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Purpose The correct classification of salivary gland pathologies is crucial for choosing a treatment method and determining the prognosis. Better outcomes are now achievable thanks to the introduction of new therapy approaches, such as targeted therapies for malignant salivary gland tumors. To apply these in clinical routine, a clear classification of the lesions is required. Methods The following review examines all changes from the first World Health Organization (WHO) Classification of salivary gland pathologies from 1972 to fifth edition from 2022. Possible developments in the diagnosis and classification of salivary gland pathology are also presented. Results The current WHO classification is the fifth edition. With the development of new diagnostic methods, based on genetic alterations, it provides insight into the molecular basis of lesions. This has resulted in the evolution of classification, introduction of new entities and reclassification of existing ones. Conclusions Genetic alterations will become increasingly more significant in the identification of salivary gland pathologies in the future. These alterations will be helpful as prognostic and predictive biomarkers, and may also serve as targets for anti-cancer therapies.

The molecular pathogenesis of salivary gland acinic cell carcinoma (AciCC) is poorly understood. The secretory Ca-binding phosphoprotein (SCPP) gene cluster at 4q13 encodes structurally related phosphoproteins of which some are specifically expressed at high levels in the salivary glands and constitute major components of saliva. Here we report on recurrent rearrangements [t(4;9)(q13;q31)] in AciCC that translocate active enhancer regions from the SCPP gene cluster to the region upstream of Nuclear Receptor Subfamily 4 Group A Member 3 (NR4A3) at 9q31. We show that NR4A3 is specifically upregulated in AciCCs, and that active chromatin regions and gene expression signatures in AciCCs are highly correlated with the NR4A3 transcription factor binding motif. Overexpression of NR4A3 in mouse salivary gland cells increases expression of known NR4A3 target genes and has a stimulatory functional effect on cell proliferation. We conclude that NR4A3 is upregulated through enhancer hijacking and has important oncogenic functions in AciCC. Acinic cell carcinoma (AciCC) is a rare salivary gland carcinoma that is poorly understood. Here the authors perform genomic, transcriptomic and epigenomic profiling of AciCC and find highly recurrent and specific rearrangements [t(4;9)(q13;q31)], which lead to enhancer hijacking that activates oncogenic transcription factor NR4A3.

Salivary gland cancers are rare, diverse malignancies characterized by poor response to immunotherapy. The tumor immune environment in these cancers remains poorly understood. To address this, we perform an integrative analysis of the tumor immune microenvironment in a large cohort of advanced salivary gland cancer samples. Most tumors exhibit low immune activity with limited immune cell infiltration. Inflammation is linked to higher tumor mutational burden in non-adenoid cystic carcinoma histologies. Subtype specific expression of immune checkpoints is identified with prominent expression of VTCN1 in luminal-like cells within adenoid cystic carcinoma. Macrophages with immunosuppressive properties dominate the immune microenvironment across subtypes. Responses to immunotherapy are limited and associated with a higher ratio of T-cells relative to macrophages in individual cases, warranting further investigation. Here, we show an immunosuppressive environment in salivary gland cancers and identify subtype-specific immune vulnerabilities that could inform tailored therapeutic strategies. Salivary gland cancers (SGC) respond poorly to immunotherapies and new treatment strategies are needed. Here, the authors develop an integrated analysis of advanced SGC to characterize the immune microenvironment and identify potential therapeutic vulnerabilities.

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.

This is the official guideline endorsed by the specialty associations involved in the care of head and neck cancer patients in the UK. Salivary gland tumours are rare and have very wide histological heterogeneity, thus making it difficult to generate high level evidence. This paper provides recommendations on the assessment and management of patients with cancer originating from the salivary glands in the head and neck.

Fine-needle aspiration (FNA) is a well-established procedure for the diagnosis and management of salivary gland lesions, despite challenges imposed by salivary gland tumor diversity, complexity, and cytomorphologic overlap. Until recently, the reporting of salivary gland FNA specimens was inconsistent among different institutions throughout the world, leading to diagnostic confusion among pathologists and clinicians. In 2015, an international group of pathologists initiated the development of an evidence-based tiered classification system for reporting salivary gland FNA specimens, the Milan System for Reporting Salivary Gland Cytopathology (MSRSGC). The MSRSGC consists of 6 diagnostic categories, which incorporate the morphologic heterogeneity and overlap among various nonneoplastic, benign, and malignant lesions of the salivary glands. In addition, each MSRSGC diagnostic category is associated with a risk of malignancy and management recommendations. To review the current status of salivary gland FNA, core needle biopsies, ancillary studies, and the beneficial role of the MSRSGC in providing a framework for reporting salivary gland lesions and guiding clinical management. Literature review and personal institutional experience. The main goal of the MSRSGC is to improve communication between cytopathologists and treating clinicians, while also facilitating cytologic-histologic correlation, quality improvement, and research. Since its implementation, the MSRSGC has gained international acceptance as a tool to improve reporting standards and consistency in this complex diagnostic area, and it has been endorsed by the 2021 American Society of Clinical Oncology management guidelines for salivary gland cancer. The large amount of data from published studies using MSRSGC served as a basis for the recent update of the MSRSGC.

Three pathological grading systems advocated by Perzin/Szanto, Spiro, and van Weert are currently used for adenoid cystic carcinoma (AdCC). In these systems, the amount or presence of the solid tumor component in AdCC specimens is an important index. However, the “solid tumor component” has not been well defined. Salivary AdCC cases (N = 195) were collected after a central pathology review. We introduced a novel criterion for solid tumor component, minAmax (minor axis maximum). The largest solid tumor nest in each AdCC case was histologically screened, the maximum oval fitting the solid nest was estimated, and the length of the minor axis of the oval (minAmax) was measured. The prognostic cutoff for the minAmax was determined using training and validation cohorts. All cases were evaluated for the four grading systems, and their prognostic impact and interobserver variability were examined. The cutoff value for the minAmax was set at 0.20 mm. Multivariate prognostic analyses showed the minAmax and van Weert systems to be independent prognostic tools for overall, disease‐free, and distant metastasis‐free survival while the Perzin/Szanto and Spiro systems were selected for overall survival but not for disease‐free or distant metastasis‐free survival. The highest hazard ratio for overall survival (11.9) was obtained with the minAmax system. The reproducibility of the minAmax system (kappa coefficient of 0.81) was scored as very good while those of the other three systems were scored as moderate. In conclusion, the minAmax is a simple, objective, and highly reproducible grading system useful for prognostic stratification for salivary AdCC. The amount or presence of the solid tumor component is an important index for histopathological grading of adenoid cystic carcinoma. However, the “solid tumor component” has not been well defined. We introduced a novel objective criterion for solid tumor component, minAmax (minor axis maximum), and showed that the minAmax is a simple, objective, and highly reproducible grading system useful for prognostic stratification for salivary adenoid cystic carcinoma.

While all salivary glands (SGs) can be involved in primary Sjögren's syndrome (pSS), their respective role in pathogenesis remains unclear. Our objective was to assess immunopathway activation in paired parotid and labial gland tissue from biopsy-positive and biopsy-negative pSS and non-SS sicca patients. Paraffin-embedded, paired parotid and labial salivary gland tissue and peripheral blood mononuclear cells were obtained from 39 pSS and 20 non-SS sicca patients. RNA was extracted, complementary DNA libraries were prepared and sequenced. For analysis of differentially expressed genes (DEGs), patients were subdivided based on fulfillment of ACR-EULAR criteria and histopathology. With principal component analysis, only biopsy-positive pSS could be separated from non-SS sicca patients based on SG gene expression. When comparing the transcriptome of biopsy-positive pSS and biopsy-negative non-SS sicca patients, 1235 and 624 DEGs (FDR<0.05, log2FC<-1 or >1) were identified for parotid and labial glands, respectively. The number of DEGs between biopsy-negative pSS and non-SS sicca patients was scarce. Overall, transcript expression levels correlated strongly between parotid and labial glands (R = 0.86, p-value<0.0001). Gene signatures present in both glands of biopsy-positive pSS patients included IFN-α signaling, IL-12/IL-18 signaling, CD3/CD28 T-cell activation, CD40 signaling in B-cells, DN2 B-cells, and FcRL4+ B-cells. Signature scores varied considerably amongst pSS patients. Transcriptomes of paired major and minor SGs in pSS were overall comparable, although significant inter-individual heterogeneity in immunopathway activation existed. The SG transcriptome of biopsy-negative pSS was indistinguishable from non-SS sicca patients. Different patterns of SG immunopathway activation in pSS argue for personalized treatment approaches.

The aim of this study was to investigate the potential survival advantages associated with chemoradiotherapy (CRT) compared to radiotherapy (RT) as standalone modalities in the treatment of adenoid cystic carcinoma (ACC) of the salivary glands. Patients diagnosed with resected salivary gland ACC were retrospectively enrolled and categorized into two groups based on the type of adjuvant therapy received. The overall survival outcomes between the CRT and RT cohorts were evaluated using a multivariable Cox model. Post propensity score-matching, a total of 114 patients (57 in each treatment group) were included in the analysis. In the general patient population, CRT did not confer an additional survival benefit compared to RT alone. High-grade tumors, positive surgical margins, and the presence of five or more positive lymph nodes were identified as independent prognostic factors associated with poorer overall survival. Specifically, for patients with positive surgical margins, CRT was significantly associated with improved overall survival relative to RT, displaying a hazard ratio of 0.93 (95% CI: 0.81–0.99). Furthermore, in patients with more than four metastatic lymph nodes, CRT significantly reduced the risk of mortality by 6% (95% CI: 1-24%) when compared to RT alone. Conversely, in patients with high-grade tumors, the addition of adjuvant chemotherapy to RT did not yield significant alterations in survival outcomes compared to RT alone ( p  = 0.437, HR: 0.95, 95% CI: 0.75–2.07). CRT may offer an overall survival benefit for patients with salivary gland ACC, particularly those characterized by positive margin or the presence of five or more metastatic lymph nodes.

Multi-institutional studies are required for the validation of the Milan System for Reporting Salivary Gland Cytopathology (MSRSGC). A total of 1,560 fine-needle aspirations of the salivary glands were retrieved from two institutions for a 12-year period. The diagnoses were reclassified based on the MSRSGC. Risk of malignancy (ROM) for each category was calculated based on 694 histologic follow-up cases. The ROM for each category was: 18.3% for nondiagnostic, 8.9% for nonneoplastic, 37.5% for atypia of undetermined significance (AUS), 2.9% for benign neoplasm, 40.7% for salivary gland neoplasm of uncertain malignant potential (SUMP), 100% for suspicious for malignancy, and 98.3% for malignant. The sensitivity, specificity, positive predictive rate, and negative predictive rates were 89%, 99%, 98%, and 96%, respectively. The results of the current study are in keeping with the MSRSGC. The indeterminate categories of AUS and SUMP showed intermediate ROMs at 37.5% and 40.7%, respectively.