Abstract
Background
To investigate the clinicopathologic characteristics, therapeutic methods, and prognosis of secretory carcinoma of salivary gland (SCSG).
Methods
The clinicopathologic data of 13 patients with SCSG admitted to Shanxi Cancer Hospital from January 2018 to June 2023 were retrospectively analyzed, and a literature review was performed.
Results
A total of eight males and five females aged 22–78 years old were enrolled, and they commonly presented with painless masses in the parotid or submandibular gland. They all underwent surgical treatment, accompanied by typical pathological examinations postoperatively. Fluorescence in situ hybridization (FISH) was conducted in seven cases, the results were all positive, and no gene fusion other than ETV6-NTRK3 was found. Two patients developed local relapse during follow-up, both of which were in the surgical area. By the end of the follow-up, 12 patients survived and one patient died.
Conclusions
SCSG is a rare low-grade malignancy with a good prognosis. Pathological and immunohistochemical characteristics are the key to secretory carcinoma (SC) diagnosis, and surgical excision is the major treatment means for SCSG. 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.
Keywords: Secretory carcinoma, Salivary gland tumor, Mammary analog secretory carcinoma
Introduction
Secretory carcinoma of salivary gland (SCSG) is a rare malignancy that has recently been recognized. First proposed by Skalova et al. [1] in 2010, SCSG was noted to share histomorphological and immunohistochemical (IHC) characteristics with mammary secretory carcinoma (SC), leading to its initial designation as mammary analog secretory carcinoma (MASC). In the fourth edition of the World Health Organization (WHO) Classification of Head and Neck Tumors in 2017, MASC was listed as a new classification in salivary gland tumors, and officially named SC [2]. Most cases of SCSG exhibit morphological similarities to mammary SC and are characterized by the presence of the ETV6-NTRK3 gene fusion, and it was often misdiagnosed as acinic cell carcinoma (AciCC), adenoid cystic carcinoma (ACC), and mucoepidermoid carcinoma (MEC) previously [3, 4]. Currently, SCSG is mostly reported by individual cases or small series of reports in China and internationally, and limited research is available on its clinicopathologic characteristics, treatment, and prognosis. In this study, we retrospectively analyzed the clinical data of 13 patients with SCSG, summarizing the clinical features, morphological characteristics, differential diagnosis, treatment approaches, and prognosis. Our aim is to enhance the understanding of SCSG and provide new insights for the standardized diagnosis and treatment of SCSG.
Materials and methods
Clinical data
Clinical data of 13 patients with head-neck SCSG admitted to Shanxi Cancer Hospital from January 2018 to June 2023 were retrospectively analyzed. These patients were all pathologically diagnosed with SC according to the fourth edition of the WHO Classification of Head and Neck Tumors, and had complete medical records and follow-up data. Exclusion criteria: (1) with other malignancies, (2) clinicopathologic data missing, and (3) died due to surgery-related complications within three months postoperatively. Patients all gave informed consent and signed an informed consent form.
Therapeutic methods
The therapeutic method was determined by multi-disciplinary team (MDT) discussion based on specific tumor stage, site, and basic conditions of patients. For patients who had undergone simple primary tumor resection at other hospitals before being referred to our institution, the treatment plan was determined based on a comprehensive evaluation of prior imaging and pathological examinations, surgical records and so on.
Follow-up
The patients were followed up by outpatient clinic visits every three months in the first year postoperatively, and every six months from the second year onwards. For those who did not visit our outpatient facility for follow-up, telephone follow-up was implemented.
Results
Clinical features
Eight males and five females aged 22–78 years old were enrolled, with a median age of onset of 47 years old. SCSG occurred in the parotid gland in nine cases, submandibular gland in three cases, and palate in one case. All patients presented to the clinic with complaints of painless masses which grew slowly, with an average duration from discovery to diagnosis of 21 (8–49) months. Regional lymph node metastasis occurred in two cases at the time of diagnosis, and none of the patients developed distant metastasis after SC diagnosis. The clinicopathologic characteristics of patients are shown in Table 1.
Table 1.
Clinicopathologic characteristics of patients (n = 13)
| Basic characteristic | n = 13 |
|---|---|
| Median age (years,range) | 47 (22–78) |
| Gender (male:female) | 8:5 |
| Tumor location (n, %) | |
| Parotid gland | 9 (69.23) |
| Submandibular gland | 3 (23.08) |
| Palate | 1 (7.69) |
| Clinical manifestation (n, %) | |
| Painless masses | 13 (100%) |
| Tumor characteristics | |
| Diameter(cm,range) | 2.2 (1.5-5.0) |
| Texture | Hard |
| Boundary | Clearer |
| Activity | Good |
| T stage(n,%) | |
| T1 | 3 (23.08) |
| T2 | 6(46.15) |
| T3 | 3(23.08) |
| T4 | 1(7.69) |
| N stage(n,%) | |
| N0 | 11(84.62) |
| N1 | 1(7.69) |
| N2 | 1(7.69) |
| N3 | 0 |
| M stage(n,%) | |
| M0 | 13(100) |
| M1 | 0 |
| IHC(n,%) | |
| Mammaglobin(+) | 11 (11/13) |
| S-100(+) | 13 (13/13) |
| MUC-4(+) | 6 (6/10) |
| CK7(+) | 13 (13/13) |
| AE1/AE3(+) | 13 (13/13) |
| P63(-) | 9 (9/12) |
| Dog-1(-) | 12 (12/13) |
| Ki-67 | 10 (2–15%) |
| FISH genetic testing(n,%) | |
| ETV6-NTRK3 Fusion | 7 (7/7) |
Imaging characteristics
Ultrasonographically, SCSG often exhibited heterogeneous hypoechoic masses with a more regular morphology and clear boundaries. It mostly appeared as solid nodules and a few as cystic-solid nodules, with punctate blood flow signals within the lesions. Specifically, solid nodules were observed in nine cases and cystic-solid nodules in four cases.
On Computed Tomography (CT) scan, SCSG usually appeared as oval or lobulated masses with clear boundaries and regular margins. The density was uneven, often with low-density cystic areas, and the lesions showed varying degrees of enhancement on contrast scans. Specifically, six cases showed uneven and obvious enhancement, and three cases showed mild enhancement. Typical CT features are shown in Fig. 1A and C.
Fig. 1.
CT examination of patients with right submandibular SC. A: CT plain scan shows irregular mass shadow in the right submandibular gland, with cystic-solid nodules and unclear boundaries; B and C: Enhancement scan shows uneven enhancement
On Magnetic Resonance Imaging (MRI) scan, SCSG typically presented as oval or nodular masses with clear boundaries, high signals on fat-saturated images, and low signals on apparent diffusion coefficient (ADC) images. Cystic components of varying degrees were also observed, with high signals on both T1-weighted imaging (T1WI) and T2-weighted imaging (T2WI), while the solid components showed medium to low signals on T2WI. Specifically, three cases displayed long or mixed long and short signals on T1WI or T2WI, with high signals on fat-saturated images, and uneven, mild, or obvious enhancement. Typical MRI features are shown in Fig. 2A and C.
Fig. 2.
MRI examination of patients with right parotid SC. A: Roundish nodules in the right parotid gland, with clear boundaries, smooth margins, and slightly low signals on T1WI; B: Uneven high signals on T2WI; C: Obvious high signals on DWI
Pathological characteristics
Macroscopically, nine cases had solid lesions with a hard texture, clear boundaries, and off-white or grayish-yellow sections. Four cases presented cystic-solid lesions with light-brown liquid in the cystic areas. As could be seen by hematoxylin-eosin (HE) staining, the cells were arranged in lobulated, microcystic, nodular, vacuolated, and mammillary structures, and obvious luminal secretion could be seen in some areas, with hyperplastic fibrous tissues in the surroundings. Under high magnification, the tumor cells were uniform in size, round or oval, with eosinophilic granular or vacuolated cytoplasm, clear nuclear membranes, small and uniform nuclei, and occasional vascular cancer emboli, mitoses, and necrosis. No obvious zymogen granules were observed. The results of IHC revealed that 13 cases were diffusely positive for S-100, CK7, and AE1/AE3, 11 cases were strongly positive for mammaglobin, six cases had MUC4(+), nine cases had P63(-), and 12 cases had Dog-1(-), and the positive rate of Ki-67 was 2-15%. Besides, characteristic ETV6-NTRK3 gene fusion was exposed by FISH in seven cases. Representative HE staining and IHC can been seen in Fig. 3A and H. Detailed results of IHC are displayed in Table 2.
Fig. 3.
Pathological examination of parotid SC patient. A: Tumor cells arranged in a lobulated and nodular pattern with surrounding fibrous tissue proliferation, HE ×10; B: Under high magnification, tumor cells are relatively uniform in size, round or oval in shape, with eosinophilic granular cytoplasm, distinct nuclear membranes, and visible nucleoli, HE×20; C: Mammaglobin(+), ×20; D: S-100 (+), ×20; E: CK7 (+), ×20; F: Dog-1 (-), ×20; G: Ki-67 approximately 10% ,×20; H: ETV6 gene breakage
Table 2.
IHC characteristics of 13 SCSG cases
| Case | Mammaglobin | S-100 | MUC-4 | CK7 | AE1/AE3 | P63(-) | Dog-1 | Ki-67 | FISH | |
|---|---|---|---|---|---|---|---|---|---|---|
| 1 | + | + | + | + | + | + | - | 10% | Fusion | |
| 2 | + | + | + | + | + | - | - | 8% | NP | |
| 3 | + | + | NP | + | + | + | - | 10% | NP | |
| 4 | + | + | - | + | + | + | - | 5% | Fusion | |
| 5 | + | + | + | + | + | + | - | 2% | NP | |
| 6 | + | + | - | + | + | - | - | 15% | Fusion | |
| 7 | - | + | - | + | + | + | - | 10% | Fusion | |
| 8 | + | + | + | + | + | - | - | 5% | NP | |
| 9 | + | + | NP | + | + | + | - | 10% | NP | |
| 10 | + | + | NP | + | + | + | - | 10% | Fusion | |
| 11 | - | + | + | + | + | + | - | 15% | Fusion | |
| 12 | + | + | + | + | + | + | + | 5% | NP | |
| 13 | + | + | - | + | + | NP | - | 7% | Fusion |
Note: NP = Not performed
Treatment and survival status
Thirteen cases underwent surgical treatment, all of which achieved radical operation(RO) resection. The specific treatments and follow-up outcomes are detailed in Table 3. Among these cases, four patients initially had simple excisions performed at other hospitals and were subsequently referred to our hospital after a pathological diagnosis of SC. Of these, three patients underwent secondary extended resection with cervical lymph node dissection. Postoperative findings showed no residual cancer cells in two cases, while the remaining case revealed residual cancer cells with regional lymph node metastasis. The multidisciplinary team (MDT) recommended regular follow-ups without the need for further surgery for the fourth patient. The remaining nine cases underwent primary lesion excision, with four of them also receiving simultaneous cervical lymph node dissection. One patient, who presented with a left periauricular mass, was treated with a left parotidectomy, excision of the marginal mandibular branch of the facial nerve, and left cervical lymph node dissection. Postoperatively, this patient was pathologically diagnosed with SC. It was later discovered that the patient had undergone a left buccal mass excision and skin grafting from the right lower abdomen at our hospital before 2009, with a postoperative diagnosis of acinic cell carcinoma (AciCC). Upon reviewing the histopathologic slide of the buccal mass and consulting with pathologists, additional IHC staining was performed, leading to a revised diagnosis of SC.
Table 3.
Treatment and follow-up results of 13 SCSG cases
| Case | Site | Surgical mode | Lymph node metastasis | Adjuvant therapy | Relapse/metastasis | Follow-up time |
|---|---|---|---|---|---|---|
| 1 | Left parotid gland | Left parotidectomy and mass excision, excision of marginal mandibular branch of the facial nerve, and left cervical lymph node dissection | Yes | Radiotherapy | No | 54 months |
| 2 | Left parotid gland | Left superficial parotidectomy and mass excision | - | No | No | 39 months |
| 3 | Right parotid gland | Right superficial parotidectomy and mass excision, and right cervical lymph node dissection | No | No | Relapse in the surgical area | 47 months |
| 4 | Right parotid gland | Right parotidectomy and mass excision, and right cervical lymph node dissection | No | No | No | 35 months |
| 5 | Right parotid gland | Right parotidectomy and mass excision, and right cervical lymph node dissection | No | Radiotherapy | No | 28 months |
| 6 | Right parotid gland | Right superficial parotidectomy and mass excision | - | No | Relapse in the surgical area with lymph node metastasis | 29 months |
| 7 | Left parotid gland | Left superficial parotidectomy and mass excision | - | No | No | 43 months |
| 8 | Right submandibular gland | Right submandibular gland and mass excision, partial mandibulectomy, and right cervical lymph node dissection | Yes | Neoadjuvant chemotherapy, postoperative radiotherapy | No | 19 months |
| 9 | Right parotid gland | Right superficial parotidectomy and mass excision, and right cervical lymph node dissection | No | No | No | 61 months |
| 10 | Palate | Extended excision of palatal mass, and biomembrane repair | - | No | No | 7 months |
| 11 | Right submandibular gland | Right submandibular gland and mass excision, and right cervical lymph node dissection | No | Radiotherapy | No | 26 months |
| 12 | Right submandibular gland | Right submandibular gland and mass excision | - | No | No | 14 months |
| 13 | Right parotid gland | Right superficial parotidectomy and mass excision | - | No | No | 8 months |
As of March 2024, all 13 patients were followed up, of which 12 patients survived and one patient died. Two patients had local relapse during follow-up, both of which were in the surgical area and treated with surgery again, and one of which was accompanied by cervical lymph node metastasis. The remaining patients achieved tumor-free survival.
Discussion
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 [14–16]. 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, 13–40].
Table 4.
A review of the current literature on secretory carcinoma of salivary glands
| Author | Patients | Gender | Age | Location | Tumor size(cm) | T1/T2/T3/T4/Tx | N0/N1/N2/N3 | M0/M1 | Immunohistochemistry |
|---|---|---|---|---|---|---|---|---|---|
|
Sun J et al. (2021) |
23 |
Male 13(56.5%) Female1(43.5%) |
45 (10–69) |
Parotid gland21(91.3%) Submandibular gland 2(8.7%) |
2.6 (0.8–4.8) |
6/14/3/0/0 | 18/1/4/0 | 21/2 | S-100/MMG/CK7/GATA3 (+);Calponin/P63/DOG1 (-) |
| Serrano-Meneses GJ et al. (2024) | 1 | Male | 11 | Left maxillary soft tissue | 5 | T3N0M0 |
AE1-3/CK7/GATA3/S-100(+); Actin/P63(-); Ki-67 20% |
||
|
Higuchi K et al. (2014) |
7 |
Male 3(42.9%) Female4(57.1%) |
51.6 (39–68) |
Parotid gland 5(71.4%) Accessory paroid 1(14.3%) Submandibular gland 1(14.3%) |
1.8 (0.8–3.5) |
7/0/0/0/0 | 7/0/0/0 | 7/0 |
S-100/MMG/vimentin/MUC1(+); Ki-67 7.8%(5-12.5%) |
|
Min FH et al. (2021) |
1 | Male | 32 | Parotid gland | 2 | T1N0M0 |
S-100/MMG/CK5/6/7/8/Vim/SMA/p63(+); DOG1/calponin(-); Ki-67 2% |
||
|
Salgado CM et al. (2021) |
4 |
Male 2 (50%) Female2(50%) |
11 (7–14) |
Parotid gland3(75%) Submandibular gland1(25%) |
1.5 (1.2–2.1) |
3/1/0/0/0 | 4/0/0/0 | 4/0 |
S-100/MMG/CK7/GATA3(+); CK5/6/p53(-); Ki-67 20–30% |
|
Baněčková M et al. (2023) |
215 |
Male123(57.2%) Female8(40.5%) Unknow 5(2.3%) |
47.5 (7–94) |
Parotid gland 159(74%) Submandibular gland 14(6.5%) Lip 12(5.6%) Buccal mucosa 10 (4.7%) Palate 10 (4.7%) Oral cavity 5 (2.3) Sinonasal tract 5 (2.3) |
1.98 (4–70) |
129/48/6/7/25 | 97/10/10/98 | 120/6 |
S-100(+) 206/206 MMG(+) 195/197 DOG1(-) 127/147 NOR1(-) 73/73 p63(-) 152/178 |
|
Kim SH et al. (2019) |
1 | Male | 40 | Parotid gland | 3.9 | T3N0M0 |
EMA/Vimentin/S-100(+); p63/CK5/6/C-KIT(-) |
||
|
Wu B et al. (2020) |
1 | Male | 72 | Left nasal cavity | 0.8 | T1N0M0 |
S-100/MMG/GATA3(+); p63/DOG1(+); Ki-67 10% |
||
|
Langah NA et al. (2023) |
1 | Male | 42 | Minor salivary glands | 2.3 | T1N2bMx |
GATA3/MUC4(+); AR(-) |
||
|
Xu B et al. (2017) |
1 | Male | 61 | Maxillary sinus | 4.2 | T3N0M0 | CK7/S-100/MMG/GCDFP-15(+) | ||
|
Sun L et al. (2019) |
1 | Male | 57 | Parotid gland | 1.6 | T1N0M0 |
α-1-anti-trypsin/MMG/S-100(+); AR/BRST-2/CK20/P63/SM(-); Ki-67 5–10% |
||
|
Boliere C et al. (2019) |
1 | Male | 57 | Minor salivary glands | 1.0 | T4N0M0 |
CK7/SM/P53/CK5/6/MMG/S-100(+); DOG-1(-) |
||
|
Martínez R et al. (2019) |
1 | Female | 23 | Minor salivary glands | 2.0 | T4N1M0 |
AE1/3/S-100/MMG/GATA3(+); DOG1/p63(-); Ki-67 20% |
||
|
Cai Y et al. (2019) |
5 | Male 5(100%) |
46 (34–60) |
Parotid gland |
2.72 (2-3.5) |
1/3/1/0/0 | 5/0/0/0 | 4/1 |
S-100/MMG/Vimentin/CK(+); p63(-); Ki-67 10% |
|
Gonzalez MF et al. (2017) |
1 | Male | 18 | Parotid gland | 2.7 | T2N0M0 | MMG/S-100/SOX-10/MUC-1/4/p63(focal)/GCDFP-15(+) | ||
|
Anderson JL et al. (2019) |
55 |
Male 31(56.4%) Female24(43.6%) |
48.6 (12–82) |
Parotid gland 42(76.4%) Submandibular gland 3(5.5%) Major salivary gland 10(18.2%) |
1.95 | 27/19/3/1/5 | 51/3/1 | 55/0 | - |
|
Ngouajio AL et al. (2017) |
12 |
Male 6(50%) Female6(50%) |
15 (10–17) |
Parotid gland 10(83%) Submandibular gland 1(8.5%) Lip 1(8.5%) |
2.41 (1-3.8) |
3/6/1/0/2 | 11/1/0/0 | 12/0 |
S-100(+) 11(100%) Vimentin(+) 4 CK19(+) 3 MMG(+) 2 |
|
Rooper LM et al. (2018) |
1 | Female | 59 | Submandibular gland | 4.7 | T3N2M0 |
S-100/MMG/p63(+); DOG-1/SOX10(-) |
||
|
Hsieh MS et al. (2015) |
14 |
Male 8 (57%) Female6 (43%) |
32.5 (17–55) |
- |
2.5 (1.2–4.5) |
5/6/3/0/0 | 11/2/1/0 | - |
S-100/MMG/Vimentin(+); DOG1(93%)(-) |
|
E.Boon et al. (2018) |
31 |
Male17(55%) Female14(45%) |
49 (19–83) |
Parotid gland 18(58%) Submandibular gland 1(3%) Minor salivary glands 12(39%) |
- | 19/10/0/0/2 | 30/0/1/0 | 31/0 | - |
|
Bacem A et al. (2017) |
279 |
Male 167(60%) Female 112(40%) |
45.68 |
Parotid gland 189(68%) Buccal mucosa 24(9%) Submandibular gland 22(8%) Lip 25 (9%) Hard palate 12 (4%) Soft palate 6(2%) Base of the tongue 1 (0) |
1.8 | - | - | - | - |
|
Din NU et al. (2016) |
11 |
Male 7(63.6%) Female 5(36.4%) |
27.5 (9–60) |
Parotid gland 7 Submandibular gland 3 Buccal vestibule 1 |
4.4 (2–10) |
- | - | - |
S-100(+) 5/5 EMA(+) 4/4 CK7(+) 2/2 |
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 [50–52]. 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 [53–55]. 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 [61–63]. 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.
Acknowledgements
Not Applicable.
Author contributions
All authors contributed to the study conception and design. Writing - original draft preparation: [Fei Han, Feng Liu, Xinrong Nan]; Writing - review and editing: [Fei Han, Hao Wang, Xuesong Wu]; Conceptualization: [Feng Liu, Yanchao Qin, Zhen Guo]; Methodology: [Fei Han, Qian Lu]; Formal analysis and investigation: [Feng Liu, Qian Lu, Zhen Guo]; Resources: [Xinrong Nan, Yanchao Qin, Zhen Guo]; Supervision: [Xinrong Nan, Fei Han], and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.
Funding
Not Applicable.
Data availability
No datasets were generated or analysed during the current study.
Declarations
Ethics approval and consent to participate
This study has received approval from our institution’s ethics committee (Ethics number: KY2024054), and informed consent has been duly obtained from both the patients and their families.
Consent for publication
Not applicable.
Competing interests
The authors declare no competing interests.
Footnotes
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Fei Han and Feng Liu contributed equally to this work and should be considered as co-first authors.
Change history
7/24/2025
The original article has been updated: Affiliation “First Clinical Medical School, Shanxi Medical University, Taiyuan 030001, China” has been updated to “Shanxi Medical University School and Hospital of Stomatology, Taiyuan 030001, China”.
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