Newswise — Biopsying the glands that produce saliva to test for germinal center-like formation when someone is diagnosed with primary Sjögren’s Syndrome can predict later development of non-Hodgkin’s lymphoma, according to research presented this week at the American College of Rheumatology Annual Scientific Meeting in Atlanta.

Sjögren's syndrome is an inflammatory disease that can affect many different parts of the body, but most often affects the tear and saliva glands. Patients with this condition may notice irritation, a gritty feeling, or painful burning in the eyes. Dry mouth or difficulty eating dry foods, and swelling of the glands around the face and neck are also common. Some patients experience dryness of other mucous membranes (such as the nasal passages, throat, and vagina) and skin. Between 400,000 and 3.1 million adults have Sjögren's syndrome. Primary Sjögren's syndrome occurs in people with no other rheumatic diseases. Secondary Sjögren's occurs in people who do have another rheumatologic disease, most often lupus and rheumatoid arthritis.

Germinal centers are sites within lymph nodes or lymph nodules where B cells maturate, proliferate, differentiate, and adapt as a component of the immune response. The centers develop dynamically after both B and T lymphocytes are activated after exposure to an antigen.

“Despite the fact that a connection between GC formation and lymphoma has been proposed and hypothesized, nobody has been able to prove this in an epidemiological setting in real patients,” explains Elke Theander, MD, PhD; head of the Department of Rheumatology at the Skane University Hospital, Malmö, Sweden and lead investigator in the study.

Until now, that is. Dr. Theander’s team recently followed patients from salivary gland biopsy until diagnosis of lymphoma, death, or end of follow up, which was anywhere from one month to 26 years. They reviewed 174 salivary gland biopsies from patients with primary Sjögren’s syndrome for the presence of germinal center-like structures. The samples were examined using light-microscopy, and the pathologists who examined them did not know a patient’s status with regard to lymphoma – nor did they have access to patient data such as their treatment or risk factors for Sjögren's.

Germinal center-like structures, defined for this study as a densely packed dark zone and a light zone in biopsies with classical focal infiltration within otherwise normal salivary glands, were detected in 43 biopsies. Seven of the patients studied developed non-Hodgkin’s lymphoma, six of whom had germinal center-like structures in their salivary gland biopsies at the time they were diagnosed with Sjögren’s syndrome. The median time between salivary gland biopsy and non-Hodgkin’s lymphoma diagnosis was eight years.

Overall, patients with germinal center-like structures had a 15 times greater risk of developing non-Hodgkin’s lymphoma compared to those without. Furthermore, absence of these structures had a 99 percent negative predictive value — suggesting that those patients would not go on to develop lymphoma.

“If germinal center-like structures are present in the diagnostic salivary gland biopsy, the patient should be followed and screened for possible lymphoma development, while patients without are less likely to develop the malignancy complication,” Dr. Theander says. “Being germinal-center positive might, under certain circumstances, support use of biological treatment, such as anti-B cell directed therapy. Still unclear is when to start such treatment.”

The American College of Rheumatology is an international professional medical society that represents more than 8,000 rheumatologists and rheumatology health professionals around the world. Its mission is to advance rheumatology. The ACR/ARHP Annual Scientific Meeting is the premier meeting in rheumatology. For more information about the meeting, visit Follow the meeting on twitter by using the official hashtag: #ACR2010.


Editor’s Notes: Elke Theander, MD, PhD will present this research during the ACR Annual Scientific Meeting at the Georgia World Congress Center from 9:00 – 11:00 AM on Wednesday, November 10 in Halls B1 & B2. Dr. Theander will be available for media questions and briefing at 8:30 AM on Tuesday, November 9 in the on-site press conference room, B 212.

Learn more about living well with rheumatic disease as well as rheumatologists and the role they play in health care.

Presentation Number: 1899

Germinal Center (GC) Formation in Salivary Gland Biopsies at Diagnosis of Primary Sjögren's Syndrome (pSS) Is a New and Strong Predictor of Non-Hodgkin's Lymphoma (NHL) during Follow-Up.

Elke Theander (University of Lund, Malmö)Lilian Vasaitis (University of Lund, Uppsala)Eva Baecklund (University of Uppsala, Uppsala)Gunnel Nordmark (University of Uppsala, Uppsala)Gunnar Warfvinge (University of Lund, Malmö)Rolf Liedholm (University of Lund, Malmö)Karl Brokstad (University of Bergen, Bergen)Roland Jonsson, DDS, PhD (Broegelmann Research Laboratory, University of Bergen, Bergen)Malin V Jonsson (University of Bergen, Bergen) Background: Due to increased risk of NHL in pSS the identification of better markers for lymphoma development is crucial.

Objective: Does GC formation in salivary gland biopsies from the time point of pSS diagnosis predict NHL? Does GC formation correlate with other markers of NHL?

Methods: 174 pSS minor salivary gland biopsies from the Swedish SS centers in Malmoe and Uppsala underwent blind and independent reevaluation by light-microscopy at the Broegelmann Research Laboratory, Bergen, Norway for the presence of GC-like structures.These were determined by a densely packed dark zone and a light zone in biopsies with classical focal infiltration within otherwise normal salivary glands. The presence of NHL was determined by linkage of the local SS registries to the Swedish cancer registry. Observation time was defined as time from the salivary gland biopsy until lymphoma diagnosis, death or end of follow-up. The median (IQ range) time between diagnosing pSS and biopsy was 1 week (0-16). The total observation time was 1859 patient years at risk (range:1 month - 26 yrs).Time between salivary gland biopsy and NHL diagnosis was in median 8 years (range: 2 yrs and 4 months -12 yrs and 7 months).

Statistics: Risk of developing NHL in patients with or without GC formation was compared by Cox regression analysis and Kaplan Meier statistics/log rank test. Associations between GC formation and other risk variables were determined by χ2statistics.

Results: In total 136 biopsies showed focal sialadenitis (focus score ≥1) at reevaluation. In 43 (32%) of the biopsies with focal sialadenits GC like structures were detected. Seven patients had developed NHL. Six of the 7 NHL patients (86%) had GC like structures at the time of diagnosing pSS. Patients with GC-like structures had 15 times increased risk of developing NHL compared to those without. Hazard Ratio (HR) 15.4, 95%CI: 1.85-128, p=0.01. Log-rank test: p=0.001. Positive predictive value 16%, negative predictive value 99%. GC positivity correlated with autoantibodies to SSA/SSB, lymphadenopathy, systemic disease activity (ESSDAI domains), high-risk type of SS (all p<0.05).

Conclusion: The presence of GC-like structures in the diagnostic salivary gland biopsies in pSS is highly predictive of lymphoma development with a HR of >15. This marker is an important new prognostic factor in the care of pSS patients. It may be included in guidelines for selection of pSS patients for biological B-cell directed treatment.

Disclosure: Elke Theander, nothing to disclose; Lilian Vasaitis, nothing to disclose; Eva Baecklund, nothing to disclose; Gunnel Nordmark, nothing to disclose; Gunnar Warfvinge, nothing to disclose; Rolf Liedholm, nothing to disclose; Karl Brokstad, nothing to disclose, Roland Jonsson, nothing to disclose, Malin Jonsson, nothing to disclose.

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