Salivary Gland Disorders: Rapid Evidence Review.

The major salivary glands are the paired parotid, submandibular, and sublingual glands. Salivary gland disorders can affect the glandular tissue or its excretory system. The parotid glands are the largest and produce aqueous serous secretions that are less immunogenic. They are more susceptible to infections and neoplasms. The submandibular glands produce mucinous secretions that are high in calcium and phosphate salts through a long submandibular duct that flows against gravity. The submandibular glands are responsible for more than 80% of salivary stones. Sialadenitis can be acute or chronic and caused by bacterial, viral, and obstructive etiologies; the most common bacteria is Staphylococcus aureus. The most common viral etiologies in children are mumps (globally) and juvenile recurrent parotitis (in vaccinated populations). Sialadenosis is a chronic asymptomatic enlargement of the salivary glands due to systemic disease. Sialolithiasis causes up to 50% of salivary gland disorders. It is associated with salivary stasis and inflammation caused by dehydration, malnutrition, medications, or chronic illness. Obstruction is also caused by trauma, stenosis, and mucoceles. Neoplasms are rare and typically benign, but they warrant referral and imaging with ultrasonography, computed tomography, or magnetic resonance sialography. Most disorders are managed with conservative measures by treating the underlying etiology, optimizing predisposing factors, controlling pain, and increasing salivary flow with sialagogues, hydration, massage, warm compresses, oral hygiene, and medication adjustment. Sialendoscopy is a gland-sparing technique that can treat obstructive and nonobstructive disorders. (Am Fam Physician. 2024;109(6):550-559.

Reconstruction of Sjögren's syndrome-like sialadenitis by a defined disease specific gut-reactive single TCR and an autoantibody.

Lymphocytes such as CD4+ T cells and B cells mainly infiltrate the salivary glands; however, the precise roles and targets of autoreactive T cells and autoantibodies in the pathogenesis of Sjögren's Syndrome (SS) remain unclear. This study was designed to clarify the role of autoreactive T cells and autoantibodies at the single-cell level involved in the development of sialadenitis. Infiltrated CD4+ T and B cells in the salivary glands of a mouse model resembling SS were single-cell-sorted, and their T cell receptor (TCR) and B cell receptor (BCR) sequences were analyzed. The predominant TCR and BCR clonotypes were reconstituted in vitro, and their pathogenicity was evaluated by transferring reconstituted TCR-expressing CD4+ T cells into Rag2-/- mice and administering recombinant IgG in vivo. The reconstitution of Th17 cells expressing TCR (#G) in Rag2-/- mice resulted in the infiltration of T cells into the salivary glands and development of sialadenitis, while an autoantibody (IgGr22) was observed to promote the proliferation of pathogenic T cells. IgGr22 specifically recognizes double-stranded RNA (dsRNA) and induces the activation of dendritic cells, thereby enhancing the expression of IFN signature and inflammatory genes. TCR#G recognizes antigens related to the gut microbiota. Antibiotic treatment severely reduces the activation of TCR#G-expressing Th17 cells and suppresses sialadenitis development. These data suggest that the anti-dsRNA antibodies and, TCR recognizing the gut microbiota involved in the development of sialadenitis like SS. Thus, our model provides a novel strategy for defining the roles of autoreactive TCR and autoantibodies in the development and pathogenesis of SS.

Chronic Sclerosing Sialadenitis of the Submandibular Gland and its Histopathological Spectrum in the IgG4-Related Disease: a Series of 17 Cases.

PURPOSE: This study aimed to characterize the histopathological immunohistochemical features of chronic sclerosing sialadenitis, emphasizing the IgG4-related disease. METHODS: Seventeen cases of chronic sclerosing sialoadenitis were examined for histopathological aspects, (inflammation, fibrosis, glandular parenchyma, and lymphoid follicles) and immunohistochemistry (BCL2, CD3, CD20, CD34, CD163, p63, cyclin D1, mast cell, SMA, S100A4, IgG, and IgG4) which were scored. IgG4-related disease features were investigated. Demographic and clinical data were also collected. RESULTS: Males predominated (10:7), with an average lesion size of 3.9 cm. Common histopathological findings included reduced acinar parenchyma, lymphoid follicle formation, and ductular proliferation. CD3-positive T lymphocytes and CD34- and SMA-positive stromal fibroblasts were abundant. Nine cases (53%) showed sialoliths and three cases met the criteria for IgG4-related disease. CONCLUSION: CSS of the submandibular gland represents a reactive pattern rather than IgG4-RD as only 3 cases seemed to be related to IgG4-RD. The immunohistochemical profile revealed an abundant population of CD3-positive T lymphocytes, as opposed to regulatory proteins such as cyclin D1, demonstrating that populations of CD34- and SMA-positive stromal fibroblasts contribute to the fibrosis characteristic of CSS. In addition, our results provide a comprehensive insight into the study of CSS and its relationship with IgG4-RD.

Chronic sclerosing sialadenitis of the bilateral submandibular glands in childhood - a diagnostic dilemma.

Chronic sclerosing sialadenitis (CSS), currently included in the group of immunoglobulin G4 (IgG4)-related diseases, is an under-recognized inflammatory lesion that afflicts mostly the submandibular gland of 40-60 years adults. To our knowledge, only one case of CSS located in the submandibular gland has been reported in childhood to date. We present a case of CSS in a 5-year-old male child. He presented with bilateral submandibular swellings that clinically resembled discrete lumps, suspected to be tumors. The completely resected tumors composed predominantly of dense lymphoplasmacytic inflammatory infiltrate rich in IgG4-positive cells [77-90 IgG(+) cells per high-power field; IgG4(+)∕IgG(+) cells ratio of 42.77%]. We discuss the peculiarities of this case, and we also review the literature on CSS.

Development of Presumptive Sialadenosis Following a Chronic Oropharyngeal Stick Injury in a Dog.

A 3 yr old female spayed Labrador retriever was referred for the treatment of a chronic oropharyngeal stick injury. After computed tomography scan evaluation, the cervical area was explored surgically and a right-sided cervical abscess that contained a wooden stick was identified adjacent to the vagosympathetic trunk and carotid artery. The ipsilateral mandibular salivary gland was resected concurrently given its abnormal appearance, and histology confirmed inflammation and necrosis of the gland, which was suspected to be due to direct trauma from the foreign body. The clinical signs initially improved but then recurred, and a follow-up computed tomography scan was suggestive of sialadenosis or sialadenitis in the right parotid, zygomatic, and molar salivary glands. A presumptive diagnosis of sialadenosis was made and a course of phenobarbital was initiated. The clinical signs resolved completely within a few days, and there was no recurrence several months after termination of the phenobarbital treatment. This is the first case report of presumptive sialadenosis in a dog as a suspected complication of an oropharyngeal stick injury. Informed consent was obtained from the owner of the dog and the patient was managed according to contemporary standards of care.

IgG4-related disease: an update on pathology and diagnostic criteria with a focus on salivary gland manifestations.

Immunoglobulin G4-related disease (IgG4-RD) is a multi-organ disorder characterized by a highly variable clinical presentation depending on the affected organ/s, extent of tumefactive fibroinflammatory lesions, and associated functional impairment. The disease pursues a chronic, relapsing, often asymptomatic course and hence may pose a significant diagnostic challenge. Diagnostic delay can lead to progressive fibrosis and irreversible organ damage resulting into significant morbidity and even mortality. Given its broad clinical spectrum, physicians of all specialties may be the first clinicians facing this diagnostic challenge. Outside the pancreatobiliary system, the head and neck represents the major site of IgG4-RD with variable organ-specific diffuse or mass-forming lesions. In up to 75% of cases, elevated serum IgG4 levels are observed, but this figure possibly underestimates the fraction of seronegative cases, as the disease manifestations may present metachronously with significant intervals. Together with negative serology, this can lead to misdiagnosis of seronegative cases. A standardized nomenclature and diagnostic criteria for IgG4-RD were established in 2012 and revised in 2020 facilitating scientific research and expanding the range of diseases associated with IgG4 abnormalities. In addition to orbital pseudotumor, dacryoadenitis, Riedel thyroiditis, sinonasal manifestations, and rare miscellaneous conditions, IgG4-related sialadenitis is one of the most frequent presentations in the head and neck region. However, controversy still exists regarding the relationship between sialadenitis and IgG4-RD. This review focuses on the clinicopathological features of IgG4-related sialadenitis and its contemporary diagnostic criteria.

Rare encounter: facial vein thrombosis and thrombophlebitis as a complication of acute submandibular sialadenitis.

Thrombosis and thrombophlebitis of the facial vein represent exceptionally rare diagnoses, particularly when occurring as complications of acute sialadenitis of the submandibular gland. This case report details the experience of a middle-aged man initially presenting at a tertiary care ear, nose and throat department with right submandibular gland sialadenitis. Despite initiating outpatient treatment involving oral antibiotics and sialagogues, the patient returned after a week with persistent and worsening pain, accompanied by swelling of the right submandibular gland and cheek. Using ultrasound, the accurate diagnosis was promptly identified, revealing thrombosis in the facial vein.The patient underwent a comprehensive treatment regimen involving anticoagulation and intravenous antibiotics. With a subsequent reduction in pain and swelling, the patient was discharged, continuing oral anticoagulation and antibiotics. Outpatient follow-up revealed a complete recovery 3 weeks later. This case underscores the importance of timely and precise diagnostic measures in managing rare complications associated with sialadenitis.

Improvement of active salivary gland ultrasonography findings in Sjögren's syndrome in response to short-term glucocorticoid treatment: A case report and review of the literature.

Salivary gland ultrasonography is a non-invasive imaging technique that helps in the diagnosis and assessment of disease activity in Sjögren's syndrome. However, it remains unclear whether the salivary gland ultrasonography findings are reversible in response to treatment. We present a case of a woman in her 20s who presented with parotid swelling and pain lasting for 3 months. The patient was diagnosed with anti-SS-A antibody-positive Sjögren's syndrome with active sialadenitis, and short-term glucocorticoid treatment resulted in resolution of clinical symptoms and improvement of salivary gland ultrasonography findings by the Outcome Measures in Rheumatology Clinical Trials scoring system. Notably, the anechoic/hypoechoic foci and vascular signals in the parotid and submandibular glands were reduced after treatment. Furthermore, peak systolic blood flow velocity of the facial artery entering the submandibular gland was decreased. Our case highlights that the findings of 'inflammatory' structural changes and vascularisation on salivary gland ultrasonography, including the Outcome Measures in Rheumatology Clinical Trials scoring system, reflect the disease active of Sjögren's syndrome and are reversible with treatment. Salivary gland ultrasonography has the potential to be a useful tool for monitoring treatment response and stratifying patients by disease activity in Sjögren's syndrome; therefore, further research is needed on the relationship of salivary gland ultrasonography findings with the pathophysiological mechanisms of sialadenitis and long-term clinical outcomes.

A nomogram based on ultrasound scoring system for differentiating between immunoglobulin G4-related sialadenitis and primary Sjögren syndrome.

OBJECTIVES: Accurate distinguishing between immunoglobulin G4-related sialadenitis (IgG4-RS) and primary Sjögren syndrome (pSS) is crucial due to their different treatment approaches. This study aimed to construct and validate a nomogram based on the ultrasound (US) scoring system for the differentiation of IgG4-RS and pSS. METHODS: A total of 193 patients with a clinical diagnosis of IgG4-RS or pSS treated at our institution were enrolled in the training cohort (n = 135; IgG4-RS = 28, pSS = 107) and the validation cohort (n = 58; IgG4-RS = 15, pSS = 43). The least absolute shrinkage and selection operator regression algorithm was utilized to screen the most optimal clinical features and US scoring parameters. A model for the differential diagnosis of IgG4-RS or pSS was built using logistic regression and visualized as a nomogram. The performance levels of the nomogram model were evaluated and validated in both the training and validation cohorts. RESULTS: The nomogram incorporating clinical features and US scoring parameters showed better predictive value in differentiating IgG4-RS from pSS, with the area under the curves of 0.947 and 0.958 for the training cohort and the validation cohort, respectively. Decision curve analysis demonstrated that the nomogram was clinically useful. CONCLUSIONS: A nomogram based on the US scoring system showed favourable predictive efficacy in differentiating IgG4-RS from pSS. It has the potential to aid in clinical decision-making.

Prophylactic effect of pilocarpine on acute sialadenitis following radioactive iodine therapy in thyroid cancer patients.

Purpose: Our aim was to evaluate the effect of prophylactic pilocarpine on acute salivary symptoms after radioactive iodine (RAI) therapy in patients with differentiated thyroid cancer. Methods: We enrolled 88 patients (76 women and 12 men; mean age: 47 years; range: 20-74 years) with differentiated thyroid cancer who received RAI. Patients were divided into pilocarpine (51 patients) and control (37 patients) groups. Pilocarpine was given orally, at a dose of 5 mg three times a day, from 2 days before and 12 days after RAI therapy. Symptoms and signs of acute sialadenitis within 3 months of RAI therapy were recorded. Results: During the 3 months after RAI therapy, 13 of the 88 patients (14.7%) developed acute symptomatic sialadenitis (swelling or pain of salivary glands). Acute salivary symptoms were reported by 4 (7.8%) and 9 (24.3%) patients in the pilocarpine and control groups, respectively. Acute salivary symptoms were less frequent in the pilocarpine than control group (p = 0.04), but did not differ by age, sex, or RAI dose (p = 0.3357, p = 0.428, and p = 0.2792). Conclusions: Pilocarpine reduced the likelihood of acute sialadenitis after RAI therapy in patients with differentiated thyroid cancer.

Suture Stenting After Sialendoscopy: A Novel Technique That Reduces Risk of Recurrent Parotitis.

OBJECTIVE: Chronic sialadenitis is associated with decreased quality of life and recurrent infections. While sialendoscopy with stenting is effective in relieving symptoms of sialadenitis, currently available stents are rigid and poorly tolerated by patients, leading to early removal and potential for adverse scarring. This study examines whether sutures can be used as a stenting material to improve patient comfort and reduce recurrence risk. METHODS: This is a retrospective cohort study of a consecutive series of adult patients with chronic sialadenitis undergoing sialendoscopy with or without suture stenting. Data were collected between 2014 and 2018 with a 3-year follow-up period ending in 2021. The primary outcome measure was recurrence of sialadenitis within 3 years of surgery. Secondary outcomes were stent dislodgement and patient-reported discomfort. RESULTS: We included 63 patients with parotid sialadenitis of whom 28 underwent suture stenting and 35 did not receive stenting after sialendoscopy. Stents were well tolerated, with a mean duration of 34.5 days, and only 2 of 28 stents (7.1%) accidentally dislodged within the first week. Suture stenting significantly reduced symptom recurrence after sialendoscopy (OR = 0.09, 95% CI 0.02-0.45, p = 0.003; 3-year sialadenitis recurrence rate: 7.1% vs. 45.7%, p = 0.005). Cox multivariate regression for clinicodemographic variables showed an HR of 0.04 (95% CI 0.01-0.19, p < 0.001) for the risk of symptom recurrence. CONCLUSIONS AND RELEVANCE: Suture stenting after sialendoscopy is low cost, available across all institutions, well-tolerated by patients, and highly efficacious in reducing risk of recurrent sialadenitis after sialendoscopy. LEVEL OF EVIDENCE: 3 Laryngoscope, 134:614-621, 2024.

Sialendoscopy Findings Associated with Positive Minor Salivary Gland Biopsy.

OBJECTIVES: To determine the sialendoscopy findings associated with positive findings on minor salivary gland biopsy. STUDY DESIGN: Single-center retrospective study. METHODS: Patients ≥18 years old who underwent sialendoscopy from 2016 to 2022 and were evaluated for SS via labial minor salivary gland biopsy. Biopsy positive and negative patients were compared on the primary outcome measure of sialendoscopy findings. Data were abstracted from the sialendoscopy operative notes and included involved gland, location of ductal pathology, and the presence of scarring, stenosis, mucus plugs, webs, and dilations. Additional characteristics included demographics, presenting symptoms, caffeine or tobacco, use of drying medications, and need for additional treatments. RESULTS: The final cohorts included 22 biopsy positive and 21 biopsy negative patients with a total of 42 glands in the biopsy positive and 37 glands in the biopsy negative groups. Biopsy positive patients were found to require dilation at the hilum and distal duct at significantly higher rates than biopsy negative patients (p < 0.0001). However, there was no statistical difference in scarring, stenosis severity, mucus, webs, or dilations between each group. CONCLUSION: The outcomes of this study suggest that there are no distinct sialendoscopy findings associated with biopsy positive patients. The presence of significant distal stenosis on sialendoscopy may be associated with positive minor salivary biopsy. Other endoscopic parameters are likely more consistent with non-specific chronic sialadenitis. LEVEL OF EVIDENCE: 3 Laryngoscope, 134:1183-1189, 2024.

Salivary Mucinous Adenocarcinoma Masquerading as Chronic Submandibular Sialolithiasis.

A patient with chronic submandibular sialolithiasis underwent conservative treatment with appropriate imaging and multiple biopsies that continually revealed chronic inflammation. Due to continued symptoms, the patient underwent eventual excision and finaly pathology revealed salivary mucinous adenocarcinoma, which is a rare and poorly understood salivary malignancy. Persistent diagnostic workup and a high suspicion for salivary gland lesions is important for appropriate diagnosis and treatment. More attention and research on this specific entity can help future clinicians better diagnose and treat patients with a similar presentation. Laryngoscope, 134:2258-2261, 2024.

Extraction of characteristic serum microRNAs and prediction of target genes in IgG4-related dacryoadenitis and sialadenitis.

OBJECTIVES: To identify the specific microRNAs (miRNAs) in IgG4-related dacryoadenitis and sialadenitis (IgG4-DS) and predict the targeted genes. METHODS: miRNAs in the serum of nine patients with IgG4-DS, three patients with primary Sjögren's syndrome, and three healthy controls were analysed using the human miRNA chip, and miRNAs that exhibited significant fluctuation in expression in IgG4-DS patients were extracted. The respective target genes were predicted using an existing database, and expression of the target genes was evaluated in actual submandibular gland tissues affected by IgG4-DS. RESULTS: Serum miR-125a-3p and miR-125b-1-3p levels were elevated in IgG4-DS. Six candidate target genes (glypican 4, forkhead box C1, protein tyrosine phosphatase non-receptor type 3, hydroxycarboxylic acid receptor 1, major facilitator superfamily domain containing 11, and tumour-associated calcium signal transducer 2) were downregulated in the affected submandibular gland tissue. CONCLUSION: Overexpression of miR-125a-3p and miR-125b-1-3p is a hallmark of IgG4-DS. These miRNAs appear to be involved in the pathogenesis of IgG4-DS.

Value of Quantitative Salivary Gland SPECT/CT for the Detection of Saliva Leakage.

ABSTRACT: A 47-year-old woman presented to our emergency department with a 10-day history of pain, halitosis, and swelling below the left jaw. The patient was diagnosed with left sialadenitis and left submandibular abscess by tissue biopsy. An otolaryngologist performed transcervical incision and drainage of the abscess 1 day after admission. Postoperatively, the patient complained of a sensation of fluid leakage from the mouth, and a continuous purulent discharge was observed. One month postoperatively, a salivary gland scan and SPECT/CT were performed to investigate the sialorrhea and the cause of the discharge. Salivary gland SPECT/CT images localized the saliva leakage site.

Histopathologic findings in ointment pseudo-cheilitis: An alert to dermatopathologists.

Ointment pseudo-cheilitis is a recently recognized distinctive type of self-induced cheilitis. Lesions consist of a variable amount of crusts adhered to the vermilion. These crusts consist of dried saliva and dead cells mixed with applied medications attached to the lip surface. Patients are typically severely anxious or depressed; the condition impacts quality of life. Ointment pseudo-cheilitis is frequently misdiagnosed as exfoliative cheilitis or cheilitis glandularis. Biopsy reports are often non-revealing because there are no established histopathological criteria for this disease, and clinicians usually do not formulate the correct diagnostic hypothesis. Here, we present the histopathological findings of four cases of ointment pseudo-cheilitis. The most consistent finding was the presence of laminated parakeratotic material detached from the epithelium in biopsies that are devoid of other significant diagnostic changes. This material at the lip surface possibly represents physiologic labial desquamation mixed with dried saliva and applied medication. With this report, we intend to alert dermatopathologists to the diagnosis of ointment pseudo-cheilitis if they receive biopsies from patients who present clinically exuberant labial lesions that show only minimal histopathological changes.

Venous malformation phleboliths mimicking submandibular sialadenitis in children.

To report one paediatric patient who presented with a rare venous vascular malformation as a mass in the left submandibular region with a clinical picture compatible with sialadenitis. Phleboliths are a specific feature of venous malformations due to venous stasis and may mimic sialoliths on various imaging modalities. Thus venous malformations are often misdiagnosed as sialadenitis due to sialolithiasis. Sialoliths are extremely rare in paediatric patients. In an early adolescent presenting with a submandibular mass and suspected sialadenitis arising from sialoliths, a detailed history, clinical examination and careful review of the radiological findings will allow the diagnosis of venous vascular malformation and provide the complete surgical resection. Our patient was initially referred with a presumed diagnosis of submandibular sialadenitis, and instead a venous malformation with phlebolith was diagnosed.

Is the neutrophil-to-lymphocyte ratio a marker for differentiating between benign and malignant submandibular gland masses?

OBJECTIVE: This study aimed to evaluate the effect of the neutrophil-to-lymphocyte ratio on the differentiation of benign and malignant masses in the submandibular triangle. METHODS: We retrospectively evaluated 48 patients who underwent surgery for submandibular gland masses between January 2013 and February 2023. The patient's age, gender, preoperative complete blood count and imaging findings, postoperative histopathological diagnosis, and hemogram data were analysed. Patients were evaluated according to their postoperative histopathological diagnoses and categorised into four main groups: sialolithiasis, sialadenitis, benign tumours, and malignant tumours. Benign submandibular gland disease formations were evaluated under group B and malignant tumour formations under group M. RESULTS: A preoperative fine needle aspiration biopsy was performed on 19 patients due to sialadenitis, pleomorphic adenoma, and malignant diseases other than sialolithiasis. One patient died among the patients with malignant disease and the remaining 7 patients were compared with the benign group of 40 patients regarding preoperative and postoperative neutrophil-to-lymphocyte ratio. In the benign group, the neutrophil-to-lymphocyte ratio was 2.64 preoperatively and decreased to 2.34 in the first postoperative year. The preoperative neutrophil-to-lymphocyte ratio decreased from 4.79 to 1.77 postoperatively in the malignant group. A statistically significant difference was observed (p<0.05). CONCLUSION: This is the first study to demonstrate that the neutrophil-to-lymphocyte ratio can be used as a biomarker in submandibular gland masses and has prognostic significance in malignant masses. In addition to fine needle aspiration biopsy results, neutrophil-to-lymphocyte ratio can be used as a biomarker.

Network pharmacology identifies the inhibitory effect of Yiqiyangyinquyu prescription on salivary gland inflammation in Sjögren's syndrome.

This study aimed to explore the mode of action of Yiqiyangyinquyu prescription (YP) against Sjögren's syndrome (SS) by combining network pharmacology with molecular docking techniques. YP's active components and target proteins were identified using the BATMAN-traditional Chinese medicine database. Concurrently, targets associated with SS were extracted from databases, including Genecards, Online Mendelian Inheritance in Man, and Therapeutic Target Database. The standard targets were then imported into the STRING database to construct a protein-protein interaction network. We then conducted gene ontology and Kyoto encyclopedia of genes and genomes enrichment analyses, which were succeeded by molecular docking studies to validate core active components and key targets. Finally, in vitro experiments and molecular dynamics simulation were conducted to substantiate the therapeutic efficacy of YP in treating SS. A total of 206 intersection targets and 46 active compounds were identified. Gene ontology analysis unveiled that YP targets were primarily enriched in cellular responses to chemical stress, inflammation, and cell proliferation. Key enriched signaling pathways encompassed the interleukin 17, hypoxia-inducible factor-1, tumor necrosis factor (TNF-α), and advanced glycation end products-receptor for AGEs (AGE-RAGE) signaling pathways. Molecular docking results demonstrated high-affinity between neotanshinone C, tanshiquinone B, miltionone I, TNF-α, interleukin 1 beta (IL-1ß), and interleukin 6 (IL-6). Noteworthy, TNF-α, considered the most important gene in YP against SS, binds to YP most stably, which was further validated by molecular dynamics simulation. In vitro experiments confirmed YP's capacity to reduce TNF-α, IL-1ß, and IL-6 expression, effectively alleviating SS-related inflammation. YP demonstrated a significant anti-inflammatory effect by suppressing inflammatory cytokines (TNF-α, IL-6, and IL-1ß), providing experimental evidence for its clinical application in treating SS.