a result of the tumor and one was alive at the conclusion of the study.They reported an additional literature review of eight cases where the local recurrence, disease-specific death, and OS were 38%, 18%, and 86%, respectively; however, some of the tumors analyzed were termed "ceruminous adenocarcinomas" and it is unclear whether they represent true mucoepidermoid carcinomas or another adenocarcinoma subtype. 15stopathologically, the microscopic findings of cMEC are similar to those in the salivary glands.It consists of a dermal-based proliferation of mucous, epidermoid, intermediate cells, and occasionally clear cells with variable duct, cyst, and papillary formation.
There is often mucin spillage and a lymphohistiocytic infiltrate surrounding the tumor.Although not frequent, an epidermal attachment can sometimes be seen.[21] Given the rarity of these tumors, they usually prompt several diagnostic considerations and subsequent workup.Primary cutaneous mucinous carcinoma or metastatic mucinous adenocarcinoma from visceral sites such as breast and colon are important diagnostic considerations when cMEC has a glandular and/or goblet cell predominance or when there is abundant mucin spillage.In this situation, negative reactivity for ER, PR, and GCDFP-15 immunohistochemical stains supports a diagnosis of cMEC over primary cutaneous mucinous carcinoma or metastatic mucinous adenocarcinoma from the breast.Likewise, positive reactivity for CK7 and negative reactivity for CK20 and CDX2 argue against a colonic adenocarcinoma metastasis. 22Immunohistochemical positivity for p63 also favors a primary neoplasm over a metastasis. 16Direct extension or metastasis from a primary salivary gland MEC requires careful clinical and/or radiologic evaluation, especially when a tumor directly overlies the parotid gland.Features that favor a cutaneous origin include an epidermal connection, presence of the tumor bulk in the dermis with only small tumor nests in the parotid gland, lymphocytic inflammation at the interface of the tumor and the parotid gland, and the presence of p63 reactivity. 6Adenosquamous carcinoma is another diagnostic consideration, which is regarded as a high-grade and clinically aggressive neoplasm with high rate of local recurrence and metastasis.In contrast to adenosquamous carcinoma, cMEC does not have an overlying dysplastic squamous epithelium and lacks true squamous and well-differentiated adenocarcinoma features.Moreover, it shows intermediate cells, peritumoral fibrosis/inflammation, and true mucous cells rather than intracellular or intraluminal mucin production. 17Cutaneous hidradenoma represents another significant diagnostic consideration due to its overlapping features with MECs.In addition to ductal structures and the presence of mucous, epidermoid, intermediate, and clear cells, hidradenoma may exhibit plasmacytoid cells, as well as apocrine differentiation, which can include decapitation secretion and apical snouting.A commonly associated feature is the presence of a sclerotic stroma. 23Hidradenoma's malignant counterpart, hidradenocarcinoma, contains the same cellular composition; however, it typically displays architectural features of malignancy, such as asymmetry, infiltrative growth, intravascular invasion, necrosis, pleomorphism, and atypical mitotic figures, among others.Despite these distinctions, differentiating between the two can prove challenging.In some cases, the presence of a residual benign hidradenoma portion may assist in diagnosis. 24 salivary gland tissue, the most common genomic alteration of MEC is translocation t(11;19)(q21;p13) which results in fusion of exons 2-5 of a member of the Mastermind-like gene family (MAML2) on chromosome 11 with exon 1 from CRTC1 (CREB regulated transcription coactivator) on chromosome 19. 25In another study using fluorescent in situ hybridization (FISH), the MAML2 rearrangement has shown a sensitivity and specificity of 82% and 100%, respectively, for the diagnosis of MEC in salivary glands. 3A rearrangement involving the MAML2 gene has also been reported in up to 90% of cases of cutaneous hidradenomas. 23The CRTC1::MAML2 and CRTC3::MAML2 gene fusions have been previously detected in 47.6% 26 and 5% 27 of the cases, respectively.In hidradenocarcinomas, the CRTC1::MAML2 fusion has been found in 29% of cases. 24On the other hand, molecular drivers of cMECs remain less well-characterized.In a rare series involving eight cMECs, none exhibited MAML2 rearrangements, whereas five presented CRTC1 rearrangements.Notably, none of the tumors were located in the external auditory canal. 4To the best of our knowledge, no molecular features have been reported in the literature regarding cMECs in this specific location, which may explain the absence of CRTC1::MAML2 fusion detection in the previously mentioned study.This is a rare report of the canonical CRTC1::MAML2 translocation in a case of cMEC of the external auditory canal.Awareness of the histopathologic and molecular features that characterize MEC, and its uncommon location in the skin may help differentiate this primary cutaneous neoplasm from histopathologic mimics such as adenosquamous carcinoma and other high-grade tumors with worse clinical prognosis.

A
39-year-old female presented with constant right ear pain and hearing loss for 3 months.Clinical examination revealed a 1.5 Â 1.0 Â 0.5 cm mass in the anterior external auditory ear canal.The lesion was initially managed as an abscess, but incision and drainage with antibiotics provided no resolution of the symptoms.The patient underwent excision 1 month later and histopathologic examination revealed an infiltrative proliferation of variably sized glandular and cystic structures lined by intermediate, epidermoid, and mucous cells associated with lymphoplasmacytic inflammation, fibrosis, and extracellular mucin (shown in Figure 1A-C, whole slide image can be found at https://dsa.sca.iu.edu/dsa/#item/ 642c553e1b6e43f91e900a96). A focal epidermal attachment was noted (shown in Figure 1D).The tumor cells demonstrated strong diffuse reactivity for CK7, p63 (shown in Figure 1E,F), and CK5/6, and no reactivity for CK20, S-100, calponin, estrogen receptor (ER), progesterone receptor (PR), and CDX2 immunohistochemical stains.No high-grade areas were seen.Based on these findings, a diagnosis of mucoepidermoid carcinoma was favored.Whole transcriptome sequencing analysis (Tempus xT-version 4) 5 identified a CRTC1::MAML2 rearrangement.The findings confirmed the diagnosis of cMEC.Clinical examination of the major salivary glands identified no masses, which supported the interpretation of cMEC of the external auditory canal.