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.
Objectives/Hypothesis
To obtain summary estimates of the sensitivity and specificity of core needle biopsy for assessment of salivary gland lesions and to investigate sources of variation in accuracy ...between study locations.
Study Design
Data sources were PubMed, Embase, CAB s, CINAHL, BIOSIS, LILACS, PakMediNet, Trip Database, and the National Guideline Clearinghouse. Scopus was used to perform forward (citation) and backward (reference) searches of all potentially relevant studies.
Methods
Screening, data extraction, and quality assessment were independently performed by two different assessors. Meta‐analysis was performed using bivariate mixed‐effects binary regression as implemented in Stata 12. Quality assessment was performed using the QUADAS‐2.
Results
The summary estimates of sensitivity and specificity of core needle biopsy for diagnosis of malignancy were 96% (95% confidence interval CI = 87–99) and 100% (95% CI = 84–100), respectively. There was no significant heterogeneity in accuracy between studies. The quality of included studies was high, with low risk of verification bias. The risk of hematoma was 1.6% per procedure.
Conclusions
Core needle biopsy has high sensitivity and specificity, and has low risk of complications. There is no significant variation in accuracy between study locations. Laryngoscope, 124:695–700, 2014
Aims
Secretory carcinoma (SC) of the salivary gland typically harbours ETV6–NTRK3 fusion, which can be utilised clinically to assist with diagnosis. Pan‐Trk inhibitor therapy has demonstrated drastic ...responses in patients with NTRK‐translocated tumours, including SC. Pan‐Trk immunohistochemistry (IHC) is emerging as a sensitive and specific tool for detecting NTRK1, NTRK2 and NTRK3 fusions in various cancers. We aimed to establish the specificity and sensitivity of pan‐Trk IHC in diagnosing SC and detecting ETV6–NTRK3 fusion. A literature review on the utility of pan‐Trk IHC was conducted.
Methods and results
Pan‐Trk IHC was performed on 83 salivary gland neoplasms (29 SCs and 54 non‐SCs). ETV6–NTRK3 fusion status was established in 25 cases. With any staining (nuclear or cytoplasmic) as a positive threshold, the sensitivity and specificity of pan‐Trk IHC were 90% and 70% in diagnosing SC, and 100% and 0% in detecting NTRK3 fusion. When only pan‐Trk nuclear staining was considered as positive, the sensitivity and specificity were 69% and 100% in diagnosing SC, and 92% and 100% in detecting NTRK3 fusion.
Conclusions
Nuclear pan‐Trk IHC is highly specific for SC diagnosis, with a specificity approaching 100%, making it a useful and precise diagnostic tool for differentiating SC from its histological mimics. On the other hand, any pan‐Trk staining (nuclear or cytoplasmic) is highly sensitive for SC, and can serve as an attractive, cheap, fast and accessible screening tool for selecting patients to undergo confirmative molecular testing for clinical trials using TRK inhibitors.
Introduction
Fine needle aspiration (FNA) has been widely utilized in establishing the nature of salivary gland lesions and guiding the clinical management. This study aimed to determine the accuracy ...of FNA in detecting salivary gland neoplasms and malignancies, employing the “Milan System for Reporting Salivary Gland Cytopathology” (MSRSGC).
Method
A systematic search was conducted. The data on FNA and histologic diagnosis were extracted and categorized based on the MSRSGC and risk of malignancy (ROM) was calculated. The risk of publication bias and level of heterogeneity were evaluated. A mixed‐effects model was used to estimate FNA accuracy. Meta‐regression was conducted to assess the potential effect of different variables on FNA accuracy.
Results
Ninety‐two studies with a total of 16 456 FNA with surgical follow‐up were included. ROM was estimated as 17%, 8%, 34%, 4%, 42%, 58%, and 91%, in nondiagnostic, nonneoplastic, atypia of undetermined significance, benign neoplasm, salivary gland neoplasm of uncertain malignant potential, suspicious for malignancy, and malignant groups, respectively. High level of heterogeneity was detected (P‐value <.001). Including cases with definite FNA diagnosis of neoplasm or malignancy, summary estimates of FNA sensitivity, specificity, diagnostic odds ratio, and positive and negative likelihood ratio in detecting neoplasms and malignancies were 96.9%, 95.3%, 636.8, 20.5, and 0.03, and 80.5%, 97.9%, 189.5, 37.8, and 0.2, respectively. Meta‐regression showed several variables significantly impacting FNA accuracy; however, subgroup analysis did not reduce the level of heterogeneity.
Conclusion
FNA can be used as a reliable diagnostic tool in the preoperative evaluation and management of salivary glands lesions. Concise of is using Milan system for reporting salivary gland FNA could increase FNA reliability, facilitate communication, and improve patient care.
Aging-related salivary dysfunction commonly induces the poor oral health, including decreased saliva flow and dental caries. Although the clinical significance of the salivary glands is well-known, ...the complex metabolic pathways contributing to the aging-dysfunction process are only beginning to be uncovered. Here, we provide a comprehensive overview of the metabolic changes in aging-mediated salivary gland dysfunction as a key aspect of oral physiology. Several metabolic neuropeptides or hormones are involved in causing or contributing to salivary gland dysfunction, including hyposalivation and age-related diseases. Thus, aging-related metabolism holds promise for early diagnosis, increased choice of therapy and the identification of new metabolic pathways that could potentially be targeted in salivary gland dysfunction.
Salivary gland stones, or sialoliths, are the most common cause of the obstruction of salivary glands. The mechanism behind the formation of sialoliths has been elusive. Symptomatic sialolithiasis ...has a prevalence of 0.45% in the general population, is characterized by recurrent painful periprandial swelling of the affected gland, and often results in sialadenitis with the need for surgical intervention. Here, we show by the use of immunohistochemistry, immunofluorescence, computed tomography (CT) scans and reconstructions, special dye techniques, bacterial genotyping, and enzyme activity analyses that neutrophil extracellular traps (NETs) initiate the formation and growth of sialoliths in humans. The deposition of neutrophil granulocyte extracellular DNA around small crystals results in the dense aggregation of the latter, and the subsequent mineralization creates alternating layers of dense mineral, which are predominantly calcium salt deposits and DNA. The further agglomeration and appositional growth of these structures promotes the development of macroscopic sialoliths that finally occlude the efferent ducts of the salivary glands, causing clinical symptoms and salivary gland dysfunction. These findings provide an entirely novel insight into the mechanism of sialolithogenesis, in which an immune system-mediated response essentially participates in the physicochemical process of concrement formation and growth.
Salivary gland tumors are relatively rare and morphologically diverse and heterogeneous tumors; therefore, histogenesis-based tumor markers are sorely needed to aid in diagnosing and determining the ...cell type of origin. SRY-related HMG-box 10 (SOX10) protein is a transcription factor known to be crucial in the specification of the neural crest and maintenance of Schwann cells and melanocytes. In addition, positive expression has also been implicated in the major salivary gland. Here, we examined SOX10 expression in various salivary gland tumors to correlate this expression with myoepithelial markers. Overall, 76 malignant and 14 benign tumors were examined. SOX10 expression clearly delineated two distinct subtypes of human salivary gland tumors; acinic cell carcinomas, adenoid cystic carcinomas, epithelial-myoepithelial carcinomas, myoepithelial carcinomas, and pleomorphic adenomas, including the pleomorphic adenoma component of carcinoma, were SOX10 positive, while salivary duct carcinomas, mucoepidermoid carcinomas, an oncocytic carcinoma, Oncocytomas, and Warthin tumors were SOX10 negative. Also, SOX10 was expressed in solid-type or non-specific morphology salivary gland tumors, but was not expressed in poorly differentiated squamous cell carcinomas. In normal human salivary gland tissue, SOX10 expression was specific to the nuclei of acini and both luminal and abluminal cells of intercalated ducts but not in other sites. Moreover, the murine model suggested that SOX10 continued to be expressed from the developmental stage to adulthood in the acinar and both luminal and abluminal intercalated ducts in the major salivary gland. Thus, SOX10 is a novel marker for diagnosing and understanding the histogenesis of salivary gland tumors.
Background
Fine‐needle aspiration cytology (FNAC) is a noninvasive, safe, cost‐effective, diagnostic procedure for the evaluation of salivary gland lesions and the selection of patients for surgery. ...The aim of this study was to analyze the risk of malignancy (ROM) according to the Milan reporting system of salivary gland FNA specimens using a liquid‐based cytology (LBC) technique.
Methods
The cytological diagnosis of 459 cases between 2014 and 2017 was revised according to the Milan reporting system. The FNAC results of 129 cases with a histological diagnosis were compared with respect to the final diagnosis. The ROM for each category calculated.
Results
The ROM was high in the indeterminate and malignant categories, while the ROM in the benign neoplasm category was low. Sensitivity and specificity analyzed in two different ways were 95.1% and 88.8%, 81%, and 77.7%, respectively.
Conclusions
When salivary gland lesions are evaluated together with clinical and radiological data, the LBC technique can be applied to salivary gland specimens based on the high diagnostic sensitivity and specificity in liquid‐based samples reported according to the Milan system.
Organoids generated from pluripotent stem cells are used in the development of organ replacement regenerative therapy by recapitulating the process of organogenesis. These processes are strictly ...regulated by morphogen signalling and transcriptional networks. However, the precise transcription factors involved in the organogenesis of exocrine glands, including salivary glands, remain unknown. Here, we identify a specific combination of two transcription factors (Sox9 and Foxc1) responsible for the differentiation of mouse embryonic stem cell-derived oral ectoderm into the salivary gland rudiment in an organoid culture system. Following orthotopic transplantation into mice whose salivary glands had been removed, the induced salivary gland rudiment not only showed a similar morphology and gene expression profile to those of the embryonic salivary gland rudiment of normal mice but also exhibited characteristics of mature salivary glands, including saliva secretion. This study suggests that exocrine glands can be induced from pluripotent stem cells for organ replacement regenerative therapy.
•Molecular profiling is changing treatment landscape of salivary gland carcinomas.•HER2 and androgen receptors are well studied with encouraging data.•NTRK, HRAS, and BRAF will be the new targetable ...alterations.•NOTCH and PI3K pathways are under investigation.
Salivary Gland carcinomas (SGCs) are rare tumors accounting for less than 1% of all cancers with 21 histologically diverse subtypes. The rarity of the disease presents a challenge for clinicians to conduct large size randomized controlled trials. Surgery and radiotherapy remain the only curative treatment for localized disease, whereas treatments for recurrent and metastatic disease remain more challenging with very disappointing results for chemotherapy.
The different histological subtypes harbor various genetic alterations, some pathognomonic with a diagnostic impact for pathologists in confirming a difficult diagnosis and others with therapeutic implications regardless of the histologic subtype. Current international guidelines urge pathologists to identify androgen receptor status, HER-2 expression that could be determined by immunohistochemistry, and TRK status in patients with non-adenoid cystic salivary gland carcinoma that are eligible to initiate a systemic treatment, in order to offer them available targeted therapies or refer them to clinical trials based on their mutational profile. A more advanced molecular profiling by next generation sequencing would offer a larger panel of molecular alterations with possible therapeutic implications such as NOTCH, PI3K, BRAF, MYB, and EGFR. In the following review, we present the most common genetic alterations in SGCs as well as actionable mutations with the latest available data on therapeutic options and upcoming clinical trials.
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