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Rational: Pleomorphic adenoma (PA) is a rare benign tumor mainly affecting the major salivary glands, known for its diverse histological appearances that can mimic malignancies. When it occurs in the hard palate it present diagnostic and management challenges compared to other sites due to the anatomical location and potential proximity to critical structures. This case reports a rare presentation PA starting as an ulcer, alongside a review of rare cases of PA reported in last 5 years. We aim to highlight clinical challenges and emphasize the need for awareness in diagnosis of this diverse entity amongst the clinicians before reaching a definitive conclusion., Patient Concerns: A 41-year-old female reported an asymptomatic large swelling on the right side of the posterior palatal region. Clinical diagnosis revealed a firm, rubbery, and non-tender swelling of approximately 4 cm × 4 cm diameter. A triangular incisional biopsy was performed to confirm the diagnosis., Diagnosis: The histopathological evaluation confirmed the presence of a PA with a well-encapsulated and compressed salivary gland. A wide surgical dissection was made to remove the entire encapsulated tumor mass, including the mucoperiosteum and eroded bone of the palate. The borderline of the tumor was carefully identified in the surrounding healthy tissue. The hemostasis was obtained using a simple interrupted suture., Lesson: The diagnosis of PA is difficult as it usually involves extensive squamous and mucous metaplasia, confusing it with malignant disorders. Histopathological and clinical examinations are important for differentiating this lesion from other tumors. Complete surgical excision is reported as the first line of treatment., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Introduction: Tumors of minor salivary gland origin are uncommon lesions, representing 2-3 % of all malignant neoplasms of the upper aerodigestive tract and 9-23 % of all salivary gland tumors. The aim of this study is to report the demographic features, sites, histological types and the management and outcomes of oral and oropharyngeal minor salivary gland tumors diagnosed and treated in a University Hospital with a multidisciplinary head and neck team., Materials and Methods: A single-center retrospective observational study was conducted in a cohort of patients who received diagnosis of minor salivary gland carcinoma of oropharynx and oral cavity between July 30th 2000 and 30th September 2021. The following data of the included patients were collected: age, gender, smoke history, alcohol consumption, past medical history, comorbidities, anatomic location of the tumor, histopathology, staging, management, and outcomes., Results: A total of 30 cases (16 females, 14 males) of oral and oropharyngeal minor salivary gland tumors were reviewed. The most frequent histotype was polymorphous adenocarcinoma (12 patients). The majority of patients presented with low stage at diagnosis, with 66,66 % of the population classified as stage I or II at diagnosis. On the whole, 29 patients out of 30 benefitted from a surgical approach as first treatment. In 11 patients, adjuvant radiotherapy was performed and in 6 cases it was associated with chemotherapy. Brachytherapy with different timing was performed in 5 cases. The recurrence rate was 26.66 %. Overall disease specific survival at five and ten years was found to be approximately 81 % and 33 % respectively., Conclusions: Surgery is still considered to be the gold standard of the treatment of minor salivary gland tumors. Radiation therapy, in spite of not being considered as a curative primary treatment for salivary malignancies, is extensively used as an adjuvant treatment., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Background: Salivary gland cancers (SGC)-social determinants of health (SDoH) investigations are limited by narrow scopes of SGC-types and SDoH. This Social Vulnerability Index (SVI)-study hypothesized that socioeconomic status (SES) most contributed to SDoH-associated SGC-disparities., Methods: Retrospective cohort of 24 775 SGCs assessed SES, minority-language status (ML), household composition (HH), housing-transportation (HT), and composite-SDoH measured by the SVI via regressions with surveillance and survival length, late-staging presentation, and treatment (surgery, radio-, chemotherapy) receipt., Results: Increasing social vulnerability showed decreases in surveillance/survival; increased odds of advanced-presenting-stage (OR: 1.12, 95% CI: 1.07, 1.17), chemotherapy receipt (OR: 1.13, 95% CI: 1.03, 1.23); decreased odds of primary surgery (0.89, 0.84, 0.94), radiotherapy (0.91, 0.85, 0.97, p = 0.003) for SGCs. Trends were differentially correlated with SES, ML, HH, and HT-vulnerabilities., Conclusions: Through quantifying SDoH-derived SGC-disparities, the SVI can guide targeted initiatives against SDoH that elicit the most detrimental associations for specific sociodemographics., (© 2024 The Authors. Head & Neck published by Wiley Periodicals LLC.)

Objective: To evaluate and compare the expression of E-cadherin, Snail1 and Twist1 in pleomorphic adenomas (PAs), adenoid cystic carcinomas (AdCCa) and carcinoma ex-pleomorphic adenomas (CaexPA) of salivary glands, as well as investigate possible associations with clinicopathological parameters., Study Design: E-cadherin, Snail1 and Twist1 antibody immunostaining were analyzed semiquantitatively in 20 PAs, 20 AdCCas and 10 CaexPAs. Cases were classified as low and high expression for analysis of the association with clinicopathological parameters., Results: Compared to PAs, AdCCas and CaexPAs exhibited higher nuclear expression of Snail1 (p = 0.021 and p = 0.028, respectively) and Twist1 (p = 0.009 and p = 0.001). Membranous and cytoplasmic expression of E-cadherin were positively correlated in PAs, AdCCas and CaexPAs (r = 0.645, p = 0.002; r = 0.824, p < 0.001; r = 0.677, p = 0.031). In PAs, positive correlation was found between nuclear expression of Snail1 and membrane expression of E-cadherin (r = 0.634; p = 0.003), as well as between nuclear expression of Snail1 and Twist1 (r = 0.580; p = 0.007). Negative correlations were detected between membrane expression of E-cadherin and cytoplasmic expression of Snail1 in AdCCas (r = - 0.489; p = 0.029)., Conclusions: E-cadherin, Twist1, and Snail1 may participate in modulating events related to cell differentiation and adhesion in PAs and to biological behavior in AdCCas and CaexPAs, which indicates the involvement of EMT in these processes. Furthermore, the expression of these proteins in these carcinomas may reflect the plasticity feature of EMT., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

Competing Interests: Die Autorinnen/Autoren geben an, dass kein Interessenkonflikt besteht.

Fine-needle aspiration represents a valid tool for the diagnosis/management of salivary gland lesions. The past years assessed the lack of uniform diagnostic reports for salivary cytopathology leading to interpretative issues. In 2015, an international group of cytopathologists developed an evidence-based tiered classification system for reporting salivary gland fine-needle aspiration (FNA) specimens, the "Milan System for Reporting Salivary Gland Cytopathology" (MSRSGC). The present landscape of salivary cytology is represented by the growing adoption of the MSRSGC and the assessment of its diagnostic role. The future landscape is characterized by the increasing role of ancillary techniques for diagnostic and prognostic purposes., Competing Interests: Disclosure The authors have nothing to disclose. This research did not receive any specific grant from any funding agency in the public, commercial, or not-profit sectors., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Purpose: Distant metastases (DM) are the primary cause of treatment failure and death of patients with salivary gland carcinomas (SGC). The purpose of present study was to evaluate factors predictive on DM development in a cohort of patients with high-grade salivary gland carcinomas., Methods: This was a retrospective cohort study of consecutive patients surgically treated with curative intention at the authors' institution from January 1993 to December 2018. Outcomes evaluated were overall survival (OS), disease specific survival (DSS), recurrence free survival (RFS), locoregional recurrence free survival (LRFS) and distant metastasis free survival (DMFS)., Results: A total of 213 patients, 117 males (55%) and 96 females (45%), were included in the study. Parotid gland malignancies accounted for 56% of all cases. Adenoid cystic carcinoma (119 cases; 56%) was the most common tumor type. Cumulative OS for the 5-and 10-year follow-up period was 80% and 58% respectively. DM occurred with 75 patients (35%). The most common locations for DM were lung (55 cases; 73%) and liver (12 cases; 16%). Pathological nodal status, particularly the number of metastatic nodes, was the independent prognostic factor for OS, DSS, RFS and DMFS., Conclusion: Number of metastatic lymph nodes, instead of extranodal extension and largest nodal diameter, was the contributing factor related to DMFS. Since the main function of staging system is to predict outcomes, the significance of extranodal extension and nodal dimension in salivary gland cancer staging system requires further clarification. The elective neck dissection could be considered therapeutic approach for high-grade SGC since occult metastases were detected in 33% of cases., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Comprehensive information on genetic alterations in salivary gland cancer (SGC) is limited. This study aimed to elucidate the genetic and clinical characteristics of patients with SGC using the Center for Cancer Genomics and Advanced Therapeutics (C-CAT) database, a Japanese national genomic database. We analyzed data of 776 patients with SGC registered in the C-CAT database between June 1, 2019, and June 30, 2023. Adenoid cystic carcinoma was the most common histologic type, followed by salivary duct carcinoma (SDC) and adenocarcinoma not otherwise specified. Genetic data of 681 patients receiving FoundationOne® CDx were analyzed. We identified specific features of the combination of TP53 and CDKN2A alterations among the histological types. Specific LYN amplification was mainly detected in carcinoma ex pleomorphic adenoma and myoepithelial carcinoma. For SDC, the frequency of ERBB2 and BRAF alterations were higher in cases with metastatic lesions than in those with primary lesions. Although 28.6% patients were offered recommended treatment options, only 6.8% received the recommended treatments. This study highlights the differences in genetic alterations among the histological types of SGC, with comprehensive genomic profiling tests revealing lower drug accessibility. These findings could contribute to the development of personalized treatment for patients with SGC., (© 2024 UICC.)

Background: Adenoid cystic carcinoma (ACC) is a rare and malignant tumor of the salivary glands. Despite its slow-growing nature, this clinical entity is notorious for presenting with distant metastasis (DM) which significantly worsens patient outcomes. The role of surgery in patients with ACC and distant metastasis (DM) remains controversial., Methods: We conducted a retrospective analysis of 47 patients with ACC who underwent surgery for the primary tumor and presented with DM at baseline or developed DM during follow-up. We compared survival outcomes between patients with DM at baseline (Group A) and those who developed DM during follow-up (Group B)., Results: The median overall survival (OS) for the entire cohort was 88%. Patients with DM at baseline (Group A) had significantly worse OS (51%) compared to those without DM at baseline (Group B) (91%; P = .04). Local recurrence (LR) was associated with poor survival in both groups. However, salvage surgery for LR+DM was associated with improved OS compared to palliative treatment (100% vs 77%; P = .79)., Conclusion: Our findings suggest that surgery for the primary tumor of ACC may provide survival benefits in patients with DM. Salvage surgery should be considered particularly for patients who develop local recurrence and distant metastasis during follow-up., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Canonical transient receptor potential channels play a crucial role in cancer cell proliferation. While TRPC6 subtype detection in submandibular glands and the relevance of some TRPC channels in this gland have been shown in animal models, its histological detection in human lacrimal and submandibular glands, as well as related tumors, lacks systematic study. Studying TRPC6 in humans could lead to new therapeutic options. This research aimed to immunohistochemically detect TRPC6 in human samples of physiological lacrimal and submandibular glands and of adenoid cystic carcinoma and mucoepidermoid carcinoma., Methods: Seven fixed body donors and samples of six cancer patients were examined. The ten tissue samples collected from the submandibular and lacrimal glands were then processed into histological slides and stained with hematoxylin-eosin. Tumor samples were provided as sections. TRPC6 presence was determined by immunohistochemistry, which was performed by indirect detection with a primary TRPC6 antibody, a secondary HRP-conjugated antibody and the chromogen diaminobenzidine., Results: Results confirm TRPC6 expression in all ten physiological gland samples: all samples showed a immunohistochemical signal with varying intensity. No significant gender-specific differences could be observed. TRPC6 was detected in four of six submandibular adenoid cystic carcinoma and the mucoepidermoid carcinoma samples, especially in tumor cells' cytoplasma and nuclei. Excretory ducts consistently showed TRPC6. Mucous tubules, their nuclei and the nuclei of adipocytes generally showed no signal while serous acini and their nuclei showed a weak TRPC6 signal., Conclusion: The discovery of TRPC6 in glandular tissue indicates a role in salivary gland function and calcium homeostasis is a basis for further research into its significance for tumor development in adenoid cystic carcinoma and mucoepidermoid carcinoma of salivary glands. TRPC6 could be used as a target for treatment of these tumors. However, the correlation between TRPC6 and submandibular and lacrimal gland diseases requires further exploration., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests., (Copyright © 2024 The Authors. Published by Elsevier GmbH.. All rights reserved.)

Salivary duct carcinomas (SDC) of the parotid gland are rarely occurring highly malignant tumors. A 65-year-old man presented with a preauricular mass. After surgical treatment and histologic examination, the findings were interpreted as a squamous cell carcinoma (SCC) metastasis of the parotid gland deriving from a cancer of unknown primary DD primary SCC of the parotid gland. Adjuvant platinum-based radiochemotherapy was administered in domo. However, re-staging revealed multiple size-progressive pulmonary round lesions. After resection and histological examination of a pulmonary mass and in synopsis with the primary tumor, the initial diagnosis of SCC was revised to SDC of the parotid gland. With positive HER-2 status, off-label trastuzumab/docetaxel was initiated in an individual healing attempt, during which the pulmonary metastases showed clear progression. Consequently, the patient received immunotherapy with nivolumab according to his negative PD-L1 status. After 57 cycles of nivolumab, the patient presents with partial remission and in good condition. We report, for the first time, a robust response of metastatic SDC to checkpoint inhibition with nivolumab without additional radiotherapy., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Mucoepidermoid carcinoma arising from minor salivary glands at the base of the tongue is rare. Surgical excision of the tumours remains the primary treatment of choice. The prognosis of this tumour depends on optimum clearance of the disease surgically, clinical staging and histopathological grading. Postoperatively, radiotherapy depends on the grading and histopathological features of the tumour. Long-term follow-up is a must to detect early recurrences of oropharyngeal tumours. In our case, the tumour was removed by the transoral route because it was a limited tumour and for better postoperative functional outcomes. Concurrent chemoradiotherapy was advised to address the perineural invasion and residual tumour of the base of the tongue region., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Although immune checkpoint inhibitors (ICIs) are effective in some patients with salivary gland carcinoma (SGC), biomarkers which predict the efficacy and prognosis of SGC patients treated with pembrolizumab have not been identified. We conducted a multi-institutional retrospective cohort study to evaluate the efficacy and safety of pembrolizumab monotherapy in patients with recurrent and/or metastatic SGC and to determine optimal cut-off values of the combined positive score (CPS) and tumor proportion score (TPS) as numerical expression levels of programmed death-ligand 1 (PD-L1), which predict the efficacy of pembrolizumab. Furthermore, we investigated the association of patient characteristics and hematological markers with clinical outcomes, including overall response rate (ORR), progression-free survival (PFS), and overall survival (OS). From 2016 to 2021, 27 patients were included in the analysis. ORR of SGC was 25.9%. Optimal cut-off values of CPS and TPS were 15 and 25%, respectively. ORRs of CPS-high and TPS-high were 55.6 and 75.0%, respectively, and significantly higher than those of CPS-low and TPS-low. Furthermore, patients with a low platelet-lymphocyte ratio (PLR) had a significantly longer PFS. No grade 4 or greater adverse events were observed. This study demonstrated the efficacy and safety of pembrolizumab monotherapy and identified optimal cut-off values of CPS and TPS., (© 2024. The Author(s).)

Palisading adenocarcinoma is a morphologically distinct salivary gland neoplasm that has been recently described with predilection to the sublingual gland. We report our experience with this neoplasm to corroborate and enrich the literature and further clarify its phenotype., (© 2024. The Author(s).)

Purpose: To assess the efficacy and safety of apalutamide plus goserelin for androgen receptor (AR)-positive unresectable or recurrent/metastatic salivary gland carcinoma., Patients and Methods: This trial was an open-label, single-arm, multicenter phase II study. Patients with histologically confirmed unresectable or recurrent/metastatic salivary gland carcinoma with AR expression were included. The primary endpoint was the overall response rate (ORR) according to RECIST v1.1 by an independent central radiology review in the first 24 response-evaluable (RE) patients who had been observed at least 24 weeks from study initiation (primary RE patients). The efficacy was to be declared when at least 8 of the 24 primary RE patients responded., Results: A total of 31 patients were enrolled. In the first 24 primary RE patients with a median follow-up of 7.4 months, confirmed ORR by independent central radiology review was 25.0% [6/24 patients; 95% confidence interval, 9.8%-46.7%; P = 0.11 (one-sided)], which did not meet the predefined criteria of efficacy. Clinical benefit rate (ORR + rate of stable disease for at least 24 weeks) and median progression-free survival were 50.0% and 7.4 months, respectively. Both median duration of response and overall survival were not reached. Exploratory analyses showed a better ORR of 54.5% (6/11) in patients with AR positivity ≥70% and no history of prior systemic therapy. Grade 3 or higher treatment-emergent adverse events were reported in 35.5% (11/31), which included skin rash, anemia, leukopenia, and cancer pain., Conclusions: Although this study did not meet the predefined efficacy criteria, apalutamide plus goserelin showed clinically meaningful efficacy in a subset of patients with AR-positive salivary gland carcinoma and safety consistent with prior experience in prostate cancer., (©2024 American Association for Cancer Research.)

Salivary gland tumors are highly variable in clinical presentation and histology. The World Health Organization (WHO) classifies 22 types of malignant and 11 types of benign tumors of the salivary glands. Diagnosis of salivary gland tumors is based on imaging (ultrasound, magnetic resonance imaging) and fine-needle aspiration biopsy, but the final diagnosis is based on histopathological examination of the removed tumor tissue. In this pilot study, we are testing a new approach to identifying peptide biomarkers in saliva that can be used to diagnose salivary gland tumors. The research material for the peptidomic studies was extracts from washings of neoplastic tissues and healthy tissues (control samples). At the same time, saliva samples from patients and healthy individuals were analyzed. The comparison of the peptidome composition of tissue extracts and saliva samples may allow the identification of potential peptide markers of salivary gland tumors in patients' saliva. The peptidome compositions extracted from 18 tumor and 18 healthy tissue samples, patients' saliva samples (11 samples), and healthy saliva samples (8 samples) were analyzed by LC-MS tandem mass spectrometry. A group of 109 peptides was identified that were present only in the tumor tissue extracts and in the patients' saliva samples. Some of the identified peptides were derived from proteins previously suggested as potential biomarkers of salivary gland tumors (ANXA1, BPIFA2, FGB, GAPDH, HSPB1, IGHG1, VIM) or tumors of other tissues or organs (SERPINA1, APOA2, CSTB, GSTP1, S100A8, S100A9, TPI1). Unfortunately, none of the identified peptides were present in all samples analyzed. This may be due to the high heterogeneity of this type of cancer. The surprising result was that extracts from tumor tissue did not contain peptides derived from salivary gland-specific proteins (STATH, SMR3B, HTN1, HTN3). These results could suggest that the developing tumor suppresses the production of proteins that are essential components of saliva.

Background: ETV6 gene rearrangement is the molecular hallmark of secretory carcinoma (SC), however; the nature, frequency, and clinical implications of atypical ETV6 signal patterns by fluorescence in situ hybridization (FISH) has not yet been systematically evaluated in salivary gland neoplasms., Methods: The clinical, histopathologic, immunohistochemical and molecular features of seven salivary SCs, including four cases with atypical ETV6 FISH patterns, were retrospectively analyzed along with a critical appraisal of the literature on unbalanced ETV6 break-apart in SCs., Results: The patients were four males and three females (31-70 years-old). Five presented with a painless neck mass and two patients with recurrent disease had a history of a previously diagnosed acinic cell carcinoma of the buccal mucosa. Histologically, there were varied combinations of microcystic, papillary, tubular, and solid patterns. All tumors were diffusely positive for S100 and/or SOX10, while 2 cases also showed luminal DOG1 staining. Rearrangement of the ETV6 locus was confirmed in 5/7 cases, of which 3 cases showed classic break-apart signals, 1 case further demonstrated duplication of the ETV6 5`end and the other loss of one copy of ETV6. Two cases harbored ETV6 deletion without rearrangement. Two of the 4 cases with atypical ETV6 FISH patterns represented recurrent tumors, one with widespread skeletal muscle involvement, bone and lymphovascular invasion. Surgical treatment resulted in gross-total resection in all 7 cases, with a median follow up of 9.5 months post-surgery for primary (n = 3) and recurrent disease (n = 1)., Conclusion: Duplication of the distal/telomeric ETV6 probe represented the most common (26/40; 65%) variant ETV6 break-apart FISH pattern in salivary SC reported in the literature and appears indicative of an aggressive clinical course., (© 2024. The Author(s).)

Objective: While several studies reported epidermal growth factor receptor (EGFR) expression in salivary gland cancer (SGC), results varied due to a lack of unified definition of EGFR positivity. In this study, we assessed the EGFR expression level using both EGFR positive score and cumulative EGFR score in the patients with SGC., Methods: Between January 2010 and April 2021, 102 patients with SGC who underwent surgical resection were reviewed retrospectively by immunohistochemistry. The membrane staining intensity was scored as follows: no staining (0), weak staining (1+), intermediate staining (2+), and strong staining (3+). The cumulative EGFR score was determined on a continuous scale of 0-300 using the formula:1 × (1+: percentage of weakly stained cells) + 2 × (2+: percentage of moderately stained cells) + 3 × (3+: percentage of strongly stained cells)., Results: EGFR expression in SGC varied widely even among the same as well as different histopathological types. The average EGFR positive scores were 46.0 %, 55.7 %, 51.6 %, 1.0 %, 26.8 %, 50 %, and 76.8 % for mucoepidermoid carcinoma (MEC), salivary duct carcinoma (SDC), adenoid cystic carcinoma (AdCC), acinic cell carcinoma (AcCC), adenocarcinoma NOS (ACNOS), carcinoma ex pleomorphic adenoma (CAexPA), and squamous cell carcinoma (SqCC), respectively. The average cumulative EGFR scores were 82, 91, 80, 1, 52, 93, and 185 for MEC, SDC, AdCC, AcCC, ACNOS, CAexPA, and SqCC, respectively., Conclusions: EGFR positive scores and cumulative EGFR scores in SGCs varied among the various histological types, and even in the same histological type. These scores may predict the clinical outcome of SGC treated with EGFR-targeting therapies, such as head and neck photoimmunotherapy, and need to be evaluated in future studies., (Copyright © 2024. Published by Elsevier B.V.)

Salivary gland and odontogenic neoplasms with extensive clear cell change are rare lesions but have been increasingly characterized over the past decade. Among this heterogeneous group of neoplasms, hyalinizing clear cell carcinoma (HCCC), clear cell odontogenic carcinoma (CCOC), and clear cell myoepithelial carcinoma (CCMC) share a monophasic clear cell morphology and an EWSR1 gene rearrangement. While HCCC is relatively well characterized, there are a limited number of EWSR1-reaarranged CCMC of salivary glands reported, and its clinicopathologic features in relation to HCCC and nonclear cell myoepithelial carcinoma (MC) have not been clarified. This report describes the clinical, morphologic, and immunophenotypic features of 3 carcinomas composed predominantly of clear cells and with EWSR1 rearrangements by fluorescence in situ hybridization. A comparative literature analysis suggests that HCCC, CCMC, and nonclear cell MC of salivary glands are clinically, histopathologically, and molecularly distinct., Competing Interests: DECLARATION OF INTERESTS The authors state that there are no conflicts of interest to disclose., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Aims: Salivary gland neoplasms (SGN) exhibiting the HMGA2::WIF1 fusion are recognized by their resemblance to histology found in canalicular adenoma. Recently, ~20% of cases among 28 HMGA2::WIF1-rearranged-SGN showed malignancy and adverse outcomes (recurrence, distant metastasis, and disease-specific mortality). Among them, MDM2/CDK4 amplifications were identified in one case. This outcome suggests that the MDM2/CDK4 amplifications could be useful to predict an aggressive course of carcinoma ex-pleomorphic adenoma (CEPA)., Methods and Results: We investigated the correlation between HMGA2 fusion and MDM2 amplification in four salivary gland neoplasms, providing detailed clinicopathological features and outcomes. Cases were selected from different institutions. Histological examination, immunohistochemistry, fluorescence in situ hybridization (FISH), RNA sequencing, and whole-exome capture were performed. The cohort included four CEPA cases, all female, aged between 32 and 89 years. Tumours arose from the parotid gland with an average size of 24.5 mm. None exhibited recurrence or distant metastases during the 4-5 months of follow-up. Pathologically, all cases displayed a peculiar atypical nuclei with 'gear-like appearance'. Immunohistochemically, tumours exhibited a biphasic pattern with myoepithelial and ductal differentiation markers. All cases showed HMGA2 overexpression and MDM2 amplification by FISH and RNA sequencing. In a control cohort of MDM2 nonamplified CEPA cases, not exhibiting the peculiar nuclear atypia., Conclusions: Our findings suggest a strong correlation between HMGA2 alteration/MDM2 amplification and a peculiar nuclear atypia, advocating for their evaluation in biphasic tumours to facilitate accurate diagnosis and tailored posttumour removal monitoring. Further studies are warranted to validate these observations and elucidate their prognostic implications., (© 2024 The Authors. Histopathology published by John Wiley & Sons Ltd.)

True malignant mixed tumors, also known as salivary gland carcinosarcoma (SCS), are uncommon yet highly aggressive lesions associated with a poor prognosis. These tumors exhibit a distinctive biphasic structure characterized by both epithelial and mesenchymal components. Recent research has shown that the majority of SCS cases stem from pre-existing pleomorphic adenomas (PAs), suggesting a stepwise developmental pattern. In this report, we present a case of a 73-year-old female with SCS and describe the clinical, radiographic, and pathologic observations. Notably, the SCS was associated with a residual PA. The SCS displayed a CTNNB1::PLAG1 gene rearrangement, providing a molecular basis for its origin from the PA. Further DNA genomic analysis exposed mutations in BAP1, PER1, and LRPB1. Our findings provide support to the theory that SCS emerges from a pre-existing PA while highlighting the multiple genetic changes that could contribute to malignant transformation., Competing Interests: Declaration of interests None., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objective: Undergoing surgery and adjuvant radiotherapy (aRT) at the same facility has been associated with higher overall survival (OS) in head and neck squamous cell carcinoma. Our study investigates whether undergoing surgery and aRT at the same academic facility is associated with higher OS in major salivary gland cancer (MSGC)., Methods: The 2006-2018 National Cancer Database was queried for patients with MSGC undergoing surgery at an academic facility and then aRT. Multivariable binary logistic and Cox proportional hazards regression models were implemented., Results: Of 2801 patients satisfying inclusion criteria, 2130 (76.0%) underwent surgery and aRT at the same academic facility. Residence in a less populated area (adjusted odds ratio [aOR] 1.69, 95% confidence interval [CI] 1.16-2.45), treatment without adjuvant chemotherapy (aOR 1.97, 95% CI 1.41-2.76), and aRT duration (aOR 1.02, 95% CI 1.01-1.04) were associated with undergoing surgery and aRT at different facilities on multivariable logistic regression adjusting for patient demographics, clinicopathologic features, and adjuvant therapy (p < 0.01). Five-year OS was higher in patients undergoing surgery and aRT at the same academic facility (68.8% vs. 61.9%, p < 0.001). Undergoing surgery and aRT at different facilities remained associated with worse OS on multivariable Cox regression (aHR 1.41, 95% CI 1.10-1.81, p = 0.007)., Conclusion: Undergoing surgery and aRT at the same academic facility is associated with higher OS in MSGC. Although undergoing surgery and aRT at the same academic facility is impractical for all patients, academic physicians should consider same-facility treatment for complex patients who would most benefit from clear multidisciplinary communication., Level of Evidence: 4 Laryngoscope, 134:3620-3632, 2024., (© 2024 The Authors. The Laryngoscope published by Wiley Periodicals LLC on behalf of The American Laryngological, Rhinological and Otological Society, Inc.)

Objective: To determine the indications for neck dissection in the management of parotid, submandibular or minor salivary gland cancers depending on the clinical situation: i.e., clinical lymph node involvement (cN+) or not (cN0); low or high risk of occult nodal metastasis; diagnosis of malignancy before, during or after surgery., Material and Methods: The French Network of Rare Head and Neck Tumors (REFCOR) formed a steering group which drafted a narrative review of the literature published on Medline and proposed recommendations. The level of adherence to the recommendations was then assessed by a rating group according to the formal consensus method., Results: In cN+ salivary gland cancer, ipsilateral neck dissection is recommended. In cN0 salivary gland cancer, ipsilateral neck dissection is recommended, except for tumors at low risk of occult nodal metastasis. If definitive pathology reveals a high risk of occult nodal involvement, additional neck treatment is recommended: ipsilateral neck dissection or elective nodal irradiation., Conclusion: The rate of occult lymph node involvement, and therefore the indication for elective neck dissection, depends primarily on the pathologic grade of the salivary gland cancer., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

Epithelial-myoepithelial carcinoma (EMC) is a rare tumor that occurs mainly in the major salivary glands. Cases occurring in the nasal cavity are rarely reported. The patient was a 48-year-old woman with a postoperative pathological diagnosis of EMC. The patient recovered well after surgery. We consulted and summarized all previous cases of nasal EMC. We also discuss the clinical presentation, treatment, and prognosis of EMC of the nasal cavity and paranasal sinuses., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Objective: To determine the indications for radiotherapy in salivary gland cancer and to specify the modalities and target radiation volumes., Material and Methods: The French Network of Rare Head and Neck Tumors (REFCOR) formed a steering group which drafted a narrative review of the literature published on Medline and proposed recommendations. The level of adherence to the recommendations was then assessed by a rating group, according to the formal consensus method., Results: Postoperatively, radiotherapy to the primary tumor site±to the lymph nodes is indicated if one or more of the following adverse histoprognostic factors are present (risk>10% of locoregional recurrence): T3-T4 category, lymph node invasion, extraglandular invasion, close or positive surgical margins, high tumor grade, perineural invasion, vascular emboli, and/or bone invasion. Intensity-modulated radiation therapy (IMRT) is the gold standard. For unresectable cancers or inoperable patients, carbon ion hadrontherapy may be considered., Conclusion: Radiotherapy in salivary gland cancer is indicated in postoperative situations in case of adverse histoprognostic factors and for inoperable tumors., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

Background: Salivary gland tumors (SGTs) are a heterogenous group of pathologies, which still represents a challenge regarding differential diagnosis and therapy. Although histological findings govern SGTs management, detection of molecular alterations is emerging as an effective additional tool. The aim of this study was to analyze the relative expression levels of three micro RNAs (miR-26a, miR-26b, and miR-191), and three pro-oncogenic molecular markers (PLAG1, MTDH, and HIF2) in SGTs and normal salivary gland (NSG) tissues and evaluate them as potential differential diagnosis markers., Methods: This cross-sectional study included 58 patients with SGTs (23 pleomorphic adenomas, 27 Warthin tumors, and 8 malignant SGTs) and 10 controls (normal salivary gland tissues). Relative gene expression levels of all investigated molecules were determined by reverse transcriptase-real-time polymerase chain reaction., Results: All three micro RNAs exhibited highest expression levels in benign SGTs, whereas miR-26a And miR-191 were significantly more expressed in PAs compared to WTs (p = 0.045 and p = 0.029, respectively). PLAG1 And HIF2 were both overexpressed in WTs compared to PAs (p = 0.048 and p = 0.053, respectively). Bioinformatic analysis suggested that all investigated micro RNAs function as negative regulators of MTDH., Conclusion: The results of this study suggest that all three micro RNAs have a considerable negative impact on MTDH oncogene expression in malignant tumors, while the differences between levels of miR-26a, miR-191, PLAG1, and HIF2 in PA and WT represent possible differential diagnosis markers., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: The preoperative diagnosis of salivary gland cancer (SGC) is crucial for the application of appropriate treatment, particularly involving the extension of the resection., Methods: Retrospective search of medical database identified 116 patients treated surgically with malignant tumors of salivary gland between 2010 and 2020. Analysis included the demographical data, clinical course, type of surgical and adjuvant treatment, histology type and margin status, perivascular invasion (LVI), perineural invasion (PNI), metastatic lymph nodes (LN). Facial nerve function, recurrence-free and overall survival were evaluated. Adequate statistics were used for data analysis., Results: The final cohort included 63 SGC patients, with adenoid cystic carcinoma the most common pathological type (27%, n = 17), followed by adenocarcinoma (17.4% n = 11). T1 and T2 patients accounted for majority cases (n = 46). The lymph node metastases were confirmed with the histopathology in 31.7% (n = 20). Distant metastases were observed in 4.8% of cases (n = 3). 38% (n = 24) of SGC were treated selectively with surgery, 49.2% (n = 31) had postoperative radiotherapy and 15.9% (n = 10)-radio-chemotherapy. The final facial nerve function was impaired in 38% of patients. Mean overall survival (OS) for all patients was 108.7 (± 132.1) months, and was the most favorable for acinar cell carcinoma (118.9 ± 45.4) and the poorest for squamous cell carcinoma (44 ± 32). Cox regression analysis of disease-free survival and OS identified significant association only with patients' age over 65 years, the hazard ratio of 7.955 and 6.486, respectively., Conclusions: The efficacy of treatment modalities for SGC should be verified with regard to the histopathological type, but also the patients' age should be taken into account., (© 2024. The Author(s).)

Background: Pleomorphic adenoma (PA), the most common benign salivary gland epithelial lesion, has a biphasic epithelial-mesenchymal pattern and great histopathological diversity., Methods: This study's objective was to conduct a retrospective clinicopathological analysis, focusing on the histopathology characteristics of salivary gland PA., Results: There were ten cases of pleomorphic adenoma. The mean age was 33.5 years and no gender predilection was observed. All the patients presented with an asymptomatic mass and the duration of presentation was 31.2 ± 19.4 months. The cellular subtype (50 %) of PA was the most common. Capsular infiltration and incomplete capsules occurred in 20 % of cases. All the cases had round (100 %) and myxoid stroma. The cellular subtype was more common in the major salivary glands; showed capsular abnormalities (incomplete capsule, absent capsule, and tumor infiltration); and had more plasmacytoid, angular, spindled non-luminal cells as well as inflammation and cystic degeneration. The classic subtype had more clear and oncocytic cells along with sebaceous and squamous differentiation. The stroma-rich subtype had the shortest duration of complaints (three months) and showed giant cell reaction., Conclusions: These findings confirm previous studies on the clinicopathological features of pleomorphic adenomas and highlight important morphologic characteristics like capsular invasion and squamous metaplasia, which can otherwise indicate malignancy., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Benign and malignant salivary gland disorders are uncommon in the pediatric population; however, these can be frequently seen in pediatric otolaryngology or oral and maxillofacial surgery practices. The astute clinician should be aware of the clinical presentation, diagnosis, and management options for common inflammatory, infectious, benign, and malignant disorders of salivary glands., Competing Interests: Disclosure Dr SN Amin and Mr KT Patterson were supported by the T32DC000018 from the National Institute on Deafness and Other Communication Disorders during their work on this article. The authors have no conflicts of interest to disclose., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Competing Interests: The authors have no conflict of interest to declare.

Rationale: Salivary duct carcinoma (SDC) is an aggressive form of cancer, with cutaneous metastasis being a rare occurrence. Furthermore, cutaneous metastasis of SDC secondary to a scald is even rarer, and to the best of our knowledge, our case represents the first such instance. Considering the involvement of the fingers in the metastatic site, which may affect limb function and quality of life, we present this case to explore the reason why scald could lead to distant recurrence and better treatment options., Patient Concerns: An 85-year-old man diagnosed with SDC in the parotid gland found enlarged masses at the fingertips as a consequence of a burn, 6 years after his initial treatment., Diagnoses: Cutaneous metastasis of SDC in the parotid gland and left thumb loss due to surgery., Interventions: Radiotherapy was offered, targeting at the masses on the fingers, with dose at 15 Gy in 3 fractions, 12 Gy in 3 fractions, 15 Gy in 3 fractions for both hands and additional 21 Gy in 7 fractions only for left hand., Outcomes: The tumors shrank after 2 months of radiotherapy and the patient recovered well. Side effects included nail hyperplasia and paronychia., Lessons: Connections between scald and distant metastasis of malignant tumors in this case needed further investigation. Considering reserving function of the fingers while dealing with metastasis, radiotherapy is recommended rather than surgery., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Objective: The aim of this study was to investigate the potential survival benefits associated with chemoradiotherapy (CRT) as opposed to radiotherapy (RT) in patients with resected high-risk salivary gland cancer (SGC), with a specific focus on determining whether these benefits are influenced by the number of high-risk variables., Methods: Patients who underwent surgical treatment for high-risk SGC were retrospectively enrolled and categorized into either CRT or RT groups. The impact of adjuvant therapy on locoregional control (LRC) and overall survival (OS) was assessed using a multivariable Cox model., Results: A total of 152 patients were included following propensity score-matching. In comparison to RT, CRT did not demonstrate a significant survival advantage in terms of LRC (p = 0.485, HR: 1.14, 95%CI: 0.36-4.22) and OS (p = 0.367, HR: 0.99, 95%CI: 0.17-3.87) in entire population. But among patients with T3/4 stage, high-grade tumors, and 5 or more positive lymph nodes, the addition of chemotherapy to RT significantly (p = 0.042) correlated with a 15% reduction in the risk of cancer recurrence (95%CI: 4-54%). Conversely, in other subgroups with varying combinations of high-risk variables, CRT did not provide additional survival benefits for LRC and OS compared to RT., Conclusion: Adjuvant chemotherapy may be considered in conjunction with RT specifically in cases where there is a presence of T3/4 stage, high-grade tumors, and 5 or more metastatic lymph nodes in high-risk SGC., (© 2024. The Author(s).)

Microsecretory adenocarcinoma (MSA) is a new type of salivary gland neoplasm identified in the 2022 World Health Organization Classification of Head and Neck Tumour (Skalova et al., Head Neck Pathol 16:40-53, 2022) and is characterized by a unique set of histomorphologic and immunohistochemical features and a recurrent MEF2C::SS18 fusion. MSA was initially misdiagnosed as another salivary gland tumour due to its similar morphology; until recently, only fewer than 50 cases were reported. We present a case of MSA of the hard palate with diverse architectural growth patterns, bland cytological features, abundant basophilic intraluminal secretions and fibromyxoid stroma. The tumour cells were positive for the SOX10, S100, and p63 protein and negative for the p40 protein according to immunohistochemistry. SS18 gene rearrangement was demonstrated via break-apart fluorescence in situ hybridization. We also provided a comprehensive literature review and integrated the clinicopathological features, immunophenotype, and molecular alterations of the disease. A comprehensive understanding of MSA enables us to accurately distinguish and categorize MSA from other salivary gland tumours with analogous morphologies., (© 2024. The Author(s).)

Adenoid cystic carcinoma (AdCC) is a slow-growing salivary gland malignancy that relapses frequently. AdCCs of the submandibular gland exhibit unique differences in prognosis and treatment response to adjuvant radiotherapy compared to other sites, yet the role of tumor anatomic subsite on gene expression and tumor immune microenvironment (TIME) composition remains unclear. We used 87 samples, including 48 samples (27 AdCC and 21 normal salivary gland tissue samples) from 4 publicly available AdCC RNA sequencing datasets, a validation set of 33 minor gland AdCCs, and 39 samples from an in-house cohort (30 AdCC and 9 normal salivary gland samples). RNA sequencing data were used for single sample gene set enrichment analysis and TIME deconvolution. Quantitative PCR and multiplex immunofluorescence were performed on the in-house cohort. Wilcoxon rank-sum, nonparametric equality-of-medians tests and linear regression models were used to evaluate tumor subsite differences. AdCCs of different anatomic subsites including parotid, submandibular, sublingual, and minor salivary glands differed with respect to expression of several key tumorigenic pathways. Among the three major salivary glands, the reactive oxygen species (ROS)/nuclear factor erythroid 2-related factor 2 (NRF2) pathway signature was significantly underexpressed in AdCC of submandibular compared to parotid and sublingual glands while this association was not observed among normal glands. Additionally, the NRF2 pathway, whose expression was associated with favorable overall survival, was overexpressed in AdCCs of parotid gland compared to minor and submandibular glands. The TIME deconvolution identified differences in CD4 + T cell populations between AdCC of major and minor glands and natural killer (NK) cells among AdCC of minor, submandibular, and parotid glands while plasma cells were enriched in normal submandibular glands compared to other normal gland controls. Our data reveal key molecular differences in AdCC of different anatomic subsites. The ROS and NRF2 pathways are underexpressed in submandibular and minor AdCCs compared to parotid gland AdCCs, and NRF2 pathway expression is associated with favorable overall survival. The CD4 + T, NK, and plasma cell populations also vary by tumor subsites, suggesting that the observed submandibular AdCC tumor-intrinsic pathway differences may be responsible for influencing the TIME composition and survival differences., (© 2024. The Author(s).)

Background: Neurotrophic tyrosine receptor kinase (NTRK) gene fusions are oncogenic drivers. Using the Auria Biobank in Finland, we aimed to identify and characterize patients with these gene fusions, and describe their clinical and tumor characteristics, treatments received, and outcomes., Material and Methods: We evaluated pediatrics with any solid tumor type and adults with colorectal cancer (CRC), non-small cell lung cancer (NSCLC), sarcoma, or salivary gland cancer. We determined tropomyosin receptor kinase (TRK) protein expression by pan-TRK immunohistochemistry (IHC) staining of tumor samples from the Auria Biobank, scored by a certified pathologist. NTRK gene fusion was confirmed by next generation sequencing (NGS). All 2,059 patients were followed-up starting 1 year before their cancer diagnosis., Results: Frequency of NTRK gene fusion tumors was 3.1% (4/127) in pediatrics, 0.7% (8/1,151) for CRC, 0.3% (1/288) for NSCLC, 0.9% (1/114) for salivary gland cancer, and 0% (0/379) for sarcoma. Among pediatrics there was one case each of fibrosarcoma (TPM3::NTRK1), Ewing's sarcoma (LPPR1::NTRK2), primitive neuroectodermal tumor (DAB2IP::NTRK2), and papillary thyroid carcinoma (RAD51B::NTRK3). Among CRC patients, six harbored tumors with NTRK1 fusions (three fused with TPM3), one harbored a NTRK3::GABRG1 fusion, and the other a NTRK2::FXN/LPPR1 fusion. Microsatellite instability was higher in CRC patients with NTRK gene fusion tumors versus wild-type tumors (50.0% vs. 4.4%). Other detected fusions were SGCZ::NTRK3 (NSCLC) and ETV6::NTRK3 (salivary gland cancer). Four patients (three CRC, one NSCLC) received chemotherapy; one patient (with CRC) received radiotherapy., Conclusion: NTRK gene fusions are rare in adult CRC, NSCLC, salivary tumors, sarcoma, and pediatric solid tumors.

Purpose: This study describes a large, well-documented case series of salivary gland polymorphous adenocarcinomas (PAC) from a single Brazilian center., Methods: Demographic data, clinical presentation, histopathological and immunohistochemical features from 26 cases of PAC were analyzed and discussed in detail., Results: Most patients were females (n = 21), with a ratio of 1:4.2 (male: female) with a mean age of 58.8 years (ranging from 36 to 84 years). The most common clinical presentation was a fibrocollagenous, firm nodular lesion, with a mean size of 2.46 cm (ranging from 0.5 to 3 cm). Most lesions occurred on the palate (n = 16), followed by buccal mucosa (n = 3), upper lip (n = 3), buccal vestibule (n = 2) and alveolar ridge (n = 1). Histologically, various growth patterns were observed, including tubular, solid, cribriform, papillary, and cystic. Additionally, glomeruloid slit-like structures, mucous, and clear cells were noted. Surface papillary epithelial hyperplasia was observed in a few cases. Nine cases exhibited myxoid and collagenous areas, while two cases showed fusiform areas and another case demonstrated squamous differentiation. Clear cell predominance was noted in two cases, and peri- and intraneural invasion was seen in eight cases. Immunohistochemical analysis revealed positivity for S-100, p63 and CK7, and negativity for p40 in all cases. The Ki-67 proliferation index was markedly low in most cases, with a mean of 2.5%., Conclusion: We have provided a broad, detailed description of the clinical and microscopic features of PAC in a large, Brazilian cohort. These findings, in a resource-limited area, may be quite useful for establishing a proper diagnosis., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Diagnosis of salivary gland neoplasms is challenging, especially on cytological specimens acquired by fine-needle aspiration. The recently implemented standardized Milan system for reporting salivary gland cytopathology provides an estimated risk of malignancy (ROM); yet, for two of the categories, the diagnosis of the lesion remains unclear. However, a precise diagnosis is desirable for optimal patient management, including planning of surgery and imaging procedures., Methods: Cytological specimens (n = 106) were subjected to molecular analysis using the SalvGlandDx panel. The risk of malignancy was calculated for each detected alteration based on the diagnosis of the resection specimen. By taking into account the molecular alterations, their associated ROM, the clinical and cytological features, and the current literature, the Milan category was evaluated., Results: Of n = 63 technically valid cases, 76% revealed a molecular alteration. A total of 94% of these molecularly altered cases could be assigned to a different Milan category when additionally taking molecular results into account. In only 2% of the salivary gland neoplasms of uncertain malignant potential, in which a molecular alteration was detected, the classification remained salivary gland neoplasms of uncertain malignant potential., Conclusion: Molecular analysis of cytological specimens provides a benefit in classifying salivary gland neoplasms on fine-needle aspiration. It can improve the ROM estimation and thus help to assign cases of formerly unknown malignant potential to clearly benign or malignant categories., (© 2024 The Authors. Cancer Cytopathology published by Wiley Periodicals LLC on behalf of American Cancer Society.)

Basaloid salivary gland neoplasms are a diverse and varied group of benign and malignant tumors. The term 'basaloid' is broadly used in reference to cells with elevated nuclear to cytoplasmic ratio, sparse cytoplasm, and hyperchromatic nuclei. However, a subset may also fit within the "small round blue cell tumor" morphologic category or the "biphasic" salivary gland tumor category. Furthermore, there are no established thresholds for the proportion of basaloid tumor cells needed to consider a tumor within the basaloid spectrum. Given the implicit variability in what is considered a basaloid salivary gland tumor, one may question the inclusion of certain entities (canalicular adenoma, HMGA2::WIF1 pleomorphic adenoma, polymorphous adenocarcinoma) in this review based on classic morphologic features. However, salivary gland tumors with even minor basaloid components may appear 'basaloid' in small biopsy specimens and, thus, a choice was made to focus on common and uncommon diagnostic differentials with this in mind. Entities that will be covered in this review also include basal cell adenoma and basal cell adenocarcinoma, adenoid cystic carcinoma, lymphoepithelial carcinoma, sialoblastoma, adamantinoma-like Ewing Sarcoma, NUT carcinoma, and carcinoma showing thymus-like differentiation., Competing Interests: Declaration of competing interest I certify that I have no affiliations with or involvement in any organization or entity with any financial interest or non-financial interest in the subject matter or materials discussed in this manuscript., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Salivary gland squamous cell carcinomas (SG-SCCs) constitute a rare type of head and neck cancer which is linked to poor prognosis. Due to their low frequency, the molecular mechanisms responsible for their aggressiveness are poorly understood. In this work we studied the role of the phosphatase DUSP1, a negative regulator of MAPK activity, in controlling SG-SCC progression. We generated DUSP1 KO clones in A253 human cells. These clones showed a reduced ability to grow in 2D, self-renew in ECM matrices and to form tumors in immunodeficient mice. This was caused by an overactivation of the stress and apoptosis kinase JNK1/2 in DUSP1 -/+ clones. Interestingly, RNAseq analysis revealed that the expression of SOX2, a well-known self-renewal gene was decreased at the mRNA and protein levels in DUSP1 -/+ cells. Unexpectedly, CRISPR-KO of SOX2 did not recapitulate DUSP1 -/+ phenotype, and SOX2-null cells had an enhanced ability to self-renew and to form tumors in mice. Gene expression analysis demonstrated that SOX2-null cells have a decreased squamous differentiation profile -losing TP63 expression- and an increased migratory phenotype, with an enhanced epithelial to mesenchymal transition signature. In summary, our data indicates that DUSP1 and SOX2 have opposite functions in SG-SCC, being DUSP1 necessary for tumor growth and SOX2 dispensable showing a tumor suppressor function. Our data suggest that the combined expression of SOX2 and DUSP1 could be a useful biomarker to predict progression in patients with SG-SCCs., (© 2024. The Author(s).)

Mucoepidermoid carcinoma (MEC) is the most common malignant salivary gland tumor. Varying sized cysts and sheets composed of three cell types (epidermoid, intermediate, and mucous cells) with varying degrees of atypia form the characteristic histological appearance of MEC. MEC frequently contains a wide variety of modified tumor cells and can be entirely cystic or completely solid. Under these circumstances, MEC requires critical differentiation from many mimickers, ranging from simple cysts and benign tumors to high-grade carcinomas. Tumor-associated lymphoid proliferation and sclerotic changes in the stroma also contribute to diagnostic difficulties. Several well-known diagnostically challenging variants (oncocytic, clear cell, spindle cell, and sclerosing) exist in MEC. With the advent of studies on specific CRTC1/3::MAML2 fusion genes in MEC, newly proposed subtypes have emerged, including Warthin-like and non-sebaceous lymphadenoma-like MECs. In addition to the recently defined mucoacinar variant with a serous cell phenotype, MEC devoid of squamous differentiation has also been reported, implying the need to reconsider this basic concept. In this article, we outline the general clinical features and MAML2 status of conventional MEC and review the cytoarchitectural subtypes, with an emphasis on a pitfall in the interpretation of this histologically diverse single entity., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

There is a limited amount of data on the role of programmed cell death ligand (PD-L) -1 and PD-L2 in salivary gland carcinomas. We aimed to evaluate the prognostic value of PD-L1 and PD-L2 expressions, which are closely related to immune mechanisms, with respect to salivary gland tumor types and stages. Data from patients with salivary gland masses surgically removed between 2006 and 2021, diagnosed with a malignant salivary gland neoplasm, were retrospectively analyzed. Immunoreactivity for PD-L1 and PD-L2 was performed on resection materials. The mean age of 90 patients was 52.1±18.8 and 46.7% were male. Overall, 55.6% of patients were diagnosed with adenoid cystic carcinoma (ACC), 23.3% with mucoepidermoid carcinoma (MEC), 16.7% with acinic cell carcinoma (AciCC), 3.3% with ductal carcinoma (DC), and 1 patient with pleomorphic adenoma ex carcinoma (PA-ex-CA). In all, 52% of ACC, 12% of AciCC, 24% of MEC, and 12% of DC cases were at stage IV. The tumor diameter, frequencies of lymphovascular invasion, metastasis, positive surgical margin, recurrence, and mortality rates of patients at stages III and IV were significantly larger than those at stages I and II ( P <0.05). The percentages of tumor cell score (TCS) and immune cell score (ICS) for PD-L1 were significantly higher among patients with MEC compared with those with other types of tumors ( P =0.0011). However, the percentages of combined score (CS) for PD-L1 and tumor cell score for PD-L2 were comparable among tumor types ( P >0.05). No significant difference was found in these scores for PD-L1 between tumor stages ( P >0.05), but for PD-L2, all patients at stage I had TCS <1% for PD-L2, while all patients at stages II and III, and 92% of patients at stage IV had TCS ≥1% ( P <0.0001). High expression of PD-L1 was mostly observed in MEC cases ( P =0.0016), while all patients with AciCC had a low PD-L1 expression level ( P =0.0206). The mean tumor diameter, rate of lymphovascular invasion, perineural invasion, metastasis, positive surgical margin, recurrence, type of treatment, mortality, and TILs ratio did not differ significantly according to PD-L1 expression level ( P >0.05). The percentage of tumor-infiltrating lymphocytes was comparable among negative and positive PD-L1 scores according to both 1% and 5% threshold values ( P >0.05). High PD-L1 expression is rare in AciCC, while PD-L1 expression is high in MEC. Our findings underline the importance of future screening for PD-L1 and PD-L2 before patients undergoing immunotherapies in all salivary gland tumors., Competing Interests: The authors declare no conflict of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

The differential diagnosis of salivary gland lesions with epithelial components and lymphoid stroma is often challenging. Salivary gland carcinoma with tumor-associated lymphoid proliferation, tumors composed of both epithelial and lymphoid components, lymphoid neoplasms in the salivary gland, and inflammatory lesions are all included in this category. It encompasses inflammatory lesions and neoplastic lesions. With the exception of Warthin tumors, these lesions are rare, making them more difficult to diagnose. Carcinoma showing thymus-like elements has recently been reported in the salivary gland. Similar to thymic carcinoma, tumor cells are positive for CD5 and are accompanied by T lymphocytes., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Salivary gland cancers are rare in general and salivary duct carcinoma and epithelial myoepithelial carcinomas are rare subtypes. This topic discussion will review the characteristics of these uncommon cancers. Additionally, it will briefly discuss available guidelines for salivary cancers and summarize author opinions on the role of adjuvant radiation therapy for these cases., Competing Interests: Disclosures None., (Copyright © 2024 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.)

Competing Interests: Declaration of competing interest The author declares no conflicts of interest in association with the present study. The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. The author is an Editorial Board Member/Editor-in-Chief/Associate Editor/Guest Editor for [Journal name] and was not involved in the editorial review or the decision to publish this article. The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Masato Nakaguro.

Background: The Milan System for Reporting Salivary Gland Cytopathology (MSRSGC) is widely accepted and endorsed by professional societies. Although several studies focusing on the MSRSGC have been published, few have been prospective studies. The objective of this study was to evaluate the effectiveness of the MSRSGC in cytopathology practice., Methods: A comprehensive literature search was conducted to identify all prospective studies on the MSRSGC. The risk of malignancy (ROM), risk of neoplasm, and diagnostic accuracy for each diagnostic category were calculated. Data were tabulated in Microsoft Excel, and analyses were performed with the Open Meta-Analyst program., Results: Seven prospective and seven retrospective studies were identified. The total number of fine-needle aspirations (FNAs) was 1587 in the prospective studies and 1764 in the retrospective studies. The ROM values for the nondiagnostic, nonneoplastic, atypia of undetermined significance, benign neoplasm, salivary gland neoplasm of uncertain malignant potential, suspicious for malignancy, and malignant categories in prospective versus retrospective studies were 21.0% versus 26.6%, 9.4% versus 8.1%, 34.9% versus 39.6%, 2.4% versus 2.1%, 36.6% versus 31.2%, 86.0% versus 66.0%, and 97.0% versus 96.7%, respectively. Sensitivities, specificities, and diagnostic odds ratios were 83.1% (95% confidence interval [CI], 71.1%-90.8%) versus 89.1% (95% CI, 83.6%-92.9%), 98.4% (95% CI, 96.6%-99.3%) versus 94.9% (95% CI, 91.9%-96.9%), and 310.7 (95% CI, 121.2-796.6) versus 218.8 (95% CI, 107.3-438.1)., Conclusions: This meta-analysis indicated that the MSRSGC works well in FNA cytopathology practice and improves diagnostic accuracy in all diagnostic categories. The ROMs of prospective studies were in concordance with the MSRSGC reference values., (© 2024 The Authors. Cancer Cytopathology published by Wiley Periodicals LLC on behalf of American Cancer Society.)

High-grade carcinomas of the salivary glands are a group of several tumor entities with highly malignant histologic appearances, and have an aggressive biological behavior accompanied by poor a prognosis. In general, they require more intensive treatment than low- or intermediate-grade carcinomas. High-grade salivary carcinomas are rare and the microscopic features often overlap between different tumor types, making an appropriate diagnosis challenging in daily practice settings. However, with recent rapid advances in molecular pathology and molecular-targeted therapy in this field, there is a growing need to properly classify tumors, rather than just diagnosing the cases as "high-grade carcinomas". This leads to specific treatment strategies. In this article, we review representative high-grade salivary gland carcinomas, including salivary duct carcinoma and its histologic subtypes, high-grade mucoepidermoid carcinoma, solid-type adenoid cystic carcinoma, and high-grade transformation of low- or intermediate-grade carcinomas, and discuss their differential diagnoses and clinical implications. Other rare entities, such as neuroendocrine carcinoma, NUT carcinoma, and metastatic carcinoma, should also be considered before diagnosing high-grade carcinoma, NOS. Of these tumors, salivary duct carcinoma has received the most attention because of its strong association with androgen deprivation and anti-HER2 therapies. Other tumor-type-specific treatments include anti-TRK therapy for high-grade transformation of secretory carcinoma, but further therapeutic options are expected to be developed in the future. It should be emphasized that detailed histological evaluation with adequate sampling, in addition to the effective use of molecular ancillary tests, is of the utmost importance for a suitable diagnosis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)