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.

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.

Mammary analogue secretory carcinoma of the parotid gland: A rare tumour entity.

Mammary analogue secretory carcinoma (MASC) is a salivary gland tumour with low-grade potential and specific FTV6 derangement having translocation of chromosomes t (12;15) (p13;q25). It shares a similar morphological as well as an immunohistochemical profile with secretory carcinoma (SC) of the breast making it a diagnostic enigma. In this report, we discuss the case of a 65-year-old male patient, who presented with a complaint of right-sided facial swelling. To rule out the differential, he underwent various diagnostic modalities, including magnetic resonance imaging, fine-needle aspiration and it's the tumour's microscopic and immunohistochemical properties were also reviewed. Parotidectomy along with concurrent chemo-radiotherapy was performed to eradicate the growing mass.

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.

Atypical Presentation of Mammary Analogue Secretory Carcinoma of the Lip.

Mammary analogue secretory carcinoma (MASC) of the salivary gland is a rare tumor that was first described by Skalova et al in 2010, and since then, only a few hundred cases have been reported in the literature. Prior to Skalova's report, MASC was histologically misclassified as acinic cell carcinoma (ACC), pleomorphic adenoma, mucoepidermoid carcinoma, or adenocarcinoma, not otherwise specified. Mammary analogue secretory carcinoma has a low incidence rate overall, accounting for less than 0.3% of all salivary gland tumors. Histopathologic and cytogenic analysis of MASC is identical to secretory carcinoma of the breast, leading to the proposed name by Skalova. The purpose of this case presentation is to describe an atypical presentation of MASC, to compare this case with the classic description of MASC, and to contrast the various features of MASC to ACC in order to improve the accuracy of future diagnoses and help guide treatment.

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.

Cytomorphological features of Mammary Analog secretory carcinoma of parotid gland: Report of 3 cases and review of literature.

Mammary analog secretory carcinoma (MASC) of salivary gland is a recently described entity. Due to its rarity and cytomorphological overlap with other salivary gland tumors, it is often difficult to recognize on cytology. Here we describe three such cases with their histopathological correlation. All the three tumors arose in the parotid gland. They were misdiagnosed as mucoepidermoid carcinoma, acinic cell carcinoma and salivary duct adenocarcinoma, respectively. Final diagnosis of MASC was established on their follow-up histopathology and immunochemistry evaluation. Cytosmears of these tumors showed high cellularity with papillary architecture lying within fluid background rich in foamy macrophages. Nuclear atypia varied from minimal to marked with frequent mitosis and presence of necrosis. Cytoplasmic vacuolation was a consistent finding. Although the cytomorphological features of MASC are not specific, a diagnosis of MASC should be strongly considered in the presence of papillary architecture, prominent cytoplasmic vacuolations of the tumor cells and a background of cyst fluid. Immunohistochemistry on cell block may be done to confirm the diagnosis.

Secretory carcinoma of the skin with lymph node metastases and recurrence in both lungs: A case report.

Secretory carcinoma of the skin is an extremely rare adnexal tumor, histopathologically identical to homologous lesions in the salivary glands and breast tissue. Although this tumor was previously reported as indolent, we report a case of secretory carcinoma of the skin with metastases and recurrence. The patient, a 31-year-old women, had a subcutaneous mass in the right axilla. The resected specimen contained a circumscribed mass, with proliferating tumor cells that exhibited prominent nucleoli. They exhibited glandular and papillary growth patterns and there were amphophilic secretions in the glands. Immunohistochemically, the tumor cells were positive for mammaglobin and S100. The tumor was surrounded by sweat glands and there was no mammary glandular tissue, suggesting that it was derived from axillary sweat glands. Accordingly, we made a diagnosis of secretory carcinoma of the skin. Four years after the operation, there were metastases in both lungs. The resected specimen revealed a tumor identical to that of the original skin tumor. Next-generation sequencing-based multiplex gene assay performed on the metastatic tissue revealed an ETV6-NTRK3 fusion gene. This is a rare case report of secretory carcinoma of the skin with lymph node metastases and recurrence in both lungs.

A case of "ETV6-FISH-negative" secretory carcinoma of the parotid gland: immunohistochemical study.

Secretory carcinoma of the salivary glands is a relatively new disease concept, and is characterized by "morphological resemblance to mammary secretory carcinoma and ETV6-NTRK3 gene fusion." Herein we describe a confusing case and briefly discuss practical diagnostic problems. The patient was a 71-year-old Japanese man who had a tumor consistent with secretory carcinoma at the microscopic and immunohistochemical levels. Immunohistochemically, EMA and S100 protein were noted to be positive along with various cytokeratins as well as mammaglobin and pSTAT5. Moreover, vimentin was focally positive. Smooth muscle actin, p63, p40, and androgen receptor were negative. However, a search using fluorescence in situ hybridization did not reveal a definite split signal for the ETV6 gene. It is presumed that confirming the diagnosis of secretory carcinoma without genetic retrieval will be accepted as a diagnostic method, and we hope that worldwide general recognition may earlier reach "gradual acceptance."

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.

MUC4 is a valuable marker for distinguishing secretory carcinoma of the salivary glands from its mimics.

AIMS: Secretory carcinoma (SC) (synonym: mammary analogue secretory carcinoma) is a low-grade salivary gland tumour that occurs in both major and minor salivary glands. SC is known for its wide morphological, architectural and immunohistochemical spectrum, which overlaps with those of several salivary gland neoplasms, including acinic cell carcinoma (AciCC) and intercalated duct-type intraductal carcinoma (IDC) in major salivary glands, and polymorphous adenocarcinoma (PAC) in minor salivary glands. These tumours share with SC some morphological features and SOX10 immunoreactivity; also, with the exception of AciCC, they all coexpress S100 and mammaglobin. METHODS AND RESULTS: We compared MUC4 and mammaglobin expression in 125 salivary gland carcinomas (54 genetically confirmed SCs, 20 AciCCs, 21 PACs, and 30 IDCs) to evaluate the potential of these two markers to differentiate these entities. Moderate to strong diffuse MUC4 positivity was detected in 49 SCs (90.7%), as compared with none of the IDCs and PACs. In contrast, mammaglobin was frequently expressed in SCs (30 of 36 cases; 83.3%), IDCs (24/28; 85.7%), and PACs (7/19; 36.8%). Two of three high-grade SCs lost MUC4 expression in the high-grade tumour component. No significant correlation was found between MUC4 expression and the fusion variant in SC (ETV6-NTRK versus non-ETV6-NTRK). CONCLUSION: The results of our study identify MUC4 as a sensitive (90.7%) and specific (100%) marker for SC, with high positive (100%) and negative (93.4%) predictive values. Thus, MUC4 may be used as a surrogate for SC in limited biopsy material and in cases with equivocal morphology.

Mammary analog secretory carcinoma of the thyroid gland: A rare cancer harboring TRK fusion.

Mammary analog secretory carcinoma (MASC), or secretory carcinoma of the thyroid is an extremely rare disease harboring ETV6-NTRK3 gene fusion with TRK activation. Here we report the twelfth case of MASC of the thyroid worldwide. A 36-year-old female was diagnosed with poor-differentiated thyroid carcinoma (PDTC). Pathology consultant and immunochemical workups showed the tumor cells were negative for TTF1, TG, PAX8, positive for S100, Vimentin, GATA-3, and focally positive for mammaglobin. Fluorescence in situ hybridization (FISH) assay using a dual-color break-apart probe showed ETV6 translocation t(12p13) (ETV6) was present and established the diagnosis of MASC. Next-generation sequencing (NGS) of a 47-gene panel identified exon 1-5 of ETV6 gene were fused with exons 15-19 of NTRK3 gene. The patient experienced three loco-regional recurrences within 12 months and eventually developed inoperable local disease as well as bilateral lung metastasis. She is currently receiving anti-TRK treatment with a follow-up time of 33 months. A literature review of MASC in the thyroid was also conducted.

Carcinoma secretor de mama multicéntrico: a propósito de un caso y revisión de la literatura / Multicentric secretory carcinoma of the breast: case report and review of the literature

El carcinoma secretor de mama es una entidad poco frecuente caracterizada por un material eosinófilo, acelular y PAS diastasa positivo intra- y extracelular. Su curso clínico es benigno sin presentar recidivas ni metástasis pese a su fenotipo triple negativo. Suele presentarse en gente joven y la multicentricidad es muy inusual. Presentamos el caso de una mujer de 32 años con un carcinoma secretor de mama multicéntrico, realizando un análisis de la literatura y estudiando las principales características de esta entidad

Secretory carcinoma of the breast is a rare entity, characterized by the presence of intra- and extracellular, eosinophilic and acelular secretions. They are negative for hormone receptors and do not express human epidermal growth factor receptor HER-2/neu. However, the clinical outcome is favorable. Multicentricity is very unusual. We report a case of a 32-year-old woman with a multicentric secretory carcinoma of the breast. The main pathological features are discussed together with a review of the pertinent literature

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.

Macrocystic (Mammary Analogue) Secretory Carcinoma: An Unusual Variant and a Pitfall in the Differential Diagnosis of Cystic Lesions in the Head and Neck.

Mammary analogue secretory carcinoma (MASC) is a relatively recently described salivary gland adenocarcinoma characterized by ETV6-NTRK3 gene fusion and in most cases indolent clinical behavior. The majority of tumors show an admixture of microcystic, solid, and tubular growth patterns but only a few cases with dominant macrocystic growth have been reported. We report 15 cases of macrocystic MASC. There were 11 men and 4 women (17 to 88 y age range, average 47 y). The patients presented with a painless cystic mass, the majority in the region of the parotid gland (n=13), as well as in submandibular gland (n=1) and the neck (n=1). All tumors were circumscribed measuring 1.0 to 4.0 cm in greatest diameter (mean: 1.75 cm). Twelve tumors were unilocular, while 3 were multilocular. The cystic spaces were predominantly lined by a single epithelial cell layer with focal areas in which the epithelium was multilayered with papillary and hobnail features. In 3 of the cases there were more solid foci of intracystic tumor characterized by papillary and/or microcystic growth. The neoplastic cells were round to oval with hyperchromatic to vesicular nuclei with centrally located nucleoli and eosinophilic or vacuolated cytoplasm. Tumor cells showed strong positivity for S100 protein and mammaglobin, while DOG1 was uniformly negative. A minority of cases showed focal p63 reactivity predominantly limited to the periphery of the cystic lining. ETV6 gene rearrangement was identified in 9 cases. Macrocystic MASC can simulate benign and malignant salivary gland lesions and needs to be included in the differential diagnosis of cystic lesions in the head and neck. To the best of our knowledge, our report represents the first series of macrocystic MASCs wholly focusing on this unusual variant.

Higher Ki67 Index, Nodal Involvement, and Invasive Growth Were High Risk Factors for Worse Prognosis in Conventional Mammary Analogue Secretory Carcinoma.

PURPOSE: The prognostic factors of salivary (mammary analogue) secretory carcinoma (SC) are unclear because of the rarity of the tumor. This report presents the largest case series to investigate the prognosis-related clinicopathologic factors in conventional SC. MATERIALS AND METHODS: This study was based on a retrospective cohort study from 1993 to 2015 of patients whose sections were reviewed and who were newly diagnosed as having SC by the detection of ETV6 rearrangement. Clinicopathologic features, including age, gender, involvement site, tumor category, node category, histopathologic subtype, cellular atypia, tumor necrosis, growth pattern (noninvasive vs invasive), perineural invasion, margin, hyalinized fibrous septa, Ki67 expression, and postoperative treatment, were analyzed as primary predictors. Patients' final outcomes-including no evidence of disease, recurrence, metastasis, and death-were collected during follow-up. Survival analysis was performed only for conventional SC using the Kaplan-Meier method and the Cox proportional hazards regression model. RESULTS: Sixty-two cases of SC were retrospectively confirmed. Fifty-nine cases were identified as conventional SC, whereas 3 cases were identified as high-grade SC. In conventional SC, univariate analyses showed that nodal metastasis, invasive growth, and a Ki67 index of at least 10% were related to decreased recurrence-free survival (RFS), distant disease-free survival (DDFS), and disease-free survival (DFS). Age older than 44 years, T3 and T4 stages, and markedly hyalinized fibrous septa were associated with decreased DDFS. T3 and T4 stages, positive margins, and tumor necrosis were associated with decreased overall survival. By multivariate analysis, the Ki67 index was found to be an independent prognostic factor for RFS (P = .008) and DFS (P = .003). CONCLUSION: Although most patients with conventional SC had a favorable clinical prognosis, patients with nodal involvement, invasive growth, and a Ki67 index higher than 10% showed a poor clinical outcome by exhibiting local recurrence or distal metastasis. Patients with a higher Ki67 index especially need close observation for local recurrence.

Primary Mammary Analog Secretory Carcinoma (MASC) of the Vulva With ETV6-NTRK3 Fusion: A Case Report.

Mammary analog secretory carcinoma is a primary salivary gland neoplasm with histologic, immunophenotypic, and molecular features identical to those of secretory carcinoma of the breast. Similar neoplasms have now been reported to occur in various nonmammary sites including the parotid gland, submandibular gland, sinuses, lip, skin, thyroid gland, and lung. We report, to our knowledge, the first example of a primary vulvar neoplasm with pathologic features identical to secretory carcinoma of the breast and an ETV6-NTRK3 fusion.