SCSG is a low-grade malignancy characterized by features similar to mammary secretory carcinoma (SC) and a distinctive ETV6 translocation [5, 6]. In 2017, SC was officially included in the WHO Classification of Head and Neck Tumors, before which SCSG was mostly misdiagnosed as AciCC, MEC, or other types of salivary gland tumors [7]. Statistics indicate that SCSG is responsible for < 0.3% of all salivary gland malignancies, and its incidence may increase with the growing understanding of the disease and advancements in molecular detection techniques [8, 9].

SCSG can occur at any age, but it is more common in adults, with a slight male predominance [10, 11]. SCSG in children is even rarer clinically, and only a few case reports are available in China and beyond [12, 13]. In this paper, the median age of onset was 47 years old, and the male-to-female ratio was 1.6:1, consistent with previous reports. SCSG primarily presents as slow-growing painless masses with a relatively long course, and it may have grown for months or even years before diagnosis. The parotid gland is involved most frequently, responsible for about 75-80% of SCSG, followed by submandibular gland and minor salivary gland, with other sites being less common [14,15,16]. In our study, SCSG occurred in the parotid gland in nine cases, submandibular gland in three cases, and palate in one case. None of these cases showed nerve involvement, consistent with other findings. A review of the current literature on secretory carcinoma of salivary glands see Table 4 [3, 11, 13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40].

Ultrasound, CT and MRI are commonly used for screening of head-neck tumors and have been widely applied in clinical practice. Ultrasound is a simple and cost-effective tool that helps determine tumor location, size, blood flow, and internal echo. CT and MRI are superior for assessing tumor size, extent, and its relationship with surrounding tissues and nerves, with MRI providing clearer images for soft tissue evaluation. Ultrasonographically, SCSG typically appears as a heterogeneous hypoechoic mass, either solid or cystic-solid, with clear boundaries and no significant blood flow signals [41]. On CT scan, SCSG mostly exhibits roundish slightly hypodense lesions with clear boundaries, and uneven enhancement, and the surrounding muscle and bone tissues may be involved in SC in the parotid or submandibular gland [42, 43]. MRI scans typically show SCSG as oval or nodular cystic-solid masses, sometimes with convex papillary projections. The cystic component exhibits high signals on both T1-weighted imaging (T1WI) and T2-weighted imaging (T2WI), while the solid component shows high signals on T1WI and medium to low signals on T2WI, which can be a characteristic imaging feature of SCSG [44]. In our study, cervical ultrasound revealed hyperechoic solid nodules with clear boundaries in nine cases and cystic-solid nodules in four cases, with no significant blood flow signals, suggesting a low-grade tumor. Nine cases underwent CT scan, of which eight cases had clear boundaries and one case exhibited an irregular mass in the submandibular gland with unclear boundaries, invading the mandible and the surrounding soft tissues; uneven and obvious enhancement was found in six cases, and mild enhancement in three cases. MRI scans were performed in three cases, with two showing oval solid tumors with high signals on T1WI and low signals on T2WI, and one case with a cystic component featuring nodular septation and high signals on both T1WI and T2WI. Preoperative imaging suggested malignant potential in seven cases, but failed to accurately diagnose SC.

Prior to the fourth edition of the WHO Classification of Head and Neck Tumors, SCSG was mostly classified as other types of tumors, especially zymogen granule-poor AciCC, due to its similar histological morphology and structural patterns to other salivary gland tumors (AciCC, ACC, and MEC). Therefore, SCSG should be differentially diagnosed from AciCC first [45]. AciCC lacks nodular structures with distinct fibrous septation and contains PAS-positive zymogen-like granules, which are absent in SCSG, allowing for differentiation between the two [46]. In addition, AciCC has a diversity of tumor cells, including serous alveoli, intercalated duct-like cells, and clear cells. IHC markers are crucial for the differential diagnosis of SCSG. SCSG is typically positive for S-100, mammaglobin, CK7, and MUC4, whereas Dog-1 is usually not expressed or only limited around the cancer nest. On the contrary, AciCC is usually negative for S-100 and mammaglobin but strongly positive for Dog-1 [47]. Recent studies have shown that MUC4 is moderately to strongly expressed in over 90% of SCSG cases, making it a sensitive and specific marker for SCSG diagnosis, whereas MUC4 is negative in AciCC [48]. While a combination of different IHC markers enhanced the sensitivity of SCSG diagnosis, it lacked specificity, making FISH the gold standard for SCSG diagnosis [49]. Nowadays, increasingly more retrospective studies also confirmed the ability of histomorphometric features and IHC markers to diagnose more than 95% of cases, and significantly reduce the need for molecular detection, thereby saving healthcare resources. Moreover, genetic analysis can be still carried out for very few atypical cases [50,51,52]. In our study, HE staining revealed lobulated or nodular cell arrangements in six cases, with mammillary structures and luminal secretion in some areas. At high magnification, the cells appeared relatively uniform in size, round or oval in shape, with mild atypia. The nuclear membrane was distinct, small nucleoli were visible, and the cells exhibited low-grade atypia with abundant cytoplasm. Immunohistochemistry revealed strong positivity for Mammaglobin and S-100, and negativity for Dog-1. Based on these typical cytological and immunohistochemical features, a diagnosis of SC was made without further FISH testing. Seven cases underwent FISH, with some showing larger and more atypical tumor cells arranged in solid sheets. Two cases were negative for mammaglobin, with one case was also negative for MUC4. Preliminarily, AciCC was not excluded, and genetic testing was further performed to achieve accurate diagnosis, typical ETV6-NTRK3 fusion was detected, so it was diagnosed with SC. Therefore, FISH is necessary when the cells microscopically have an atypical morphology, high atypia, and prominent nucleoli, and IHC for mammaglobin, S-100, and Dog-1 does not verify the diagnosis.

During the development of SCSG, high-grade transformation may occur in a small number of patients, where the tumor loses its differentiation potential and becomes more aggressive [53, 54]. In high-grade transformation, SCSG typically exhibits infiltrative growth, with tumor cells arranged in solid, glandular, or trabecular structures, accompanied by single-cell infiltration, increased cell atypia, thickened nuclear chromatin, more frequent mitoses, and necrosis. Invasion of surrounding soft tissues and nerves is also more common [53,54,55]. In our study, none of patients developed high-grade transformation, which was probably attributed to the small sample size.

Similar to mammary SC, SCSG is usually characterized by a characteristic t(12;15)(p13;q25) translocation, resulting in the ETV6-NTRK3 gene fusion, which is unique among salivary gland tumors [56]. ETV6-NTRK3 gene fusion has also been reported in other non-salivary gland tumors, such as infantile fibrosarcoma, acute myeloid leukemia, inflammatory myofibroblastoma, and cellular congenital mesodermal nephroma [57]. With the growing understanding of SCSG, it has been discovered that besides NTRK3, RET [58], MET [59], and MAML3 [60] are also the ETV6 fusion partners in SCSG. In 2020, Black M [43] reported an even rarer case of double-gene fusion (ETV6-RET and EGFR-SEPT14), further expanding the molecular spectrum of SC. In our study, seven cases were tested for the ETV6 gene and they were all positive, with no gene fusions other than ETV6-NTRK3 detected.

According to the American Society of Clinical Oncology (ASCO) guidelines, SCSG is classified as a low-invasive salivary gland carcinoma, and, similar to other salivary gland tumors, radical excision is the treatment of choice [61,62,63]. Relevant studies suggest that about 70% of SCSG is in the early stage with a less than 20% regional lymph node metastasis rate at the time of diagnosis, so simultaneous cervical lymph node dissection and postoperative adjuvant radiotherapy and chemotherapy are not required for SCSG [8, 64, 65]. Postoperative comprehensive antitumor therapies such as radiotherapy, chemotherapy, and targeted therapy are recommended for SCSG with high-risk factors, such as positive lymph node metastasis, vascular invasion, positive margins, and positive peripheral neuromuscular invasion [62, 65, 66]. Although SCSG is a low-grade malignancy, high-grade transformation can occur in a few patients, resulting in significantly higher malignancy and a high rate of cervical lymph node metastasis. In such cases, sialoadenectomy and cervical lymph node dissection with adjuvant chemoradiotherapy are recommended [53]. Targeted therapy with tropomyosin receptor kinase (TRK) inhibitors may also be considered for patients with typical gene fusion (ETV6-NTRK3) [67]. The prognosis for patients with typical SCSG is generally favorable, with a disease-specific survival rate of about 95-98% and disease-free survival of about 87-89% following radical excision [14, 15]. However, patients with high-grade transformation tend to have a poorer prognosis, with survival typically ranging from 2 to 6 years postoperatively [68]. Genetic testing and targeted therapy should be considered for advanced patients with recurrent, metastatic, or inoperable tumors [69]. In our study, cervical lymph node dissection was performed in seven cases, with pathological detection of cervical lymph node metastasis in two cases. One of these cases involved invasion of surrounding soft tissues and the mandible, as well as one case of invasion into the facial nerve. Therefore, attention should be paid to the regional lymph nodes in the face of large tumors or high-risk factors such as surrounding tissue invasion, and cervical lymph node dissection can be performed when necessarily. In our study, during follow-up, two patients experienced tumor recurrence at the surgical site, with one of them also developing cervical lymph node metastasis. Both of these patients had undergone superficial parotidectomy along with tumor resection during their initial surgery, and postoperative pathological examination showed Ki-67 positive rate was 10% and 15%, respectively. However, no recurrences were observed in patients who underwent total parotidectomy. Based on these findings, we hypothesize that a high Ki-67 index and partial parotidectomy may be associated with local recurrence in our study. It’s also suggest that preoperative assessment of the tumor’s nature, size, and extent is crucial for selecting the appropriate surgical plan and comprehensive treatment. Radical excision and regional lymph node dissection may be one of the effective means for reducing the relapse rate in patients with associated high-risk factors. In our study, one patient died of acute myocardial infarction, and no relapse was detected by imaging during follow-up.

In conclusion, SCSG is a rare low-grade malignancy with a good prognosis. Pathological and IHC characteristics are the key to SC diagnosis, and ETV6 translocation is considered the gold standard for its diagnosis. Surgical excision is the primary treatment for SCSG, and whether to perform simultaneous cervical lymph node dissection and other adjuvant therapies should be determined based on the pathological stage and the presence or absence of high-risk factors.