ABSTRACT Aim Secretory carcinoma (SC), also known as mammary analogue secretory carcinoma, is a rare malignant neoplasm of the salivary glands, named for its histological and molecular resemblance to mammary secretory carcinoma. The aim of this study is to present a new case of SC occurring in the lower lip, initially diagnosed as a mucocele, and to provide a comprehensive review of reported cases in minor salivary glands. Materials and Methods A 40‐year‐old woman presented with a nodular lesion of the lower lip clinically diagnosed as a mucocele. An excisional biopsy was performed, and histopathological and immunohistochemical analyses confirmed the diagnosis of SC. The patient was referred to an oncology referral centre for therapeutic planning. In addition, a literature review was performed. Results Identifying 55 articles published between 2010 and 2025 and documenting 96 cases of SC in minor salivary glands. SC showed a slight female predominance (48.9%, n = 47), with a mean age of 46.27 ± 17.47 years, and most commonly affected the lip (34.3%, n = 33). Local recurrence (44.7%, n = 43) and metastasis (41.6%, n = 40) were infrequently reported, and most patients remained alive without evidence of disease at follow‐up (55.2%, n = 53). Conclusion SC is a rare malignant tumour with overlapping clinical and histological features that may mimic other soft tissue lesions. This case, combined with data from the literature, highlights the importance of considering SC in the differential diagnosis of nodular lesions of the oral mucosa and emphasises the need for accurate diagnosis and long‐term follow‐up.

Tissue-agnostic therapy has transformed oncology by enabling treatment selection based on molecular alterations rather than tumor origin. Since 2017, nine U.S. Food and Drug Administration approvals across six biomarker classes have defined this paradigm. Thoracic and head and neck (H&N) cancers have been underrepresented in the registrational evidence supporting these approvals. This review systematically evaluated biomarker representation, histologic distribution, and clinical applicability of tissue-agnostic therapies in thoracic and H&N malignancies. A narrative systematic review was conducted using PubMed, ClinicalTrials.gov, and regulatory documents for all tissue-agnostic approvals between January 2017 and October 2025. Data were extracted from pivotal trials, including total enrollment, objective response rate (ORR), histologic distribution, and thoracic/H&N representation. Emerging biomarkers and resistance mechanisms were assessed from phase I-III studies and basket trials. Nine tissue-agnostic approvals encompassing six biomarkers were identified: MSI-H/dMMR, TMB-High, NTRK, RET, BRAF V600E, and HER2 (IHC 3+). Across pivotal datasets (3800 patients), thoracic and H&N cancers accounted for fewer than 8% (n = 290) of enrolled patients. Thoracic representation was dominated by non-small-cell lung cancer (NSCLC) in RET, NTRK, and HER2 programs (150 patients, 4%), while small-cell lung, mesothelioma, and thymic carcinomas contributed <1% combined. H&N cancers comprised 140 patients (3-4%), primarily secretory salivary carcinoma in NTRK trials (n = 12-20), thyroid carcinoma in BRAF (n = 36) and RET (n = 45) programs, and rare HER2-positive salivary duct carcinomas. Conventional HNSCC and sinonasal cancers were limited to 1-2 cases per trial. Only two of nine trials (22%) reported prespecified CNS endpoints, and RNA-based fusion testing was employed in <40%, underscoring diagnostic variability and limited applicability. Although tissue-agnostic therapy has expanded the reach of precision oncology, thoracic and H&N cancers remain underrepresented in registrational evidence. Most approvals rely on single-arm basket studies with small, heterogeneous subsets that preclude histology-specific conclusions. Future research should prioritize histology-enriched trial designs, standardized molecular diagnostics, and real-world validation to establish reliable, equitable standards of care for these underrepresented malignancies.

Comparative analysis of convolutional neural network models for the histopathological differentiation of acinic cell carcinoma and secretory carcinoma.

Oncocytic carcinomas of the salivary glands represent a rare and diverse group of malignancies characterised by granular eosinophilic cytoplasm due to abundant mitochondria. This review provides a comprehensive overview of oncocytic salivary gland carcinomas, categorised by their morphological patterns: monophasic, biphasic, and complex. Monophasic entities include oncocytic intraductal carcinoma (OIDC), oncocytic salivary duct carcinoma (OSDC), acinic cell carcinoma (ACC), and secretory carcinoma (SC). These tumours vary significantly in histological architecture, immunohistochemical profiles, and genetic alterations, ranging from TRIM33::RET fusions and BRAF V600E mutations in OIDC to NR4A3 rearrangements in ACC and ETV6::NTRK3 fusions in SC. Biphasic tumours, such as oncocytic epithelial-myoepithelial carcinoma (OEMC) and oncocytic adenocarcinoma not otherwise specified (OANOS), further complicate diagnosis due to dual cellular composition and overlapping features with other neoplasms. Complex-pattern tumours, particularly oncocytic mucoepidermoid carcinoma (OMEC), highlight diagnostic challenges and underscore the need for advanced molecular diagnostics. This article emphasises the critical role of integrated histopathological examination, immunohistochemical staining, and molecular profiling in the accurate classification of these neoplasms. Despite diagnostic advancements, some entities, like OANOS, remain provisional, pending widespread access to transcriptomic tools. Recognising the molecular heterogeneity and clinicopathologic nuances of oncocytic carcinomas is essential for improving diagnostic precision, prognostication, and guiding targeted therapy.

Secretory breast carcinoma (SBC) is an exceptionally rare type of breast carcinoma, accounting for less than 0.15% of all breast cancers. Only few cases have been reported in literature and even less with axillary lymph node metastasis and there is emerging application of use of Sentinel Lymph node biopsy (SLNB) or Low axillary sampling to assess the nodal status. There is a lack of consensus regarding the exact management and the role of targeted therapy is evolving. We report a case of SBC in a 2 year 7-month-old child. The child presented with a painless mobile peri areolar lump with blood-stained nipple discharge. She underwent excision biopsy outside followed by wide excision of residual lump with Low axillary sampling of the axilla showing axillary lymph node metastasis in our Centre and was subjected to level III axillary clearance. The tumor showed positivity for Estrogen receptor (ER) and the characteristic translocation, t (12; 15) (p13; q25) that results in the expression of the ETV6-NTRK3 fusion gene. After careful analysis of the case in Multidisciplinary team meeting, the child was started on Tamoxifen due to ER positivity and was decided to avoid use of chemoradiotherapy considering the age and doubtful benefit. Later when the tumour turned out to be positive for the fusion gene, she was started on targeted therapy with Entrectinib. To our knowledge, this is the youngest case reported in literature. The increasing use of targeted agents has been an evolving trend in the management of SBC with successful treatment outcomes. After careful analysis of our case and available literature, we have come to a conclusion that the treatment of choice for SBC should be conservation surgery with SLNB or Low axillary sampling followed by hormonal treatment if hormone responsive and the use of targeted agents. There is no reliable data regarding the role of adjuvant chemotherapy in SBC. Regarding adjuvant Radiotherapy, though it has been used in adults, its use in children should be limited.

Secretory carcinoma is a histological type mostly found in salivary gland tumors, but also in breast and skin tumors. These tumors share pathological characteristics and the presence of an ETV6-NTRK3 gene fusion. Secretory lacrimal gland carcinoma is even rarer. Our case is a middle-aged man who presented with a left orbital tumor with proptosis, diplopia and mass effect on the globe. Multimodal imaging revealed a heterogeneous tumor enhanced with gadolinium. There were no granulomatous foci. Total excision was preferred over diagnostic biopsy because of the intense vascularization of the tumor. Histopathology revealed a secretory carcinoma of the lacrimal gland. The FISH study showed ETV6 gene fission in 90% of enumerated cells. After consultation, it was decided not to irradiate because of the risk of xerophthalmia, cataract and meningioma. After eighteen months, follow-up imaging showed local recurrence, treated then by surgery and stereotactic radiation therapy. During follow-up, chemotherapy was added when a second recurrence at the orbital site occurred. To support our diagnostic approach, we found only two other cases of secretory carcinoma of the lacrimal gland in the medical literature, both treated by isolated excision. The characterization of histological subtypes of carcinomas has direct implication in the therapeutic approach with the use of targeted therapies. Thus, tyrosine kinase inhibitors can provide valuable options in the treatment of secretory carcinomas.

Hepatocellular carcinoma (HCC) is a global health challenge, with disproportionately high mortality rates in low- and middle-income countries (LMICs). Tumor markers such as alpha-fetoprotein (AFP), carcinoembryonic antigen (CEA), and carbohydrate antigen 19-9 (CA19-9) are used for diagnostic purposes and for monitoring treatment results. The relationship between these markers, individually or in combination, with clinical presentation, metastatic patterns and survival outcomes has not been extensively researched. In this South African retrospective study, we assess the association of the tumor marker levels on presentation, diagnosis, and prognosis. Data was analyzed using chi-square tests, t-tests, and Kaplan-Meier survival analysis. The study included 501 patients, treated between 2010 and 2024. Elevated AFP levels were associated with chronic hepatitis B virus (HBV) infection, hepatomegaly, and pulmonary metastases, while elevated CA19-9 levels were associated with more advanced liver disease. Survival analysis confirmed shorter survival for patients with elevated AFP and CA19-9 levels compared to normal levels (p < 0.001). Elevated CEA levels were not significantly associated with survival. Patients with no elevated markers (i.e., "triple-negative" for AFP, CEA, and CA19-9) had the longest survival, compared to those with multiple elevated markers (p < 0.001). AFP and CA19-9 elevations were associated with more advanced disease and poorer survival outcomes. We emphasize the importance of integrating tumor marker levels with imaging and histopathology for a multimodal diagnostic approach. Further research is needed to validate these associations to better define the role of biomarkers in HCC management.

Salivary gland carcinomas (SGC) are rare, heterogenous malignancies with limited treatment options in recurrent or metastatic (r/m) disease. We investigated the impact of immunohistochemical and molecular markers on treatment choice and patient outcomes. We retrospectively investigated clinical, pathological and molecular characteristics of 51 patients (pts) with r/m SGC treated at the University Hospital Zurich between 2010 and 2024. Immunohistochemical and molecular profiles were evaluated in respect to treatment selection, response and survival. Salivary duct carcinoma (SDC) and adenoid-cystic carcinoma (AdCC) were the most common subtypes. In the SDC group, in 15/20 pts personalized first-line treatment based on immunohistochemical or molecular findings resulted in higher response rates and longer duration of response compared to chemotherapy. In 20 pts of the AdCC group, no actionable alterations were identified. Yet, pts in this group demonstrated the longest overall survival despite low response rates. Among 11 pts with other subtypes, one pt with secretory carcinoma and ETV6::NTRK3 fusion experienced a sustained response to larotrectinib. HER2 IHC2 + expression without gene amplification was observed in 15 pts. Two pts responded to trastuzumab deruxtecan (TDxd) after progression on first line therapy. The impact of immunohistochemical or molecular markers on treatment selection and response was most pronounced in SDC. HER2 IHC2 + expression was observed across multiple subtypes, indicating that TDxd may represent a potential treatment option for more pts than previously anticipated. The impact of comprehensive genomic profiling on targeted treatment options is currently still modest.

A tailored histology-driven molecular profiling algorithm proposal for salivary gland cancers

Abstract Background: NTRK gene fusions are oncogenic drivers across various pediatric and adult tumor types. The prevalence of NTRK gene fusions varies widely, from high (up to 90%) in rare tumors such as infantile fibrosarcoma and secretory carcinoma of the breast to low (&amp;lt;0.5%) in common cancers like non-small cell lung and colorectal carcinoma. Larotrectinib is the first-in-class, highly selective, central nervous system (CNS)-active TRK inhibitor approved for tumor-agnostic use in patients with TRK fusion cancer based on a robust and durable objective response rate in both adult and pediatric patients with various tumor types. Here, we report updated data on larotrectinib-treated pediatric patients with TRK fusion non-primary CNS tumors. Methods: This analysis included patients from 2 clinical trials (NCT02637687 [SCOUT], NCT02576431 [NAVIGATE]). Responses were independent review committee-assessed (Response Evaluation Criteria in Solid Tumors [RECIST] v1.1). In SCOUT, patients could stop larotrectinib in the absence of on-treatment progression (“wait-and-see”). Responses in patients who were re-treated due to progression were assessed by investigators (RECIST v1.1). Results: Ninety-nine patients with non-primary CNS tumors were eligible for analysis as of July 2024, including 49% with infantile fibrosarcoma, 41% with soft tissue sarcoma, and 9% with other solid tumors. Overall response rate was 86% (95% confidence interval [CI] 77–92). In total, 53 patients had complete responses (CR; including 17 pathological CR), 32 had partial responses (PR), 9 had stable disease (SD), and 3 had progressive disease (PD); responses were undefined in 2 patients. Median time to response was 1.8 months (range 0.9–7.3). Median duration of response was 51 months (95% CI 31-not estimable [NE]). Median progression-free survival and overall survival (OS) were 49 months (95% CI 32–NE) and not reached (NR), respectively. The 5-year OS rate was 87% (95% CI 80–95). Median time to investigator-assessed treatment failure (from larotrectinib initiation to earliest documented on-treatment disease progression, start of other anticancer treatment, or death) was NR. Of 54 patients who entered a first “wait-and-see” period (median duration 33 months [range 1–72]), 18 resumed treatment due to PD. Of these, 11 had a response (6 CR and 5 PR [including 2 pending confirmation]), 5 had SD, 1 was not evaluable, and 1 was undefined. Most treatment-related adverse events (TRAEs) were Grade 1/2. Three patients (3%) discontinued due to a TRAE. Conclusions: Larotrectinib demonstrated rapid and durable responses, extended survival, and favorable safety in pediatric patients with TRK fusion cancer. This supports the wider adoption of next-generation sequencing panels that include NTRK gene fusions to identify pediatric patients who may benefit from targeted treatment. Citation Format: Leo Mascarenhas, Theodore W. Laetsch, Birgit Geoerger, Steven G. DuBois, Miranda P. Dierselhuis, Catherine M. Albert, Claudia Blattmann, Helen Toledano, Noah Federman, Ramamoorthy Nagasubramanian, Alberto Pappo, Tanya Watt, Domnita-Ileana Burcoveanu, Esther De La Cuesta, Natascha Neu, Daniel H. Orbach, Yizhuo Zhang. Larotrectinib long-term efficacy and safety in pediatric patients with TRK fusion non-primary CNS tumors: Analysis update [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Fusion-Positive Cancer: From Discovery to Therapy; 2026 Jan 13-15; Philadelphia PA. Philadelphia (PA): AACR; Cancer Res 2026;86(1_Suppl):Abstract nr A029.

This study aimed to comprehensively analyze salivary gland secretory carcinoma (SGSC) using a large population-based cohort to determine temporal patterns, identify independent survival predictors, and evaluate treatment effectiveness for optimizing clinical management. We conducted a retrospective cohort study using data from the Surveillance, Epidemiology, and End Results (SEER) database. A total of 212 patients diagnosed with SGSC between 2011 and 2021 were included. We analyzed clinicopathological features, incidence trends, and prognostic factors using Kaplan-Meier analysis and Cox proportional hazards models. With a median follow-up duration of 36.5 months, the overall 5-year and 10-year survival rates were 89.93% and 86.53%, respectively. The incidence of SGSC has shown a significant upward trend, increasing from an average of 6.3 cases per year in 2011-2013 to 29.3 cases per year in 2019-2021. This increase was predominantly driven by early-stage (I/II) tumors (75.9%), with the parotid gland being the most common primary site. Multivariable analysis identified age > 55 years and AJCC Stage IV disease as independent poor prognostic factors. Surgical intervention, including local tumor excision and glandectomy, was significantly associated with improved overall survival. Notably, patients who received a combination of surgery and radiotherapy had better outcomes compared to those who received either treatment alone. This large-scale study with extended follow-up clarifies the rising incidence and early-stage predominance of SGSC. Age, TNM stage, and surgical treatment were identified as key prognostic factors.

Male breast cancer constitutes to be <1% of all breast cancer cases with pediatric male secretory breast carcinoma (SBC) reported only in isolated case reports.SBC is typically triple-negative and indolent, driven by the characteristic ETV6-NTRK3 fusion.However, the molecular landscape of aggressive pediatric male SBC remains poorly understood.The objective of this study was to identify clinically actionable molecular alterations in the pediatric male SBC case using integrated next-generation sequencing (NGS).whole exome sequencing (WES) and transcriptome profiling using an Illumina platform were done on post-treatment retrospective samples from the fifth year of illness.Expression profiles were compared with HER2 -stratified male breast cancers from TCGA-BRCA cohort.Immune checkpoint and fusion interactome analyses were conducted to identify activated pathways.WES identified fifteen somatic exonic mutations, implicating pathways involved in metabolism, cell adhesion, signaling, and inflammatory responses, but were not actionable.On the other hand, transcriptomic profiling revealed appreciable expression of HER2, may be attributable to gemcitabine-induced NF-B activation or initial false-negative IHC.Interestingly, fusion analysis of the transcriptome itself identified the canonical ETV6-NTRK3 rearrangement with validated breakpoints and evidence of MAPK/ERK and PI3K/AKT pathway activation.In addition, high expression of secretory lineage genes (SCGB2A2, SCGB1D2) among many were noted.Hormone receptors (ESR1, PGR, AR) were negligible, whereas Immune checkpoint analysis showed elevated HMGB1, LAG3, LGALS9, PD-L1, and CD86 expression.Thus, transcriptomic analysis uncovered multiple clinically actionable alterations in a rare pediatric male SBC.These findings demonstrate the diagnostic value of comprehensive and integrative genome-transcriptome analysis, especially in rare, aggressive tumours to guide precision oncology.

ABSTRACT Transmission electron microscopy (TEM) has historically been pivotal in diagnosing neoplasms with challenging histopathology. However, its use has declined due to cost and the advent of ancillary techniques like immunohistochemistry. This study compares the diagnostic utility of formalin-fixed paraffin-embedded (FFPE) tissue versus wet glutaraldehyde-paraformaldehyde fixed tissue (WT) for TEM in neoplasms. A retrospective analysis of 746 cases (2014–2023) from the National Cancer Institute of Mexico – Instituto Nacional de Cancerología de Mexico (INCan) was performed. Cases were divided into Group A (FFPE, n = 270) and Group B (WT, n = 476). Diagnostic utility was assessed based on ultrastructural preservation and concordance with histopathological reports. Key ultrastructural features, such as microvilli in mesothelioma, cytoplasmic organelles in chondroblastoma, luminal microvilli in secretory breast carcinoma, continuous basal lamina in schwannoma, and abundant rough endoplasmic reticulum in fibroblastic tumors were identifiable in both groups despite artifacts in FFPE. Exact Fisher’s test showed no significant difference in diagnostic utility between groups (p = .0548), with 87.03% (235/270) of FFPE cases and 88.66% (422/476) of WT deemed diagnostically useful. Specificity for WT was 100% versus comparable values for FFPE. This study challenges the notion that paraffin embedding severely compromises TEM diagnostic value. FFPE allows precise sampling of archived tissues, expanding TEM’s applicability in retrospective studies. Further validation is warranted to confirm these findings.

High-grade transformed breast secretory carcinoma with small cell morphology: Report of a rare case

Special Subtypes of Triple Negative Breast Carcinoma.

Clinicopathological features of secretory carcinoma across anatomical sites: A retrospective study with emphasis on high-grade transformation and molecular alterations

Background and Objectives: Low-grade triple-negative breast carcinomas (LG-TNBCs) represent a rare subset of breast cancers that deviate from the aggressive clinical course typically associated with triple-negative tumors. This narrative review aims to consolidate current knowledge on LG-TNBCs, highlighting their diagnostic features, molecular characteristics, and clinical implications to guide appropriate patient management and prevent overtreatment. Materials and Methods: We conducted a comprehensive narrative review using PubMed/MEDLINE, Embase, and Scopus databases up to September 2025. Search terms included combinations of "triple-negative breast carcinoma", "low-grade", "adenoid cystic carcinoma", "secretory carcinoma", "acinic cell carcinoma", "tall cell carcinoma with reversed polarity", "low-grade adenosquamous carcinoma", and "fibromatosis-like metaplastic carcinoma." Studies reporting clinicopathologic, immunohistochemical, or molecular data were included. Results: LG-TNBCs include seven distinct entities: adenoid cystic carcinoma, secretory carcinoma, acinic cell carcinoma, tall cell carcinoma with reversed polarity, low-grade adenosquamous carcinoma, fibromatosis-like metaplastic carcinoma, and mucoepidermoid carcinoma. These neoplasms are characterized by distinct morphologic patterns, specific immunohistochemical profiles, and recurrent molecular alterations such as ETV6-NTRK3 fusions and MYB rearrangements. Despite their triple-negative immunoprofile, they demonstrate indolent clinical behavior with excellent prognosis and low metastatic potential, although local recurrence is reported in variants exhibiting infiltrative, locally aggressive behavior. Conclusions: Recognition of LG-TNBCs is essential to prevent overtreatment and guide personalized patient management. Molecular characterization provides diagnostic confirmation and therapeutic opportunities, particularly for NTRK-fusion-positive tumors treatable with targeted inhibitors, highlighting the importance of precision medicine in rare breast tumors.

Abstract Introduction/Objective Secretory carcinoma (SC) is a rare, low-grade malignancy originally described in salivary glands- later recognized in breast, lung. In lung, SC is thought to arise from bronchial salivary glands which mimics salivary SC both morphologically and genetically. Due to its rarity and histologic overlap with other pulmonary neoplasms, including adenocarcinoma, neuroendocrine tumors, acinic cell carcinoma, and metastatic SC, accurate diagnosis can be challenging. We present first reported case of primary pulmonary SC coexisting with primary lung adenocarcinoma. Methods/Case Report A 55-year-old female smoker with treated adenocarcinoma of the left lung underwent surveillance imaging and bronchoscopy, which showed an incidental right endobronchial lesion. The biopsy from the lesion revealed oncocytic tumor forming papillary and micropapillary architectures with mild to moderate cytologic atypia and intranuclear inclusions. Neoplastic cells are positive for CK7, GATA3, SOX10, S100, and pan-TRK and negative for TTF-1, NapsinA, CDX2, synaptophysin, chromogranin, SMA, p63, CK20, DOG1, PAX8, AR, NR4A3 supporting diagnosis of SC. Head-neck imaging and mammography ruled out metastatic disease. Results NA Conclusion Fewer than ten cases of primary pulmonary secretory carcinoma have been reported. We describe the first known case of synchronous primary lung secretory carcinoma and adenocarcinoma, highlighting the importance of comprehensive pathologic analysis for accurate classification of rare pulmonary neoplasms.

Secretory breast carcinoma (SBC) is a rare tumour defined by ETV6‐NTRK3 rearrangement, but its clinicopathological spectrum and potential for aggressive behaviour remain incompletely characterised. We retrospectively reviewed 29 SBCs diagnosed between 2014 and 2024, including 28 females and one male aged 12–63 years (median 44). Twenty‐eight tumours arose in the breast parenchyma and one in axillary accessory breast tissue. Histologically, microcystic and tubular patterns predominated and carcinoma in situ was common. Most tumours were nuclear grade 1 with rare mitoses (0–1/10 high‐power fields, HPF). A single patient with distant metastasis harboured a solid‐predominant tumour showing nuclear grade 2–3, brisk mitoses (6/10 HPF), and multifocal necrosis. All tumours demonstrated diffuse S100 and pan‐TRK expression. Oestrogen and/or progesterone receptor staining was observed in 16 of 29 cases (2–30% of tumour cells), and all were HER2 negative or low (0–1+). Ki‐67 ranged from 3% to 20% (mean 7%). Fluorescence in situ hybridisation (FISH) was positive in 17 of 17 tested tumours (14 ETV6‐NTRK3 dual‐fusion; 3 NTRK3 break‐apart). In the metastatic case, RNA sequencing confirmed canonical ETV6‐NTRK3 fusion, while targeted DNA sequencing identified additional variants of uncertain significance (VUS) – RANBP2 p.S1843R, NUP107 p.K382Q, NCOR1 p.A1947V (missense), and PREX2 p.G606G (synonymous). All patients underwent surgery, and 14 received adjuvant chemotherapy. During follow‐up ranging from 6 to 135 months (median 76), one patient developed lung metastasis and was alive with disease at 88 months; the remaining 28 patients were alive without recurrence or metastasis. In summary, SBC is typically indolent and characterised by ETV6‐NTRK3 rearrangement with diffuse pan‐TRK/S100 positivity. A solid‐predominant pattern with increased cytological atypia, mitotic activity, and necrosis may indicate aggressive potential. Routine NTRK testing supports diagnosis and may help identify patients who could benefit from TRK‐inhibitor therapy in advanced disease.

Most salivary gland tumors are found to have genetic fusions driving their oncogenesis, with an explosion of such findings in recent years. They typically represent previously identified and well-characterized tumors and the fusions are generally not necessary for diagnosis but rather serve as diagnostic arbitrators in challenging cases. That said, occasional unexpected molecular findings are broadening our understanding of these common tumors and have led to the emergence of new entities, some of which were "hiding in plain sight" and are quite common, like secretory carcinoma. In contrast, others are sufficiently rare that molecular testing was required to identify them in small cohorts, combining cases from multiple institutions, such as microcribriform adenocarcinoma. Recently, we identified a rare case of tongue adenocarcinoma with EWSR1::BEND2 fusion with an unusual morphology, and 2 additional cases were subsequently briefly reported in the literature. In this study, we collected and analyzed a total of 7 cases that show variable but consistent morphology, including a fenestrating glandular appearance, occasional squamous or basaloid growth, and focal mucinous cells. The tumors showed a predilection for the pharynx with 4 cases in the base of the tongue, one case in the tonsil/oropharyngeal wall, one case in the nasopharynx, and only one nonpharyngeal case in the trachea. No oral cavity or major salivary gland tumors were found with this set of findings to date. The tumors showed some aggressive tendencies, with 2/4 with follow-up information having adverse outcomes, including lymph node metastases in 2 cases and 1 of these cases also having brain metastases, recurrence, and death from disease. All cases tested showed EWSR1::BEND2 fusion by NGS, as well as CK7/BEND2 positivity, and S100 negativity by immunohistochemistry. The tumors showed variable p63 staining depending on whether squamous or basaloid features were present. A tissue microarray (TMA) stained with an antibody directed against the BEND2 protein showed no significant staining in any other salivary tumor type. The constellation of findings in this cohort is highly suggestive of a specific entity, and we propose the appellation "Fenestrating Adenocarcinoma (FAC)" of the salivary gland.