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.

Secretory Carcinoma in Children and Young Adults: A Case Series.

Secretory carcinoma (SC), previously known as mammary analogue secretory carcinoma, is a rare salivary gland neoplasm that typically presents as a slow-growing painless lesion in the head and neck. SC occurs mainly in adults but has been described in children with the youngest reported patient diagnosed at five years of age. In children the gender distribution has been reported as female to male ratio of 1:1.2. SC is generally considered a low-grade malignancy with characteristic morphological features and immunological profile. SC also harbors ETV6-NTRK3 fusion (t(12;15)(p13:q25)). Surgical resection with or without lymph node dissection is the standard treatment, with generally favorable clinical outcomes. Here we present a single institution case series of six patients (ages 9-21) with SC and a review of the previously described pediatric cases. Our small series showed male predominance in pediatric patients with predominantly low-grade and stage tumors. All cases underwent complete surgical resections and when follow up is available there was no evidence of recurrences or metastases. To the best of our knowledge, this is the only SC case series comprised exclusively of pediatric and youth patients.

Imaging identification of primary mammary analogue secretory carcinoma and acinic cell carcinoma in major salivary glands.

OBJECTIVE: The present study aimed to characterize and differentiate the ultrasonography (US) and computed tomography (CT) features of mammary analogue secretory carcinoma (MASC) and acinic cell carcinoma (AciCC). METHODS AND PATIENTS: A total of 83 patients with clinically proven MASC and AciCC were analyzed. The following characteristics were assessed on US, CT, and magnetic resonance imaging: lesion size, shape, margin, echogenicity, echotexture, cystic components, posterior echo, vascularity, density, degree of enhancement, enhancement pattern, signal intensity (SI) on T1- and T2-weighted images (WI), hemorrhages, and lymph node enlargement. RESULTS: Similarities were observed between the imaging performance of MASC and AciCC. Differences between the two characteristics of shape on US and cystic components on CT were statistically significant. The proportion of MASC to regular shape on US (p = 0.006) and cystic components on CT (p = 0.027) was significantly higher than that of AciCC. Regular shape on US had the highest sensitivity in the identification of MASC and AciCC, while regular shape on US + cystic component on CT had the highest specificity. CONCLUSIONS: The shape on US and cystic components on CT are key characteristics for distinguishing MASC and AciCC.

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.

Secretory carcinoma of the sinonasal cavity and pharynx: A retrospective analysis of four cases and literature review.

Secretory carcinoma (SC) is a recently recognized type of salivary gland tumor characterized by t(12;15) (p13;q25) translocation resulting in an ETV6-NTRK3 gene fusion. Most SCs are located in a main salivary gland, and primary sinonasal secretary carcinoma is rare. We describe three cases of primary SC in the sinonasal cavity with high-grade transformation (HGT) in one case, and the first case in the pharynx. All tumors comprised slightly atypical cells with solid, tubular, microcystic growth patterns. The case with HGT included two components with distinct sharp boundaries and comedo necrosis, high mitotic figures and obvious cellular atypia. Tumor cells were positive for vimentin, S100, and Gata-3 and negative for p63 and DOG-1. Three cases showed nuclear staining of pan-TRK and one showed cytoplasmic staining. All cases harbored ETV6 gene rearrangement, and ETV6-NTRK3 gene fusion was detected in three cases. Most patients were treated with radical resection and adjuvant therapy. After excision, all remained tumor-free for 65-164 months (medium 98.5 months). SC in the sinonasal cavity and pharynx is a low-grade malignant tumor with histologic features overlapping those of other salivary gland tumors. Immunohistochemical analysis and fluorescence in situ hybridization are useful techniques for its differential diagnosis.

Mammary analogue secretory carcinoma of parotid gland: Literature review and experience of a dedicated cancer institution in Pakistan.

Mammary Analogue Secretory Carcinoma (MASC) is a rare pathology of the salivary gland, most commonly involving the parotid gland. The objective of this study was to identify the characteristic features of MASC and its treatment outcomes. A retrospective review of 12 patients with histological diagnosis of MASC, who were managed between 2010 to 2019, was carried out at the Shaukat Khanum Memorial Cancer Hospital & Research Centre, Lahore. Their mean age was 34±16 years. There were 9 (75%) male and 3 (25%) female patients. Painless slow growing swelling was the most common presenting symptom. All the patients had undergone surgical excision with or without neck dissection, followed by adjuvant treatment. Of these, six patients had T2 tumours, while four had cervical lymph node metastasis. The mean follow-up period was 23±21 months. Local recurrence was seen in one patient. MASC is considered a low-grade tumour with good prognosis which can be treated with curative intent of surgery followed by radiotherapy effectively.

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.

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."

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.

Mammary analogue secretory carcinoma of salivary gland diagnosed on submandibular gland cytology: A case report and review of the literature.

Mammary analogue secretory carcinoma of the salivary glands has morphological shares molecular similarities to secretory carcinoma of the breast. Here, we report a 46-year-old woman who presented with a right submandibular gland mass. Fine needle aspiration differential diagnosis included oncocytosis, oncocytoma, acinic cell carcinoma and mammary analogue secretory carcinoma. We also review the current literature regarding clinical presentation and diagnostic workup of this entity.

Primary cutaneous secretory carcinoma: A previously overlooked low-grade sweat gland carcinoma.

INTRODUCTION: Twelve cases of primary cutaneous secretory carcinoma (PCSC) have been published, 9 showing ETV6-NTRK3 translocation, a characteristic finding shared with secretory breast carcinoma and mammary analogue secretory carcinoma. CASE REPORT: A 34-year-old female presented a solitary nodule on the right groin. Biopsy revealed a secretory carcinoma staining positive with CK7, CAM5.2, mammaglobulin and S100 and negative with GATA3, CK20, podoplanin, calponin and CDX2. ETV6-NTRK3 was demonstrated by Fluorescence in situ hybridization (FISH). DISCUSSION: PCSC is a rare neoplasm, described in the skin in 2009, that affects more frequently females with a mean age of 42.3 years and it is most commonly located in axilla. Histopathologically, these tumor cells are characterized by bubbly eosinophilic secretions diastase-resistant and bland nuclei and they are arranged in various growth patterns, including microcystic, tubular, solid and papillary. S100, mammoglobin and CK7 are usually positive. We review the main histopathological features to rule out histopathologic mimics such as breast metastasis, salivary tumors, cribriform carcinoma and primary cutaneous adenoid cystic carcinoma. GATA3 negative staining, as in our case, can help to rule out breast metastasis. Moreover, long-term benign follow up (144 months) in this case as well as follow-up data on outcomes from literature review support that PCSC is a low-grade sweat gland carcinoma.

Mammary Analog Secretory Carcinoma With ETV6 Rearrangement Arising in the Conjunctiva and Eyelid.

Mammary analog secretory carcinoma (MASC) of salivary gland is a recently described neoplasm that morphologically and immunohistochemically resembles secretory carcinoma of the breast. Genetically, both of them harbor ETV-6-NTRK-3 fusion rearrangement. One case of primary MASCs arising from the eyelid is reported. The patient was a 52-year-old man. Microscopically, the tumor exhibited nodular aggregation of solid, tubular, and microcystic/macrocystic structures. Characteristic "colloid-like" eosinophilic secretory material was present within intraluminal spaces. Immunohistochemically, the tumor cells were positive for mammaglobin, S-100, STAT5a, vimentin, GCDFP-15, AE1/AE3, EMA, and CK7 and were negative for DOG-1, CK5/6, and SMA. A dual color break-apart fluorescence in situ hybridization probe identified rearrangement of the ETV6 gene locus on chromosome 12. The patient had no history of breast or salivary gland tumor. The tumor was completely excised, and the patient has no evidence of recurrent disease or metastasis after 1-year follow-up. A diagnosis of primary MASC was rendered. MASC has never been reported occurring in ocular region. This type of secretory carcinoma probably originates from sweat glands or accessory lacrimal glands, Wolfring and Krause. This unique case expands the clinicopathologic landscape of MASCs for better characterization of this rare entity.

Secretory carcinoma of the parotid with adenoid cystic carcinoma cytological pattern: A cytological-pathological correlation with literature review.

Secretory carcinoma (SC) is a rare low-grade malignant tumor, defined by ETV6-NTRK3 fusion, identifiable by FISH. We describe a case in a 58-year-old male with a painless slowly growing 16mm palpable mass within left superficial parotid. FNA of the mass showed highly cellular specimen with moderate to large pleomorphic cells with round to ovoid nuclei with vesicular chromatin and distinct nucleoli. Cells had moderate to large amounts of vacuolated cytoplasm. Abundant globular metachromatic material, resembling that of adenoid cystic carcinoma, was noted. This material was seen extracellularly and intracytoplasmic, and stained magenta on Diff-Quik and blue-green on Papanicolaou-stained slides. The tumor cells on a cell block preparation were positive for Mammaglobin and S-100. PAS stain highlighted extracellular and intracytoplasmic secretions. FNA diagnosis was "Positive for Malignancy. Morphologic features most compatible with Mammary Analogue Secretory Carcinoma". ETV6 FISH studies as well as histologic examination of excised tumor confirmed the diagnosis. Finding the globular metachromatic material in SC, that is generally seen in adenoid cystic carcinoma, broadens a cytological differential diagnosis of both entities. Cytological differential diagnosis, clinical, histological, immunohistochemical, and molecular features of secretory carcinomas are discussed in this study.

Genomic profiling of breast secretory carcinomas reveals distinct genetics from other breast cancers and similarity to mammary analog secretory carcinomas.

Secretory carcinomas of the breast are rare tumors with distinct histologic features, recurrent t(12;15)(p13;q25) translocation resulting in ETV6-NTRK3 gene fusion and indolent clinical behavior. Mammary analog secretory carcinomas arising in other sites are histopathologically similar to the breast tumors and also harbor ETV6-NTRK3 fusions. Breast secretory carcinomas are often triple (estrogen and progesterone receptor, HER2) negative with a basal-like immunophenotype. However, genomic studies are lacking, and whether these tumors share genetic features with other basal and/or triple negative breast cancers is unknown. Aside from shared ETV6-NTRK3 fusions, the genetic relatedness of secretory carcinomas arising in different sites is also uncertain. We immunoprofiled and sequenced 510 cancer-related genes in nine breast secretory carcinomas and six salivary gland mammary analog secretory carcinomas. Immunoprofiles of breast and salivary gland secretory carcinomas were similar. All the tumors showed strong diffuse MUC4 expression (n=15), and SOX10 was positive in all nine breast and in five out of six salivary gland tumors. All breast secretory carcinomas were triple negative or weakly ER-positive, and all tumors at both the sites expressed CK5/6 and/or EGFR, consistent with a basal-like phenotype. Sequencing revealed classic ETV6-NTRK3 fusion genes in all cases, including in carcinoma in situ of one breast tumor. Translocations were reciprocal and balanced in six out of nine breast and three out of six salivary gland tumors and were complex in three others. In contrast to most breast basal carcinomas, the mutational burden of secretory carcinomas was very low, and no additional pathogenic aberrations were identified in genes typically mutated in breast cancer. Five (56%) breast and two (33%) salivary gland tumors had simple genomes without copy number changes; the remainder had very few changes, averaging 1.3 per tumor. The ETV6-NTRK3 derivative chromosome was duplicated in one breast and one salivary gland tumor, and was the only copy number change in the latter. The findings highlight breast secretory carcinoma as a subtype more closely related to mammary analog secretory carcinoma than to basal/triple negative breast cancers of no special type. Lack of pathogenic mutations in common cancer-related genes suggests that ETV6-NTRK3 alone may suffice to drive these tumors and likely helps explain their indolent behavior.

Newly described salivary gland tumors.

This review concentrates on three salivary gland tumors that have been accepted in the recent literature as new neoplastic entities: mammary analog secretory carcinoma (MASC), sclerosing polycystic adenoma (SPA) and cribriform adenocarcinoma of tongue and other minor salivary glands (CAMSGs). MASC is a distinctive low-grade malignant salivary cancer that harbors a characteristic chromosomal translocation, t(12;15) (p13;q25) resulting in an ETV6-NTRK3 fusion. SPA is a rare lesion often mistaken histologically for low-grade salivary carcinoma. Previously thought to be a reactive fibroinflammatory process, but recent evidence of clonality, recurrences in up 30%, and dysplastic foci suggest it may be truly neoplastic. CAMSG is a distinct tumor entity that differs from polymorphous low-grade adenocarcinoma (PLGA) by location (ie, most often arising on the tongue), by prominent nuclear clearing, alterations of the PRKD gene family and clinical behavior with frequent metastases at the time of presentation of the primary tumor. Early metastatic disease seen in most cases of CAMSG associated with indolent behavior makes it a unique neoplasm among all low-grade salivary gland tumors. Salivary glands may give rise to a wide spectrum of different tumors. They are often diagnostically challenging as morphological features often overlap between different entities. Although conventional morphology in combination with immunohistochemical findings still provide the most important clues for diagnosis, recent advances in molecular pathology offer new diagnostic tools in investigating the differential diagnosis, as well as providing potentially valuable prognostic indicators. In the last two decades, several new salivary gland tumor entities have been described, namely MASC, SPA and CAMSGs.

[Clinicopathologic features of mammary analogue secretory carcinoma of salivary glands].

Objective: To investigate the clinicopathological features of mammary analogue secretory carcinoma (MASC) of salivary glands, and its diagnosis, differential diagnosis, immunohistochemistry and molecular pathology. Methods: Seventeen cases of MASC were enrolled, with 9 cases of salivary acinar cell carcinoma and 18 cases of adenoid cystic carcinoma as control groups from Nanjing General Hospital from 1997 to 2014 were included in this retrospective study, combined with immunohistochemistry and molecular detection of ETV6-NTRK3 gene fusion. All cases were histologically reviewed with immunohistochemical staining (EnVision) for S-100 protein, SOX10, GATA3, CD117 expression in each group. Fluorescence in situ hybridization (FISH) was used to detect the ETV6-NTRK3 gene fusion. Results: The age of MASC patients ranged from 27 to 74 years with mean age of 47 and ratio of male and female was 4∶3. All cases showed infiltrative growth and diverse cytology and histology, including lobular (8 cases), cystic papillary (3 cases), cribriform mixed with papillary and glandular structures (6 cases) at various proportions. Some tumors of MASC also exhibited solid growth areas with occasional microcystic honeycombed pattern composed of small cysts merged into larger cysts resembling thyroid follicles. S-100 protein and SOX10 were strongly positive in all MASC cases (17/17). In addition, there was insignificant positivity for GATA3 (3/17) and CD117 (4/17). ETV6 gene fusion detection was informative in 12 MASC cases by FISH with 10 positive cases and 2 negative cases. Conclusions: Combined immunohistochemical positivity of S-100 protein, CD117 and SOX10 are useful in the diagnosis and differential diagnosis of MASC. FISH detection of ETV6-NTRK3 fusion offers an additional molecular diagnostic marker for the diagnosis.

What hides behind the MASC: clinical response and acquired resistance to entrectinib after ETV6-NTRK3 identification in a mammary analogue secretory carcinoma (MASC).

BACKGROUND: Mammary analogue secretory carcinoma (MASC) is a recently described pathologic entity. We report the case of a patient with an initial diagnosis of salivary acinic cell carcinoma later reclassified as MASC after next-generation sequencing revealed an ETV6-NTRK3 fusion. PATIENTS AND METHODS: This alteration was targeted with the pan-Trk inhibitor entrectinib (Ignyta), which possesses potent in vitro activity against cell lines containing various NTRK1/2/3 fusions. RESULTS: A dramatic and durable response was achieved with entrectinib in this patient, followed by acquired resistance that correlated with the appearance of a novel NTRK3 G623R mutation. Structural modeling predicts that this alteration sterically interferes with drug binding, correlating to decreased sensitivity to drug inhibition observed in cell-based assays. CONCLUSIONS: This first report of clinical activity with TrkC inhibition and the development of acquired resistance in an NTRK3-rearranged cancer emphasize the utility of comprehensive molecular profiling and targeted therapy for rare malignancies (NCT02097810).

Mammary analog secretory carcinoma of the thyroid gland: A primary thyroid adenocarcinoma harboring ETV6-NTRK3 fusion.

ETV6-NTRK3 fusion was identified in several cancers including the recently described mammary analog secretory carcinoma (MASC) of the salivary glands and a minority of papillary thyroid carcinomas. We describe three cases of primary MASC of the thyroid gland and provide a detailed clinical and pathological characterization of the tumor morphology, immunoprofile, and genetic background. Immunohistochemistry for PAX8, TTF-1, thyroglobulin, mammaglobin, GCDFP-15, S-100 protein, and p63 was used to define the tumor immunophenotype. Fluorescence in situ hybridization for ETV6 rearrangement was performed in three, and the next-generation sequencing assay MSK-IMPACT™ (Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets) was performed in two cases. Primary MASC of the thyroid occurred in two women and one man, age 47-72 years. All patients presented with high T stage, infiltrative, locally aggressive tumors with extrathyroidal extension. Two cases were associated with well-differentiated papillary thyroid carcinoma. Histologically, they appeared as low-grade tumors, resembling MASC of the salivary glands and labeled positive for mammaglobin, GCDFP-15, S-100 protein, p63, weakly positive for PAX8, and negative for TTF-1 and thyroglobulin. Fluorescence in situ hybridization revealed ETV6 rearrangement in all cases. In two tested cases MSK-IMPACT™ confirmed the presence of ETV6-NTRK3 gene fusion. Two patients had at least two local recurrences, one was alive with disease, and one was alive and free of disease after 14 and 17 years, respectively. The third patient was alive and free of disease after 2 years. MASC of the thyroid is histologically, immunophenotypically, and genetically similar to its salivary gland counterpart. Thyroid MASC can be associated with a well-differentiated papillary thyroid carcinoma component, supporting follicular cell origin. Clinically, these carcinomas may show frequent recurrences but are associated with long-term survival. Patients with MASC of the thyroid may potentially benefit from Trk molecular-targeted therapy.

Carbonic anhydrase VI: a novel marker for salivary serous acinar differentiation and its application to discriminate acinic cell carcinoma from mammary analogue secretory carcinoma of the salivary gland.

AIMS: Carbonic anhydrase VI (CA6) is present in serous acinar cells of human salivary glands. The aim of this study was to investigate the diagnostic utility of CA6 in differentiating acinic cell carcinoma (AciCC) from its morphological mimic mammary analogue secretory carcinoma (MASC) of the salivary gland. METHODS AND RESULTS: CA6 immunostaining was performed in 28 cases of AciCC and 14 cases of MASC. All cases of AciCC showed positive CA6 staining. The staining pattern correlated with the number of serous acinar cells in tumours. All MASCs stained negatively for CA6. The results were compared with those obtained with currently used markers, including DOG1, mammaglobin, S100, and vimentin. CA6 showed sensitivity and specificity as high as those of DOG1 in diagnosing AciCC. CA6 expression was focally observed in basal cell adenoma and in one case of cystadenocarcinoma (1/3), but not in other salivary gland tumours, including mucoepidermoid carcinoma, adenoid cystic carcinoma, salivary duct carcinoma, lymphoepithelial carcinoma, epithelial-myoepithelial carcinoma, and pleomorphic adenoma. CONCLUSIONS: CA6 is a specific marker for serous acinar cells of salivary glands and AciCC. CA6 has sensitivity and specificity equal to those of DOG1 in the differential diagnosis between AciCC and MASC. A combination of CA6 and DOG1 could be an ideal immunohistochemical panel for AciCC.