Metastatic salivary gland mammary analogue secretory carcinoma (MASC) of parotid gland – A rare case report in the literature review

Abstract We present a patient diagnosed with a parotid tumor whose histopathology was MASC. A 58-year-old female presented with a 5-month history of an enlarging right parotid mass. Ultrasonography showed a 48 × 30 mm heterogeneous solid lesion with a lobulated contour in the right parotid gland. A neck computed tomography (CT) with intravenous (IV) contrast showed a 28 × 34 mm pathological mass in the right parotid gland. After FNA, parotidectomy, and modified radical neck dissection, pathology showed that the surgical margin was positive for tumor, and one lymph node was metastatic in the right neck. This case was classified as T2N1M1 staged MASC of the salivary gland. She completed seven weeks of radiation therapy (RT) after surgery, and no recurrence or metastasis was observed at the 32nd-month follow-up. We aimed to report a rare parotid gland tumor with this case and inspire new research on diagnosing and treating rare salivary gland tumors


Introduction
Firstly Sk alov a et al. in 2010 reported Mammary Analogue Secretory Carcinoma (MASC) as a tumor of the salivary gland that mimics histologically and genetically breast Secretory Carcinoma (SCs) [1].MASC was present in the mid-40s with a slight male dominance.It was usually misdiagnosed as salivary Acinic Cell Carcinoma (AciCC), because the central nuclei in tumor cells found in salivary gland malignancies are similarly based on their histological features, such as cytoplasm with pink granules or vacuoles.Reclassifying salivary gland pathologies was needed as retrospective scans revealed misdiagnosis cases [1][2][3].Several methods must be combined to distinguish MASC from other tumors definitively.If there is a suspected histopathological pre-diagnosis, such as Acinic Cell Carcinoma, two diagnostic methods should be added: Immunohistochemistry and Genetranslocation determination.In immunohistochemistry, markers such as DOG1, PASD, S100, and mammaglobin should be used.Only the characteristic t(12;15) (q13;q25) translocation that results in the ETV6 gene and the ETV6-NTRK3 fusion gene should be determined to confirm the diagnosis of MASC.In some studies, t(12;15) (q13;q25) translocation, NTRK3 gene on chromosome 15, and ETV6 fusion on chromosome 12 were reported in the tumor [4,5].But ETV6-NTRK3 gene fusion is not typical for AciCC.The complaint of a slowly growing and painless mass can usually be observed in the parotid glands and sometimes in other minor salivary glands Although over 80 cases of MASC have been reported in the available literature by January 2022, definitive guidelines for clinical evaluation and management for this tumor, have not yet been defined [1][2][3][6][7][8][9].To contribute to the literature, we present the management of a patient who underwent deep lobe parotidectomy and neck dissection and whose final histopathology was MASC.This case report is eligible for the SCARE criteria [10].

Case presentation
A 58-year-old female presented with an asymptomatic enlarging mass in the right parotid gland to the ENT outpatient clinic for her anamnesis; there was no history of surgery or medication other than smoking one pack a day for 15 years.An ultrasonographic (USG) examination showed a 48 Â 30 mm heterogeneous solid lesion with a lobulated contour in the right parotid gland.There were several hypoechoic nodules with 5 mm in diameter in the anterior of the right SCM and 2.5 mm in the right thyroid lobe.In the neck, intravenous (IV) contrasted computed tomography (CT) reported a 28 Â 34 cm enhancing and heterogeneously pathological lesion in the deep lobe of the right parotid gland.The left parotid and neck regions were normal (Figure 1).The Fine-Needle Aspiration (FNA) biopsy reported papillary features with epithelial neoplasm.Right deep lobe parotidectomy with modified radical neck dissection was performed.The facial nerve was fully preserved while performing parotidectomy (Figure 2).We removed a 3 Â 4 cm lesion from the parotid gland.(Figure 3(A)) The operation ended without complication, and the patient was discharged two days later.Postoperative pathology showed that the surgical margin was positive, and one lymph node was metastatic in the right neck.The tumor cells in the immunohistochemical analysis were positive for Cytokeratin7, Vimentin, S100, Cytokeratin, EMA, keratin 8/18, mammaglobin, GCDFP15 (focal), pancytokeratin, Ki67 (3-4%) and were negative for Calponin, Smooth muscle actin, Synaptophysin, ChromograninA, HMB45, pax8, CD56, cytokeratin 5/6, cytokeratin 14, p53, cytokeratin20, CD117, CD10, DOG1, GFAP, RCC, p63, calponin, and CEA.FISH analysis indicated a rearrangement of the ETV 6 gene at 12p13.2, which had been reported in MASC.(Figure 3(B-D)) The tumor with the invasive cystic morphology, immunostaining, and FISH profile was diagnostic for salivary gland MASC.This case was classified as T2N1M1 stage MASC of the salivary gland.She was referred to the oncology department and began radiation therapy (RT) three weeks after surgery.The patient subsequently completed a 7-week course of RT and showed no evidence of recurrence at the 32-month follow-up (Figure 4).

Differential diagnosis
Differential diagnoses of the case include all masses of the parotid gland, especially acinic cell carcinoma    (AciCC), low-grade cribriform cystadenocarcinoma, low-grade mucoepidermal carcinoma (MEC), polymorphic low-grade adenocarcinoma, and malignant lymphoepithelial lesions of the parotid gland.AciCC is the most common tumor easily misdiagnosed with MASC [8].
At the time of diagnosis, MASC patients may sometimes appear at a higher T stage than expected [8].It was reported that 58% of 65 patients were at the T1 stage in the T-stage screening, and a higher rate of regional nodal metastases was observed at the time of diagnosis compared to patients with AciCC [1,10,17,20,22].We identified the T2N1M1 stage in our case.
Chiosa et al. found that 4 (22%) of 18 MASC and 3 (7.9%) of 38 AciCC-diagnosed patients who performed neck dissection had nodal involvement; the difference was statistically significant [8].However, if they included additional 17 nodal status known cases from reported studies, the significance was lost, and the proportion of MASC patients with nodal metastases (6/34 or 17.6%) was higher than AciCC.Also, we perform neck dissection in our case.
Clinical outcomes of the patients with AciCC diagnosis are well-known; however, it is complex by the possible asset of subgroups of MASC-diagnosed patients [27][28][29].AciCC patients with high grades had poorer prognoses; many had nodal and distant metastasis and died in the following five years [27].According to the results of the studies, histology was not of prognostic significance for MASC [30].MASC was classified as a low-grade malignant tumor, but it has also been reported that it can recur and metastasize, albeit slightly [1][2][3]6,7].In some studies, MASC is even considered an aggressive tumor compared to AciCC based on the positive lymph node count and high recurrence rate at surgical excision.But, these are not provided with statistical significance for the few numbers of patients.There is currently no official histopathological grading classification of MASC [4][5][6]12].
There is no standard treatment protocol according to the rareness of the disease [4][5][6][7][8]12].Nearly all patients performed surgical excision of the mass and superficial or total parotidectomy in the literature.Commonly accepted clinical indications for neck dissection in patients diagnosed with MASC are not standardized [1][2][3][4][5][6][7][8].Suzuki et al. reported a rare MASC, which featured a metastatic lymph node without a primary source.The patient performed radical neck dissection without adjuvant treatment and showed no symptoms within nine months of follow-up [31].The currently accepted management for MASC is in 2 ways: 1.In local and less aggressive, low-grade malignant tumor diseases: complete surgical resection and close follow-up.
2. In cases with invasive metastasis or positive surgical margins: complete resection, neck dissection, and chemo-and radiotherapy.
The clinical management importance of postoperative radiotherapy (PORT) and its effect on survival is unknown.Although there are many studies on this, the final standards regarding the dose and duration of treatment have not yet been established.However, other studies have preferred PORT in all T3-T4 stage MASC tumors [32,33].Totally 60-66 Gy doses in parts of 1.8-2 Gy for 5-6 per week were delivered in Terhaard's 386 patients' study in 2005 [33].

Conclusion
A rare clinical and histopathological presentation of MASC has been reported in the last two years.We aim to increase the awareness of the diagnosis and treatment options for head and neck oncologic care providers.This article presents a patient with a parotid tumor who underwent right deep lobe parotidectomy with modified radical ND and a 7-week PORT diagnosis of MASC to contribute to the literature.More research is required to determine the clinical progression and prevalence of the MASC, understand its prognostic significance, and define an appropriate treatment algorithm.

Figure 1 .
Figure 1.Computed Tomography (CT) scan of the neck.Right parotid mass invading neighboring muscle.The parotid mass is encircled with black dots.(A) Coronal axis.(B) Axial axis.

Figure 2 .
Figure 2. Image of the facial nerve preserved after the tumor is completely removed.The facial nerve is marked with white dots.

Figure 4 .
Figure 4. Images of the patient three months after surgery.(A) Smiling.(B) Whistling.