The genetic and immune features of salivary gland secretory carcinoma with high-grade transformation.

OBJECTIVES: To compare the clinicopathological, molecular, and immune features of conventional and high-grade transformation (HGT) secretory carcinoma (SC) in salivary glands. MATERIALS AND METHODS: The clinicopathological data of 88 cases including 74 conventional SCs and 14 SCs with HGT were reviewed. Targeted next-generation sequencing was performed in 11 SCs with HGT and 7 conventional SCs. The level of PD-L1 and CD8+ TILs was determined by immunohistochemistry. RESULTS: Compared with the conventional group, the rates of nodal metastasis, local recurrence, distant metastasis and mortality were significantly higher in the HGT cohort. Mutations of ARID1A/B, KMT2A, HOXD13, NRG1 and ETV6 genes were identified in HGT SCs. A recurrent E307G mutation in GATA6 gene was also observed in two cases. Two deceased HGT patients with distant metastasis harboured NOTCH3 mutations. ETV6-RET translocation was prone to occur in the HGT SCs. Additionally, PD-L1 expression was low, and CD8+ TILs were sparse in most HGT cases. CONCLUSION: Our findings reveal novel gene alterations involved in the progression of HGT in SCs. Most HGT SCs patients cannot benefit from PD-L1 blocking and may be approached with a distinct treatment strategy including the lymph node dissection and application of molecular target drugs in precision oncology.

Mammary-analog secretory carcinoma in children: Surgery or TRK inhibitors first?

We report two cases of pediatric mammary-analog secretory carcinoma (MASC), a male operated on at age 8 and a female operated on at 12, who are in remission 2 years after surgery. The diagnosis of MASC was challenging and established by identifying the ETV6::NTRK3 fusion transcript in both cases. Given the excellent results of TRK inhibitor treatments in adult MASC and pediatric tumors expressing an ETV6::NTRK3 fusion, they should probably be prescribed as first-line treatment in cases requiring surgery with foreseeable serious sequelae or metastatic disease.

Diagnostic accuracy of pan-TRK immunohistochemistry in differentiating secretory carcinoma from acinic cell carcinoma of salivary gland-A systematic review.

BACKGROUND: Secretory carcinoma (SC) is a well-established salivary gland malignancy that has earned its popularity for its unique clinicopathological behavior. Although it is an indolent malignancy, few of them have been reported with high grade transformation making it mandatory to differentiate it from its prime histological mimicker, acinic cell carcinoma (AciCC). Recently, many studies have been directed toward validating the sensitivity and specificity of pan-TRK IHC for confirming ETV6::NTRK3 gene fusion in SCs involving salivary gland. AIM: The aim of the present systematic review was to establish the diagnostic utility of pan-TRK immunostaining in histological differentiation of SC from AciCC. MATERIAL AND METHODS: An electronic search was carried out using MEDLINE by PubMed, Scopus, Google scholar, Trip, Cochrane library and EMBASE databases. Articles in which SC assessed with pan-TRK immunohistochemical expressions were included for systematic review and their staining pattern (cytoplasmic, nuclear and/or combined), sensitivity, specificity, positive as well as negative predictive were gathered. Risk of bias was analyzed for each study using QUADAS-2 tool. RESULTS: Thirteen eligible articles were included for the quantitative analysis, which revealed positive immunostaining of pan-TRK by nearly all the ETV6::NTRK3 fusion prevalent SCs alongside negative expression in almost all the cases of AciCC with 100% of sensitivity as well as specificity. CONCLUSION: The evidence from the included studies supports that pan-TRK immunostaining could be used as a reliable preliminary screening tool for discerning SC from AciCC. PROSPERO No: CRD42022308913.

A Pediatric Case of High-Grade Secretory Carcinoma of the Maxillary Sinus With ETV6::NTRK3 Gene Fusion, Therapeutic Implications, and Review of the Literature.

Secretory carcinoma (SC) is a salivary gland tumor with a generally low grade microscopic appearance, a characteristic immunophenotype, and a recurrent translocation leading to ETV6::NTRK3 fusion gene. Rare cases are reported in children. The maxillary sinus is an unusual localization. SC have an overall favorable prognosis, but cases with high grade morphology have been described in adult population and are related to a more aggressive clinical course. We present a pediatric case of secretory carcinoma involving the maxillary sinus with high grade morphology, with a review of the literature of secretory carcinomas with high grade component.

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.

Secretory carcinoma of the salivary gland is rich in lactoferrin: a possible lactational-like differentiation?

PURPOSE: It has been hypothesised that secretory carcinoma of the salivary gland (SCsg) might have a lactational-like differentiation. Therefore, we aimed to assess the immunoexpression of breast hormonal receptors and milk-related proteins in cases of SCsg and other salivary gland tumours with prominent secretory activity. METHODS: Immunohistochemistry against prolactin and growth hormone receptors, lactoferrin, human milk fat globule 1, MUC 1 and MUC4 was performed in twelve cases of SCsg and 47 other salivary gland tumours. RESULTS: Most cases of SCsg were negative for prolactin and growth hormone receptors. All cases of SCsg showed enhanced membranous-cytoplasmic staining for human milk fat globule 1, a pattern seen in other tumour groups. Only SCsg showed widespread strong staining for lactoferrin, concomitantly in the cell compartment and secretion. The other positive tumour types exhibited restricted staining. MUC1 and MUC4 showed no distinct pattern of expression. CONCLUSION: Although SCsg failed to demonstrate a complete lactational-like differentiation, lactoferrin showed a distinctive expression pattern in SCsg compared to other tumour types, which makes it a good marker to help in its differential diagnosis.

Utility of MUC4 in the diagnosis of secretory carcinoma of salivary glands.

Salivary gland tumors are diverse in morphology and both benign and malignant tumors may pose diagnostic challenges especially in small biopsies. Secretory carcinoma (SC) is histologically characterized by microcysts, follicles, solid growth pattern and occasional papillary structures, and absence of zymogen granules. SC is molecularly defined by the presence of novel gene fusion ETV6::NTRK3. Among the positive stains (S100 and mammaglobin), MUC4 is now another promising marker for the diagnosis of SC, that would enable the pathologists to exclude other morphologically close simulators. Aim of this study was to report clinicopathological features and assess utility of MUC4 in the diagnosis of SC. MUC4 was performed on 22 cases of SC. Glass slides were reviewed to record morphological patterns and staining of S100, mammaglobin, DOG1 and MUC4. Age ranged from 9 to 63 years with mean age of 34.41 ± 16.28 years. The male: female ratio was 72.7 %:27.3 %. The majority occurred in major salivary glands. A combination of patterns was seen; microfollicles were the most prevalent (90 %) followed by papillary-cystic and macrofollicles. MUC4 was positive in 19/21 (90 %) cases with almost equal number of 2+ and 3+ staining. MUC4 was negative in all cases of acinic cell carcinoma, polymorphous adenocarcinoma, adenoid cystic carcinoma, salivary duct carcinoma, myopepithelioma and myoeithelial carcinoma, cystadenoma and cribriform adenocarcinoma and all except 3 cases of mucoepidermoid carcinoma tested. Overall sensitivity of MUC4 was 95.4 %, specificity 90 %, p-value being <0.01, positive predictive value 87.5 % and negative predictive value 96.4 %. A characteristic cytoplasmic granular pattern was observed in 76.1 % tumors. S100 and mammaglobin were positive in all the performed cases. DOG1 was positive in 6/11 (28.5 %) tumors. In conclusion, MUC4 is a useful addition to a diagnostic immunohistochemical panel for SC, and to distinguish it from close potential mimickers such as acinic cell carcinoma, especially in practice settings where molecular testing is unavailable.

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.

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.

Approaches to the diagnosis of secretory carcinoma of the salivary glands: a case series and review.

Secretory carcinoma (SC) is a salivary gland neoplasm included in the latest World Health Organization Classification of Head and Neck Tumours. Its morphologic and immunohistochemical characteristics resemble those of breast secretory carcinoma, and the tumors share the same fusion gene, ETV6::NTRK3. This chromosome translocation can be confirmed through reverse transcription-polymerase chain reaction or located using ETV6 fluorescent in situ hybridization. These techniques are expensive, and few laboratories can carry out molecular analysis. In addition, some of these tumors are related to non-NTRK fusion types and non-ETV6 translocation. Therefore, recognition of the typical histopathologic features of SC is the first step in considering this disease among the diagnostic hypotheses. In this case series, morphologic findings combined with immunohistochemical profiles were sufficient to make the correct diagnosis.

Secretory carcinoma of major and minor salivary glands with ETV6-NTRK3 gene fusion: overcoming misdiagnosis in the era of tumour-agnostic therapy with TRK inhibitors.

Introduction: Secretory carcinoma (SC) of the salivary gland is an extraordinarily rare tumour. Accurate diagnosis of SC is crucial for understanding the clinical course, prognosis, and selection of optimal therapy. The aim of this research was to analyse retrospectively the clinical and pathological characteristics of patients diagnosed with SC of the salivary gland from 2017 onwards, which aligns with its addition to the World Health Organization classification. Material and methods: We conducted a retrospective, single-centre, clinicopathological analysis of patients diagnosed with SC of the salivary gland between 2017 and 2022. The analysis included the evaluation of NTRK3 gene rearrangements and immunohistochemical (IHC) profiling. Results: The study included 6 patients, comprising 4 women and 2 men. The average age of the patients was 50 years (standard deviation 26). Three cases presented with tumours in the parotid gland, while one case each involved the submandibular gland, sinonasal tract, and buccal mucosa. Interestingly, despite the characteristic IHC profile, each case was initially diagnosed as a different type of salivary gland cancer. Next-generation sequencing analysis was performed in 3 cases, revealing the presence of the ETV6-NTRK3 fusion gene. This cohort notably features an intriguing case: the youngest patient documented in literature, distinguished by extended follow-up and delayed recurrence. Conclusions: In summary, emphasizing the risk of misdiagnosis is pivotal in the context of SC of the salivary gland, which can manifest across diverse glandular sites. Accurate diagnosis, underscored by the assessment of NTRK3 gene rearrangements, assumes a critical role in guiding effective management and treatment decisions.

PTHrP induces STAT5 activation, secretory differentiation and accelerates mammary tumor development.

BACKGROUND: Parathyroid hormone-related protein (PTHrP) is required for embryonic breast development and has important functions during lactation, when it is produced by alveolar epithelial cells and secreted into the maternal circulation to mobilize skeletal calcium used for milk production. PTHrP is also produced by breast cancers, and GWAS studies suggest that it influences breast cancer risk. However, the exact functions of PTHrP in breast cancer biology remain unsettled. METHODS: We developed a tetracycline-regulated, MMTV (mouse mammary tumor virus)-driven model of PTHrP overexpression in mammary epithelial cells (Tet-PTHrP mice) and bred these mice with the MMTV-PyMT (polyoma middle tumor-antigen) breast cancer model to analyze the impact of PTHrP overexpression on normal mammary gland biology and in breast cancer progression. RESULTS: Overexpression of PTHrP in luminal epithelial cells caused alveolar hyperplasia and secretory differentiation of the mammary epithelium with milk production. This was accompanied by activation of Stat5 and increased expression of E74-like factor-5 (Elf5) as well as a delay in post-lactation involution. In MMTV-PyMT mice, overexpression of PTHrP (Tet-PTHrP;PyMT mice) shortened tumor latency and accelerated tumor growth, ultimately reducing overall survival. Tumors overproducing PTHrP also displayed increased expression of nuclear pSTAT5 and Elf5, increased expression of markers of secretory differentiation and milk constituents, and histologically resembled secretory carcinomas of the breast. Overexpression of PTHrP within cells isolated from tumors, but not PTHrP exogenously added to cell culture media, led to activation of STAT5 and milk protein gene expression. In addition, neither ablating the Type 1 PTH/PTHrP receptor (PTH1R) in epithelial cells nor treating Tet-PTHrP;PyMT mice with an anti-PTH1R antibody prevented secretory differentiation or altered tumor latency. These data suggest that PTHrP acts in a cell-autonomous, intracrine manner. Finally, expression of PTHrP in human breast cancers is associated with expression of genes involved in milk production and STAT5 signaling. CONCLUSIONS: Our study suggests that PTHrP promotes pathways leading to secretory differentiation and proliferation in both normal mammary epithelial cells and in breast tumor cells.

Secretory carcinoma of the salivary gland: a multi-institutional clinicopathologic study of 90 cases with emphasis on grading and prognostic factors.

Secretory carcinoma (SC) is a rare form of salivary carcinoma that was first described in 2010 and is characterized by ETV6::NTRK3 fusion in most cases. In this large retrospective study, we aimed to identify adverse clinicopathologic factors and propose a prognostically relevant grading scheme for SC. METHODS: A detailed clinicopathologic review was conducted on 90 SCs from the major and minor salivary glands. RESULTS: The median age at presentation was 50 years (range: 7-93). Sixty-nine (77%) tumours originated from major salivary glands, whereas the remaining 21 involved minor salivary glands.Six cases (7%) had cervical nodal metastasis. Only lymphovascular invasion (LVI) was associated with a risk of nodal metastasis (P < 0.05). The 5-year disease-specific survival and disease-free survival (DFS) were 98% and 87%, respectively. On univariate survival analysis, adverse prognostic factors associated with decreased DFS included minor salivary gland origin, atypical mitosis, high mitotic index, high-grade transformation (HGT), necrosis, nuclear pleomorphism, infiltrative tumour border, fibrosis at the invasive front, LVI, positive margin, and advanced pT stage (P < 0.05). When adjusted for pT stage and margin status, mitotic index, LVI, nuclear pleomorphism, and HGT remained as independent prognostic factors. CONCLUSION: We therefore propose a two-tiered grading system for SC. The low-grade SC is defined as those with <5 mitoses /10 high-power fields and no tumour necrosis, and high-grade SC as those with ≥5 mitoses /10 high-power fields and/or necrosis. This proposed grading system can be useful to risk stratify patients with SC for appropriate clinical management.

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.

Dedifferentiated secretory breast carcinoma with fibrosarcomatous features harboring an ETV6-NTRK3 fusion in both components.

Secretory carcinomas are low-grade translocation-driven carcinomas occurring in patients over a wide age range. These tumors most frequently arise in the breast and salivary gland, but may occasionally arise at other anatomic sites, such as the skin, the thyroid gland or the upper or lower respiratory tract. In concert with their low-grade morphology, secretory carcinomas most often follow an indolent clinical course. However, rare cases have shown dedifferentiation (also known as high-grade transformation) and aggressive clinical behavior. To date, the dedifferentiated component in all molecularly confirmed cases of secretory carcinoma has taken the form of a high-grade carcinoma. Here we present a case of an ETV6-NTRK3 fusion-positive secretory carcinoma of the breast with sarcomatous dedifferentiation. The sarcomatous component showed an infantile or adult fibrosarcoma-like morphology including a herringbone fascicular pattern and a hemangiopericytic vascular pattern. By immunohistochemistry, the sarcomatous component showed focal CD34 immunoreactivity and loss of all of the markers expressed in the conventional secretory carcinoma component, including SOX10, S100, GATA-3, AE1/AE3 and E-cadherin. Fluorescence in situ hybridization analysis revealed that the sarcomatous component retained the ETV6-NTRK3 fusion, but also acquired homozygous deletion of CDKN2A. The tumor followed an aggressive clinical course and the patient eventually succumbed to her disease 14 months after diagnosis. The histomorphologic and molecular genetic features of this tumor are discussed, including its ability to mimic kinase-rearranged infantile or adult fibrosarcomas at extramammary sites and the theragnostic importance of its distinction from conventional metaplastic spindle cell carcinomas in the breast.

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.

Locally Recurrent Secretory Carcinoma of the Breast with NTRK3 Gene Fusion.

Enhanced understanding of the molecular events underlying oncogenesis has led to the development of "tumor-agnostic" treatment strategies, which aim to target a tumor's genomic profile regardless of its anatomic site of origin. A classic example is the translocation resulting in an ETV6-NTRK3 gene fusion, a characteristic driver of a histologically diverse array of cancers. The chimeric ETV6-NTRK3 fusion protein elicits constitutive activation of the tropomyosin receptor kinase (TRK) C protein, leading to increased cell survival, growth, and proliferation. Two TRK inhibitors, larotrectinib and entrectinib, are currently approved for use in the metastatic setting for the treatment of advanced solid tumors harboring NTRK fusions. Here we report a rare case of recurrent secretory carcinoma of the breast (SCB) with NTRK3 gene fusion. Whereas most cases of SCB represent slow-growing tumors with favorable outcomes, the case detailed here is the first to the authors' knowledge of recurrence within 1 year of surgery. We review the molecular findings and potential clinical significance. KEY POINTS: The translocation resulting in the ETV6-NTRK3 gene fusion is a known oncogenic driver characteristic of secretory carcinoma of the breast (SCB). Whereas most cases of SCB represent slow-growing tumors with favorable outcomes, the case here with ETV6-NTRK3 gene fusion had local recurrence within 1 year of surgery. Two tropomyosin receptor kinase (TRK) inhibitors, larotrectinib and entrectinib, are approved to treat NTRK fusion-positive tumors, demonstrating sustained high overall response rates in the metastatic setting. Approval of TRK inhibitors necessitates optimization of NTRK fusion detection assays, including detection with liquid biopsies.