Epithelial-Myoepithelial Carcinoma of The Minor Salivary Glands: Report of Two Cases with Literature Review

Epithelial-myoepithelial carcinoma (EMC) is a rare malignant salivary gland tumor, which is especially uncommon in the minor salivary glands (MSG). We report literature review of EMC of the MSGs with our experience of two cases. Case 1 is a 75-year-old woman with a hard elastic mass in the hard palate, sized 2.5 × 2 cm without ulceration. Incisional biopsy was suggestive of pleomorphic adenoma. Tumor resection was performed with adequate surgical margin. Case 2 is a 44-year-old woman with a mass in the hard palate, sized 1.8 × 1.6 cm without ulceration. Incisional biopsy was suggestive of pleomorphic adenoma or a low-grade salivary gland carcinoma and intraoral tumor resection was performed. Both have good postoperative courses and are alive with no evidence of local recurrence or metastasis at 25 and 10 months. The Ki-67 labeling index in Case 1 and 2 were 10.6 and 3.8 %. Considering that the anatomy, structure, and size of salivary glands are quite different from MSGs, EMCs of the MSG cannot be predicted similarly to EMCs of the major salivary glands. The present review with 18 cases revealed no consensus on treatment methods for MSG cases other than surgery.


Background
Epithelial-myoepithelial carcinoma (EMC) is a rare malignant salivary gland tumor that accounts for < 1% of all salivary gland epithelial neoplasms and approximately 2% of malignant salivary gland neoplasms [1,2]. The mean age of patients with EMC at diagnosis is 60 years, and it shows a slight female predilection [3]. Most EMCs develop in the parotid gland, while some develop in the submandibular gland [1,4]. In general, EMC is indicated by the recurrence rate of 30-50%, lymph node metastasis rate of 15-20%, and 5-and 10-year survival rates of 80-94% and 72-90%, respectively [1,[4][5][6]. However, these were evident in most of major salivary gland cases. The minor salivary glands (MSG) cases are an uncommon anatomic site for the origin of EMCs.
Due to its rare occurrence, the clinicopathological features and optimal treatment strategies of EMCs of the MSGs have not been fully described, and the relevant literature mostly comprises case reports. Herein, we report two cases of EMC originating from the MSG, and review the relevant literature and assessed our cases.

Case Presentation
Case 1 A 75-year-old woman referred to our department with a complaint of an abnormal swelling on the hard palate for a few months. The patient did not have any history of speci c underlying systemic disease or trauma. Intraoral examination revealed a hard, elastic mass in the right side of the hard palate, sized 2.5 × 2 cm and without ulceration. Histopathological analysis of the sample obtained from incisional biopsy was suggestive of pleomorphic adenoma (PA) of the hard palate. The patient refused excision; therefore, regular follow-up visits for monitoring the tumor had been performed. After a follow-up period of about 14 months, the tumor showed rapid growth. Computed tomography (CT) and magnetic resonance imaging (MRI) revealed an internal non-uniformly enhanced tumor mass, which led to pressure absorption of the palatal bone but invasion of the sinus and nasal cavity was not evident. Although the imaging examinations could not indicate the signi cant ndings of malignancy, it guided a presumptive diagnosis of malignancy, based on the intratumoral heterogeneity. The signi cant cervical adenopathy was not evident. After 1 year and 3 months from the rst examination, tumor resection with adequate surgical margins through an intraoral approach was nally performed under general anesthesia. Intraoperatively, the tumor was resected including the surrounding gingiva and the periosteal, and a layer of the palatal bone was shaved off.

Case 2
A 44-year-old healthy woman presented at our department with a complaint of a swelling in the hard palate. It had been followed up by her regular dentist for 2 months, but the swelling was not improved. Intraoral examination revealed a hard, elastic mass in the right side of the hard palate, sized 1.8 × 1.6 cm and without ulceration. Histopathological analysis of the incisional biopsy sample was suggestive of PA or a low-grade salivary gland carcinoma of the hard palate. CT and MRI revealed an internal nonuniformly enhanced tumor mass, which led to pressure absorption of the palatal bone but invasion of the sinus and nasal cavity and signi cant cervical adenopathy were not evident. Thereafter, the treatment was restricted because of the SARS-CoV-2 infection pandemic in Japan. There was no evidence of rapid tumor growth or metastasis. After four months from the rst examination, since the treatment restrictions were released, intraoral tumor resection was performed under general anesthesia. Similar to Case 1, the tumor was peeled off including the periosteal and a layer of the palatal bone was shaved off. Both patients have good clinical courses on surgical sites and are alive with no evidence of local recurrence or cervical lymph node / distant metastasis at 25 and 10 months after the surgery, respectively.

Microscopical ndings
In our cases, a biphasic glandular structure consisting of glandular cavities with acidophilic vesicles and neoplastic myoepithelial cells with clear vesicles outside the cavities was observed under high magni cation. IHC showed that the tumor was diffusely positive for AE1/AE3; neoplastic myoepithelial cells were positive for p63, S100, calponin, and α-smooth muscle actin (α-SMA), and glandular ductforming cells were positive for epithelial membrane antigen (EMA). In Case 1, the tumor was diagnosed as EMC due to the active ssion images and the high score of Ki-67 labeling index (10.6%) (Figure 1). In Case 2, although Ki-67 labeling index score was 3.8% and ssion images were not frequent, as invasion into the existing MSGs was evident (Figure 1), the tumor was diagnosed as EMC. Both cases were negative at the surgical margin. EMCs in the major salivary glands in a signi cant proportion, demonstrates the low credibility to apply directly for the MSG cases. Moreover, since the anatomy, structure, and the size of major salivary glands are different from MSGs [31], the size of the tumor also cannot be directly considered as a factor to decide treatment for the MSG cases. In the present review, in fact, tumor size of MSG cases ranged from 1 × 1 to 3.7 × 2.5 cm: their sizes were all under 4 cm. Other, the disease duration (range: 1 month -8 years) had a large width, means MSGs cases always cannot be found earlier than that in major salivary gland cases.

Review of literature
Regarding the treatment, the present review could not establish no consensus in the optimal treatment strategy of EMCs of the MSGs due to the limited number of the MSG cases. The role of radiotherapy in EMCs of the MSGs is not discussed adequately. Adjuvant radiotherapy is recommended in major salivary gland tumors where the primary tumor is > 4 cm in size or where the surgical margins are positive [33,34,35]. However, no signi cancy in the survival has been reported in adjuvant radiotherapy [6]. The data from the present review cannot also validate radiotherapy (n = 5, Table 1). The role of adjuvant chemotherapy in EMC is also not well documented. According to Cerda et al., chemotherapy should be considered when irradiation is delivered in doses of 65 Gy or more in the patients with locoregional high-risk salivary gland tumors (close or positive margins) [36].
The diagnostic methods in EMCs of the MSG have basically remained unchanged: combined routine HE with multi-IHC staining ( Table 2). Our cases were stained with almost the same variation. However, these accepted diagnostic methods do pose di culties in the differential diagnosis of EMCs. On microscopic examination, PA is composed of epithelial and myoepithelial cells within variable stroma that may comprise of myxoid, brous, chondroid, mucinous, or even osseous/cartilage tissue: the biphasic pattern of epithelial and myoepithelial cells in this tumor resembles EMC. Most EMCs show a multinodular pattern with evidence of invasion and a classic arrangement of myoepithelial cells with clear cytoplasm that strikingly contrast with the inner low-cuboidal luminal cells. The biphasic structures of EMCs have an interface of a thickened, hyaline-like basement membrane, which is distinct from the chondromyxoid matrix intermingling with the outer myoepithelial cells in PAS staining [15]. Cases of an EMC arising in a PA have been described in the literature, and the diagnosis of malignancy in such cases is predicated on the presence of invasion [5,37,38]. According to Eneroth et al., the risk of malignancy in PA varies from 1.6 to 7.5% [39]. Our Case 1 might be this type. Also, an analysis of recurrent PAs indicated that 7.1% undergo malignant transformation and that the risk of malignancy increases with disease progression [40]. In general, carcinoma arising in a PA is di cult to diagnose because the mixed tumor component is often small and easily overlooked and the malignant component may be di cult to classify [41]. From this viewpoint, it can be deduced that the diagnostic accuracy of incisional biopsy is not high. In this review, only 3 cases (16.7%) could be diagnosed as EMC by incisional biopsy, indicated the limit of the microscopical diagnosis of EMC of the MSG using a part of small mass. In contrast, El Hallani et al.
indicated that 80% of EMCs arising in a PA and the genetic pro le of patients with EMCs varies between the absence or presence of preexisting PA and its cytogenetic signature [37]. This study followed the Declaration of Helsinki on medical protocol and ethics, and the regional Ethical Review Board of Tokyo Medical and Dental University approved the study (Permission no. D2015-600).
Patient consent for publication was acquired.
Consent for publication: The written informed consent to publish the personal and clinical details of the participant was obtained and a copy of the written consent is available for review by the Editor of this journal. Supplementary Files