Genetic Rearrangements in Different Salivary Gland Tumors: A Systematic Review.

Salivary gland tumors (SGT) encompass a wide range of neoplasms, each with its own unique histological type and clinical presentation. This review hones in on prevalent subtypes of SGTs, including adenoid cystic carcinoma (ACC), salivary duct carcinoma (SDC), and polymorphous adenocarcinoma (PAC). The articles, identified through specific keywords, were meticulously screened in databases like PubMed, Scopus, Google Scholar, and Web of Science from 2018 to 2023. Eight articles delved into genetic modifications among the selected SGT types. A fusion protein known as MYB-NF1B is typically associated with ACC, promoting cell proliferation while inhibiting apoptosis. The presence of MYB modifications in ACCs is a beacon of hope, as it is linked to a more favorable prognosis. In contrast, SDCs often exhibit HER2 expression. The invasive nature of SGTs contributes to their resistance to treatment. In the case of PAC, the role of PRKD1 is particularly noteworthy. PRKD1, integrated with other genes from the PRKD1/2/3 cluster, helps to differentiate PAC from other diseases. Furthermore, the genetic profiles of KTN1-PRKD1) and PPP2R2A:PRKD1 are distinct. The significant genetic variability among SGTs necessitates meticulous examination. This field is in a constant state of evolution, with new discoveries reshaping our understanding. Genetics is a key player in deciphering SGTs and tailoring treatments. This complex neoplasm demands ongoing research to uncover all genetic influences, thereby enhancing diagnostic methodologies, therapeutic strategies, and patient outcomes.

Clinical and laboratory characteristics of salivary gland ultrasonography-positive patients with primary Sjögren's syndrome.

OBJECTIVE: This study aimed to investigate the clinical and laboratory characteristics of salivary gland ultrasonography (SGUS)-positive patients with primary Sjögren's syndrome (pSS) compared to SGUS-negative patients and to analyse the diagnostic value of SGUS and labial salivary gland biopsy (LSGB) grading in pSS. METHODS: A retrospective analysis of patients admitted to the Affiliated Hospital of Yangzhou University between May 2019 and November 2023 was conducted. According to the OMERACT scoring system, patients with pSS were divided into an SGUS-negative group (score <2) and an SGUS-positive group (score ≥2). The patient's age, gender, clinical symptoms, laboratory parameters and diagnostic examinations were compared and analysed, and Spearman correlation analysis was used to analyse the correlation between SGUS, LSGB and influencing factors. RESULTS: There was no significant difference in dry mouth, dry eyes, tooth loss, fever, joint pain, fatigue, interstitial lung disease or renal tubular acidosis between the two groups, although there were more patients with salivary gland enlargement in the SGUS-positive group (p < 0.05). In terms of high levels of immunoglobulin G (IgG), high levels of rheumatoid factor (RF), anti-nuclear antibody ≥1:320, anti-Sjögren's syndrome A-52KD and anti-Sjögren's syndrome B, the number of cases in the SGUS-positive group was greater than that in the SGUS-negative group (p < 0.05). LSGB samples were graded per the Chisholm-Mason system with significant differences between multiple groups. SGUS score negatively correlated with age and positively correlated with LSGB grade. CONCLUSION: This study showed that the SGUS score positively correlated with LSGB grade in pSS patients and negatively correlated with patient age. Thus, SGUS and LSGB are consistent in the diagnosis of pSS to reflect the degree of salivary gland involvement, and patients who are SGUS positive have high RF and IgG levels, a variety of autoantibodies positive and a tendency toward salivary gland enlargement.

Impact of childhood/adolescent cancer history on prognosis in parotid mucoepidermoid carcinoma.

Our goal was to assess the impact of childhood/adolescent cancer history on overall survival (OS) and disease-specific survival (DSS) in patients with parotid mucoepidermoid carcinoma (MEC). Patients who underwent surgical treatment for primary parotid MEC and those with a second malignancy of parotid MEC were retrospectively identified from the Surveillance, Epidemiology, and End Results (SEER) database. The primary outcome variables were OS and DSS. The hazard ratios (HRs) of these survival rates associated with cancer history were analysed using Cox regression models. In total, 2681 patients were included, 263 of whom had a second malignancy. The 10-year OS rates in the primary (72%) and second malignancy groups (59%) were significantly different. Cox regression confirmed that a history of cancer tended to decrease OS (p = 0.062, HR: 1.28, 95% confidence interval: 0.99 to 1.64). Subgroup analyses showed that a history of solid tumour as opposed to haematological cancer predicted worse OS, with central nervous system tumours exhibiting a more significant influence than others (p = 0.030 vs p = 0.088). Cancer history was not related to DSS. A history of childhood/adolescent cancer negatively influenced the prognosis of patients with parotid MEC, and this effect was primarily driven by a history of solid malignancy.

PIEZO1 activation may serve as an early tissue biomarker for the prediction of irradiation-induced salivary gland dysfunction.

Irradiation (IR)-induced xerostomia is the most common side effect of radiation therapy in patients with head and neck cancer (HNC). Xerostomia diagnosis is mainly based on the patient's medical history and symptoms. Currently, no direct biomarkers are available for the early prediction of IR-induced xerostomia. Here, we identified PIEZO1 as a novel predictive tissue biomarker for xerostomia. Our data demonstrate that PIEZO1 is significantly upregulated at the gene and protein levels during IR-induced salivary gland (SG) hypofunction. Notably, PIEZO1 upregulation coincided with that of inflammatory (F4/80) and fibrotic markers (fibronectin and collagen fibers accumulation). These findings suggest that PIEZO1 upregulation in SG tissue may serve as a novel predictive marker for IR-induced xerostomia.

Traversing the Terrain: Potential Pitfalls within the AJCC 8th Edition Staging System for Lip and Oral Cavity Cancers.

In 1977, the American Joint Committee on Cancer (AJCC) introduced the inaugural Cancer Staging Manual, which implemented the T (tumor extent), N (regional lymph node status), and M (presence or absence of distant metastasis) staging system. This systematic approach aimed to convey the extent of disease across various cancer types, providing clinicians with a practical framework to plan treatment strategies, predict prognosis, and assess outcomes. The AJCC 8th edition, effective from January 1, 2018, continues this tradition. However, certain shortcomings persist in the AJCC 8th edition, as identified through clinical experience. Specifically, challenges arise in accurately assessing depth of invasion in unique histological variants of oral squamous cell carcinoma (e.g., Oral verrucous carcinoma, Carcinoma cuniculatum, and Papillary squamous cell carcinoma) and minor salivary gland tumors. Additionally, discrepancies exist in the perception of bone invasion patterns and in reporting practices. There is also a need for staging guidelines for malignant odontogenic tumors and multifocal tumors of the oral cavity, supplemented by diagrammatic representations. Lastly, there is a call for comprehensive staging criteria for carcinomas of the ear, external auditory canal, and temporal bone. We advocate for the inclusion of these considerations in future editions of the AJCC Cancer Staging Manual.

Clinicopathological Features of 26 Intraoral Polymorphous Adenocarcinomas from a Single Brazilian Institution.

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.

How important are the cytomorphologic subtypes of the salivary gland neoplasm of uncertain malignant potential (SUMP) category in the Milan system for reporting salivary gland cytology? An institutional experience 2018-2024.

INTRODUCTION: Salivary gland neoplasm of uncertain malignant potential (SUMP) is an important diagnostic category of the Milan System for reporting salivary gland cytology (MSRSGC). Further subcategorization by cytomorphologic subtypes has been recommended to risk-stratify cases. In this study, our institutional experience with the risk of neoplasm (RON) and risk of malignancy (ROM) based on cytomorphologic subcategorization of SUMP is reported. We also report the prevalence of malignancy (POM) at our institution. METHODS: The pathology database was queried for cases of fine-needle aspiration (FNA) diagnosed as SUMP along with follow-up at our institution from 2018-February 2024. This study was approved by an institutional review board. RESULTS: Of 1159 cases of salivary gland FNA specimens reported as per MSRSGC at our institution, 14.8% (171/1159 cases) were diagnosed as SUMP, with these reports verified by at least 16 cytopathologists. Surgical follow-up was available for 139/171 (81.3%) of these cases, for which the original cytomorphologic subgroups were as follows: 65 (46.8%) basaloid, 48 (34.5%) oncocytic/oncocytoid, 14 (10.1%) myoepithelial, 9 (6.5%) other, 2 (1.4%) clear cell, and 1 (0.7%) mucinous. The POM within SUMP at our institution is within a range of 29.8%-36.7%. When considering all cases, our institutional RON for SUMP was 97.8% (136/139), and the ROM was 36.7% (51/139). Notably, a significant portion of cases (36%, 50/139) underwent review at a daily intradepartmental consensus conference. Analysis revealed that SUMP cases that underwent consensus review had a ROM of 46% (23/50), versus 31.5% (28/89) in independently verified cases (p = .13). Of the cytomorphologic subgroups, basaloid SUMP in particular was more likely to be benign on resection when the case had been independently verified than after consensus review (p = .0082). When considering only the independently verified cases, the ROM for each subgroup was as follows: 38.7% (12/31) in oncocytic/oncocytoid, 20% (9/45) in basaloid, 33.3% (2/6) in myoepithelial, 60% (3/5) in "other", and 100% (1/1) in both mucinous and clear cell (p = .0407). CONCLUSION: While the RON is high across all cytomorphologic subgroups of SUMP, the ROM does vary across the groups, with basaloid cytomorphology having the lowest ROM. This effect is seen in independently verified cases but not in cases having undergone consensus review.

Early Clinical Mapping of Submandibular Gland Fistula: A Case Report and Systematic Review.

Introduction Submandibular gland fistula (SGF) is a rare subset of salivary gland fistulas. It is seldom tough to diagnose them prior to surgical exploration, and it is often clinically confused with close differentials. An early diagnosis based on pertinent clinical features and focused radiological findings can be pivotal in optimal management and help prevent recurrence and avoid unnecessary investigations/interventions. Objective To review articles that discuss SGF and provide vital etiological, clinical, and imaging features of this rare entity that can aid in early clinical diagnosis. Data Synthesis An extensive review involving PubMed and Google Scholar and reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) standards. Conclusion Submandibular gland fistula is a rare entity. It can be confused with close differentials, including branchial fistulas, if not thoroughly examined. Discharge from fistulae along with submandibular pain/tenderness and/or swelling are important diagnostic clues. A history of trauma, nodule at the site of discharge, prior submandibular disease/calculi, or discharge aggravated with food further increases a clinical suspicion. Optimal radiological investigation looking for calculi/foreign body and delineating the fistula tract is vital to affirm a diagnosis. Gland with fistula excision is a commonly advocated treatment of choice with no reports of recurrence, although conservative management and gland preserving surgery have also reported a favorable prognosis.

Whole phenotype of patients with systemic sclerosis and sicca manifestations: Comparison with sicca manifestations from other causes.

INTRODUCTION & OBJECTIVES: This study aimed to characterize the whole phenotype of Systemic sclerosis (SSc) patients with sicca symptoms, using major salivary glands Ultrasound (SGUS) parameters, minor salivary glands biopsies (mSGB) and clinical findings, and to compare these characteristics with those from patients with Sjogren's Disease (SjD), and patients with sicca manifestations from other causes. METHODS: Sixty SSc patients fulfilling the 2013 ACR/EULAR classification criteria and with subjective self-declared sicca symptoms were consecutively recruited and had SGUS and mSGB. Fifteen SSc patients without subjective sicca symptoms and 65 patients with sicca symptoms from other causes (including 37 SjD with no SSc). RESULTS: SSc patients with subjective sicca symptoms had frequent objective clinical (up to 83 %), histological (44 % of Focus score≥1/ mm2) and US anomalies (63 % of OMERACT ≥2). 53 % patients without subjective clinical complaint also had abnormal objective tests, suggesting the existence of a sub clinical involvement of salivary glands in SSc. SjD-SSc patients had more severe glandular involvement as compared to patients with isolated SjD and isolated Sicca-SSc patients (70%, 48,6 % and 38% of patients with OMERACT ≥2 respectively) suggesting additive impact of both diseases on glandular physiology and structure. CONCLUSION: SjD-SSc overlap have more severe sicca features as compared to isolated sicca-SSc and isolated SjD, suggesting a specific impact of SSc on salivary gland physiology. Further translational studies are needed to identify the underlying pathways that could serve as therapeutic targets.

Prognostic prediction model for salivary gland carcinoma based on machine learning.

Although rare overall, salivary gland carcinomas (SGCs) are among the most common oral and maxillofacial malignancies. The aim of this study was to develop a machine learning-based model to predict the survival of patients with SGC. Patients in whom SGC was confirmed by histological testing and who underwent primary extirpation at the authors' institution between 1963 and 2014 were identified. Demographic and clinicopathological data with complete follow-up information were collected for analysis. Feature selection methods were used to determine the correlation between prognosis-related factors and survival in the collected patient data. The collected clinicopathological data and multiple machine learning algorithms were used to develop a survival prediction model. Three machine learning algorithms were applied to construct the prediction models. The area under the receiver operating characteristic curve (AUC) and accuracy were used to measure model performance. The best classification performance was achieved with a LightGBM algorithm (AUC = 0.83, accuracy = 0.91). This model enabled prognostic prediction of patient survival. The model may be useful in developing personalized diagnostic and treatment strategies and formulating individualized follow-up plans, as well as assisting in the communication between doctors and patients, facilitating a better understanding of and compliance with treatment.

Microsecretory adenocarcinoma of the hard palate: a case report and literature review.

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.

Case report: The diagnostic pitfall of Warthin-like mucoepidermoid carcinoma.

Warthin-like mucoepidermoid carcinoma (WL-MEC) is a newly reported variant of mucoepidermoid carcinoma. Its histological feature is easy to confused with metaplastic Warthin Tumor, and its relationship with Warthin tumor in histogenesis is controversial. In this study, we presented two cases of WL-MEC, discussing their clinicopathological and molecular features. Notably, one case was initially misdiagnosed during the first onset of the tumor. Case 1 was a 60-year-old female with a mass in the right parotid gland. Case 2 featured a 29-year-old male who developed a lump at the original surgical site 6 months after a "Warthin tumor" resection from the submandibular gland. Histologically, both tumor exhibited a prominent lymphoid stroma and cystic pattern, accompanied by various amounts of epithelial nests composed of squamoid cells, intermediate cells and mucinous cells. The characteristic eosinophilic bilayer epithelium of Warthin tumor was not typically presented in either case. Both cases tested positive for MAML2 gene rearrangement. To contextualize our findings, we conducted a comprehensive review of forty-eight WL-MEC cases documented in the English literature, aiming to synthesizing a reliable differential diagnostic approach. WL-MEC is a rare yet clinically relevant variant, posing a diagnostic pitfall for pathologists. Our study underscores the importance of a meticulous evaluation of both clinical and histological features, coupled with the detection of MAML2 rearrangement, as a credible method for distinguishing WL-MEC from other benign and malignant lesions, particularly metaplastic Warthin tumor.

Upregulation of Amy1 in the salivary glands of mice exposed to a lunar gravity environment using the multiple artificial gravity research system.

Introduction: Space is a unique environment characterized by isolation from community life and exposure to circadian misalignment, microgravity, and space radiation. These multiple differences from those experienced on the earth may cause systemic and local tissue stress. Autonomic nerves, including sympathetic and parasympathetic nerves, regulate functions in multiple organs. Saliva is secreted from the salivary gland, which is regulated by autonomic nerves, and plays several important roles in the oral cavity and digestive processes. The balance of the autonomic nervous system in the seromucous glands, such as the submandibular glands, precisely controls serous and mucous saliva. Psychological stress, radiation damage, and other triggers can cause an imbalance in salivary secretion systems. A previous study reported that amylase is a stress marker in behavioral medicine and space flight crews; however, the detailed mechanisms underlying amylase regulation in the space environment are still unknown. Methods: In this study, we aimed to elucidate how lunar gravity (1/6 g) changes mRNA expression patterns in the salivary gland. Using a multiple artificial gravity research system during space flight in the International Space Station, we studied the effects of two different gravitational levels, lunar and Earth gravity, on the submandibular glands of mice. All mice survived, returned to Earth from space, and their submandibular glands were collected 2 days after landing. Results: We found that lunar gravity induced the expression of the salivary amylase gene Amy1; however, no increase in Aqp5 and Ano1, which regulate water secretion, was observed. In addition, genes involved in the exocrine system, such as vesicle-associated membrane protein 8 (Vamp8) and small G proteins, including Rap1 and Rab families, were upregulated under lunar gravity. Conclusion: These results imply that lunar gravity upregulates salivary amylase secretion via Rap/Rab signaling and exocytosis via Vamp8. Our study highlights Amy1 as a potential candidate marker for stress regulation in salivary glands in the lunar gravity environment.

Molecular characterization of the salivary adenoid cystic carcinoma immune landscape by anatomic subsites.

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.

Duct ligation/de-ligation model: exploring mechanisms for salivary gland injury and regeneration.

Sialadenitis and sialadenitis-induced sialopathy are typically caused by obstruction of the salivary gland ducts. Atrophy of the salivary glands in experimental animals caused by duct ligation exhibits a histopathology similar to that of salivary gland sialadenitis. Therefore, a variety of duct ligation/de-ligation models have been commonly employed to study salivary gland injury and regeneration. Duct ligation is mainly characterised by apoptosis and activation of different signaling pathways in parenchymal cells, which eventually leads to gland atrophy and progressive dysfunction. By contrast, duct de-ligation can initiate the recovery of gland structure and function by regenerating the secretory tissue. This review summarizes the animal duct ligation/de-ligation models that have been used for the examination of pathological fundamentals in salivary disorders, in order to unravel the pathological changes and underlying mechanisms involved in salivary gland injury and regeneration. These experimental models have contributed to developing effective and curative strategies for gland dysfunction and providing plausible solutions for overcoming salivary disorders.

Tumor budding - a potential biomarker in low grade salivary gland carcinomas?

Background: Low-grade salivary gland carcinoma is regularly treated with surgical therapy of the salivary gland without elective neck dissection in T1/2 carcinomas, either alone or with adjuvant radiation therapy. However, occult metastasis and locoregional recurrence influence therapy and outcome. Tumor budding is an emerging prognostic pathological factor in many carcinomas, but has not yet been adequately considered in salivary gland carcinomas. Methods: We conducted a retrospective single-center study of 64 patients diagnosed with low-grade carcinoma of the major salivary glands treated between 2003 and 2017. Pathological risk factors and TNM classification were thoroughly assessed for each case. All hematoxylin and eosin (HE)-stained histological specimens underwent careful examination, and tumor budding was identified following the guidelines set forth by the International Tumor Budding Consensus Conference in 2016. Results: Tumor budding was not statistically significant concerning 5-year survival rate (5-YSR) (p=0.969) and mean overall survival (log-rank p=0.315). Whereas 5-year disease-free survival rate (5-YDFSR) was 87% in the low tumor budding group and 61.1% in the intermediate and high tumor budding group (p=0.021). Mean disease-free survival accounted for 100.2 months (CI: 88.6;111.9) in the low budding score group and 58.7 months (CI: 42.8;74.6) in the other group (log-rank p=0.032). Notably, pT1/2 showed significantly lower tumor buds than pT3/4 stages (2.43 tumor buds/0.785 mm2 vs. 4.19 tumor buds/0.785 mm2, p=0.034). Similar findings were noted comparing nodal-positive and nodal-negative patients, as well as patients with and without lymphovascular invasion and perineural invasion (each p<0.05). Conclusions: Tumor budding might be used as an additional prognostic factor for recurrence in low-grade salivary gland carcinoma, seemingly associated with a higher nodal metastasis rate and advanced tumor stages and a worse 5-YDFSR. Consequently, the evaluation of tumor budding in resection specimens of low-grade salivary gland tumor may prove valuable in decision-making for neck dissection and follow-up strategy.

Pure Apocrine Intraductal Carcinoma of Salivary Glands: Reassessment of Molecular Underpinnings and Behavior.

BACKGROUND: Intraductal carcinoma (IDC) of the salivary glands is a confounding entity, our understanding of which continues to evolve. At least four forms have been elucidated based on histomorphology, immunophenotype, and molecular profile: (1) intercalated duct-like, S100/SOX10+ with frequent NCOA4::RET fusions; (2) oncocytic, S100/SOX10+ with TRIM33::RET, NCOA4::RET, and BRAF V600E; (3) apocrine, AR+ with PI3 kinase pathway mutations; and (4) mixed/hybrid intercalated duct-like/apocrine, with S100/SOX10+ and AR+ areas and frequent TRIM27::RET. The revelation that myoepithelial cells harbor the same fusion as luminal cells suggested that fusion-positive cases are not in situ carcinomas as previously believed. To this point, purely apocrine IDC with entirely intraductal growth has not been found to harbor fusions, but very few cases have been tested. METHODS: IDCs with pure apocrine morphology, entirely intraductal growth, and no precursor lesion (pleomorphic adenoma or sclerosing polycystic adenoma) were retrieved from the authors' archives. Several immunostains (S100, SOX10, GCDFP-15, AR, p40/SMA) and targeted next generation sequencing (NGS) panel including 1425 cancer-related genes were performed. RESULTS: Seven entirely IDC with pure apocrine type were collected. The cases arose in the parotid glands (mean, 1.9 cm) of 5 men and 2 women ranging from 51 to 84 years (mean, 69.7 years). Histologically, tumors consisted of rounded to angulated ductal cysts lined by epithelial cells with abundant finely granular eosinophilic cytoplasm and large nuclei with prominent nucleoli. Pleomorphism was mild to moderate, the mitotic rate was low, and necrosis was absent. Conventionally invasive foci or areas of intercalated duct-like morphology were not identified. In all cases, luminal cells were diffusely positive for AR and GCDFP-15 while negative for S100/SOX10, and the ducts were completely surrounded by myoepithelial cells highlighted by p40 and SMA. Molecular analysis was successful in 6 cases. Three harbored fusions: one with NCOA4::RET, another with STRN::ALK and one with both CDKN2A::CNTRL and TANC1::YY1AP1. The three fusion-negative cases all harbored HRAS mutations; additional mutations (PIK3CA, SPEN, ATM) were found in 2 of 3 cases. All patients were treated by surgery alone. Six of them are currently free of disease (follow up 12-190 months), but the case harboring NCOA4::RET developed lymph nodes metastasis in the form of a fusion-positive invasive salivary duct carcinoma. CONCLUSIONS: Purely apocrine IDC is a heterogeneous disease. A subset seems to be genetically similar to salivary duct carcinoma and may indeed represent carcinoma in situ. The other group harbors fusions, similar to other forms of IDC. Moreover, the occurrence of lymph node metastasis discredits the idea that any fusion-positive IDC with a complete myoepithelial cell layer has no metastatic potential. With the wide use of RET-and ALK-based targeted therapies, our findings further underscore the importance of fusion analysis for IDC.

Current Developments in Diagnosis of Salivary Gland Tumors: From Structure to Artificial Intelligence.

Salivary glands tumors are uncommon neoplasms with variable incidence, heterogenous histologies and unpredictable biological behaviour. Most tumors are located in the parotid gland. Benign salivary tumors represent 54-79% of cases and pleomorphic adenoma is frequently diagnosed in this group. Salivary glands malignant tumors that are more commonly diagnosed are adenoid cystic carcinomas and mucoepidermoid carcinomas. Because of their diversity and overlapping features, these tumors require complex methods of evaluation. Diagnostic procedures include imaging techniques combined with clinical examination, fine needle aspiration and histopathological investigation of the excised specimens. This narrative review describes the advances in the diagnosis methods of these unusual tumors-from histomorphology to artificial intelligence algorithms.

Role of Tumor-Infiltrating Lymphocytes and the Tumor Microenvironment in the Survival of Malignant Parotid Gland Tumors: A Two-Centre Retrospective Analysis of 107 Patients.

Background: This study aims to retrospectively investigate the prognostic significance of the tumor microenvironment, with a focus on TILs (tumor-infiltrating lymphocytes), in relation to survival in a large cohort of patients with parotid gland cancer, and it uses the method proposed by the International TILs Working Group in breast cancer. Methods: We included a cohort of consecutive patients with biopsy-proven parotid cancer who underwent surgery between January 2010 and September 2023. A retrospective review of medical records, including surgical, pathological and follow-up reports, was performed. The density of TILs was determined according to the recommendations of the International TILs Working Group for breast cancer. Results: A weak negative correlation (p = 0.3) between TILs and time of survival and a weak positive correlation (p = 0.05) between TILs and months of survival (high TILs were correlated with longer survival in months) were identified. High TILs were weakly negatively, but not statistically significantly p (0.7), correlated with the grading of tumor; this means that high TILs were associated with low-grade tumors. Conclusions: Contrary to previous preliminary reports, this retrospective work found no statistically significant prognostic role of TILs in parotid gland malignancies. This case series represents the largest cohort ever reported in the literature and includes all malignant histological types. Future larger molecular studies may be useful in this regard.

The Spread of Southern Rice Black-Streaked Dwarf Virus Was Not Caused by Biological Changes in Vector Sogatella furcifera.

The pandemic of Southern rice black-streaked dwarf virus (SRBSDV) in and after the late 2000s caused serious yield losses in rice in Southeast and East Asia. This virus was first recorded in China in 2001, but its exclusive vector insect, Sogatella furcifera, occurred there before then. To clarify the evolutionary origin of SRBSDV as the first plant virus transmitted by S. furcifera, we tested virus transmission using three chronological strains of S. furcifera, two of which were established before the first report of SRBSDV. When the strains fed on SRBSDV-infected rice plants were transferred to healthy rice plants, those established in 1989 and 1999 transmitted the virus to rice similarly to the strain established in 2010. SRBSDV quantification by RT-qPCR confirmed virus accumulation in the salivary glands of all three strains. Therefore, SRBSDV transmission by S. furcifera was not caused by biological changes in the vector, but probably by the genetic change of the virus from a closely related Fijivirus, Rice black-streaked dwarf virus, as suggested by ecological and molecular biological comparisons between the two viruses. This result will help us to better understand the evolutionary relationship between plant viruses and their vector insects and to better manage viral disease in rice cropping in Asia.