SCSGs are generally low-grade salivary gland carcinomas characterized by morphological resemblance to mammary analog secretory carcinoma and ETV6–NTRK3 gene fusion.2,7 In 2017, SCSGs were added to the WHO classification of head and neck tumors.3
The age at onset of SCSG reportedly varies widely. Although these tumors generally develop in adults, they can also occur in children and adolescents; however, no apparent sex-based bias has been reported.8 In the present study group, the median age was 45 years (range: 10–69 y) with a male:female ratio of 1.3:1. Moreover, the parotid gland represents the most common site of SCSG, although small salivary glands, including the buccal, upper lip, and palatal glands, can also be involved.9–11 Indeed, the tumors of 21 patients in the current study were located in the parotid gland, those of 17 in the right parotid gland, and those of four in the left parotid gland, differing only slightly from previously reported findings.12 SCSGs most commonly present as painless, slow-growing, well-circumscribed masses that are often misdiagnosed as pleomorphic adenoma or acinar cell carcinoma.13 Consistent with the present study, most patients presented with a painless mass, with only a few recurrences sensitive to touch. Moreover, no specific preoperative ultrasonography, CT, or MRI findings were identified. The tumors presented as well-demarcated masses of uneven density, sometimes with cystic changes that could easily be misdiagnosed as pleomorphic adenomas. Additionally, only three patients presented with T3 tumors, whereas the others were T1 or T2 tumors. Moreover, T4 tumors have been reported by other groups.12
Before their official characterization, SCSGs were frequently classified as ACCs owing to their nearly identical histological growth patterns.14 Although no significant clinical differences have been described between SCSGs and ACCs, they may exhibit considerable histopathological morphological differences. For instance, unlike ACCs, SCSGs have no secretory zymogen cytoplasmic granules that undergo true positive periodic acid–Schiff reactions.15 Additionally, the nuclei of SCSGs have prominent pseudo-inclusion bodies; however, SCSGs do not contain other cell types, such as serous, intermediate, and clear cells, as are commonly observed in ACCs.16 As for immunophenotypes, SCSGs can express various markers of breast secretory carcinomas, including mammaglobin, S-100 protein, STAT5A, MUC1, MUC4, GCDFP-15, CK7, CK8, CK18, CK19, and epithelial cell membrane proteins.17 However, they characteristically do not express DOG-1, estrogen, androgen, progesterone receptors, or HER2.18 In contrast to SCSGs, ACCs do not express mammaglobin, or exhibit only weak local expression; however, they express DOG-1 diffusely.18 Khalele et al. reported that SCSG can be diagnosed via the detection of mammaglobin and S-100 protein in the salivary gland tumor, in the absence of DOG-1.19 It has also been reported that if mammaglobin and S-100 are strongly positive, SCSG can be diagnosed without resorting to molecular biological methods,20 making mammaglobin a particularly important tumor marker for SCSG diagnosis.
Similar to secretory carcinomas of the breast, SCSGs have been shown to contain the translocation t(12; 15) (p13; q25), resulting in ETV6–NTRK3 fusion,4 which has not been found in other types of salivary gland tumors. However, this has been reported in congenital fibrosarcoma, mesodermal renal tumor, and acute myeloid leukemia.21,22 Recent findings have expanded the molecular profile of SCSG to include multiple novel ETV6 fusion partners, including ETV6-RET and EGFR–SEPT14.23 Rupture of the ETV6–NTRK3 fusion may lead to the production of functional tyrosine kinases, or affect the signaling pathways of certain transcriptional activators, leading to strong expression of mammaglobin and S100, but not DOG-1.24 Hence, the detection of ETV6 rearrangement is likely the most specific method and, therefore, the gold standard for diagnosing SCSGs.
Gene therapy may offer new hope to patients with this tumor type in the future.25 In fact, 15 patients who had not been definitively diagnosed by immunohistochemistry were all diagnosed on the basis of ETV6 gene rearrangement in the current study. Additionally, Chiosea et al.26 reviewed 81 cases of ACC for ETV6 fluorescence by in situ hybridization and found that all classical ACCs had intact ETV6, whereas 10 of 17 zymogen granule-poor ACCs showed ETV6 translocation; these were subsequently reclassified as mammary analog secretory carcinomas. Other differential diagnoses include adenoid cystic carcinoma, mucoepidermoid carcinoma, and salivary ductal carcinoma, all of which can be identified by immunohistochemistry and ETV6 gene detection. In fact, prior to immunohistochemistry and ETV6 gene detection in the current study, four of the 23 patients’ tumors were misdiagnosed as acinar cell carcinomas, three as mucoepidermoid carcinomas, two as adenoid cystic carcinomas, one as low-grade ductal carcinoma, and one as squamous cell carcinoma. Thus, the rate of misdiagnosis with routine pathology was 47.8%.
As SCSGs behave similarly to ACCs, the treatment of SCSGs is primarily centered on surgical interventions. However, currently, no consensus exists for the optimal treatment of these tumors. Some researchers believe that SCSGs are indolent tumors that rarely produce distant metastases, making surgery alone a sufficient therapeutic strategy.27 Moreover, other reports have indicated that surgery combined with postoperative radiotherapy is more effective.28 In the present study, 11 patients were treated with surgery alone, one of whom had postoperative recurrence. In addition, one patient received postoperative chemotherapy and later had a recurrence, whereas four of the seven patients who received postoperative chemoradiotherapy had recurrences. The overall recurrence rate was 26.1%.
Interestingly, six patients with recurrences underwent their first surgeries in local primary hospitals, and their recurrences were considered to have resulted from incomplete resection after the first surgery. Although, currently, few reports are available on the different surgical procedures for SCSGs, some advocate for the simultaneous total resection of the affected lobe of the parotid gland and cervical lymph node dissection.29 Indeed, Chiosea et al.26 reported a higher incidence of lymph node metastases from SCSGs than from ACCs (33% vs. 8%); however, cervical dissection is still rarely performed.30 Within the current study, five patients developed cervical lymphatic metastases, and two developed distant metastases (both to the lung) after local recurrences. All six patients with local recurrences only underwent tumor enucleation or partial parotid gland resection; none of the patients who underwent excision of the tumor or the superficial lobe of the parotid gland had recurrences or distant metastases. Taken together, these results suggest that preoperative determination of the size and extent of the tumor is vital to successful surgical interventions.
Recently, MRH of salivary gland ducts has been shown to clearly establish the three-dimensional relationship between the tumor and parotid duct, while also detecting dilation, stenosis, displacement, and destruction of main ducts and branch ducts, potentially guiding preoperative planning.31 For instance, if the tumor has invaded the main duct, retaining the gland is meaningless; instead, superficial or total parotid gland resection should be performed where possible. Moreover, if the tumor is sufficiently distant from the main duct, regional parotid gland resection with preservation of a portion of the gland can be considered. Thus, detailed MRH can accurately guide the planning of parotid gland preservation surgery, potentially enabling retention of some functional glands, while completely resecting the tumor. In the present study, two patients underwent preoperative MRH and regional resection of the parotid gland without any further postoperative treatment. To date, they remain in remission, with an average follow-up time of 26 months.
The prognosis of SCSG is related not only to the first operative procedure but also to age, clinical stage, and Ki-67 proliferation index. Although six of the 23 patients in this study had local recurrences (mean age 53 years) and one patient died, the overall prognosis was good, which is consistent with previously reported results.32 Additionally, children and young patients generally have better prognoses, whereas adult patients have more aggressive tumors, with older patients (more than 60 years) having the most aggressive tumors and the highest recurrence rates. This may be related to differences in pathological features at different ages and the characteristically poor immune function of older patients.33 Furthermore, advanced clinical stage and high grade represent the primary adverse prognostic factors. Specifically, lymph node involvement and extra-parenchymal glandular invasion are associated with a greater risk of local recurrence and metastasis.34 In the present study, five patients developed lymph node metastases, all of whom underwent therapeutic neck dissection and postoperative radiotherapy and/or chemotherapy. However, they all experienced postoperative recurrences, with pulmonary metastases detected in two patients, one of whom died. Additionally, the tumor of the patient who died had a Ki-67 proliferation index of 50%+ and had recurred three times. This is consistent with reports that patients with a Ki-67 proliferation index of more than 10% have poor prognoses.35
In summary, SCSG is a rare type of low-grade malignant salivary gland tumor that commonly occurs in the parotid gland, rarely invades surrounding tissues, and has a good prognosis. Moreover, histomorphological and immunohistochemical characteristics are key to distinguishing SCSGs from other salivary gland tumors, with the detection of ETV6 translocation considered the gold standard for diagnosis. Surgical resection is the main treatment, and the success of the first operation represents the major determinant of prognosis. Considering the low rate of cervical lymphatic metastasis, functional excision of SCSGs with facial nerve preservation is generally performed, depending on preoperative MRH findings concerning salivary gland duct status. Postoperative I125 implantation or local radiotherapy can be performed to reduce the recurrence rate. If distant metastases occur, neck dissection and postoperative treatment are necessary.
Considering that SCSG is a relatively newly described tumor type, few clinical findings have been reported, resulting in only a small number of patients included in this study cohort. Thus, definitively ascertaining the optimal treatment and outcomes of SCSG requires studies to be performed with a larger patient cohort and long-term follow-up.