Efficacy of Fine-Needle Aspiration Cytology in Diagnosing Secretory Carcinoma of Salivary Gland: A Systematic Review and Meta-Analysis.

INTRODUCTION: The diagnosis of salivary gland secretory carcinoma (SC) in fine-needle aspiration specimens is challenging because its low-grade nature makes it difficult to differentiate it from various benign or malignant salivary gland neoplasms. Currently, the gold standard is demonstration of ETV6-NTRK3 fusion gene. However, the decision for ordering this costly molecular testing can be facilitated by the correct recognition of its cytomorphological features. The aim of the review was to determine the accuracy of fine-needle aspiration cytology (FNAC) in diagnosis of salivary gland SC. The secondary objective was to recognize varied cytomorphological patterns, characteristic features of SC and differentiate it from other neoplasms. METHODS: PubMed/MEDLINE, Science Direct, Embase, Cochrane review, and PROSPERO databases were searched for studies having the following key search terms: ("secretory carcinoma of salivary gland" OR "mammary analogue secretory carcinoma of salivary gland") AND ("Cytology" OR "Cytological features" OR "aspirate" OR "cytodiagnosis") published in the time frame of 2010 to June 2023. Studies reporting cytological features of the salivary gland tumors which were confirmed/diagnosed as SC on molecular investigation, were included in the systematic review. Finally, seventeen studies reporting a total of 45 cases were included in the metanalysis. RESULTS: The sensitivity of the FNAC in diagnosing SC in salivary gland is 27.7% (95% CI: 16.6-42.5%). The LR+ (positive likelihood ratio) was 0.654 (0.344-1.245), LR- (negative likelihood ratio) was 1.023 (0.538-1.946), and diagnostic odds ratio was 0.421 (0.129-1.374). The molecular testing and/or immunohistochemistry performed on cell block increased the diagnostic accuracy. CONCLUSION: Recognition of subtle cytomorphological patterns, i.e., papillary formation, clusters, and singly dispersed cells along with presence of fine intracytoplasmic vacuolations were the characteristic findings in majority of cases, confirmed with diagnostic molecular profiling. This may be helpful in identification of this rare entity with limited published literature and help in increasing diagnostic accuracy.

Secretory Carcinoma with ETV6-NTRK3 Gene Fusion and Lymph Node Metastasis in Maxillary Gingiva: A Case Report with Pathological and Molecular Correlative Studies.

Secretory carcinoma (SC), also known as mammary analogue secretory carcinoma (MASC), is a rare salivary gland neoplasm with distinctive morphology that harbors a diagnostic ETV6 gene rearrangement. MASC was first described as a type of salivary gland neoplasm in 2010 and resembles breast secretory carcinoma. It is often mistaken for other neoplasms. It usually acts as an indolent tumor but can occasionally behave in an aggressive manner. We present a rare case of a patient with an aggressive SC/MASC of maxillary gingivobuccal sulcus with microcystic, solid and papillary patterns that showed ETV6 gene rearrangement by fluorescence in situ hybridization. Next-generation sequencing revealed t(12;15)(p13;q25) ETV6-NTRK3 translocation. Because SC/MASCs harbor the ETV6-NTRK3 translocation, molecular studies and immunostains are crucial to confirm the diagnosis and direct therapy.

Salivary Gland Secretory Carcinoma: Clinicopathologic and Genetic Characteristics of 215 Cases and Proposal for a Grading System.

Salivary gland secretory carcinoma (SC), previously mammary analog SC, is a low-grade malignancy characterized by well-defined morphology and an immunohistochemical and genetic profile identical to SC of the breast. Translocation t(12;15)(p13;q25) resulting in the ETV6 :: NTRK3 gene fusion is a characteristic feature of SC along with S100 protein and mammaglobin immunopositivity. The spectrum of genetic alterations for SC continues to evolve. The aim of this retrospective study was to collect data of salivary gland SCs and to correlate their histologic, immunohistochemical, and molecular genetic data with clinical behavior and long-term follow-up. In this large retrospective study, we aimed to establish a histologic grading scheme and scoring system. A total of 215 cases of salivary gland SCs diagnosed between 1994 and 2021 were obtained from the tumor registries of the authors. Eighty cases were originally diagnosed as something other than SC, most frequently acinic cell carcinoma. Lymph node metastases were identified in 17.1% (20/117 cases with available data), with distant metastasis in 5.1% (6/117). Disease recurrence was seen in 15% (n=17/113 cases with available data). The molecular genetic profile showed ETV6 :: NTRK3 gene fusion in 95.4%, including 1 case with a dual fusion of ETV6 :: NTRK3 and MYB :: SMR3B . Less frequent fusion transcripts included ETV6 :: RET (n=12) and VIM :: RET (n=1). A 3-tiered grading scheme using 6 pathologic parameters (prevailing architecture, pleomorphism, tumor necrosis, perineural invasion (PNI), lymphovascular invasion (LVI), and mitotic count and/or Ki-67 labeling index) was applied. Grade 1 histology was observed in 44.7% (n=96), grade 2 in 41.9% (n=90), and grade 3 in 13.5% (n=29) of cases. Compared with low-grade and intermediate-grade SC, high-grade tumors were associated with a solid architecture, more prominent hyalinization, infiltrative tumor borders, nuclear pleomorphism, presence of PNI and/or LVI, and Ki-67 proliferative index >30%. High-grade transformation, a subset of grade 2 or 3 tumors, seen in 8.8% (n=19), was defined as an abrupt transformation of conventional SC into high-grade morphology, sheet-like growth, and a tumor lacking distinctive features of SC. Both overall survival and disease-free survival (5 and 10 y) were negatively affected by tumor grade, stage, and TNM status (each P <0.0001). SC is a low-grade malignancy with predominantly solid-microcystic growth patterns, driven by a gene fusion, most commonly ETV6 :: NTRK3 . There is a low risk for local recurrence and a good overall long-term survival, with a low risk for distant metastasis but a higher risk for locoregional lymph node metastasis. The presence of tumor necrosis, hyalinization, PNI and/or LVI, and positive resection margins correlate with higher tumor grade, less favorable prognosis, and increased mortality. The statistical results allowed us to design a 3-tiered grading system for salivary SC.

A challenging diagnosis of mammary analogue secretory carcinoma (MASC) on fine needle aspiration cytology and cell block: A cytopathologist's perspective.

Mammary analogue secretory carcinoma (MASC) is a recently described salivary gland carcinoma that resembles the secretory carcinoma of the breast and is characterised by t(12;15) (q13;q25) translocation, which results in an ETV6-NTRK3 gene fusion product. On cytomorphology, it is characterised by papillary fragments, clusters, and singly dispersed tumour cells. These tumour cells are large and have abundant vacuolated cytoplasm. Acinic cell carcinoma of the salivary gland is the most common differential diagnosis of MASC. Other differentials include mucoepidermoid carcinoma, salivary duct carcinoma, pleomorphic adenoma, and oncocytic salivary gland neoplasms. Immunohistochemistry and morphology are critical in establishing the correct diagnosis. We present a case of a 46-year-old male patient diagnosed as MASC of the parotid gland on fine needle aspiration cytology and cell block.

A Parotid Gland Mammary Analogue Secretory Carcinoma in a 4-Year-Old Boy: Case Report and Literature Review.

Background: Mammary analogue secretory carcinoma (MASC) is characterized by similar histologic, immunohistochemical, and molecular features with breast secretory carcinoma. MASC usually occurs in adults. Case report: A 4-year-old boy presented with a right infra-auricular mass. Features of the tumor include solid, tubular, and papillary growth patterns, with homogenous eosinophilic secretions inside microcystic structures. Immunohistochemical stains showed strong, diffuse staining for CK7, S100, pan-TRK protein. P63 was positive in a peripheral pattern. Fluorescence in situ hybridization (FISH) analysis showed the characteristic ETV6-NTRK3 gene fusion. Conclusion: Typical histological, immunohistochemical, and molecular features are present in MASC occurring early in childhood.

Secretory Carcinoma of the Salivary Gland: A Rarity in Children.

Originally described as mammary analog secretory carcinoma (SC), SC of the salivary gland is a rare malignancy with morphologic and molecular similarities to SC of the breast. We present 2 children with salivary gland SC with the classic ETV6-NTRK3 gene fusion, including 1 with lymph node metastases. Both patients underwent surgical resection and were in remission 24 months postsurgery. One patient was additionally found to have synchronous papillary thyroid carcinoma with a TFG-MET fusion. A review of published cases highlights the expanding molecular profile and confirms the favorable course of salivary gland SC after surgical resection.

An Underappreciated Cytomorphological Feature of Secretory Carcinoma of Salivary Gland on Fine Needle Aspiration Biopsy: Case Report with Literature Review.

Secretory carcinoma (SC) of salivary gland, previously known as mammary analogue secretory carcinoma, is a rare low-grade malignancy harboring a diagnostic ETV6-NTRK3 gene fusion. SC of salivary gland shares histopathological, immunohistochemical and genetic characteristics with SC of the breast. There are several previous cytomorphological characterizations of SC of salivary gland reported in the literature. The most commonly reported patterns are of epithelial clusters with papillary architectural features, or of single dispersed epithelial cells on a background of abundant histiocytes. Tumor cells exhibit vacuolated eosinophilic cytoplasm and round to oval nuclei with regular nuclear contours and inconspicuous or small nucleoli. The cytomorphology of SC may closely mimic that of acinic cell carcinoma or low-grade mucoepidermoid carcinoma. Moreover, when cohesive epithelial clusters do not appear on the smears, it may be very difficult to distinguish dispersed tumor cells from histiocytes. In this article, we review the literature pertaining to SC cytomorphology and we report a fine needle aspiration biopsy case of SC in salivary gland showing well-defined intracytoplasmic hyaline globules, a feature that has not been previously reported. This novel cytomorphological feature may be helpful in distinguishing the tumor cells of SC from histiocytes and from other low-grade salivary gland tumors.

Mammary analogue secretory carcinoma: A challenging case arising in a young man with radiation exposure.

Mammary Analogue Secretory Carcinoma (MASC) is a recently described salivary gland tumor frequently sampled via fine-needle aspiration. The cytologic features of MASC are not entirely distinctive and can simulate acinic cell carcinoma, but the tumor harbors an ETV6 gene rearrangement resulting in an ETV6-NTRK3 fusion gene. We present a case of MASC arising in a 31 year old man with a history of multiple radio-embolization procedures.

ETV6-NTRK3-positive parotid mammary analogue secretory carcinoma: a case report.

INTRODUCTION: Mammary analogue secretory carcinoma (MASC) is a recent discovered entity of salivary glands tumors, reported for first time in 2010. The presence of a translocation encodes the ETS variant transcription factor 6-neurotrophic tyrosine receptor kinase (ETV6-NTRK3) gene fusion differences MASC from other tumors. CASE PRESENTATION: A 68-year-old male showed a non-painful right parotid enlargement, came from dermatology service, and followed by some facial squamous cell carcinomas. A computed tomography (CT) scan showed a 1.7×1.6 cm right parotid enlargement in superficial lobe. The patient underwent a right superficial parotidectomy. The final pathology confirmed the presence of ETV6-NTRK3-positive MASC. Complete right deep parotidectomy and functional cervical emptying were performed. DISCUSSIONS AND CONCLUSIONS: It is necessary to establish an appropriated differential diagnosis between salivary gland tumors. MASC is a low-grade malignancy cancer that sometimes can evolve to a high-grade tumor that might produce local and distance dissemination. Most times, these tumors are only treated by surgical resection and evaluating by a multidisciplinary team the need of more treatments. In our case, the patient showed a primary parotid tumor, removed surgically with free edges, and being identified as MASC. We decided to underwent neck dissection and discovered a second MASC focus on cervical salivary gland; however, there was no nodal dissemination. The patient remains disease-free after 14 months from last surgery. It is important to keep studying genetic therapy targets to ETV6-NTRK3 to obtain a new therapy line to treat those cases that require.

Clinical Activity of Selitrectinib in a Patient With Mammary Analogue Secretory Carcinoma of the Parotid Gland With Secondary Resistance to Entrectinib.

NTRK gene fusions are found in <1% of all cancers but are uniformly present in mammary analog secretory carcinomas (MASC) of the salivary glands. Two selective histology-agnostic tropomyosin receptor kinase (TRK) inhibitors are currently approved for malignancies with these oncogenic fusions. Resistance to TRK inhibition has been recognized, and the mediating mechanisms are presently being studied. This report describes a patient diagnosed with an MASC of the parotid gland who after undergoing multiple lines of treatment was found to have an ETV6-NTRK3 fusion and initiated TRK-targeted therapy using entrectinib. Upon disease progression, we performed tumor genetic sequencing that showed a secondary resistance mutation. The patient subsequently responded to selitrectinib, a next-generation TRK inhibitor.

Clinicopathologic and Molecular Characterization of Four Cases of Pediatric Salivary Secretory Carcinoma (SSC), One with ETV6-RET Fusion.

Salivary gland secretory carcinoma (SSC) is a neoplasm with characteristic histologic features, similar to those of secretory carcinoma of the breast. Only a few pediatric SSC cases have been reported, all with ETV6-NTRK3 fusion. We present four new pediatric SSC examples, one with a novel ETV6-RET fusion. Four cases of SSC were diagnosed between 2010 and 2020: 2 boys, 7 and 9 year-old with parotid tumors (1.5 and 1.3 cm, respectively); and two 14 year-old girls: one with a submandibular tumor (2.1 cm), and one with a parotid lesion (1.2 cm). Histologically, all tumors were similar: well-circumscribed lesions composed by mid-size, monotonous cells with eosinophilic and sometimes vacuolated cytoplasm. The nuclei are oval to round with open chromatin and a single nucleolus. There are duct-like structures and microcysts with colloid-like material. Immunohistochemically, tumor cells are positive for S100, CK7, mammaglobin and GATA3. A classic ETV6-NTRK3 translocation was confirmed in the three parotid tumors; an ETV6-RET fusion was demonstrated in the submandibular lesion. All patients underwent complete surgical resection and are alive without tumor recurrence after a follow-up time ranging from one to 4 years. Pediatric SSC is extremely rare but their characteristic morphology and immunohphenotype facilitate their diagnosis. We describe the first pediatric case with the recently reported ETV6-RET fusion. Similar to adult cases, this tumor is morphologically undistinguishable from those carrying the classic ETV6-NTRK3 translocation. Thus, in pediatric cases with morphology suggestive of SSC and negative ETV6-NTRK3 by RT-PCR, other possible fusions should be investigated.

A clinicopathologic study of secretory carcinoma of minor salivary gland: a series of 4 cases and diagnostic considerations.

OBJECTIVE: Secretory carcinoma (SC) of salivary gland is a recently described low-grade malignant neoplasm of the salivary gland, characterized by rearrangement of the ETV6 gene. SC of salivary gland shares striking morphologic, immunophenotypic, and molecular similarity to SC of breast. STUDY DESIGN: We report the clinicopathologic features of 4 ETV6-rearranged SCs of minor salivary gland and histopathologic diagnostic considerations. RESULTS: Two cases were located in the lip, 1 in the soft palate, and 1 in the mandibular vestibule. No patient presented with regional or distant metastases at diagnosis. All cases were positive for S100 protein and mammaglobin, and all cases were negative for p63. All cases were positive for ETV6 rearrangement. CONCLUSIONS: SC of the minor salivary glands are rare. Because of its shared histopathologic features with other salivary gland tumors, positivity for ETV6 gene rearrangements is recommended before rendering a diagnosis of SC of salivary gland.

Expanding the Molecular Spectrum of Secretory Carcinoma of Salivary Glands With a Novel VIM-RET Fusion.

BACKGROUND: Secretory carcinoma (SC), originally described as mammary analogue SC, is a predominantly low-grade salivary gland neoplasm characterized by a recurrent t(12;15)(p13;q25) translocation, resulting in ETV6-NTRK3 gene fusion. Recently, alternative ETV6-RET, ETV6-MAML3, and ETV6-MET fusions have been found in a subset of SCs lacking the classic ETV6-NTRK3 fusion transcript, but still harboring ETV6 gene rearrangements. DESIGN: Forty-nine cases of SC revealing typical histomorphology and immunoprofile were analyzed by next-generation sequencing using the FusionPlex Solid Tumor kit (ArcherDX). All 49 cases of SC were also tested for ETV6, RET, and NTRK3 break by fluorescence in situ hybridization and for the common ETV6-NTRK3 fusions using reverse transcription polymerase chain reaction. RESULTS: Of the 49 cases studied, 37 (76%) occurred in the parotid gland, 7 (14%) in the submandibular gland, 2 (4%) in the minor salivary glands, and 1 (2%) each in the nasal mucosa, facial skin, and thyroid gland. SCs were diagnosed more frequently in males (27/49 cases; 55%). Patients' age at diagnosis varied from 15 to 80 years, with a mean age of 49.9 years. By molecular analysis, 40 cases (82%) presented the classic ETV6-NTRK3 fusion, whereas 9 cases (18%) revealed an alternate fusion. Of the 9 cases negative for the ETV6-NTRK3 fusion, 8 cases presented with ETV6-RET fusion. In the 1 remaining case in the parotid gland, next-generation sequencing analysis identified a novel VIM-RET fusion transcript. In addition, the analysis indicated that 1 recurrent high-grade case in the submandibular gland was positive for both ETV6-NTRK3 and MYB-SMR3B fusion transcripts. CONCLUSIONS: A novel finding in our study was the discovery of a VIM-RET fusion in 1 patient with SC of the parotid gland who could possibly benefit from RET-targeted therapy. In addition, 1 recurrent high-grade case was shown to harbor 2 different fusions, namely, ETV6-NTRK3 and MYB-SMR3B. The expanded molecular spectrum provides a novel insight into SC oncogenesis and carries important implications for molecular diagnostics, as this is the first SC-associated translocation with a non-ETV6 5' fusion partner. This finding further expands the definition of SC while carrying implications for selecting the appropriate targeted therapy.

Mammary analogue secretory carcinoma: A case report.

BACKGROUND: Mammary analogue secretory carcinoma is a rare new entity of low-grade malignant tumor of salivary glands. It shared the same histologic features and the chromosomal translocation t(12;15)(p13;q25) as secretory carcinoma of the breast. AIM: To highlight the diagnosis approaches and the attitude of management in a case of MASC which is the first case reported in Tunisia. Reported case: A case of MASC of the lower left jugal mucosa was reviewed for its microscopic and immunohistochemical features. Fluorescence in situ hybridization (FISH) for the ETV6-NTRK3 translocation was performed. Surgery was the only treatment required in this case. No signs of local or regional recurrence during the one-year follow-up were noticed. COMMENTARIES: Secretory carcinoma was confused with other salivary gland tumors especially acinic cell carcinoma due to their morphological similarities, making diagnosis dilemma. Fluorescence in-situ hybridization (FISH) is the one definitive finding to confirm the diagnosis of MASC and to differentiate it from the other types of salivary gland tumor. At the present time, no specific therapy is available for patients with MASC.

Mammary analogue secretory carcinoma: An Indian experience of a novel entity.

AIMS: To explore clinical, histopathological and immunohistochemistry (IHC) features of mammary analogue secretory carcinoma (MASC) with systematic literature review. SETTINGS AND DESIGN: Hospital based cross-sectional study. SUBJECTS AND METHODS: The data of all cases of MASC diagnosed over a period of 1 year i.e., from July 2017 to July 2018 were retrieved. The haematoxylin and eosin (H and E) sections, and IHC sections were studied. A strict histological and recently updated criteria were applied and patients with a confirmed diagnosis of MASC were included in the study. A systematic literature review was conducted by searching the PubMed and National Centre for Biotechnology Information database. STATISTICAL ANALYSIS USED: Microsoft Excel 2010. RESULTS: The present case series is 27th in the English literature and 1stcase series describing its histopathology in the Indian literature. The mean age of presentation is 43 years. Female preponderance was found i.e., M:F ratio of 0.5. CONCLUSION: Histopathology and if necessary, followed by IHC is required for the confirmation of diagnosis of MASC. We should be aware about this recently described entity which is usually mistaken for other low grade salivary gland carcinomas like Acinic cell carcinoma (AciCC) and Mucoepidermoid carcinoma (MEC). The knowledge about its typical morphology, high degree of suspicion and IHC confirmation with both S-100 and Mammaglobin help in precise diagnosis.

(Mammary Analogue) Secretory Carcinoma of the Nasal Cavity: Report of a Rare Case with p63 and DOG1 Expression and Uncommon Exon 4-Exon 14 ETV6-NTRK3 Fusion Diagnosed with Next Generation Sequencing.

We present a 72 years old male with a left nasal cavity (mammary analogue) secretory carcinoma (SC) which exhibited classical morphological features on light microscopical examination, diffuse strong S100 and mammoglobin positivity on immunohistochemistry, and ETV6-NTRK3 gene fusion on next generation sequencing (NGS) analysis. Unusual features of this tumor are expression of p63 and DOG1 on immunohistochemistry and the atypical junction between Exon 4 of the ETV6 gene and Exon 14 of the NTRK3 gene.

Concurrent Identification of Novel EGFR-SEPT14 Fusion and ETV6-RET Fusion in Secretory Carcinoma of the Salivary Gland.

Salivary gland secretory carcinoma, also termed mammary analogue secretory carcinoma (MASC), is a recently described salivary gland neoplasm with characteristic histomorphologic findings similar to those of secretory carcinoma of the breast and harboring recurrent ETV6-NTRK3 fusions. Recent findings have expanded the molecular profile of salivary gland secretory carcinoma to include multiple novel ETV6 fusion partners, including RET, MET, and MAML3. Here, we report a case of cystic MASC with cribriform and papillary histology harboring two gene fusions, ETV6-RET and EGFR-SEPT14, identified by targeted RNA sequencing. The presence of the rearrangements was confirmed by FISH, RT-PCR, and Sanger sequencing. This is the first EGFR-SEPT14 fusion reported in secretory carcinoma as a single event or in association with an ETV6 rearrangement. This finding adds to the expanding molecular profile of this tumor entity, and may translate into novel treatment strategies.

Novel gene fusions in secretory carcinoma of the salivary glands: enlarging the ETV6 family.

Secretory carcinoma (SC) of the salivary gland is a low-grade malignancy associated with a well-defined clinical, histologic, immunohistochemical, and cytogenetic signature. Although the t(12;15) (p13;q25) translocation resulting in an ETV6-NTRK3 gene fusion is well documented, advances in molecular profiling in salivary gland tumors have led to the discovery of RET as another ETV6 gene fusion partner in SC. Here, we applied an RNA-based next-generation sequencing (NGS) approach for fusion detection on 14 presumed SC. The cases included 7 SC with classic ETV6-NTRK3 gene fusion and 3 SC harboring ETV6-RET gene fusion. In addition, 2 cases revealed a NCOA4-RET gene fusion and were subsequently reclassified as intraductal carcinomas. One case with an unusual dual-pattern morphology revealed a novel translocation involving ETV6, NTRK3, and MAML3 gene rearrangements. Interestingly, no ETV6-NTRK3 or ETV6-RET SC was ever documented to have this unique dual-pattern morphology or harbor a MAML3 mutation. The remaining case had no detected chromosomal abnormalities. Advances in molecular profiling of SC have led to the discovery of novel fusion partners such as RET and now MAML3. Further molecular characterization of salivary gland neoplasms is needed as these mutations may present alternative therapeutic targets in patients with these tumors.