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.

OBJECTIVE: 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. METHODS: 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 American­European 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. RESULTS: 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. CONCLUSION: 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.

Lamivudine is not effective in primary Sjögren's syndrome.

BACKGROUND: Retroviral infection has been implicated in the pathogenesis of primary Sjögren's syndrome. OBJECTIVE: To examine the efficacy of the reverse transcriptase inhibitor lamivudine in patients with this syndrome. METHODS: 16 patients with primary Sjögren's syndrome were randomised to receive either lamivudine 150 mg twice daily or placebo for three months. Measures of lacrimal and salivary function, including minor salivary gland biopsies, were obtained before and after treatment. RESULTS: Treatment with lamivudine did not result in significant improvement in the primary outcome measure of unstimulated whole salivary flow or other secondary measures, including minor salivary gland biopsy focus scores. CONCLUSION: Lamivudine is not effective in patients with primary Sjögren's syndrome, suggesting either that a retroviral aetiology is not present or that it may be important only in early disease.

Classification criteria for Sjögren's syndrome: a revised version of the European criteria proposed by the American-European Consensus Group.

Classification criteria for Sjögren's syndrome (SS) were developed and validated between 1989 and 1996 by the European Study Group on Classification Criteria for SS, and broadly accepted. These have been re-examined by consensus group members, who have introduced some modifications, more clearly defined the rules for classifying patients with primary or secondary SS, and provided more precise exclusion criteria.

Advanced diagnostic methods in oral and maxillofacial pathology. Part I: molecular methods.

The practice of pathology is currently undergoing significant change, in large part due to advances in the analysis of DNA, RNA, and proteins in tissues. These advances have permitted improved biologic insights into many developmental, inflammatory, metabolic, infectious, and neoplastic diseases. Moreover, molecular analysis has also led to improvements in accuracy of disease diagnosis and classification. It is likely that, in the future, these methods will increasingly enter into the day-to-day diagnosis and management of patients. The pathologist will continue to play a fundamental role in diagnosis and will likely be in a pivotal position to guide the implementation and interpretation of these tests as they move from the research laboratory into diagnostic pathology. The purpose of this 2-part series is to provide an overview of the principles and applications of current molecular biologic and immunologic tests. Part I will discuss the biologic fundamentals of DNA, RNA, and proteins and the methods that are currently available or likely to become available to the pathologist in the next several years for their isolation and analysis in tissue biopsies.

Evaluation, differential diagnosis, and treatment of xerostomia.

The salivary component of Sjögren's syndrome (SS) is defined as xerostomia (dry mouth). However, xerostomia is a common symptom associated with quantitative and qualitative changes in saliva, which are generally referred to as salivary hypofunction. This can be caused by various systemic diseases (including SS), anticholinergic effects of many drugs, psychological conditions, and physiological changes. Chronic salivary hypofunction is clinically significant because it can cause oral dysfunction, dental destruction, and mucosal infection. Evaluating patients complaining of xerostomia requires particular attention to their current medications and physical examination of the major salivary glands, teeth, and oral mucosa. Based on that information and the differential diagnosis of salivary hypofunction, appropriate tests can then be selected to develop a final diagnosis. Effective treatment of patients with chronic salivary hypofunction requires a combination of: (1) ongoing dental decay prevention and treatment supervised by their dentist; (2) salivary flow stimulation; (3) recognition and treatment of chronic oral candidiasis; (4) selective use of saliva substitutes; and (5) prescription drug review.

Xerostomia--clinical evaluation and treatment in general practice.

Xerostomia is a common symptom with various causes that, if ignored, can lead to serious oral consequences. Clinical evaluation of patients complaining of dry mouth must include some additional history and specific examination of the salivary glands, oral mucosa, and teeth. Additional evaluation may include consultation with the patient's physician, request for microbial culture, or labial salivary gland biopsy. No one form of treatment for patients with chronic xerostomia is sufficient, but comprehensive treatment is effective in improving patient oral comfort and function and preventing unnecessary loss of teeth. This treatment must include ongoing dental caries prevention and treatment, salivary flow stimulation, recognition and treatment of oral candidiasis, selective use of saliva substitutes, and possible changes in the patients' prescription and nonprescription drug use.

Tear lysozyme activity in frozen Schirmer strips and salivary gland biopsy as parameters of lacrimal gland function.

PURPOSE: The lysozyme concentration in human tears is an important parameter for tear gland function. The decline of lysozyme in tears reflects lacrimal gland destruction. In Sjögren's patients, lacrimal gland destruction parallels labial salivary gland destruction. The objective of this study was to determine whether human tear lysozyme that was frozen on Schirmer strips at -20 degrees C for several years maintained activity and whether there was a linear relation with inflammatory changes in labial salivary glands. METHODS: A total of 200 frozen Schirmer strips were processed. They were collected from 20 randomly selected patients each year of five consecutive years, all attending the UCSF Sjögren's Clinic. The tear lysozyme in the Schirmer strips was measured by a colorimetric assay. The average lysozyme concentration each year was calculated and compared. One third of the patients underwent labial salivary gland biopsy. The correlation was calculated between the tear lysozyme concentration and the lymphocytic focus scores in biopsy specimens. RESULTS: No significant difference of average lysozyme concentration in the Schirmer strips was found when the five different years of collection were compared. The linear relation between the tear lysozyme concentrations and the focus score in labial salivary gland biopsies showed a coefficient of r = -0.41. The linear relation between other diagnostic measurements, like Schirmer test, tear breakup time, or rose bengal staining pattern, and the focus score was lower. CONCLUSIONS: Human tear lysozyme in Schirmer strips can be stored at -20 degrees C for at least five years. There is little difference in lysozyme activity of frozen compared to unfrozen specimens. The lysozyme concentration in tears correlates better with the lymphocytic focus score in labial salivary gland biopsy than does clinical assessment and is therefore a parameter for the actual degree of tear gland destruction.

Apoptosis-associated proteins in oral lymphomas from HIV-positive patients.

Extranodal oral lymphomas, seen with increasing frequency in HIV infection, may have dysfunctional apoptotic mechanisms that favor tumor progression. The purpose of this study was to evaluate extranodal lymphomas from HIV-positive patients for expression of apoptosis-associated proteins. Correlations were made with 10 histologically comparable extranodal lymphomas from HIV-negative patients and 6 hyperplastic lymph nodes from otherwise healthy young adults. Formalin-fixed tissue sections were immunohistochemically stained for apoptosis-associated proteins (Bcl-2, Bcl-x, Bax, Bak, p53, MDM2, BHRF). In situ hybridization was also done on deparaffinized sections for Epstein-Barr virus EBER mRNA. Eighteen consecutive oral lymphomas were studied in HIV/AIDS-positive patients. Four of 5 intermediate-grade lymphomas expressed Bcl-2 to a greater degree than did high-grade lymphomas (4 of 13). Most lymphomas were positive for Bcl-x and Bax, and few expressed Bak. The staining patterns for these proteins were similar to those seen in HIV-negative patients. Staining patterns were relatively consistent in the hyperplastic lymph nodes, whereas such patterns were irregular in lymphomas. Positive p53 staining was seen in 11 of 18 HIV-positive cases; 9 of these were also MDM2-positive. Double stains suggested that both p53 and MDM2 proteins were expressed in the same cells in these nine cases. Epstein-Barr virus-EBER mRNA was detected in 14 of 18 cases and in 3 of 10 cases from HIV-negative patients. BHRF staining was evident in only a few cells of three HIV-positive lymphomas. The irregular expression of Bcl-2, Bcl-x, Bax, and Bak in oral lymphomas indicates dysfunctional apoptotic mechanisms in these tumors. Bcl-2 staining differs with tumor grade. Positive staining for p53 and MDM2 proteins is a notable feature of lymphomas in HIV-positive patients and may relate to binding of MDM2 to wild-type p53. Epstein-Barr virus is more commonly associated with oral lymphomas in HIV-positive patients, although the Epstein-Barr virus-produced protein BHRF, which has Bcl-2-like activity, is minimally expressed.

Comparison of cytopathic changes in oral hairy leukoplakia with in situ hybridization for EBV DNA.

OBJECTIVE: It has been observed that the cytopathic changes in hairy leukoplakia (HL) correlate with ultrastructural evidence of intra-keratinocyte herpes-type viral particles. In situ hybridization is considered to be the definitive confirmation of Epstein-Barr virus (EBV)-induced HL. This study evaluated the consistency of histopathological findings, which many believe to be diagnostic, with in situ hybridization for EBV-DNA in 60 patients with lesions clinically suggestive of HL. MATERIALS AND METHODS: Hematoxylin and eosin (H&E)-stained sections were reviewed independently by three oral pathologists who did not know the hybridization results. The presence in keratinocytes of nuclear inclusions and/or homogenization, believed to be specific for EBV in these lesions, was used as an indicator for infection. Cytoplasmic changes were evaluated separately. RESULTS: With in situ hybridization, 48 cases were positive and 12 were negative. When the two methods were compared, pathologist concurrence ranged from 83% to 92%. False negatives ranged from 6% to 19%, and false positives ranged from 8% to 25%. Cytoplasmic ballooning, homogenization, and perinuclear clearing were evident in all cases of hybridization-confirmed HL; however, these changes were also noted in 75% (9/12) of the cases with negative hybridization results. Most confirmed HL cases exhibited both nuclear homogenization and inclusions, although the former was more consistently seen. CONCLUSION: Cytoplasmic changes did not agree well with EBV-DNA hybridization results, whereas nuclear changes demonstrated good, but not complete, agreement. In appropriate clinical settings, the finding of nuclear inclusions and/or homogenization may be of diagnostic value. However, because the potential for false positives and negatives is high, H&E cytopathology should not be used as a substitute for in situ hybridization in the definitive diagnosis of oral hairy leukoplakia.

Sarcoidosis Mimicking Sjögren's Syndrome: Histopathologic Observations.

The clinical manifestations of Sjõgren's syndrome (SS) and sarcoidosis can be identical. Of the 1600 patients whom we have evaluated for dryness of the mouth and eyes, 300 proved to have SS and 5 had sarcoidosis. The patients with sarcoidosis had combinations of salivary gland enlargement, elevated antinuclear antibody titers, reduced salivary flow rates, and keratoconjunctivitis sicca, findings typically associated with SS. Finding non-caseating granulomas in a labial salivary gland biopsy specimen may be the only way to definitively differentiate these two disorders.

Oral mucosal melanomas: the WESTOP Banff workshop proceedings. Western Society of Teachers of Oral Pathology.

A workshop to discuss primary oral melanomas was convened at the annual Western Society of Teachers of Oral Pathology meeting in Bannf, Alberta, Canada. Fifty oral melanomas, identified from the files of the participants, were reviewed in order to better understand the clinical features, histologic spectrum, and natural history of these perplexing lesions. Results confirmed that oral melanomas occur in adults almost three times more frequently in men than women and have a decided predilection for the palate and gingiva. Some lesions exhibit a clinically detectable and prolonged in situ growth phase, whereas others seem to lack this property and exhibit only or predominantly invasive characteristics. Recurrences, metastases, and death from tumor were characteristic of the follow-up of a limited number of patients. Until definitive prospective data are collected that elucidate natural history, oral mucosal melanomas should be tracked separately from cutaneous lesions. All oral pigmented lesions that are not clinically diagnostic should be biopsied. Lesions with equivocal histopathologic features might be referred to as "atypical melanocytic proliferation" and should be excised. Recognition of lesions in an early in situ phase and aggressive treatment should have a favorable effect on prognosis. To enhance future or prospective study of these rare neoplasms, guidelines for reporting oral melanomas are suggested.

Sjogren's syndrome: clinical spectrum and current diagnostic controversies.

Although we have had a useful and internationally agreed-upon definition of Sjögren's syndrome (SS) for more than 30 years, we have not yet agreed upon criteria for diagnosing it. Understanding the clinical spectrum of SS and the various tests used to diagnose its components provides a basis for discussing controversies about diagnostic criteria. A review of the clinical features of SS and their diagnostic tests is followed by assessments of seven sets of diagnostic criteria and a proposal for future criteria. The various existing criteria use different combinations of clinical features and tests, which results in populations of different sizes and homogeneities being given the diagnosis of SS. Some criteria propose alternative tests in diagnosing components of SS, while others do not. Internationally accepted diagnostic criteria for SS that are as disease-specific as possible are needed for us to learn the epidemiology, pathogenesis, treatment, and prognosis of this clinically and scientifically important disease.

Is sialography effective in diagnosing the salivary component of Sjögren's syndrome?

Parotid sialography has been used for many years as a means of assessing salivary glands in Sjögren's syndrome (SS), and it is occasionally used as a diagnostic criterion for the salivary component of SS. To assess its diagnostic effectiveness, we reviewed studies in which sialography was applied to patients with SS and control subjects for the purpose of estimating its diagnostic sensitivity and specificity or comparing it with other means of assessing salivary glands. Sialography appears to be diagnostically less sensitive but more specific than salivary flow rate measurement and more sensitive but less specific than labial salivary gland (LSG) biopsy. Such calculations are based on the diagnosis of SS established in each study, but the various studies used widely different criteria to establish that diagnosis. Therefore, these calculations are not based on a consistent standard, and comparison between the calculations may be misleading, which underscores the need to develop internationally accepted diagnostic criteria for SS. Studies conducted so far have not shown that parotid sialography is either a sensitive indicator of the salivary component of SS or more closely associated than LSG biopsy with keratoconjunctivitis sicca, the only other component of primary SS with which ultimately to assess diagnostic specificity.

Association between proliferative verrucous leukoplakia and infection with human papillomavirus type 16.

Proliferative verrucous leukoplakia (PVL) is a recently described clinical entity characterized by multifocal oral lesions that frequently progress to oral cancer despite abstinence from tobacco use by most patients. To determine if this condition is associated with human papillomavirus (HPV), a polymerase chain reaction (PCR) for HPV DNA was performed on 9 lesions from 7 patients with PVL, histologically diagnosed with focal keratosis (1), papilloma (1), epithelial dysplasia (5) and squamous cell cancer (2). Eight (89%) were HPV positive, 7 for HPV 16. For comparison, we studied 55 non-PVL-associated oral specimens, including 24 oral squamous cell cancers. Of the cancers, 8 (33%) were HPV positive, 4 for HPV 16. These data suggest that HPV 16 infection may play an important role in the pathogenesis of PVL-associated oral dysplasia and possibly cancer, but is found in only a small proportion of the more common, non-PVL associated-oral lesions.

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

OBJECTIVE: To determine the association between patterns of inflammation in labial salivary glands (LSG) and the ocular component of Sjögren's syndrome (SS). METHODS: 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. RESULTS: 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). CONCLUSION: 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.

Increased submucosal factor XIIIa-positive dendrocytes in oral lichen planus.

Factor XIIIa+ "dendrocytes", normal residents of the submucosa and dermis, are a morphologically and phenotypically distinctive subset of the monocyte-macrophage system. Because these cells are believed to participate in the regulation of immune responses, we postulated that they may play a role in the pathogenesis of lichen planus, a condition of immune dysregulation. Tissue sections of oral lichen planus were evaluated immunohistochemically for evidence of differences in dendrocyte populations in lesional and non-lesional areas from the same patient. In addition to factor XIIIa, sections were stained for antigens (CD68, S-100 protein, CD36) that may be expressed by other cells that occasionally exhibit dendritic profiles. CD18 (found on leukocytes and dendrocytes) and its ligand ICAM-1 (intercellular adhesion molecule) were also identified in sections to determine if these antigens are operative in lichen planus. Results showed that XIIIa+ dendrocytes were significantly increased in number (and size) in lichen planus. The mean number of dendrocytes in connective tissue subjacent to basement membrane (0.064 mm2) was 27 in lichen planus as compared to 10 in adjacent unaffected tissue. Similar increases were also evident in connective tissue deep to this zone (mean of 20 dendrocytes vs. mean of 8). CD68+ macrophages were also abundant in the lichen planus infiltrate, and S-100+ connective tissue cells were frequently seen. CD36+ dendritic cells were seen in relatively small numbers in the same sites where dendrocytes were found. ICAM-1+ connective tissue dendritic cells of undetermined lineage were also evident in the diseased areas.(ABSTRACT TRUNCATED AT 250 WORDS)

Oral melanocytic lesions: differences in expression of HMB-45 and S-100 antigens in round and spindle cells of malignant and benign lesions.

Immunohistochemistry and melanin bleaching were used to assess the expression of antigens identified by anti-S-100 and anti-HMB-45 antibodies on melanomas and intramucosal and blue nevi from the oral mucosa of 18 patients. Both antibodies reacted with cells in all three types of lesions, but there were differences in the expression of these antigens between the round and spindle cells within the lesions. In melanomas composed of round cells, the intensity and distribution of staining with HMB-45 was greater than with S-100. The opposite was true in melanomas composed of spindle-shaped cells, and one spindle-cell melanoma was HMB-45-negative. The round cells of intramucosal nevi expressed S-100 more intensely and more frequently than HMB-45. The spindle-shaped cells of blue nevi strongly expressed both S-100 and HMB-45. Whereas intradermal nevi from the skin do not express HMB-45, intramucosal nevi consistently express this antigen in the lesion and overlying mucosa. Oral melanomas composed of round and spindle-shaped cells show differences in their expression of S-100 and HMB-45 antigens, making the use of both antibodies complementary in the diagnosis of undifferentiated tumors.