Focal Lymphocytic Sialadenitis Research Articles

Obstructive Sleep Apnea and Lymphocytic Sialadenitis: The Focus isn’t Just Sjögren’s Syndrome

Objective: We examined the presence of lymphocytic infiltration and measured focus scores in uvular specimens of patients with obstructive sleep apnea (OSA). Methods: We reviewed the histopathology of 101 uvular specimens obtained from patients with OSA and uvular hypertrophy. A lymphocyte focus score assessment was performed for each case. Results: Of the 101 cases, 42 (42%) cases had a positive focus score (score ≥ 1). Of those cases with a positive focus score, 22 (52%) had a focus score of 1, 14 (33%) had a focus score of 2, 4 (9%) had a focus score of 3, and 2 (5%) had a focus score of 4. Of the 59 patients (58%) with negative focus scores, 39 (66%) had minor lymphocytic infiltrates; 17 (29%) had features of chronic sialadenitis or extensive fibrosis; 3 (5%) had salivary mucosa without any apparent lymphocytes. Conclusion: Our findings indicate that patients with OSA may exhibit focal lymphocytic sialadenitis (FLS). It remains to be determined whether mucosal changes occur elsewhere in the oral cavity of patients with OSA. If so, the presence of OSA may complicate the histologic evaluation of Sjogren’s syndrome. Further investigations to determine the prevalence of FLS in the uvulae of individuals without history of OSA, the extent of FLS elsewhere within the oral cavity of patients with OSA and the relationship between the local inflammatory reaction and the systemic consequences of OSA are needed.

Reliability of histopathological salivary gland biopsy assessment in Sjögren's syndrome: a multicentre cohort study.

The aim of this study was to assess intraobserver and interobserver reliability of minor salivary gland biopsy (MSGB) in SS. All MSGBs available from the Tolerance and Efficacy of Rituximab in Primary Sjögren's Syndrome (TEARS) study were subjected to a standardized blinded assessment by a single specifically trained pathologist twice at a 2 month interval; both the Chisholm-Mason (CM) grade and the focus score (FS) were determined. Baseline histopathological reports by local pathologists at each study centre were compared with the first standardized blinded assessment. Agreement was assessed for the dichotomized FS (dFS) and dichotomized CM (dCM) grade, as well as for nine other histopathological features. Eighty-nine MSGBs were studied. Intraobserver κ values were 1 for dFS, 0.80 for dCM, 0.67 for germinal centre-like structures, 0.44 for fibrosis and 0.29 for confluent foci. Most of the local histopathological reports based their diagnosis on the CM grade, although the FS was often reported or the data needed to determine it were provided. Interobserver agreement κ values were 0.71 for dFS, 0.64 for dCM, 0.46 for focal lymphocytic sialadenitis, 0.42 for non-specific chronic inflammation and 0.16 for fibrosis. Although FS reliability was good, disparities were noted in the assessment methods used by local pathologists. The protocol for FS determination was not followed routinely, with the result that the FS was often overestimated. Germinal centre-like structures, which predict lymphoma, showed good reliability but were inconsistently reported.

Histopathological environment besides the focus score in Sjögren's syndrome.

To compare the prevalence of diverse histopathologic features among patients with Sjögren's syndrome (SS) and controls, and to evaluate their relationship with age, a focus score (FS) ≥1 and some clinical and serological SS features. A blinded pathologist examined 63 SS and 11 control minor salivary gland biopsies. Focal lymphocytic sialadenitis (FLS) was defined as a focus score (FS) ≥1. We also evaluated lymphoepithelial lesions, germinal centers (GCs), epithelial metaplasia, dilatation and hyperplasia in the main secretory duct, perivascular cell infiltrate, adipose infiltration, acinar atrophy, interstitial fibrosis and lymphocytes/plasma cells remote from the FLS. We registered demographics, anti-Ro/La status and clinical features. We used Kendall's tau coefficients and logistic regression analysis. Sjögren's syndrome patients had a higher frequency of FS ≥1 (92% vs. 27%), acinar atrophy (78% vs. 18%), lymphocytes and plasma cells external to the FSL (92% vs. 64%) and stromal fibrosis (68% vs. 36%). A FS ≥1 correlated with the presence of GCs and acinar atrophy; whereas age correlated with duct dilation, duct epithelial hyperplasia, adipose infiltration and fibrosis. SS patients with hepatic involvement exhibited more frequent duct dilatation. After adjusting by age, anti-Ro/SSA (odds ratio [OR] 30.8, 95% CI 2.2-423.5, P=0.01), a FS ≥1 (OR 54.3, 95% CI 4.8-612, P=0.001) and fibrosis (OR 15.2, 95% CI 1.2-186.2, P=0.03) were associated with SS. Other histologic findings coexist with FLS, but only GC formation and acinar atrophy correlated with a FS ≥1. Age is mostly correlated with the remaining histological features. However, the clinical relevance of these findings is unknown.

Comparison of labial minor salivary gland biopsies from childhood Sjögren syndrome and age-matched controls.

To determine an appropriate focus score cutoff for childhood Sjögren syndrome (SS). Labial salivary gland tissue from specimens from children with SS and age-matched controls was retrospectively identified and reviewed by a blinded oral pathologist. The presence of any focal sialadenitis (focus score > 0 foci/4 mm(2)) was common among childhood SS samples but present in only 1 of 8 control samples. The presence of any focal lymphocytic sialadenitis in minor labial salivary gland tissue is suggestive of childhood SS and should be included in future childhood SS-specific diagnostic or classification criteria.

Importance of salivary gland focus score in the diagnosis of Sjögren's syndrome

To explore the correlation between labial salivary gland focus score (FS) and severity of Sjögren's syndrome patients. From January 2009 to December 2010, a total of 77 patients with primary Sjögren's syndrome were recruited to undergo minor salivary gland biopsy, Schirmer's test, unstimulated whole salivary flow, organ function and serological test. Focus score was calculated for all biopsy samples. And the correlation between focus score and serological test and organ function damage was evaluated. Their pathological examinations revealed focal lymphocytic sialadenitis (n = 62), 10 cases with non-specific or sclerosing chronic sialadenitis (n = 10) and normal features (n = 5). Among 62 cases with focal lymphocytic sialadenitis, 46 cases had FS ≥ 1 and another 16 FS < 1. The median FS was 2.4 ± 2.5 . FS ≥ 1 was strongly associated with unstimulated whole salivary flow rates and ocular staining score (P < 0.05), but not significantly with dry mouth or eyes. FS was significantly correlated with serum immunoglobin G (IgG), immunoglobin M (IgM) and rheumatoid factor level (P < 0.05). Those with positive anti-SSA had higher FS level than those with negative anti-SSA antibody (P < 0.05). In addition, FS level was not significantly associated with organ function damage. Prior to determining FS, distinguishing focal lymphocytic sialadenitis from other types of sialadenitis is essential in assessing salivary gland biopsy. And the FS level might be associated with disease activity and positive anti-SSA. No correlation exists between FS and organ function damage.

American College of Rheumatology classification criteria for Sjögren's syndrome: A data‐driven, expert consensus approach in the Sjögren's International Collaborative Clinical Alliance Cohort

We propose new classification criteria for Sjögren's syndrome (SS), which are needed considering the emergence of biologic agents as potential treatments and their associated comorbidity. These criteria target individuals with signs/symptoms suggestive of SS. Criteria are based on expert opinion elicited using the nominal group technique and analyses of data from the Sjögren's International Collaborative Clinical Alliance. Preliminary criteria validation included comparisons with classifications based on the American–European Consensus Group (AECG) criteria, a model-based “gold standard”obtained from latent class analysis (LCA) of data from a range of diagnostic tests, and a comparison with cases and controls collected from sources external to the population used for criteria development. Validation results indicate high levels of sensitivity and specificity for the criteria. Case definition requires at least 2 of the following 3: 1) positive serum anti-SSA and/or anti-SSB or (positive rheumatoid factor and antinuclear antibody titer >1:320), 2) ocular staining score >3, or 3) presence of focal lymphocytic sialadenitis with a focus score >1 focus/4 mm2 in labial salivary gland biopsy samples. Observed agreement with the AECG criteria is high when these are applied using all objective tests. However, AECG classification based on allowable substitutions of symptoms for objective tests results in poor agreement with the proposed and LCA-derived classifications. These classification criteria developed from registry data collected using standardized measures are based on objective tests. Validation indicates improved classification performance relative to existing alternatives, making them more suitable for application in situations where misclassification may present health risks.

Associations between salivary gland histopathologic diagnoses and phenotypic features of Sjögren's syndrome among 1,726 registry participants

To examine associations between labial salivary gland (LSG) histopathology and other phenotypic features of Sjögren's syndrome (SS). The database of the Sjögren's International Collaborative Clinical Alliance (SICCA), a registry of patients with symptoms of possible SS as well as those with obvious disease, was used for the present study. LSG biopsy specimens from SICCA participants were subjected to protocol-directed histopathologic assessments. Among the 1,726 LSG specimens exhibiting any pattern of sialadenitis, we compared biopsy diagnoses against concurrent salivary, ocular, and serologic features. LSG specimens included 61% with focal lymphocytic sialadenitis (FLS; 69% of which had focus scores of ≥1 per 4 mm²) and 37% with nonspecific or sclerosing chronic sialadenitis (NS/SCS). Focus scores of ≥1 were strongly associated with serum anti-SSA/SSB positivity, rheumatoid factor, and the ocular component of SS, but not with symptoms of dry mouth or dry eyes. Those with positive anti-SSA/SSB were 9 times (95% confidence interval [95% CI] 7.4-11.9) more likely to have a focus score of ≥1 than were those without anti-SSA/SSB, and those with an unstimulated whole salivary flow rate of <0.1 ml/minute were 2 times (95% CI 1.7-2.8) more likely to have a focus score of ≥1 than were those with a higher flow rate, after controlling for other phenotypic features of SS. Distinguishing FLS from NS/SCS is essential in assessing LSG biopsies, before determining focus score. A diagnosis of FLS with a focus score of ≥1 per 4 mm², as compared to FLS with a focus score of <1 or NS/SCS, is strongly associated with the ocular and serologic components of SS and reflects SS autoimmunity.

A Simplified Quantitative Method for Assessing Keratoconjunctivitis Sicca From the Sjögren's Syndrome International Registry

To describe, apply, and test a new ocular grading system for assessing keratoconjunctivitis sicca (KCS) using lissamine green and fluorescein. Prospective, observational, multicenter cohort study. The National Institutes of Health-funded Sjögren's Syndrome International Registry (called Sjögren's International Collaborative Clinical Alliance [SICCA]) is developing standardized classification criteria for Sjögren syndrome (SS) and is creating a biospecimen bank for future research. Eight SICCA ophthalmologists developed a new quantitative ocular grading system (SICCA ocular staining score [OSS]), and we analyzed OSS distribution among the SICCA cohort and its association with other phenotypic characteristics of SS. The SICCA cohort includes participants ranging from possibly early SS to advanced disease. Procedures include sequenced unanesthetized Schirmer test, tear break-up time, ocular surface staining, and external eye examination at the slit lamp. Using statistical analyses and proportional Venn diagrams, we examined interrelationships between abnormal OSS (>or=3) and other characteristics of SS (labial salivary gland [LSG] biopsy with focal lymphocytic sialadenitis and focus score >1 positive anti-SS A antibodies, anti-SS B antibodies, or both). Among 1208 participants, we found strong associations between abnormal OSS, positive serologic results, and positive LSG focus scores (P < .0001). Analysis of the overlapping relationships of these 3 measures defined a large group of participants who had KCS without other components of SS, representing a clinical entity distinct from the KCS associated with SS. This new method for assessing KCS will become the means for diagnosing the ocular component of SS in future classification criteria. We find 2 forms of KCS whose causes may differ.

Beurteilung von Lippendrüsenbiopsaten beim Sjögren-Syndrom

In the majority of cases, autoimmune sialadenitis is a feature of Sjögren's syndrome. This systemic autoimmune disease is, therefore, clinically characterised by sicca symptoms such as xerostomia and keratoconjunctivitis sicca. Since autoimmune sialadenitis affects major as well as minor salivary glands, histopathological examination is almost always carried out using labial salivary gland biopsies. A positive histopathological result is determined as a focal lymphocytic sialadenitis with at least one aggregate of 50 or more lymphocytes and histiocytes per 4 mm2 of salivary gland tissue. As one out of four objective findings, focus scoring belongs to the classification criteria for Sjögren's syndrome according to the American-European consensus group.

Systemic sclerosis–associated Sjögren's syndrome and relationship to the limited cutaneous subtype: Results of a prospective study of sicca syndrome in 133 consecutive patients

To determine the prevalence of sicca symptoms and Sjögren's syndrome (SS) in a 2-center prospective series of patients with systemic sclerosis (SSc), using the American-European Consensus Group criteria for SS. Consecutive SSc patients hospitalized for followup care were evaluated for sicca symptoms. When the initial clinical evaluation yielded positive findings, a labial salivary gland biopsy was performed; histologic analysis evaluated focal lymphocytic sialadenitis and/or glandular fibrosis. Computed tomography and respiratory function tests were used to assess pulmonary fibrosis. We included 133 SSc patients (mean +/- SD age 55 +/- 13 years; mean +/- SD disease duration 6.5 +/- 6 years). Eighty-one patients had limited cutaneous SSc (lcSSc). Ninety-one patients (68%) had sicca syndrome. Histologic analysis revealed fibrotic involvement in 50 of these 91 patients, but labial salivary gland fibrosis was not associated with any organ involvement we evaluated. Nineteen of the 133 patients (14%) had SS. In this subgroup, lcSSc was present at a significantly higher frequency (18 of 19 patients) than in the remaining patients with sicca syndrome (39 of 72 patients) and the patients without sicca syndrome (24 of 42 patients). This subgroup also had a significantly higher frequency of anticentromere antibodies (18 of 19 patients) than did the remaining patients with sicca syndrome (19 of 72 patients) and the patients without sicca syndrome (5 of 42 patients). In addition, this subgroup had a significantly lower prevalence of pulmonary fibrosis (2 of 19 patients) than did the remaining patients with sicca syndrome (29 of 72 patients) and the patients without sicca syndrome (19 of 42 patients). There was a 68% prevalence of sicca syndrome in this prospective series of SSc patients. Sicca syndrome was related primarily to glandular fibrosis, the hallmark of SSc. The prevalence of secondary SS, as defined by the American-European Consensus Group criteria, was 14% and was markedly associated with lcSSc. We believe that lcSSc should be regarded as a specific autoimmune subgroup of SSc.

Prevalence and clinical significance of lymphocytic foci in minor salivary glands of healthy volunteers.

To determine the prevalence and severity of focal lymphocytic sialadenitis in minor salivary glands of healthy, asymptomatic individuals, in whom Sjögren's syndrome (SS) has been excluded. Charts of 54 healthy volunteers who had salivary gland biopsies at the National Institutes of Health from January 1992 to August 1998 were reviewed. The healthy volunteers served as control subjects in various studies of salivary dysfunction. Significant medical conditions including SS were excluded. A biopsy with a focus score (FS) >1 was regarded as positive. Descriptive statistics were used to summarize the population's characteristics. The frequency of focal lymphocytic infiltration in the healthy volunteers was about 15% (8 of 54). None of these individuals had subjective xerostomia or dry eyes. The positive FS ranged from 2 to 6. FS did not correlate with age, smoking, serologic findings, or salivary flow in these patients. Lymphocytic infiltration in minor salivary glands is not uncommon among individuals without a history of salivary gland dysfunction. This finding is in agreement with the result of a previous autopsy survey study, indicating that focal sialadenitis may occur in the absence of SS.

Association of patterns of labial salivary gland inflammation with keratoconjunctivitis sicca. Analysis of 618 patients with suspected Sjögren's syndrome.

To determine the association between patterns of inflammation in labial salivary glands (LSG) and the ocular component of Sjögren's syndrome (SS). We classified LSG biopsy specimens from 618 patients with suspected SS as showing focal lymphocytic sialadenitis (FLS), other chronic sialadenitis (CS), or other diagnoses. We then determined the association of the other component of primary SS, keratoconjunctivitis sicca (KCS), with FLS, CS, parotid flow rate, and xerostomia. FLS, rather than CS, was associated with a diagnosis of KCS (chi 2 = 191, P < 0.0001). The severity of KCS correlated directly with the severity of FLS (r = 0.52, P < 0.0001), but not of CS, and correlated inversely with parotid flow rate in those patients who had FLS (r = -0.29), but not in those who had CS (r = -0.03). Xerostomia was marginally associated with KCS (chi 2 = 5, P = 0.02). The stronger KCS association found in patients whose LSG biopsies show FLS makes FLS the best criterion presently available for diagnosing the salivary component of SS. CS is a common feature of labial salivary glands but is neither associated with SS nor an end stage of primary SS. Histopathologic examination of salivary tissue is currently essential for diagnosing primary SS as well as secondary SS in which KCS is lacking, especially cases to be included in studies of SS.

SALIVARY AND ORAL COMPONENTS OF SJÖGREN’S SYNDROME

The intraoral symptoms and signs of SS are not specific to SS, being shared with other conditions in which salivary function is diminished. The decrease in saliva causes chronic oral discomfort and functional problems and predisposes patients to dental caries and oral candidiasis. Many methods have been used to assess SGs in SS objectively, but at present a labial salivary gland biopsy specimen showing focal lymphocytic sialadenitis provides the best diagnostic criterion for the salivary component of SS, in terms of its disease specificity, convenience, availability, and low risk. The treatment of xerostomia in patients with SS consists of (1) preventing new and recurrent dental caries by frequent and regular application of topical fluoride, careful dental supervision, and avoidance of sucrose and other metabolizable carbohydrates between meals; (2) reducing oral symptoms by diagnosing and treating oral candidiasis (repeatedly if necessary); and (3) attempting to replace lost saliva by stimulating salivary secretion with physiologic sialogogues or pilocarpine, or if adequate amounts of saliva cannot be stimulated, using some form of saliva substitute, especially for patients wearing complete dentures.

Lymphocytic sialadenitis of Sjögren's syndrome associated with chronic hepatitis C virus liver disease

Viral infection has often been suggested as a possible cause of Sjögren's syndrome or chronic lymphocytic sialadenitis, and Epstein-Barr virus has been found in the salivary glands of patients with this condition. After we had noted Sjögren's syndrome in several patients infected with hepatitis C virus (HCV), a virus also excreted in saliva, we set up a prospective study to investigate the association of chronic lymphocytic sialadenitis, with or without symptoms, to chronic HCV liver disease. The histological appearances of labial salivary glands in patients with proven HCV hepatitis or cirrhosis were compared with those in dead controls. Histological changes characteristic of Sjögren's syndrome were significantly more common in HCV-infected patients (16 of 28, 57%) compared with controls (1 of 20, 5%). Focal lymphocytic sialadenitis characteristic of Sjögren's syndrome (though only 10 patients had xerostomia and none complained of xerophthalmia) appears to be common in patients with chronic HCV liver disease; if this association is confirmed, identification of the underlying mechanism may improve our understanding of both disorders.

Palatal biopsy as a diagnostic aid in the study of connective tissue diseases

Palatal biopsies from eighty patients with known connective tissue disease were examined to determine the incidence of focal lymphocytic sialadenitis. Lymphocytic aggregates were demonstrated in 82 per cent, compared to 6 per cent in a control series of eighty ostensibly healthy patients. The palatal biopsy is innocuous, simple to perform, requires no suturing, and yields tissue of diagnostic quality.

Lymphocytic sialadenitis in the buccal mucosa, in Sjögren's disease, rheumatoid arthritis and other arthritides. A clinical and laboratory study.

SummaryThe buccal mucous membrane biopsy has been examined histologically for focal lymphocytic sialadenitis, in patients with Sjogren's syndrome, Sjogren's syndrome with rheumatoid arthritis, rheumatoid arthritis alone, and other arthritides.Focal lymphocytic sialadenitis was found in approximately 60 % of all patients with Sjogren's syndrome — with or without rheumatoid arthritis — and in 27.5 % of patients with rheumatoid arthritis. In rheumatoid arthritis, this did not correlate with symptomatic xerostomia, or possible keratoconjunctivitis sicca, both of which may be manifestations of a mild form of Sjogren's syndrome.