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Introduction: The complex nature of Sjögren's Disease (SjD) necessitates a comprehensive and patient-centered approach in both diagnosis and management. This narrative review emphasizes the need for a holistic understanding of the connection between salivary gland inflammation and oral symptoms in SjD., Areas Covered: The intricate relationship between salivary gland inflammation and dry mouth is explored, highlighting the variability in associations reported in studies. The association of the severity of xerostomia and degree of inflammation is also discussed. The frequent presence of recurrent sialadenitis in SjD further accentuates the connection of compromised salivary gland function and inflammation. The review additionally discusses local inflammatory factors assessed through salivary gland biopsies, which could potentially serve as predictors for lymphoma development in SjD. Insights into compromised quality of life and hypercoagulable state and their association with salivary gland inflammations are provided. Advancements in noninvasive imaging techniques, particularly salivary gland ultrasonography and color Doppler ultrasound, offer promising avenues for noninvasive assessment of inflammation., Expert Opinion: There is a need for longitudinal studies to unravel the connections between salivary gland inflammation and oral symptoms. This will enhance management strategies and optimize treatment outcomes for SjD patients.

Introduction: Salivary gland dysfunction, often resulting from salivary gland obstruction-induced inflammation, is a prevalent condition. Corticosteroid, known for its anti-inflammatory and immunomodulatory properties, is commonly prescribed in clinics. This study investigates the therapeutic implications and potential side effects of dexamethasone on obstructive sialadenitis recovery using duct ligation mice and salivary gland organoid models., Methods: Functional and pathological changes were assessed after administering dexamethasone to the duct following deligation 2 weeks after maintaining ligation of the mouse submandibular duct. Additionally, lipopolysaccharide- and tumor necrosis factor-induced salivary gland organoid inflammation models were established to investigate the effects and underlying mechanisms of action of dexamethasone., Results: Dexamethasone administration facilitated SG function restoration, by increasing salivary gland weight and saliva volume while reducing saliva lag time. Histological evaluation revealed, reduced acinar cell atrophy and fibrosis with dexamethasone treatment. Additionally, dexamethasone suppressed pro-inflammatory cytokines IL-1β and TNF expression. In a model of inflammation in salivary gland organoids induced by inflammatory substances, dexamethasone restored acinar markers such as AQP5 gene expression levels, while inhibiting pro-inflammatory cytokines TNF and IL6 , as well as chemokines CCL2 , CXCL5 , and CXCL12 induction. Macrophages cultured in inflammatory substance-treated media from salivary gland organoid cultures exhibited pro-inflammatory polarization. However, treatment with dexamethasone shifted them towards an anti-inflammatory phenotype by reducing M1 markers ( Tnf , Il6 , Il1b , and Cd86 ) and elevating M2 markers ( Ym1 , Il10 , Cd163 , and Klf4 ). However, high-dose or prolonged dexamethasone treatment induced acino-ductal metaplasia and had side effects in both in vivo and in vitro models., Conclusions: Our findings suggest the effectiveness of corticosteroids in treating obstructive sialadenitis-induced salivary gland dysfunction by regulating pro-inflammatory cytokines., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Hwang, Cho, Yoon, Seo, Hong and Lim.)

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., (© 2023 The American Laryngological, Rhinological and Otological Society, Inc.)

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., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

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., Competing Interests: Conflicts of interest and sources of funding: none declared., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Diagnosis of SS is a complex task, as no symptom or test is unique to this syndrome. The American-European Consensus Group (AECG 2002) and the American-European classification criteria of 2016 (ACR/EULAR 2016) emerged through a search for consensus. This study aims to assess the prevalence of Sjögren's Syndrome (SS) in patients with Systemic Lupus Erythematosus (SLE), according to AECG 2002 and ACR-EULAR 2016 classifications, as well as clinical and histopathological features in this overlap. To date, there is no study that has evaluated SS in SLE, using the two current criteria., Methods: This cross-sectional study evaluated 237 SLE patients at the outpatient rheumatology clinic between 2016 and 2018. Patients were submitted to a dryness questionnaire, whole unstimulated salivary flow (WUSF), "Ocular Staining Score" (OSS), Schirmer's test I (ST-I), and labial salivary gland biopsy (LSGB)., Results: After verifying inclusion and exclusion criteria, a total of 117 patients were evaluated, with predominance of females (94%) and mixed ethnicity (49.6%). The prevalence of SS was 23% according to AECG 2002 and 35% to ACR-EULAR 2016. Kappa agreement between AECG 2002 and ACR-EULAR 2016 were 0.7 (p < 0.0001). After logistic regression, predictors for SS were: anti/Ro (OR = 17.86, p < 0.05), focal lymphocytic sialadenitis (OR = 3.69, p < 0.05), OSS ≥ 5 (OR = 7.50, p < 0.05), ST I positive (OR = 2.67, p < 0.05), and WUSF ≤ 0.1 mL/min (OR = 4.13, p < 0.05)., Conclusion: The prevalence of SS in SLE was 23% (AECG 2002) and 35% (ACR-EULAR 2016). The presence of glandular dysfunction, focal lymphocytic sialadenitis, and anti/Ro were predictors of SS in SLE. The greatest advantage of the new ACR-EULAR 2016 criteria is to enable an early diagnosis and identify the overlapping of these two diseases. ACR-EULAR 2016 criteria is not yet validated for secondary SS and this study is a pioneer in investigating prevalence based on the new criteria., (© 2023. The Author(s).)

Objectives: To characterise the key epidemiological, clinical, immunological, imaging, and pathological features of the coexistence between sarcoidosis and Sjögren's syndrome (SS)., Methods: All centres included in two large multicentre registries (the Sjögren Syndrome Big Data Consortium and the Sarco-GEAS-SEMI Registry) were contacted searching for potential cases of coexistence between SS and sarcoidosis seen in daily practice. Inclusion criteria were the fulfilment of the current classification criteria both for SS (2016 ACR/EULAR) and sarcoidosis (WASOG). The following features were considered for evaluating a coexisting immunopathological scenario between the two diseases: non-caseating granulomas (NCG), focal lymphocytic sialadenitis (FLS) and positive anti-Ro antibodies., Results: We identified 43 patients who fulfilled the inclusion criteria (38 women, with a mean age of 53 years at diagnosis of SS and of 52 years at diagnosis of sarcoidosis). In 28 (65%) cases, sarcoidosis was diagnosed concomitantly with SS, or during the follow-up of patients with an already diagnosed SS, while in the remaining 15 (35%), SS was diagnosed during the follow-up of an already diagnosed sarcoidosis. Patients in whom sarcoidosis was diagnosed first showed a lower mean age (43.88 vs. 55.67 years, p=0.005) and were less frequently women (73% vs. 96%, p=0.04) in comparison with those in whom sarcoidosis was diagnosed concomitantly with SS, or during the follow-up of an already diagnosed SS. We identified the following immunopathological scenarios: a combination of NCG involving extrasalivary tissues and anti-Ro antibodies in 55% of patients, a coexistence of both pathological scenarios (extrasalivary NCG and FLS in MSGB) in 42% (with positive anti-Ro antibodies in two thirds of cases), and NCG involving salivary glands and anti-Ro antibodies in 3% of cases., Conclusions: We have characterised the largest reported series of patients who fulfilled the current classification criteria for both SS and sarcoidosis. This implies that sarcoidosis (and not just the presence of isolated NCG on salivary gland biopsy) may, like other systemic autoimmune diseases, coexist with SS, and that a sarcoidosis diagnosis does not preclude the development of SS in the future.

Immunoglobulin G4-related disease (IgG4-RD) is a fibroinflammatory condition of unknown etiology. Although the salivary glands are currently considered among the most commonly affected among them, oral and maxillofacial surgeons are generally not familiar with the condition. Enlargement of the major salivary glands may be the first identifiable sign of IgG4-RD. A salivary gland biopsy along with IgG4 serum level assessment may help differentiate IgG4-related sialadenitis (IgG4-RS) from malignancies, infectious diseases, and obstructive conditions. Greater knowledge and higher levels of awareness of IgG4-RS may contribute to the expansion of differential diagnostic and treatment approaches. This case report describes a patient with bilateral submandibular salivary gland swelling who was diagnosed as having IgG4-RS on the basis of the histopathologic findings of a submandibular salivary gland biopsy and subsequent IgG4 levels., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objectives: To estimate the prevalence of extra-glandular lesions in patients with immunoglobulin G4-related sialadenitis (IgG4-RS)., Methods: Six electronic databases (PubMed, EMBASE, Science Direct, Scopus, Web of Science, and China National Knowledge Infrastructure) were systematically searched from the date of inception of each database to March 2021. The Strengthening the Reporting of Observational Studies in Epidemiology statement was used to conduct methodological quality assessment, and a random-effect meta-analysis model was applied to estimate the prevalence. Publication bias was visually assessed using a funnel plot and calculated via Begg's and Egger's tests. The Stata 15 software was used to perform data analysis., Results: A total of 43 articles comprising 1,864 patients with IgG4-RS were considered to be eligible for this study. The pooled prevalence of extra-salivary gland lesions in IgG4-RS was 76.53% with a confidence interval (CI) of (69.39%, 83.04%). A higher prevalence was associated with studies published before or during 2015 (84.38%, CI [74.23%, 92.58%]) than those published after 2015 (68.55%, CI [58.44%, 77.88%]). Lacrimal gland involvement (54.68%, CI [45.61%, 63.60%]) and lymph node swelling (56.96%, CI [48.16%, 65.56%]) were the most frequent lesions., Conclusions: Extra-glandular lesions were common in patients with IgG4-RS. More high-quality prospective studies with less heterogeneity are required to determine the accurate prevalence., (© 2021 Wiley Periodicals LLC.)

Coeliac disease (CD) is a chronic immune-mediated enteropathy triggered by ingestion of gluten. The aim of this study was to investigate if the salivary glands as a component of the mucosal immune system are involved in CD, leading to sialadenitis and salivary gland dysfunction and associated oral manifestations. Twenty patients with CD aged 49.2 (SD 15.5 years) and 20 age- and gender-matched healthy controls underwent an interview regarding general and oral health, serological analysis, a clinical oral examination including bitewing radiographs, Candida smear, assessment of salivary mutans streptococci and lactobacilli levels, unstimulated and chewing-stimulated whole and parotid saliva flow rates, analysis of secretory IgA, and a labial salivary gland biopsy. Xerostomia, mucosal lesions, dry/cracked lips and focal lymphocytic sialadenitis were more prevalent and extensive in patients with CD than in healthy controls. Moreover, the patients had less gingival inflammation and higher whole saliva flow rates than the healthy controls, but did not differ regarding dental health and levels of cariogenic bacteria and Candida. The major salivary gland function appears unaffected, contributing to maintenance of a balanced microbiota and oral health in CD patients. Xerostomia and labial dryness may be related to minor salivary gland inflammation and subsequent impaired mucosal lubrication., (© 2022 Scandinavian Division of the International Association for Dental Research. Published by John Wiley & Sons Ltd.)

Hepatitis C virus (HCV) infection is the most common blood-borne chronic infection in the United States. Chronic lymphocytic sialadenitis and sicca syndrome have been reported in chronic HCV infection. Up to 55% of these patients may have xerostomia; the mechanisms of the xerostomia and salivary gland (SG) hypofunction remain controversial. The objectives of this project are to establish if xerostomia associates with SG and HCV infection and to characterize the structural changes in SG and saliva composition. Eighteen HCV-infected patients with xerostomia were evaluated for SG dysfunction; 6 of these patients (patients 1-6) were further evaluated for SG histopathological changes and changes in saliva composition. The techniques used include clinical and laboratory assessment, SG ultrasonography, histological evaluation, sialochemical and proteomics analysis, and RNA in situ hybridization. All the HCV patients had low saliva flow, chronic sialadenitis, and SG fibrosis and lacked Sjögren syndrome (SS) characteristic autoantibodies. Further evaluation of a subgroup of 6 HCV patients (patients 1-6) demonstrated diffuse lymphocytic infiltrates that are predominantly CD8 + T cells with a significant increase in the number of inflammatory cells. Alcian Blue/periodic acid-Schiff staining showed significant changes in the ratio and intensity of the acinar secretory units of the HCV patients' minor SG. The submandibular glands showed significant ultrasonographic abnormalities in the parenchyma relative to the parotid glands. Significant changes were also observed in the concentration of sodium and mucin 5b. Although no significant correlation was observed between the lymphocytic infiltrates and the years of HCV chronic infection, a positive correlation was observed between HCV RNA-positive epithelial cells and the years of HCV infection. Consistent with the low saliva flow and xerostomia, patients showed changes in several markers of SG acinar and ductal function. Changes in the composition of the saliva suggest that HCV infection can cause xerostomia by mechanisms distinct from SS.

Objective: To evaluate ultrasonic features of the major salivary glands in patients with immunoglobulin G 4 -related sialadenitis (IgG 4 -RS) and to explore the differences between IgG 4 -RS and Sjögren's syndrome (SS)., Method: We conducted the study in 150 patients with IgG 4 -RS and 100 patients with SS. Ultrasonographic variables of the static images of major salivary glands were analysed. An experienced radiologist scored the confidence rating regarding the presence of the characteristic imaging findings using a five-grade rating system. Ultrasonography scores between IgG 4 -RS and SS were compared., Results: The major salivary glands were significantly larger in patients with IgG 4 -RS than in the SS group. The main features of ultrasonography of the salivary glands in IgG 4 -RS were various hypoechoic lesions and increased colour Doppler signalling. In contrast, the major salivary glands in SS exhibited hyperechoic lines and/or spots and obscuration of the gland configuration. The scores of the summarized sonographic characteristics also showed statistically significant differences between the IgG 4 -RS and SS groups., Conclusion: This study revealed different ultrasonic features of the major salivary glands in patients with IgG 4 -RS and SS. The scored sonographic features were helpful in differentiating IgG 4 -RS from SS. Consequently, we suggest that ultrasonography of major salivary glands could be a useful imaging procedure in the evaluation of patients suspected of having IgG 4 -RS.

Although many germinal centers (GCs) have been reported in immunoglobulin (Ig) G4-related disease, the significance of GCs in IgG4-related disease has not received attention. Both T follicular regulatory cells (Tfr), which are regulatory T cells (Treg) in GCs, and T follicular helper cells (Tfh) produce the cytokine interleukin (IL)-10 and regulate GC development. In whole-slide image analysis in surgical specimens using immunohistochemistry, IgG4-related sclerosing sialadenitis (IgG4-SS, n = 17) was characterized by markedly numerous, large, and irregular-shaped GCs with increased IL-10 + cells and Tfr and Tfh in the total area of the salivary gland compared with controls, including patients with chronic sialadenitis (n = 17) and Sjögren syndrome (n = 15). In particular, the central area of GC in IgG4-SS showed a higher Tfr number and Tfr/Tfh ratio than controls. The number of Tfr in the central area was significantly correlated with the number of IgG4 + plasmacytes and the number, size, and irregularity of GCs. In the mantle area, which surrounds GCs, IgG4-SS showed a higher Treg number and Treg/T helper cells (Th) ratio than controls. In IgG4-SS, the Treg/Th ratio was highest in the mantle area outside GCs and the Tfr/Tfh ratio was highest in the central area inside GCs. However, in controls, the Treg/Th ratio gradually decreased from outside to inside GCs. Our findings reveal that the morphological abnormality of GCs and the characteristic localization and altered balance of Treg and Th in the different compartments of inside and outside GCs would be the novel hallmarks of IgG4-SS., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: To develop a novel method to quantify the amount of fibrosis in the salivary gland and to investigate the relationship between fibrosis and specific symptoms associated with Sjögren's syndrome (SS) using this method., Materials and Methods: Paraffin-embedded labial salivary gland (LSG) slides from 20 female SS patients and their clinical and LSG pathology data were obtained from the Sjögren's International Collaborative Clinical Alliance. Relative interstitial fibrosis area (RIFA) in Masson's trichrome-stained LSG sections was quantified from digitally scanned slides and used for correlation analysis. Gene expression levels were assessed by microarray analysis. Core promoter accessibility for RIFA-correlated genes was determined using DNase I hypersensitive sites sequencing analysis., Results: RIFA was significantly correlated with unstimulated whole saliva flow rate in SS patients. Sixteen genes were significantly and positively correlated with RIFA. In a separate analysis, a group of differentially expressed genes was identified by comparing severe and moderate fibrosis groups. This combined set of genes was distinct from differentially expressed genes identified in lung epithelium from idiopathic pulmonary fibrosis patients compared with controls. Single-cell RNA sequencing analysis of salivary glands suggested most of the RIFA-correlated genes are expressed by fibroblasts in the gland and are in a permissive chromatin state., Conclusion: RIFA quantification is a novel method for assessing interstitial fibrosis and the impact of fibrosis on SS symptoms. Loss of gland function may be associated with salivary gland fibrosis, which is likely to be driven by a unique set of genes that are mainly expressed by fibroblasts., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Yin, Pranzatelli, French, Zhang, Warner, Chiorini and NIDCD/NIDCR Genomics and Computational Biology Core.)

Objective: Persistent (≥2 months) major salivary gland enlargement in primary SS (pSS) patients is a well-known sign of possible involvement by B cell lymphoma. The study aimed to evaluate the diagnostic accuracy and safety of US-guided core needle biopsy (CNB) of major salivary glands compared with open surgical biopsy., Methods: Prospective pSS patients (cases) with clinically persistent salivary gland enlargement underwent US-guided CNB and were compared with retrospective pSS patients (controls) submitted to open surgical biopsy. The features analysed were pre-biopsy clinical and laboratory findings, adequacy of the material for histology and diagnostic-rendered and biopsy-related complications (reported by the patient with a questionnaire and clinically verified)., Results: Thirteen cases underwent US-guided CNB: in nine, biopsy was performed on the parotid gland and in four it was performed on the submandibular gland. Sufficient material was obtained for pathological diagnosis in all samples. The final diagnoses were 5 (38.5%) B cell lymphoma, 1 (7.7%) lymphoepithelial sialadenitis, 4 (30.7%) other sialadenitis (granulomatous consistent with sarcoidosis, IgG4-related disease, chronic sclerosing, diffuse chronic) and 3/13 (23.1%) miscellaneous lesions. Thirteen controls underwent open surgical biopsy of the parotid. In one, inadequate material was obtained, while in 12 (92.3%) the pathologic diagnoses were 4 (33.3%) B cell lymphoma, 2 (16.7%) lymphoepithelial sialadenitis, 4 (33.3%) uncertain lymphoproliferative lesions and 2 (16.7%) miscellaneous lesions. Six cases (46.1%) reported six transient complications and 12/13 (92.3%) controls had 2 persistent and 14 transient complications., Conclusion: US-guided CNB represents a novel, clinically relevant and safe approach for the management of pSS patients with parotid or submandibular persistent enlargement., (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objectives: To investigate the clinical, laboratory, radiological, histopathological, and immunohistochemical features, and the expression of allergy-related cytokines in eosinophilic sialodochitis (ES)., Methods: Thirty-eight patients diagnosed with chronic obstructive sialadenitis (COS) who had undergone glandular excision or incisional biopsy were enrolled. Seventeen patients with comorbid atopic disease and increased ductal tissue eosinophils comprised the ES group, while 21 patients comprised the COS group. The clinicopathological features and allergy-related cytokine expression were compared between groups., Results: The ES group frequently involved multiple, bilateral major salivary glands, and the number of glands was significantly greater than the COS group (2.8 ± 1.1 vs. 1.2 ± 0.4, P < .001). Serum immunoglobulin (Ig) E was elevated in 91% of patients in ES group (419 ± 357 kU/L) and peripheral blood eosinophil was significantly greater compared with the COS group (7.6% ± 4.6% vs. 2.5% ± 1.4%, P < .001). Histologically, eosinophil infiltration in ES group was observed around the main and interlobular ducts (50 ± 39/high power field [HPF]). Follicular hyperplasia (76%), epithelial mucous metaplasia (82%), and mucus plugs with eosinophils (41%) were observed. IgE-positive cell count was 20.7 ± 18.3/HPF and tryptase-positive mast cell count was 23.5 ± 15.1/HPF, which was significantly greater than the respective cell counts in COS group, which mainly infiltrated around the ducts. The levels of interleukin-4, interleukin-13, and eotaxin in tissue were significantly greater in ES than the COS group., Conclusions: The clinicopathological characteristics of ES are significantly different from COS and ES might have an allergy-related pathogenesis., Level of Evidence: 4 Laryngoscope, 131:E800-E806, 2021., (© 2020 The American Laryngological, Rhinological and Otological Society, Inc.)

Fine needle aspiration cytology (FNAC) is generally characterized by a high diagnostic accuracy in differentiating non-neoplastic/inflammatory lesions from neoplastic lesions of the salivary glands. Lymphoepithelial sialadenitis/myoepithelial sialadenitis is exceedingly rare in paediatric patients and is characterized by a diffuse, often bilateral, salivary gland enlargement and the differential diagnosis may sometimes be difficult. We report the case of a 10-year-old boy who presented with a swelling of the left parotid gland investigated by ultrasound salivary gland FNAC., (© 2020 John Wiley & Sons Ltd.)

Chronic graft versus host disease (cGVHD) remains the principal long-term life-threatening complication in hematopoietic stem cell transplant recipients. We present a case of lichenoid sialadenitis in a 23-year-old-man with systemic cGVHD. The histological examination showed a lymphocytic inflammatory infiltrate adjacent to the salivary gland duct, similar to the histological aspects described in the typical manifestations of oral lichen planus and lichen planopilaris. This consists of a band-like inflammatory infiltrate not only targeting the cutaneous epithelium but also adnexal structures, such as hair follicles and salivary gland ducts. It is well described that the oral lesions in cGVHD share most of morphological and clinical manifestations with those described in oral lichen planus. The mechanisms of lichenoid salivary gland ducts destruction might be similar, although xerostomy appears to be specific to cGVHD, which may represent a clinical sign of massive salivary gland impairment related to ductal lichenoid destruction in patients with cGVHD.

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.

Background: Juvenile Sjögren's Syndrome (jSS) is a rare phenomenon that may appear as primary jSS or associated with mixed connective tissue disease (MCTD) and other autoimmune diseases as secondary jSS. With currently no standard diagnostic procedures available, jSS in MCTD seems to be underdiagnosed. We intended to describe and identify similar distinct salivary gland ultrasound (SGUS) findings in a cohort of primary and secondary jSS patients, focusing on sicca like symptoms and glandular pain/swelling in the patients'history., Methods: We present a single-center study with chart data collection. B-mode examinations of salivary glands were obtained with a linear high-frequency transducer and evaluated using the scoring-system of Hocevar. Inclusion criteria were: (i) primary or secondary jSS and/or (ii) diagnosis of MCTD and additionally (iii) any presence of sicca like symptoms or glandular pain/swelling., Results: Twenty five patients with primary (pjSS) and secondary jSS (sjSS) were included in the study (n = 25, 21 female, 4 male), with a median age of 15.3 years at the time of first visit and a mean disease duration of 4.9 years. Pathologic SGUS findings were observed in 24 of 25 patients, with inhomogeneous parenchymal appearances with hypoechoic lesions present in 96% of patients. At least one submandibular gland was affected in 88.5% of the whole group, and all patients in the MCTD-group. Twenty of twenty five patients were scanned and scored on a second visit. Pre-malignancies or mucosa-associated lymphoid tissue (MALT) were detected in biopsies of three patients (Hocevar scoring of 40, 33, and 28)., Conclusion: SGUS in patients with pjSS and sjSS is a helpful first-line tool to detect and score salivary gland involvement, in particular when keratoconjunctivitis sicca, xerostomia, or glandular swelling occurs. Juvenile MCTD patients have a significant risk of developing secondary jSS. We propose SGUS as a method in the diagnostic workup and screening for inflammatory changes. Further studies have to determine the predictive value of SGUS for follow up.

Aging elicits quantitative and qualitative changes in different immune components, leading to disruption of tolerogenic circuits and development of autoimmune disorders. Galectin-1 (Gal1), an endogenous glycan-binding protein, has emerged as a regulator of immune cell homeostasis by shaping the fate of myeloid and lymphoid cells. Here, we demonstrate that aged Gal1-null mutant ( Lgals1 - / - ) mice develop a spontaneous inflammatory process in salivary glands that resembles Sjögren's syndrome. This spontaneous autoimmune phenotype was recapitulated in mice lacking β1,6N-acetylglucosaminyltransferase V (Mgat5), an enzyme responsible for generating β1,6-branched complex N-glycans, which serve as a major ligand for this lectin. Lack of Gal1 resulted in CD11c + dendritic cells (DCs) with higher immunogenic potential, lower frequency of Foxp3 + regulatory T cells (Tregs), and increased number of CD8 + T cells with greater effector capacity. Supporting its tolerogenic activity, Gal1 expression decreased with age in autoimmunity-prone nonobese diabetic (NOD) mice. Treatment with recombinant Gal1 restored tolerogenic mechanisms and reduced salivary gland inflammation. Accordingly, labial biopsies from primary Sjögren's syndrome patients showed reduced Gal1 expression concomitant with higher number of infiltrating CD8 + T cells. Thus, endogenous Gal1 serves as a homeostatic rheostat that safeguards immune tolerance and prevents age-dependent development of spontaneous autoimmunity., Competing Interests: The authors declare no competing interest.

IgG4-related sialadenitis (IgG4-RS) is a chronic fibro-inflammatory disease characterized by swelling of salivary glands and varying degrees of xerostomia. Tight junctions (TJs) play an essential role in maintaining secretory function by regulating the paracellular flow of ions and water. However, whether TJs are altered and contribute to the hyposecretion in IgG4-RS is not fully understood. Here, a total of 399 differentially expressed proteins were identified in IgG4-RS submandibular glands (SMGs) and enriched in the regulation of actin cytoskeleton and the salivary secretion. Real-time PCR results showed that the mRNA levels of claudin-3, -4, -6, -7, -8, -10, -12, occludin, and ZO-1 were significantly lower, whereas claudin-1 and -5 were higher in IgG4-RS SMGs. Immunohistochemical and immunofluorescence staining revealed that claudin-1, -3, -4, occludin, and ZO-1 were mainly distributed at apicolateral membranes in acini and ducts of SMGs from controls, whereas claudin-1 protein intensity at apicolateral membrane was elevated, while the staining of claudin-3, -4, and ZO-1 were reduced in IgG4-RS SMGs. Occludin was dispersed into cytoplasm of acini and ducts in SMGs of patients. Among them, claudin-3 and ZO-1 protein levels were positively correlated with saliva flow rate. Furthermore, the decreased fluorescence intensity of F-actin at peri-apicolateral membranes and the loss of ZO-1 staining at the same location were observed in acinar and ductal cells of IgG4-RS SMGs, which might be responsible for disorganization of TJ complex. Taken together, these findings indicate that the integrity of TJ complex of SMGs is impaired and might contribute to hyposalivation of IgG4-RS patients.

Objectives: To prospectively examine durability of long-term outcomes in sialendoscopy-assisted salivary duct surgery (SASDS) in chronic obstructive sialadenitis without sialolithiasis (COSWS)., Methods: A prospective cohort study of adult patients with COSWS who completed Chronic Obstructive Sialadenitis Symptoms (COSS) Questionnaire prior to and at 3 months and 1 year following SASDS. COSS scores scaled to 0 to 100 were analyzed by statistically significant improvements and previously published ranges corresponding to complete, partial, and nonresolution of symptoms., Results: Twenty-nine patients with COSWS affecting 41 glands had statistically significant improvements in COSS scores at 3 months following SASDS. These improvements usually were sustained at 1 year, supporting durability of treatment effect over time. A majority of cases (30 of 41, 73%) achieved at least a partial resolution of sialadenitis symptoms (COSS score ≤ 25) at 1-year follow-up. Symptom improvement after SASDS was noted in 14 of 18 (78%) glands with radioiodine-induced sialadenitis (RAI-IS). The highest proportion of persistent or recurrent disease at 1-year post-SASDS was found in autoimmune sialadenitis (2 of 4, 50%) and glands with proximal or multifocal stenoses (6 of 12, 50%). At 1 year, distal duct stenoses achieved a significantly higher proportion of partial or complete symptom resolution (18 of 21, 86%) than cases with proximal or multifocal stenoses (6 of 12, 50%; P = 0.044)., Conclusions: SASDS is effective in reducing symptoms in duct stenosis and RAI-IS, usually with durable treatment benefits at long-term follow-up. Distal stenoses appear to be more amenable to sialendoscopic treatment, achieving greater symptom reduction than proximal/multifocal stenoses. Additional larger multi-center studies are needed to further characterize risk factors for COSWS refractory to SASDS., Level of Evidence: 2 Laryngoscope, 129:890-896, 2019., (© 2018 The American Laryngological, Rhinological and Otological Society, Inc.)

Sjögren's Syndrome (SjS) is a common chronic autoimmune disease characterized by the B cell hyperactivation, lymphocyte infiltration, and tissue damage of exocrine glands. It can also present life-threatening extraglandular manifestations, such as pulmonary and hepatic involvement, renal inflammation and marginal zone (MZ) B cell lymphoma. Several biologic agents have been tested in SjS but none has shown significant efficacy. Here, we report the effects of Ly9 (CD229) antibody targeting, a cell surface molecule that belongs to the SLAM family of immunomodulatory receptors, using NOD.H-2 h4 mice as a model of SjS-like disease. Female mice were treated with anti-Ly9 antibody or isotype control at week 24, when all mice present SjS related autoantibodies, salivary gland infiltrates, and marginal zone (MZ) B cell pool enlargement. Antibody injection depleted key lymphocyte subsets involved in SjS pathology such as MZ, B1, and germinal center B cells in spleen and draining lymph nodes without inducing a general immunosuppression. Importantly, mice receiving anti-Ly9 mAb showed a reduced lymphocyte infiltrate within salivary glands. This reduction may be, in part, explained by the down-regulation of L-selectin and alfa4/beta7 integrin induced by the anti-Ly9 antibody. Furthermore, levels of anti-nuclear autoantibodies were reduced after anti-Ly9 treatment. These data indicate that Ly9 is a potential therapeutic target for the treatment of SjS.

Objectives To evaluate the incidence and nature of complications associated with diagnostic and interventional sialendoscopies and to report intervention failures in a prospective setup. Study Design Prospective observational study. Setting Academic tertiary care university hospital. Subjects and Methods Patients who underwent diagnostic or interventional sialendoscopy between October 2015 and December 2016 were prospectively enrolled. Patient data, operation-related factors, treatment failures, and complications were recorded into a database and analyzed. Results A total of 140 sialendoscopies were attempted or performed on 118 patients; 67 (48%) were for a parotid gland and 73 (52%) for a submandibular gland. The sialendoscopy was interventional in 81 cases (58%), diagnostic in 56 (40%), and not possible to perform in 3 (2.1%). A total of 21 complications were registered for 21 sialendoscopies (15%) and 21 patients (18%). The most common complication was infection, in 9 cases (6.4%). Other observed complications were salivary duct perforation (4 cases), prolonged glandular swelling (3 cases), transient lingual nerve analgesia (2 cases), basket entrapment (2 cases), and transient weakness in the marginal branch of the facial nerve (1 case). All complications were related to interventional procedures or papilla dilatation. Failure to treat occurred in 21 (15%) sialendoscopies: sialendoscopy itself was unsuccessful in 3 cases, and an intended intervention failed in 18 cases. Conclusion Complications in sialendoscopy are usually related to interventional procedures. The complications are mainly minor and temporary but lead to additional follow-up visits, further treatments, and sometimes hospitalization. Sialendoscopic procedures are safe but not free of complications.

Autoimmune sialadenitis (AS), chronic inflammation of the salivary glands (SGs) with focal lymphocyte infiltration, appears in autoimmune diseases such as Sjӧgren's syndrome. The pathological role of MyD88-dependent innate immune signaling in autoimmune diseases including AS has been studied using mouse models, such as NOD mice. Although AS development in NOD mice was reported to be suppressed by Myd88 deficiency, its specific role remains unclear. Here, we determined the potent suppressive effects of Myd88 deficiency on AS development in lupus-prone B6/lpr mice, which have lymphoproliferation abnormalities, and also in NOD mice, which have no lymphoproliferation abnormalities. This indicates that MyD88 signaling triggers AS through both lymphoproliferation-dependent and -independent mechanisms. To address the MyD88-dependent lymphoproliferation-independent AS manifestation, SGs from C57BL/6 mice were analyzed. Remarkable upregulation of Glycam1 and high endothelial venule (HEV)-associated changes were unexpectedly found in Myd88 +/+ mice, compared with Myd88 -/- mice. MyD88-dependent HEV-associated changes were also observed in NOD mice. Additionally, Lta, Ltb, and Ltbr in SGs of NOD mice were lowered by Myd88 deficiency. Interestingly, LTβR-induced HEV-associated gene expression in cultured cells was impaired by Myd88 deficiency. Our findings highlight novel roles for MyD88 in AS development, which imply the existence of MyD88-dependent HEV formation in ectopic lymphoid neogenesis.

Introduction: Xerostomia following radioiodine therapy (RIT) in patients suffering from differentiated thyroid cancer is a common side effect in 2 % to 67 % of patients treated with radioiodine (I-131). In order to evaluate the impact of sialendoscopy on health related quality of life (HRQOL) in patients suffering from therapy induced sialadenitis and xerostomia, we analyzed findings from two dedicated questionnaires (Xerostomy Questionnaire XQ and Xerostomy Inventory XI) in patients before and three months after sialendoscopy., Procedures: In total, 12 patients suffering from differentiated thyroid carcinoma (10 women and 2 men) were evaluated. All patients had experienced conservative management. Patients were offered a sialendoscopy procedure if no major contradictions were present. Patients who denied the procedure formed the control group. Pre- and (three months) postoperative HRQOL was measured with the Patient Reported Outcome Measures (PROM) Xerostomia Questionnaire (XQ) and the Xerostomia Inventory (XI), as well as by a pre- and post-interventional salivary gland scintigram. Patients were graded according to their sialendoscopical findings., Results: Interventional group presented with significant improvements in HRQOL measurements regarding XQ and XI-scores three months postoperatively. Control group showed no significant changes in the XQ or the XI scores. Number of RIT and cumulative activity of I-131 did not correlate with higher disease grade in regards to sialendoscopical findings nor did it correlate with higher XQand XI scores. Pre- and post-interventional salivary gland scintigram stated that parotid glands are more severely damaged than submandibular glands (SMG), but no significant scintigraphically changes could be detected after sialendoscopy., Conclusion: Sialendoscopy in patients suffering from therapy induced sialadenitis and xerostomia seems to be beneficial when evaluating the impact on HRQOL. Functional parameters measured by salivary gland scintigram did not show significant changes in post-interventional scintigrams., Competing Interests: There is no potential conflict of interest that is relevant to this article., (Georg Thieme Verlag.)

IgG4-related disease (IgG4-RD) is a rare fibroinflammatory condition that can affect almost any organ, characterized by swollen lesions and often by eosinophilia and elevated serum IgG4 concentrations. The diagnosis of IgG4-RD is a challenging task: in fact, single or multiple organs can be affected and clinical, serological, and histological findings can be heterogeneous. In IgG4-RD, the involvement of salivary glands is observed in 27% to 53% of patients. Several organ-specific conditions, now recognized as different manifestations of IgG4-related sialadenitis (IgG4-RS), were viewed in the past as individual disease entities. The study of salivary glands may sometimes be complex, because of the number of pathological conditions that may affect them, often with overlapping clinical pictures. Integration of different imaging techniques is often required in the case of swelling of salivary glands, even though biopsy remains the gold standard for a definite diagnosis of IgG4-RS. Thus, in this review, we discuss new insights in the pathogenesis of IgG4-RD, focusing on its clinical aspects and the tools that are currently available for a correct differential diagnosis when the salivary glands are involved.

Background: Immunoglobulin G4-related sialadenitis (IgG4-RS) is a newly recognized immune-mediated systemic disease. Despite its good response to steroid therapy, its treatment protocol is not standardized and the long-term outcome is controversial. The study was conducted to determine the short-term and long-term outcomes of IgG4-RS patients treated with glucocorticoids and steroid-sparing immunosuppressive agents, to analyze secretory function, serological and radiological changes in salivary glands and to assess the usefulness of serum IgG4 level as an indicator of disease activity., Methods: IgG4-RS patients who were treated for more than 3 months were enrolled. Serological tests, salivary gland function assessment and computed tomography (CT) were performed before treatment and during follow up. The treatment outcomes in the short and the long term were evaluated, and the relationship between serum IgG4 level and salivary gland volume was analyzed., Results: Glucocorticoids were used in all 43 patients and steroid-sparing immunosuppressive agents in 38 patients (88.4%). The follow-up period was 24.6 ± 14.9 months. Clinical remission was achieved in all patients after induction therapy. During short-term observation, salivary gland secretion significantly increased, and the serum IgG4 levels, the volumes and CT values of submandibular and parotid gland decreased significantly (P < 0.001). For long term, relapse occurred in 32.5% patients within 55 months in the regularly treated group, while all seven irregularly treated patients relapsed. However, the relapse-free survival curves were not significantly different between the steroid monotherapy and the combination therapy groups (P = 0.566). Submandibular glands, lacrimal glands, sublingual glands, nasal and paranasal cavity were commonly relapsing organs. In clinically stable patients, a serologically unstable condition occurred in 54.9% patients within 55 months and medication adjustment was performed accordingly. Volume changes in the submandibular and parotid glands were associated with serum IgG4 levels and time of follow up (R 2 adjusted  = 0.905, P < 0.0001 and R 2 adjusted  = 0.9334, P < 0.0001, respectively)., Conclusions: The combination of glucocorticoid and steroid-sparing agents could be effective for treating IgG4-RS, and restoring salivary gland function. Serum IgG4 levels could predict disease activity.

Long-term consumption of a high-fat diet (HFD) causes not only obese-insulin resistance, but is also associated with mitochondrial dysfunction in several organs. However, the effect of obese-insulin resistance on salivary glands has not been investigated. We hypothesized that obese-insulin resistance induced by HFD impaired salivary gland function by reducing salivation, increasing inflammation, and fibrosis, as well as impairing mitochondrial function and calcium transient signaling. Male Wistar rats (200-220 g) were fed either a ND or an HFD (n = 8/group) for 16 weeks. At the end of week 16, salivary flow rates, metabolic parameters, and plasma oxidative stress were determined. Rats were then sacrificed and submandibular glands were removed to determine inflammation, fibrosis, apoptosis, mitochondrial function and dynamics, and intracellular calcium transient signaling. Long-term consumption of an HFD caused obese-insulin resistance and increased oxidative stress, fibrosis, inflammation, and apoptosis in the salivary glands. In addition, impaired mitochondrial function, as indicated by increased mitochondrial reactive oxygen species, mitochondrial membrane depolarization, and mitochondrial swelling in salivary glands and impaired intracellular calcium regulation, as indicated by a reduced intracellular calcium transient rising rate, decay rates, and amplitude of salivary acinar cells, were observed in HFD-fed rats. However, salivary flow rate and level of aquaporin 5 protein were not different between both groups. Although HFD consumption did not affect salivation, it caused obese-insulin resistance, leading to pathophysiological alteration of salivary glands, including impaired intracellular calcium transients, increased oxidative stress and inflammation, and salivary mitochondrial dysfunction.

IgG4-related disease (IgG4-RD) has emerged as a new entity in the last decade. It comprises numerous conditions previously thought to be unrelated. Macroscopically, these diseases cause diffuse organ swelling and formation of pseudotumorous masses. Histopathologically, they are characterized by a lymphoplasmacytic infiltrate with increased IgG4+ plasma cells and storiform fibrosis. Despite rapid progress within the last years, our knowledge on these conditions is still fragmented. To date, more than forty organs have been reported to be included in IgG4-RD, and salivary gland involvement is amongst the most common organs affected [IgG4-related sialadenitis (IgG4-RS)]. Interestingly, IgG4-RS shares commonalities with Sjögren's syndrome (SS), like glandular enlargement, sicca symptoms, arthralgias, hypergammaglobulinemia, hypocomplementemia, and circulating antinuclear antibodies. Nonetheless, they differ in that the incidence of anti-Ro and anti-La reactivity is not frequently found in patients with IgG4-RS, their salivary glands are infiltrated by a large number of IgG4+ plasma cells and IgG4-RS symptoms respond promptly to steroids. The aim of this review was to describe the clinical, serological, histopathological and pathophysiological aspects of IgG4-RS in the context of IgG4-RD and highlight the differences between IgG4-RS and SS., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objectives: To develop and validate an international set of classification criteria for primary Sjögren's syndrome (SS) using guidelines from the American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR). These criteria were developed for use in individuals with signs and/or symptoms suggestive of SS., Methods: We assigned preliminary importance weights to a consensus list of candidate criteria items, using multi-criteria decision analysis. We tested and adapted the resulting draft criteria using existing cohort data on primary SS cases and non-SS controls, with case/non-case status derived from expert clinical judgement. We then validated the performance of the classification criteria in a separate cohort of patients., Results: The final classification criteria are based on the weighted sum of five items: anti-SSA/Ro antibody positivity and focal lymphocytic sialadenitis with a focus score of ≥1 foci/4 mm 2 , each scoring 3; an abnormal Ocular Staining Score of ≥5 (or van Bijsterveld score of ≥4), a Schirmer's test result of ≤5 mm/5 min and an unstimulated salivary flow rate of ≤0.1 mL/min, each scoring 1. Individuals with signs and/or symptoms suggestive of SS who have a total score of ≥4 for the above items meet the criteria for primary SS. Sensitivity and specificity against clinician-expert-derived case/non-case status in the final validation cohort were high, that is, 96% (95% CI92% to 98%) and 95% (95% CI 92% to 97%), respectively., Conclusion: Using methodology consistent with other recent ACR/EULAR-approved classification criteria, we developed a single set of data-driven consensus classification criteria for primary SS, which performed well in validation analyses and are well suited as criteria for enrolment in clinical trials., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

Objectives/hypothesis: To prospectively assess symptoms of obstructive sialadenitis before and after sialendoscopy-assisted salivary duct surgery (SASDS) using the chronic obstructive sialadenitis symptoms (COSS) questionnaire to determine and predict impact of interventions., Study Design: Prospective cohort study., Methods: Adult patients with chronic obstructive sialadenitis who underwent SASDS were asked to complete the COSS questionnaire and the Short-Form-8 (SF-8) quality-of-life (QOL) survey prior to surgery and 3 months postoperatively. Chronic obstructive sialadenitis symptoms surveys were scored on a scale from 0 to 100., Results: Forty patients undergoing SASDS, including 54 glands, completed preoperative and postoperative surveys. Overall, the mean COSS score improved from 36.1 (standard error of the mean [SEM] 2.6) preoperatively to 13.5 (SEM 2.4) 3 months postoperatively (p < 0.001). Submandibular gland cases had a significant mean score reduction of 27.8 (from 38.1 to 10.3; p < 0.005). Parotid gland cases had a significant mean score reduction of 13.6 (from 32.6 to 19.0; p < 0.0001). Patients with sialolithiasis-related sialadenitis had greater COSS score improvement after surgery than those with radioactive iodine- or inflammatory-related disease. An improvement in symptoms was seen for 100% and 47% of patients with sialolithiasis and inflammatory etiologies, respectively. The pre- and post-SASDS SF-8 QOL scores were not significantly different., Conclusions: Obstructive sialadenitis-related symptoms significantly declined 3 months after SASDS. The COSS questionnaire was able to measure changes in sialadenitis symptoms not captured in the SF-8 QOL survey. This is the first study to prospectively survey sialadenitis-specific symptoms to determine impact of surgical interventions., Level of Evidence: 4. Laryngoscope, 126:1343-1348, 2016., (© 2016 The American Laryngological, Rhinological and Otological Society, Inc.)

Sjögren's syndrome (SS) is a debilitating autoimmune disease. Patients with SS may develop xerostomia. This process is progressive, and there are no therapeutics that target disease etiology. We hypothesized BAFF receptor (BAFFR) blockade would mitigate SS disease development, and neutralization of CXCL13 and BAFF signaling would be more efficacious than BAFFR blockade alone. We treated NOD/ShiLtJ SS mice with soluble BAFF receptor (BAFFR-Fc) or anti-CXCL13/BAFFR-Fc in combination, prior to the development of clinical disease. Our results show treatment with BAFFR-Fc reduced peripheral B cell numbers and decreased sialadenitis. In addition, this treatment reduced total serum immunoglobulin as well as IgG and IgM specific anti-nuclear autoantibodies. NOD/ShiLtJ mice treated with BAFFR-Fc and anti-CXCL13 antibody were protected from salivary deficits. Results from this study suggest blockade of CXCL13 and BAFFR together may be an effective therapeutic strategy in preventing salivary hypofunction and reducing autoantibody titers and sialadenitis in patients with SS., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objective: To study the clinicopathologic characteristics of IgG4-related sialodacryoadenitis and chronic rhinosinusitis (CRS)., Methods: A total of 13 patients (patient group) were evaluated clinically and biopsy specimens from the lacrimal/salivary glands (n=12) and nasal mucosa (n=8) were reviewed and immunohistochemistry was performed to assess IgG-and IgG4-positive cells. Similarly, nine patients with IgG4-related sialodacryoadenitis without CRS and 10 patients with common CRS were included as controls., Results: There were 8 male patients and 5 female patients. The age of patients ranged from 32 to 71 years (mean 50.2 years). The patient group had higher serum IgG4 concentration than that of the control group (P<0.05). Lymphoplasmacytic infiltration, lymphoid follicle formation and sclerosis were prominent in lacrimal/salivary glands in both groups; however the magnitude of IgG4-positive plasmacytic infiltration in the patient group was significantly higher than that of the control group (P<0.05). Similarly, evaluation of nasal mucosa revealed greater lymphocytic and plasmacytic infiltration, and lymphoid follicle formation, together with significantly higher amount of IgG4-positive plasma cell infiltration in the patient group compared to the common CRS group (P<0.05)., Conclusions: IgG4-related disease (IgG4-RD) simultaneously involving lacrimal/salivary glands and nasal cavity/paranasal sinuses is rare and characterized by a combination of IgG4-positive plasma cell infiltration involving lacrimal/salivary glands and nasal mucosa along with an increased serum level of IgG4. As a systemic disease, early and accurate diagnosis is therefore of great importance, and unnecessary surgery should be avoided.

The aim of this study was to elucidate more clearly the role of interleukin (IL)-18 in modulating the IL-22 pathway in primary Sjögren's syndrome (pSS) patients and in pSS-associated lymphomas. Minor salivary glands (MSGs) from patients with pSS and non-specific chronic sialoadenitis (nSCS), parotid glands biopsies from non-Hodgkin lymphomas (NHL) developed in pSS patients, were evaluated for IL-18, IL-22, IL-22 receptor 1 (IL-22R1), IL-22 binding protein (IL-22BP) and signal transducer and activator of transcription-3 (STAT-3) expression. MSGs IL-22R1-expressing cells were characterized by confocal microscopy and flow cytometry in pSS, nSCS and healthy controls . The effect of recombinant IL-18 and IL-22 on peripheral blood mononuclear cells (PBMCs) from pSS and nSCS was studied by flow cytometry and reverse transcription-polymerase chain reaction (RT-PCR). MSGs of pSS and NHL were characterized by an imbalance between IL-22 and IL-22BP protein expression, with IL-18 and IL-22BP being expressed in a mutually exclusive manner and IL-18 and IL-22R1 being correlated directly. Aberrant expression of IL-22R1, induced by IL-18, was observed only among tissue and circulating myeloid cells of pSS patients and macrophages of NHL tissues of pSS patients, but not nSCS. IL-22R1 expression on PBMC of pSS was functional, as its stimulation with recombinant IL-22 significantly up-regulated the expression of STAT-3, IL-17 and IL-22. An IL-18-dependent aberrant expression of IL-22R1 on cells of haematopoietic origin seems to be a specific immunological signature of patients with pSS and pSS-associated lymphomas., (© 2015 British Society for Immunology.)

Introduction: Immunoglobulin G4-related disease (IgG4-RD) is a newly recognized fibro-inflammatory condition. Forty-two cases with immunoglobulin G4-related sialadenitis (IgG4-RS) confirmed by histopathological and immunohistochemical assessment were studied to clarify the clinicopathologic characteristics of the salivary glands involved in IgG4-RS, especially the relationship between the histopathologic features and function of salivary glands or serum levels of IgG4., Methods: Clinical, serologic, imaging and histopathological data of these cases were analyzed. CT volumes of submandibular, parotid, and lacrimal glands were calculated. The saliva flow rate was measured. Scintigraphy with 99mTc-pertechnetate was undertaken in 31 cases, and the concentration index (CI) and secretion index (SI) was calculated. Relationships between fibrosis severity and salivary gland function or serum IgG4 levels were analyzed., Results: The first symptom was swelling of bilateral submandibular or lacrimal glands. Physical examination showed multiple bilateral major salivary glands (including sublingual and accessory parotid glands) and lacrimal glands were enlarged in IgG4 RS. Multiple enlarged cervical lymph nodes were noted in 30 patients. Saliva flow at rest was lower than normal in 34 cases; stimulated saliva flow was lower than normal in 15 cases. Secretory function was reduced more severely in the submandibular glands than in the parotid glands. Serum levels of IgG4 were elevated in 95.2% of cases and 78.6% patients had increased IgE levels. Serum IgG4 level was higher and saliva secretion lower as glandular fibrosis increased., Conclusions: Prominent changes in the morphology, histology, immunohistochemistry and secretion of the major salivary glands of IgG4-RS patients were accompanied by involvement of the lacrimal glands and cervical lymph nodes. Elevated IgE, allergic history, eosinophil infiltration suggest allergic reactions as a potential pathogenesis of IgG4-RS. Severity of glandular fibrosis correlated with salivary function and serum levels of IgG4.

Radioactive iodine has long been used in the treatment of cancers of the thyroid. While salivary complications secondary to I-131 therapy in association with xerophthalmia are well documented, there is little in the literature addressing simultaneous nasolacrimal duct obstruction with salivary gland dysfunction. The authors present 2 patients with epiphora from bilateral nasolacrimal duct obstruction and concurrent sialadenitis following I-131 ablation therapy for papillary thyroid carcinoma. These cases highlight the lacrimal and salivary duct complications resulting from I-131 therapy, introduce the possibility of a shared mechanism of damage, and demonstrate the availability of effective treatments for both conditions. Ophthalmologists see patients with epiphora from I-131 therapy and should be aware of the possible concurrent symptoms caused by salivary duct stenosis to make timely and appropriate referrals.

Background: Fine needle aspiration cytology (FNAC) is a cytodiagnostic method based on morphologic findings of individual and small group of cells aspirated using a fine needle. The aim of the present study is to evaluate the spectrum of salivary gland lesions in our setting and to assess the diagnostic accuracy of FNAC for salivary gland lesions., Methods: The study involved 187 cases of parotid and submandibular swellings of patients who underwent FNAC at our institution. Thirty one (31) patients with a FNAC diagnosis of neoplastic lesion subsequently underwent excision biopsies. The results of FNAC and final histology were compared and accuracy of FNAC was determined., Results: Mean age of patients was 42 (± 21) years and male to female ratio was 1:1. Chronic sialadenitis was the most common non-neoplastic lesion (33.8%) followed by acute and chronic sialadenitis (29.7%) and chronic granulomatous inflammation (27.0%). Pleomorphic adenoma was the most common benign neoplasm and non-Hodgkin's lymphoma was the most common malignant lesion (38.9%) followed by acinic cell (27.8%) and adenoid cystic carcinoma (16.7%). Total 31 patients subsequently underwent surgical excision, out of which 21 were benign and 9 were malignant, 20 cases (64.5%) were of pleomorphic adenoma, 3 cases (9.6%) of acinic cell carcinoma, 2 cases (6.4%) each of warthin tumor, adenoid cystic carcinoma and non-hodgkin lymphoma and 1 case (3.2%) each of mucoepidermoid carcinoma and mucinous adenocarcinoma. The overall accuracy of FNAC in our study was found to be 83.8% with 77.7% sensitivity and 86.3%, specificity. The revised sensitivity and specificity after adjusting verification bias were 68.5% and 91% respectively. False negative diagnosis was rendered in mucoepidermoid carcinoma and acinic cell carcinoma whereas false positive diagnosis was given in cases of pleomorphic adenoma., Conclusion: We found a good concordance between FNAC and histology, however pleomorphic adenoma may impart a diagnostic challenge when inadequately aspirated and therefore we advice either immunohistochemical studies (if cell block material is available) or repeat aspiration in difficult cases.

Objectives: Immunoglobulin (Ig) G4-related dacryoadenitis and sialadenitis, the so-called Mikulicz's disease (MD), is a chronic inflammatory disease. However, little is known about its pathogenesis and pathological condition. In the present study, we used immunohistological techniques to compare the roles of cytotoxic T lymphocytes (CTLs) in MD and primary Sjogren's syndrome (SS). We examined the state of CTLs [cytotoxic granule-positive rate and programmed death-1 (PD-1) expression rate] in the salivary glands., Methods: The study samples comprised 12 submaxillary glands from untreated MD patients and 12 labial glands from SS patients. We performed immunofluorescence and multicolor immunofluorescence to stain CD8, perforin (PRF), granzyme B (GZMB), and PD-1. We measured the total number of CTLs as well as the PRF(+)CTLs, GZMB(+)CTLs, and PD-1(+)CTLs., Results: We found that the degree of infiltration of CTLs was equal in MD and SS, but the rate of CTLs with cytotoxic granules, especially PRF, in MD was less than in SS. In addition, the frequency of PD-1(+)CTLs in MD was higher than that in SS., Conclusions: Cytotoxic granule-positive CTLs were in the minority in D salivary glands, and this regulation might relate to PD-1 signals like the state of exhaustion and anergy.

Xanthogranulomatous inflammation is an uncommon subtype of chronic inflammatory processes that has been mainly reported in the kidneys, gallbladder and other less common sites. Due to the presence of tumefactive mixed inflammatory infiltrates with variable involvement of surrounding soft tissues, this benign condition is often mistaken for a malignancy on clinical examination. In the salivary glands xanthogranulomatous inflammation is rare and mainly represents reactive changes secondary to a preexisting lesion, in particular infarcted Warthin tumors as well as ruptured ductal cysts and other sialectatic ductal changes. A special type of xanthogranulomatous salivary gland disease is represented by the rare primary (idiopathic) xanthogranulomatous sialadenitis without identifiable predisposing parenchymal or ductal lesions. The histological differential diagnosis is mainly based on the dominant histological pattern and encompasses among others inflammatory pseudotumors of various etiologies (e.g. inflammatory myofibroblastic tumor, IgG4-related disease and sarcoidosis), neoplastic and paraneoplastic xanthogranulomatosis, malignant lymphoma and carcinoma with secondary xanthogranulomatous reactions. Thus, identification of the underlying lesion is necessary for correct classification and to avoid overlooking more serious neoplastic or autoimmune diseases.

Background: IgG4-related systemic disease (IgG4-RSD) is a recently recognised fibroinflammatory condition, characterized by a tissue infiltration and/or enlargement and typical histopathological findings., Methods and Results: We report on a 73-year-old male with bilateral preauricular swelling and a remote history of unexplained systemic disease. Magnetic resonance imaging showed enlargement of all major salivary glands and cervical lymph node due to a tissue infiltration with marked enhancement and restricted diffusion. Elevated serum IgG4 levels and histopathological findings on an excisional lymph node biopsy were consistent with IgG4-RSD., Conclusion: Magnetic resonance imaging seems to be a useful tool to support the diagnosis of IgG4-related systemic disease of salivary glands., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Objectives/hypothesis: To describe the findings and therapeutic role of salivary endoscopy for idiopathic chronic sialadenitis., Study Design: Retrospective case series., Methods: The records of 258 patients who underwent salivary endoscopy between November 2008 and May 2012 were reviewed. Included cases presented with recurrent inflammation and swelling of a single major salivary gland, without identifiable etiology on examination and imaging., Results: A total of 51 cases (20%) were identified. These patients had a mean age of 54.4 years (range, 23-75) and 57% were female. Mean duration of symptoms was 22.8 months (range, 1-102), with most cases (75%) involving the parotid gland. The primary imaging modalities used were ultrasound (62%) and computed tomography (31%). The most common findings on imaging included ductal dilation (42%), enlarged lymph nodes (23%), normal glandular imaging (15%), and possible sialoliths (14%). The most common findings on salivary endoscopy included stenosis (57%), strictures (27%), and inflammatory debris (18%). Occult stones were the cause of sialadenitis in only 4 (8%) cases. Outcomes included complete symptom resolution in 31 patients (61%), improved but occasional symptoms in 14 patients (27%), and no improvement in 6 patients (12%) after a mean follow-up time of 20.0 months (range, 4-45). Excision of the involved gland was required in 2 (4%) patients., Conclusion: Salivary endoscopy is a minimally invasive technique that is effective in the management of idiopathic chronic sialadenitis refractory to medical therapy. It provides diagnostic information in most patients and offers a therapeutic intervention with gland preservation., (Copyright © 2013 The American Laryngological, Rhinological and Otological Society, Inc.)

Objectives/hypothesis: To evaluate the use of diagnostic and interventional sialendoscopy in patients with prior parotidectomy or submandibular gland excision and persistent sialadenitis and/or sialolithiasis., Study Design: Retrospective case series., Methods: Retrospective review of medical records, including demographic data, clinical presentation and exam, radiologic studies, and operative reports., Results: Five patients, who had undergone prior sialadenectomy for sialadenitis and/or sialolithiasis, underwent sialendoscopy for persistent symptoms during the study period. Three patients were female and two were male, with ages ranging from 39 to 63 years (median, 47 years). Three patients had prior parotidectomy, and two had prior submandibular gland excision. The duration of time from sialadenectomy to sialendoscopy was 3.25 months to 6 years (median, 26 months). Four of the five patients had successful interventional sialendoscopy, with resolution of their symptoms. These four patients underwent extraction of stones, one of which was previously unrecognized. In one patient, duct cannulation and subsequent sialendoscopy could not be performed owing to scarring at the Stensen's papilla; the patient's symptoms initially persisted after the attempted procedure with gradual improvement. No complications occurred in any patients. Importantly, no sequelae resulted from endoscopic instrumentation and irrigation of salivary ducts that ended in blind pouches., Conclusions: Sialendoscopy is a safe and frequently effective intervention for persistent sialolithiasis and sialadenitis after salivary gland excision., Level of Evidence: 4., (© 2013 The American Laryngological, Rhinological and Otological Society, Inc.)

We report 1 case of primary Sjögren syndrome that showed histologic variation and different lymphoproliferative disorders in different salivary glands.Different salivary glands can show a different transition situation with histologic variation and lymphoproliferative disorders. The larger salivary glands have more potentially progressive transition situation than smaller glands. These findings also supported the theory that the transition of reactive B cells from lymphoepithelial sialadenitis to monoclonal lymphoma is generally a multistep process in different salivary glands within 1 person.

A 23-year-old man was referred to our Emergency Department due to an acute-onset hemoptysis and the associated bilateral swelling of all of his major salivary glands. The elevated levels of systemic inflammatory markers with hypereosinophilia and the concurrent presence of multiple lung infiltrates made it difficult to perform a differential diagnosis, as these symptoms can also be indicative of infectious, autoimmune or hematologic disorders. A histological examination of the patient's left submandibular gland revealed strong clues as to the final diagnosis of eosinophilic granulomatosis with polyangiitis with an atypical clinical presentation, thus allowing for the administration of early and successful conservative therapy. The outcome of our case suggests that systemic vasculitis represents a rare but possible cause of acute bilateral sialadenitis in young patients.

Four cases of an unusual type of thymic hyperplasia strongly resembling lymphoepithelial sialadenitis (LESA) of the salivary glands are described. The patients were 2 men and 2 women aged 37 to 53 years. On histologic examination, abundant lymphoid tissue with lymphoid follicles containing germinal centers and areas of plasma cell infiltration were seen. The epithelial component consisted of a proliferation of Hassall corpuscles and islands of thymic epithelial cells. Cystic changes and lymphoepithelial lesions were identified in all cases, but a monocytoid B-cell population was absent. On immunohistochemical examination, a mixed B- and T-cell population was identified, and polymerase chain reaction performed in 1 case showed polyclonality. Follow-up revealed that all patients were alive 5 months to 9 years after diagnosis. The cases in this series represent a distinct type of thymic hyperplasia that histologically strongly resembles LESA. The clinicopathologic and immunohistochemical features are presented, and a possible relationship with thymic mucosa-associated lymphoid tissue (MALT) lymphoma is discussed.