Sixty-two cases of minor salivary gland-originated SC have been reported between 2010 and 2017 [4, 7–11, 17–40]. These cases were identified in a literature search carried out using keywords such as ‘MASC’, ‘secretory carcinoma’, ‘oral cavity’, ‘buccal mucosa’, ‘lip’, ‘palate’, ‘gingiva’, and ‘tongue’ in the PubMed and Japan Medical Abstracts Society databases. Age, sex, location in the oral cavity, size, TNM classification, treatment, metastasis, local recurrence, follow-up period, and survival rate were all described in 19 of the 62 cases. Pooled analysis of 21 cases, which included the two patients of the present case report, was performed (Table 2). Of the 21 patients, SC developed in the lips in 9 patients and in the buccal mucosa in 6 patients, including our patients. These two locations accounted for 70% of all cases. As the labial mucosa is classified as buccal mucosa in the oral cavity category of Union for International Cancer Control classification, the buccal mucosa accounts for approximately 70% of all cases.
Histopathologically, tumor cells in SC proliferate in microcystic, papillary-cystic, and follicular patterns [4, 6]. However, as this histological morphology is similar to that of AciCC, differentiation between SC and AciCC is difficult by using HE staining alone. Bishop et al. reported that 19% of parotid gland AciCC cases were SC . Similarly, 6 of the 21 cases with oral minor salivary gland-originated SC were initially diagnosed as AciCC, suggesting that the differentiation between SC and AciCC is difficult. In our cases, immunostaining revealed that the tumor was positive for CK19, S-100, vimentin, mammaglobin, GCDFP15, GATA3, and MUC4. These markers have been reported to be useful for differentiating SC from other salivary gland tumors [4, 12–16]. The results were consistent with the findings frequently observed in the previously reported cases of SC, aiding in differentiation (Tables 1 and 3). However, these immunohistochemical findings are not uniform in all SC and AciCC cases; therefore, it is essential to confirm the presence of the ETV6-NTRK3 fusion gene by genetic analysis to make a definite diagnosis [4, 18, 37]. Thus, an accurate diagnosis of SC can be established by the sequential use of HE histological screening followed by immunohistological investigation and genetic analysis.
Surgical resection was performed as the initial treatment in all 21 patients. Local recurrence was noted in three cases, which may have been due to surgical margin positivity in two cases and a close margin in one case. As the histopathological findings of excisional biopsy revealed a close margin in case 1, additional resection was performed with a 10-mm safety margin to prevent local recurrence. Although SC is considered a low-grade malignancy, additional resection should be performed to secure a safety surgical margin in positive cases and cases with a margin close to the tumor to prevent local recurrence.
Fifteen of the 21 cases with oral minor salivary gland-originated SC were treated at cT1N0, that is, in the early stage. Late cervical lymph node metastasis to cervical lymph nodes developed in three cases (14.3%) and seven years after surgery in one case. The frequency of cervical lymph node metastasis is higher in SC than in AciCC: 8–11% in AciCC  and approximately 25% in SC [6, 21, 22, 40, 42, 43]. Sethi et al.  reported that many cases of intercalated duct-type cell-predominant AciCC are metastatic, and these are highly likely to be SC, thereby confirming that the frequency of cervical metastasis may be higher in SC than that in AciCC. Therefore, long-term post-operative observation may be necessary for SC cases considering the possibility of late cervical lymph nodes metastasis. In general, SC is considered as a low-grade malignancy and the treatment outcome is favorable . This was supported by the fact that all 21 patients with oral minor salivary gland-originated SC survived for 4 months to 9 years. However, few patients with parotid gland-originated SC developed distant metastasis and died, suggesting a slightly poor outcome, and cases of high-grade transformation containing a highly malignant tumor component with poor outcomes have also been reported . Furthermore, the possibility of differences in the disease-free survival time among AciCC cases has been previously suggested . Therefore, differentiation between the two carcinoma types is important. To evaluate true malignancy and treatment outcomes of oral minor salivary gland-originated SC and AciCC, re-investigation of the cases diagnosed as AciCC in the past may be necessary.
SC is considered as an NTRK fusion-positive cancer, together with SC of the breast and infantile fibrosarcoma . When the normal NTRK gene is fused with another gene to form an NTRK fusion gene, the tropomyosin receptor kinase (TRK) fusion protein is produced, which continuously activates the phosphoinositide phospholipase Cɣ (PLCɣ), MAPK, and Pl3K signal transmission pathways and promotes cancer cell proliferation [44, 45]. Entrectinib is a potent inhibitor of TRK A, B, and C, which has been shown to have anti-tumor activity against NTRK gene fusion-positive solid tumors, including SC. The effectiveness of entrectinib was recently demonstrated in the studies of tumor alterations responsive to targeting receptor kinases-2 involving patients with NTRK fusion-positive cancer; five of the six patients with SC also responded to the treatment. Entrectinib inhibits the phosphorylation of the TRK fusion protein, which in turn inhibits its downstream signal transmission and consequently results in inhibition of the cancer cell proliferation [44–47]. Thus, it may be a useful treatment option for patients in whom surgery is not indicated and in patients with distant metastases.