Cytomegalovirus in Adenoma and Carcinoma Lesions: Detecting Mono-Infection and Co-Infection in Salivary Glands.

Salivary glands' neoplasms are hard to diagnose and present a complex etiology. However, several viruses have been detected in these neoplasms, such as HCMV, which can play a role in certain cancers through oncomodulation. The co-infections between HCMV with betaherpesviruses (HHV-6 and HHV-7) and polyomaviruses (JCV and BKV) has been investigated. The aim of the current study is to describe the frequency of HCMV and co-infections in patients presenting neoplastic and non-neoplastic lesions, including in the salivary gland. Multiplex quantitative polymerase chain reaction was used for betaherpesvirus and polyomavirus quantification purposes after DNA extraction. In total, 50.7% of the 67 analyzed samples were mucocele, 40.3% were adenoma pleomorphic, and 8.9% were mucoepidermoid carcinoma. Overall, 20.9% of samples presented triple-infections with HCMV/HHV-6/HHV-7, whereas 9.0% were co-infections with HCMV/HHV-6 and HCMV/HHV-7. The largest number of co-infections was detected in pleomorphic adenoma cases. All samples tested negative for polyomaviruses, such as BKV and JCV. It was possible to conclude that HCMV can be abundant in salivary gland lesions. A high viral load can be useful to help better understand the etiological role played by viruses in these lesions. A lack of JCV and BKV in the samples analyzed herein does not rule out the involvement of these viruses in one or more salivary gland lesion subtypes.

Sicca syndrome/Sjögren's disease associated with cancer immunotherapy: a narrative review on clinical presentation, biomarkers, and management.

INTRODUCTION: Almost one-quarter of immune checkpoint inhibitor (ICI) recipients experience sicca syndrome, while Sjögren's disease (SjD) is estimated at 0.3-2.5%, possibly underreported. AREAS COVERED: This narrative review (Medline/Embase until January/31/2024) addresses the pathophysiology, incidence, demographic/clinical features, biomarkers, labial salivary gland biopsy (LSGB), fulfillment of the idiopathic SjD (iSjD) classificatory criteria, differential diagnosis, and management of sicca syndrome/SjD associated with ICIs. EXPERT OPINION: SjD associated with ICIs is underdiagnosed, since studies that performed the mandatory SjD investigation identified that 40-60% of patients with sicca syndrome associated with ICIs meet the iSjD classificatory criteria. LSGB played a fundamental role in recognizing these cases, as most of them had negative anti-Ro/SS-A antibody. Despite the finding of focal lymphocytic sialoadenitis in LSGB samples mimicking iSjD, immunohistochemical analysis provided novel evidence of a distinct pattern for sicca syndrome/SjD associated with ICIs compared to iSjD. The former has scarcity of B lymphocytes, which are a hallmark of iSjD. Additionally, patients with sicca syndrome/SjD associated with ICIs have demographical/clinical/serological and treatment response dissimilarities compared to iSjD. Dryness symptoms are more acute in the former than in iSjD, with predominance of xerostomia over xerophthalmia, and partial/complete response to glucocorticoids. Dryness symptoms in ICI-treated patients warrant prompt SjD investigation.

Diagnostic accuracy of ultrasonography in relation to salivary gland biopsy in Sjögren's syndrome: a systematic review with meta-analysis.

OBJECTIVES: To evaluate the accuracy of major salivary gland ultrasonography (SGUS) in relation to minor salivary gland biopsy (mSGB) in the diagnosis of Sjögren's syndrome (SS). METHODS: A systematic review and meta-analysis were performed. Ten databases were searched to identify studies that compared the accuracy of SGUS and mSGB. The risk of bias was assessed, data were extracted, and univariate and bivariate random-effects meta-analyses were done. RESULTS: A total of 5000 records were identified; 13 studies were included in the qualitative synthesis and 10 in the quantitative synthesis. The first meta-analysis found a sensitivity of 0.86 (95% CI: 0.74-0.92) and specificity of 0.87 (95% CI: 0.81-0.92) for the predictive value of SGUS scoring in relation to the result of mSGB. In the second meta-analysis, mSGB showed higher sensitivity and specificity than SGUS. Sensitivity was 0.80 (95% CI: 0.74-0.85) for mSGB and 0.71 (95% CI: 0.58-0.81) for SGUS, and specificity was 0.94 (95% CI: 0.87-0.97) for mSGB and 0.89 (95% CI: 0.82-0.94) for SGUS. CONCLUSIONS: The diagnostic accuracy of SGUS was similar to that of mSGB. SGUS is an effective diagnostic test that shows good sensitivity and high specificity, in addition to being a good tool for prognosis and for avoiding unnecessary biopsies. More studies using similar methodologies are needed to assess the accuracy of SGUS in predicting the result of mSGB. Our results will contribute to decision-making for the implementation of SGUS as a diagnostic tool for SS, considering the advantages of this method.

Primary intestinal-type adenocarcinoma: Report of a rare case involving a young patient.

The aim of this report was to describe a rare example of sporadic intestinal-type adenocarcinoma of the major salivary glands and oral cavity. A 23-year-old female patient presented an asymptomatic, progressive-growing mass involving the floor of mouth and the left submandibular gland. Fine-needle aspiration cytology, imaging exams, and surgical specimen findings were consisted with the diagnosis of primary intestinal-type adenocarcinoma, despite its similar immunohistochemical results with colorectal adenocarcinoma. Adjuvant chemotherapy and radiotherapy were performed, but the patient developed multiple metastatic lesions after one year of initial the intervention and deceased following 13 months of follow-up, despite several therapeutic efforts. We verified that sporadic cases of primary intestinal-type adenocarcinoma still lack information regarding etiology and tumorigenesis, especially in young and females. A complete diagnostic workflow is indispensable to rule out the presence of primary colorectal adenocarcinoma.

Analysis of B7-H4 Expression Across Salivary Gland Carcinomas Reveals Adenoid Cystic Carcinoma-Specific Prognostic Relevance.

B7-H4 (VTCN1), a member of the B7 family, is overexpressed in several types of cancer. Here we investigated the pattern of expression of B7-H4 in salivary gland carcinomas (SGC) and assessed its potential as a prognostic marker and therapeutic target. Immunohistochemistry (IHC) analyses were performed in a cohort of 340 patient tumors, composed of 124 adenoid cystic carcinomas (ACC), 107 salivary duct carcinomas (SDC), 64 acinic cell carcinomas, 36 mucoepidermoid carcinomas (MEC), 9 secretory carcinomas (SC), as well as 20 normal salivary glands (controls). B7-H4 expression was scored and categorized into negative (<5% expression of any intensity), low (5%-70% expression of any intensity or >70% with weak intensity), or high (>70% moderate or strong diffuse intensity). The associations between B7-H4 expression and clinicopathologic characteristics, as well as overall survival, were assessed. Among all tumors, B7-H4 expression was more prevalent in ACC (94%) compared with those of SC (67%), MEC (44%), SDC (32%), and acinic cell carcinomas (0%). Normal salivary gland tissue did not express B7-H4. High expression of B7-H4 was found exclusively in ACC (27%), SDC (11%), and MEC (8%). In SDC, B7-H4 expression was associated with female gender (P = .002) and lack of androgen receptor expression (P = .012). In ACC, B7-H4 expression was significantly associated with solid histology (P < .0001) and minor salivary gland primary (P = .02). High B7-H4 expression was associated with a poorer prognosis in ACC, regardless of clinical stage and histologic subtype. B7-H4 expression was not prognostic in the non-ACC SGC evaluated. Our comparative study revealed distinct patterns of B7-H4 expression according to SGC histology, which has potential therapeutic implications. B7-H4 expression was particularly high in solid ACC and was an independent prognostic marker in this disease but not in the other SGC assessed.

Characterization of Salivary Gland Pain: A Review of the Literature / Caracterización del Dolor de Glándulas Salivales: Revisión de la Literatura

SUMMARY: The salivary glands in pathological conditions produce countless different clinical presentations, and due to their complex neuroanatomy, their pain symptoms vary widely. However, in the literature to date, few studies characterize salivary gland pain. The aim of this study was to conduct a literature review concerning the clinical characteristics of pain in various salivary gland pathologies. A literature review was done through a systematic search of scientific articles in the Web of Science (WoS), MEDLINE, Scopus, and Elton B. Stephens Company (EBSCO) databases. The free terms "salivary gland", "parotid gland", "submaxillary gland", "sublingual gland", and "pain" were used along with the Boolean operators OR and AND. The search yielded a total of 1896 articles, of which 60 fulfilled the inclusion criteria and were ultimately included in this review. It is described that pain is a nonspecific symptom of a glandular pathology and is characterized mainly by the location of the pain, which is correlated with the anatomical location of the affected salivary gland. Among the painful salivary gland pathologies, we found inflammatory disorders, including infections, obstructions, disorders secondary to hyposalivation; systemic autoimmune diseases; neoplasms, and neuropathic pain disorders. The diagnosis and management of salivary gland pain require knowledge of the causes and mechanisms of the pain, and it is to recognize the signs and symptoms of salivary gland disorders to be able to diagnose and treat them.

Las glándulas salivales en condiciones patológicas producen un sinfín de presentaciones clínicas diferentes, y debido a su compleja neuroanatomía generan variaciones en su sintomatología dolorosa. Sin embargo, en la literatura hasta ahora son escasos los estudios que caracterizan el dolor de glándulas salivales. El objetivo de este estudio fue realizar una revisión de la literatura respecto a las características clínicas del dolor en diversas patologías de glándulas salivales. Se realizó una revisión de la literatura, a través de la búsqueda sistemática de artículos científicos en las bases de datos Web of Science (WoS), MEDLINE, Scopus y Elton B. Stephens Company (EBSCO). A través de los términos libres: "salivary gland", "parotid gland", "submaxillary gland", "sublingual gland", "pain", junto con los operadores booleanos OR y AND. La búsqueda arrojó un total de 1896 artículos, de los cuales 60 cumplieron los criterios de inclusión y fueron finalmente incluidos en esta revisión. Se describe que el dolor es un síntoma poco específico para la patología glandular y está caracterizado principalmente por la localización del dolor, el cual se correlaciona con la ubicación anatómica de la glándula salival afectada. Dentro de las patologías dolorosas de glándulas salivales encontramos los trastornos inflamatorios, incluidas infecciones, obstrucciones, trastornos secundarios a hiposalivación; enfermedades sistémicas autoinmunes; neoplasias y trastornos de dolor neuropático. El diagnóstico y manejo del dolor de glándulas salivales requiere del conocimiento de las causas y mecanismos del dolor, siendo necesario reconocer los signos y síntomas de los trastornos de glándulas salivales para ser capaces de diagnosticarlos y tratarlos.

Clinicopathological study and survival outcomes of sialoblastoma: A systematic review.

Sialoblastoma is a rare malignant salivary gland tumor. The aim of this study was to review the available published data on sialoblastoma in a comprehensive analysis of its clinicopathologic characteristics, treatment, and outcomes. An unrestricted electronic search was performed in the following databases: MEDLINE/PubMed, EMBASE, Scopus, Web of science, and gray literature databases. Eligibility criteria included publications with sufficient clinical, imaging, and histopathological information to confirm the diagnosis of sialoblastoma. Data were evaluated descriptively and analytically. A total of 52 studies met the eligibility criteria. In total, 62 patients were evaluated. There was no gender predilection, with the parotid being the most affected primary site (n = 28; 45.2%). In the log-rank test, there was a significant increase in disease-associated survival in patients younger than 1 year of age (82.8% vs. 44.4%; p = 0.003), individuals with lesions in major salivary glands (79.4% vs. 38.5%; p = 0.005), patients without metastases (77.8% vs. 14.3%; p = 0.011), encapsulated lesions (85.7% vs. 0%; p < 0.0001), congenital lesions (83.3% vs. 25.0%; p < 0.0001), and lesions that do not show perineural invasion (89.5% vs. 40%; p = 0.035). Kaplan-Meier curves estimated overall survival and disease-free survival at 5 years of 95.5% and 68.1%, respectively. In the multivariate Cox regression model, only the presence of metastasis was identified as an independent prognostic factor (hazard ratio [HR] = 9.81; p = 0.010). Although sialoblastoma presents good prognosis, the tumor has a high recurrence rate.

Secretory carcinoma of the salivary gland is rich in lactoferrin: a possible lactational-like differentiation?

PURPOSE: It has been hypothesised that secretory carcinoma of the salivary gland (SCsg) might have a lactational-like differentiation. Therefore, we aimed to assess the immunoexpression of breast hormonal receptors and milk-related proteins in cases of SCsg and other salivary gland tumours with prominent secretory activity. METHODS: Immunohistochemistry against prolactin and growth hormone receptors, lactoferrin, human milk fat globule 1, MUC 1 and MUC4 was performed in twelve cases of SCsg and 47 other salivary gland tumours. RESULTS: Most cases of SCsg were negative for prolactin and growth hormone receptors. All cases of SCsg showed enhanced membranous-cytoplasmic staining for human milk fat globule 1, a pattern seen in other tumour groups. Only SCsg showed widespread strong staining for lactoferrin, concomitantly in the cell compartment and secretion. The other positive tumour types exhibited restricted staining. MUC1 and MUC4 showed no distinct pattern of expression. CONCLUSION: Although SCsg failed to demonstrate a complete lactational-like differentiation, lactoferrin showed a distinctive expression pattern in SCsg compared to other tumour types, which makes it a good marker to help in its differential diagnosis.

Epithelial salivary gland tumors in pediatric patients: An international collaborative study.

OBJECTIVE: Salivary gland tumors (SGT) are a diverse group of uncommon neoplasms that are rare in pediatric patients. This study aimed to characterize the clinicopathological profile of pediatric patients affected by SGT from a large case series derived from an international group of academic centers. STUDY DESIGN: A retrospective analysis of pediatric patients with SGT (0-19 years old) diagnosed between 2000 and 2021 from Brazil, South Africa, and the United Kingdom was performed. SPSS Statistics for Windows was used for a quantitative analysis of the data, with a descriptive analysis of the clinicopathological characteristics and the association between clinical variables and diagnoses. RESULTS: A total of 203 cases of epithelial SGT were included. Females were slightly more commonly (56.5%), with a mean age of 14.1 years. The palate was the most common site (43.5%), followed by the parotid gland (29%), lip (10%), and submandibular gland (7.5%). The predominant clinical presentation was a flesh-colored, smooth, and painless nodule. Pleomorphic adenoma (PA) was the most frequently diagnosed SGT (58.6%), followed by mucoepidermoid carcinoma (MEC) (26.6%). Surgery (90.8%) was the favored treatment option. CONCLUSIONS: Benign SGT in pediatric patients are more commonly benign than malignant tumors. Clinicians should keep PA and MEC in mind when assessing nodular lesions of possible salivary gland origin in pediatric patients.

Prevalence of Sjögren's syndrome according to 2016 ACR-EULAR classification criteria in patients with systemic lupus erythematosus.

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.

Applicability of the Milan system for reporting salivary gland cytopathology: A single Brazilian institution experience.

INTRODUCTION: The Milan System for Reporting Salivary Gland Cytopathology (MSRSGC) emerged in 2015 as an attempt to establish protocols for a most appropriate follow-up and treatment of patients with salivary gland lesions. Through fine needle aspiration (FNA), a safe and minimally invasive way to obtain cytological samples, the lesion is classified into one of the six categories, which have different risks of malignancy (ROM) and, therefore, different management. MATERIALS AND METHODS: FNA cytology procedures performed between January 2016 and June 2020 (54 months) at the Pathology Institute of Araçatuba, São Paulo, Brazil, were analyzed by two pathologists with more than 5 years of experience. The ROM for each of the diagnostic categories was determines and compared with the ROM expected by the MSRSGC. RESULTS: A total of 99 FNA of salivary gland lesions were reviewed and retrospectively categorized. Histopathological follow-up was available for 58 of 96 patients (60.42%). The patients age ranged from 23 to 98 years with the mean of 58.15 ± 15.29 years. The parotid gland was the most affected (81.82%). The average size of the lesions was 2.59 cm. The ROM for each category was 16.67%, 0%, 0%, 2.86%, 50%, 100%, 100%, respectively. CONCLUSION: This is the first Brazilian study describing the application of the MSRSGC in the routine of a private Laboratory out of a cancer center service. Therefore, it is an effective method in the classification of salivary gland lesions, when associated with the MSRSGC, to determine the ROM and its appropriate treatment.

Clinicopathological and survival profile of patients with salivary gland myoepithelial carcinoma: A systematic review.

OBJECTIVES: In this systematic review, we aimed to evaluate the clinicopathological and prognosis data of patients with salivary gland myoepithelial carcinoma. MATERIALS AND METHODS: MEDLINE/PubMed, Scopus, and Embase search was performed with the keywords "myoepithelial carcinoma" "malignant myoepithelioma," and "salivary glands." Primary salivary glands myoepithelial carcinoma that fulfilled the World Health Organization diagnostic criteria were included. The Joanna Briggs Institute tool was used to assess the risk of bias. RESULTS: Forty-three studies (71 patients) met the inclusion criteria. The patients showed a mean age of 56.4 ± 19.6 years with no sex predilection. The parotid was the most affected gland (49.3%). The tumor presented as an asymptomatic (65.1%) mass (84%). The most common histological findings were the presence of clear tumor cells (39.7%) and multinodular growth patterns (60.7%). Multivariate analysis showed plasmacytoid cell type (p = 0.010) and solid growth pattern (p = 0.003) were related to decreased disease-free survival. Surgery alone was the most used treatment (53.5%). Patients with a combination of treatments showed a longer disease-free survival (p = 0.049). The 2-year and 5-year overall survival rates were 67.5% and 46.1%, respectively. CONCLUSION: Salivary gland myoepithelial carcinoma showed no sex predilection, with a higher incidence in the parotid gland. Cell type, growth pattern, and treatment type may be related to a lower disease-free survival. Overall, salivary gland myoepithelial carcinoma presented low recurrence and metastasis rates. Registration and protocol: This systematic review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 checklist and registered in the International Prospective Register of Systematic Reviews (PROSPERO) database (CRD42022311512).

Salivary gland tumor: atypical presentation of breast cancer

Breast cancer is a heterogeneous disease with various histological and molecular subtypes. Among them, salivary gland tumors are rare and can be divided into three groups: pure myoepithelial differentiation, pure epithelial differentiation and myoepithelial with mixed epithelial differentiation. In the last group, adenoid cystic carcinoma stands out, a rare entity with low malignant potential. It represents less than 0.1­3% of breast cancer cases and has the most frequent clinical presentation as a palpable mass. The diagnosis is confirmed by histology and immunohistochemistry. Classically, they are low-aggressive triple-negative tumors, with overall survival and specific cancer survival at five and ten years greater than 95%. However, there are rare reports of aggressive variants with a risk of distant metastasis and death. Treatment is based on surgical resection with margins. Lymphatic dissemination is rare, and there is no consensus regarding the indication of an axillary approach. Adjuvant radiotherapy is indicated in cases of conservative surgery and should be discussed in other cases. The benefit of chemotherapy remains uncertain, as most tumors are indolent. We report a case that required individualized decisions based on its peculiarities of presentation, diagnosed in an asymptomatic elderly patient during screening, in which mammography showed heterogeneous gross calcifications clustered covering 1.6 cm. Stereotacticguided vacuum-assisted biopsy was performed, and the area was marked with a clip. The anatomopathological examination led to a diagnosis of salivary gland-type carcinoma, triple-negative. The patient underwent segmental resection of the right breast and sentinel lymph node biopsy. The final anatomopathological result was similar to that of the biopsy, with an immunohistochemicalprofile of the adenoid cystic type and two sentinel lymph nodes free of neoplasia. Considering age and histological subtype, adjuvant therapy was not indicated. Follow-up for three years showed no evidence of disease

Are salivary flow rates associated with histopathologic aspects in patients with rheumatoid arthritis?

The aim of this retrospective cross-sectional study was to verify the association between salivary flow rates (SFR) and the histopathologic aspects of labial salivary glands (LSG) in patients with rheumatoid arthritis (RA). Patients presenting rheumatologic diseases referred for oral evaluation were included in the study if they had RA and had SFR measured and LSG biopsy performed. Patients were excluded if they had systemic conditions that affect SFR or if they were being treated for hyposalivation. Cases without enough material for histopathologic analysis were also excluded. Data were collected through questionnaires, oral examination, resting and stimulated SFR, and LSG biopsies. A histopathologic reevaluation was carried out in order to seek for additional histopathologic aspects. Fifty-one patients met the inclusion criteria. The mean age was 53.5 years (25-77), and 94.1% were women. The median resting and stimulated SFRs were 0.24 mL/min and 1.02 mL/min, respectively. The presence of lymphocytic focus and fibrosis were significantly associated with stimulated SFR, but not with resting SFR. The odds ratio of patients who had hyposalivation for presenting a positive lymphocytic focus was 7.33 (confidence interval CI: 1.53-35.23) by the stimulated technique, and 2.56 (CI: 0.57-11.40) in resting SFR. In the medical records, 14 (31.80%) patients had been diagnosed with secondary Sjögren's syndrome. In conclusion, stimulated SFR represent a good screening test to predict lymphocytic focus in LSG in patients with RA, which represents the most specific test to diagnose Sjögren's syndrome.

Morphological Changes in Major Salivary Glands in Mice Treated With a Choline and Methionine Deficient Diet.

BACKGROUND/AIM: It has been shown that the methionine-choline deficient (MCD) diet induces hepatocarcinogenesis, but not in extrahepatic organs, such as the testis, and pancreas, although may increase chemical-induced carcinogenesis in the colon, mammary gland, esophagus, and pancreas. Accumulating evidence suggests that salivary glands are very susceptible to stress conditions, such as radiation, hyperglycemia, and exposure to xenobiotics in vivo. This study aimed to analyze the histological changes on the major salivary glands (parotid, submandibular, and sublingual) after MCD diet administration. MATERIALS AND METHODS: Male Swiss mice were submitted to ad libitum access to the control (AIN-76) or MCD diet for 28 days. The rebound group received the MCD diet for 24 days and the control diet for 10 days. Using the AxioImager A2 microscope, the hematoxylin-eosin (HE) stained specimens (4 mm) were evaluated for tissue degeneration, nuclear hyperchromatism and atrophy. RESULTS: In the parotid gland from the MCD group, tissue degeneration, pyknosis, apoptosis and atrophy were observed, which remained in the rebound group, associated with hyperchromatism. In the submandibular gland from both MCD and rebound groups, severe tissue disorganization was associated with cell pleomorphism, hyperchromatic cells, apoptosis, increased eosinophilia, and inflammatory infiltrate. Finally, in the sublingual gland, there were no histological alterations in the experimental groups compared to the control. CONCLUSION: MCD can induce pre-neoplastic changes in the mouse parotid and submandibular glands, which are not reversed by a change in the diet.

Contribution of DNA methylation to the pathogenesis of Sjögren's syndrome: A review.

Sjögren's syndrome (SS) is a chronic systemic disease characterised by salivary and lacrimal gland dysfunction with severe implications for the well-being of bearing individuals. Although its origin has not yet been fully elucidated, it is known that genetic, environmental, and epigenetic factors are important contributors to the pathogenesis of this syndrome. DNA methylation is a relevant, widely studied epigenetic factor that is possibly related to the establishment of SS. The aim of the present study was to perform a systematic review of the literature to compile studies on the contribution of DNA methylation to the pathogenesis of SS. A literature search was performed in 4 databases (PubMed, Web of Science, Lilacs, and Scopus) using previously selected Medical Subject Headings (MESH) descriptors, and article selection considered observational studies only. After a full-text reading of the selected articles, 15 studies were in accordance with the eligibility criteria for data extraction. Methylation detection approaches included global methylation, genome-wide assessment of differentially methylated regions, and site-specific methylation. Fourteen articles reported associations of DNA methylation profiles in SS patients, both globally and in several genes in salivary glands and blood cells. Thus, DNA methylation may contribute to the pathogenesis of SS. The findings reinforce the importance of epigenetic markers in the dynamics of SS and may direct efforts toward the development of new diagnostic and therapeutic approaches.

Identificación de macrófagos y virus Epstein-Barr en biopsias de pacientes con Síndrome de Sjögren / Identification of macrophages and Epstein-Barr virus in salivary glands of Sjögren's syndrome patients

RESUMEN El síndrome de Sjögren (SS) es una enfermedad crónica mediada inmunológicamente. La presencia de macrófagos y el virus Epstein-Barr (VEB) se ha relacionado con su desarrollo y severidad. Los macrófagos contribuyen al proceso autoinmune local y la infección viral promueve el quiebre de la auto-tolerancia. Objetivos. Identificar la presencia de Macrófagos en el infiltrado inflamatorio y VEB en células inflamatorias, correlacionándolos con las características histológicas de glándulas salivales labiales. Metodología. En biopsias de glándulas salivales labiales (8 pacientes y 7 individuos controles) se realizó inmunohistoquímica antiCD-68 para identificar macrófagos. El conteo de macrófagos y células inflamatorias se efectuó en relación a su distribución en las glándulas salivales. La presencia del virus fue evaluada mediante hibridación in situ e inmunohistoquímica para LMP1. Se utilizó el test t no pareado y de Mann-Whitney para comparar los grupos, y coeficiente de correlación de Pearson para correlacionar con parámetros histológicos. Resultados. Se observó un mayor número de macrófagos en el infiltrado inflamatorio de pacientes (p=0,001**). Los macrófagos se distribuyeron difusamente en las glándulas de controles y en los focos inflamatorios de pacientes. En ambos grupos no se detectó la presencia del virus Epstein-Barr. Conclusión. Los pacientes con síndrome de Sjögren presentaron mayor presencia de macrófagos y su incremento es a expensas del foco inflamatorio.

ABSTRACT: Sjögren's syndrome (SS) is an immunologically mediated chronic disease of complex etiopathogenesis. Macrophages and Epstein-Barr virus are among the factors related to its development and severity. Macrophages contribute to the local autoimmune process and viral infection promotes the breakdown of self-tolerance. Objectives. Identify the presence of macrophages in the inflammatory infiltrate and Epstein-Barr virus in inflammatory cells, correlating them with the histological features of labial salivary glands. Methodology. In labial salivary glands biopsies of 8 patients and 7 control individuals, anti-CD-68 immunohistochemistry was performed to identify macrophages. The macrophages and inflammatory cells were counted in relation to their distribution in the salivary glands. The presence of the virus was evaluated by in situ hybridization for viral RNA and immunohistochemistry for latent membrane protein type 1. The comparison between both groups was made using the unpaired t-test and Mann-Whitney test. The correlations with histological parameters were established with the Pearson´s correlation coefficient. Results. A greater number of macrophages was observed in the inflammatory infiltrate of SS patients (p=0,001**). Macrophages in control individuals were diffusely distributed in the gland, while, SS in patients, they were mainly located in inflammatory foci. In both groups, no inflammatory or epithelial cells infected by the Epstein-Barr virus were identified. Conclusion. Patients with Sjögren's syndrome had a greater presence of macrophages and their increase is at the expense of the inflammatory focus.

Oral and maxillofacial manifestations of IgG4-related disease: A clinicopathological study.

BACKGROUND: IgG4-related disease is a fibroinflammatory and immune-mediated condition, which has extremely variable clinical manifestations. In this study, we aim to investigate the clinicopathological features of IgG4-related disease involving the oral and maxillofacial region. METHODS: Cases of IgG4-related disease manifesting in the oral and maxillofacial region were retrieved from three Brazilian institutions. Clinical and serological data were obtained from the patients' medical charts, while microscopic and immunohistochemical findings were revised by oral pathologists. Diagnosis followed the American College of Rheumatology/European League against Rheumatism criteria. RESULTS: Seven patients diagnosed with IgG4-related disease were included in this study. Women were affected in all analysed cases, with a mean age of 55.4 years. Two patients presented with the clinical involvement of more than one oral and maxillofacial anatomic site. Therefore, our sample comprised nine oral and maxillofacial anatomic sites affected by IgG4-related disease. The submandibular gland was affected in four cases, the tongue and the parotid gland in two cases each, and the palate in one case. In a few cases, exploratory lower lip biopsy was used as a diagnostic approach. A moderate-to-severe lymphoid infiltrate containing plasma cells and lymphocytes, with an increased IgG4/IgG ratio, was common. Treatment varied and steroids were the most frequently used (57.4%). Six patients remained alive, while one died from unknown causes. CONCLUSION: Although major salivary glands are commonly affected by IgG4-related disease, the oral cavity can also be involved, and lower lip biopsy may be an auxiliary diagnostic tool.

DNA Damage and Proteomic Profile Changes in Rat Salivary Glands After Chronic Exposure to Inorganic Mercury.

Mercury (Hg) is a toxic metal that became a public health problem due to environmental contamination caused by anthropogenic activity. In this sense, oral homeostasis can undergo changes due to the toxic effects of metal on the salivary glands. Therefore, our objective was to investigate the proteomic and genotoxic changes in salivary glands after exposure to inorganic mercury (IHg). Forty Wistar rats that were divided into a control group, which received distilled water, and an exposed group, which received 0.375 mg/kg of mercury chloride for 45 days via orogastric gavage. After that, the animals were euthanized, and the parotid and submandibular glands were collected for analysis of the genotoxic effects, using the comet assay and proteome global profile assessment. The results showed that IHg promoted damage to cellular DNA associated with proteomic changes that showed events such as oxidative stress, mitochondrial dysfunction, changes in the cytoskeleton, and apoptosis. Therefore, these findings show a profile of molecular changes due to the interactions of IHg with several proteins and mechanisms inherent to the cell, which consequently may result in dysfunction of the salivary glands and impaired homeostasis of the oral cavity.

Salivary gland cancer in the setting of tumor microenvironment: Translational routes for therapy.

Salivary gland carcinomas (SGC) are aggressive cancers that arise in minor and major salivary glands. Given the complexity and the multiple subtypes of this class of tumors, diagnosis and, treatment may be challenging for clinicians. Recently the tumor microenvironment, composed mainly of immune and stromal cells are been a target for treatment. Accumulating evidence indicates that cancer immunotherapies have made a significant impact on oncologic patients, however immunotherapeutic attempts in SGC have been shown limited improvement. Advances in the models that best translate aggressive SGC are needed for the development of clinical protocols grouping immunotherapies and other classes of drugs that will promote better responses in patients with advanced SGC stages. In this review, we introduced different experimental models for SGC with a focus on tumor microenvironment highlighting potential therapy applications for each model.