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Lymphoma studies in patients with Sjögren's syndrome
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.ORCID iD: 0000-0001-6715-3704
2017 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Patients with primary Sjögren’s syndrome (pSS) are at increased risk of developing malignant lymphoma. The studies in this thesis aim at broadening our understanding of the association between these two conditions.

Germinal centre (GC)-like structures were found in minor salivary gland biopsies taken at the time of pSS diagnosis in 25% of 175 studied patients. Lymphoma development was observed in 86% of the GC-positive pSS patients and 14% of the GC-negative patients. GC-like structures in salivary gland biopsies at pSS diagnosis might identify pSS patients at high risk for later lymphoma development.

We used the National Patient Register and the Cancer Register to identify pSS patients with lymphoid malignancy for the following studies. The lymphoma tissues were reviewed and classified according to the WHO classification.

In a study of 79 patients with available lymphoma tissues, we identified histopathological and clinical features compatible with IgG4-related disease (IgG4-RD) in one patient (1.3%). Histological features of IgG4-RD in lymphoma tissue in patients with an initial pSS diagnosis seem to be rare but, if present, may indicate underlying IgG4-RD.

We identified and compared pSS patients with (n=18/17%) and without (n=87) pre-existing lymphoma at pSS diagnosis and found similar pSS characteristics in both groups. Mucosa-associated lymphoid tissue (MALT) lymphoma in salivary glands was more common in patients with pre-existing lymphoma. The findings support the removal of pre-existing lymphoma as a general exclusion criterion for a pSS diagnosis in classification criteria. Further, the findings suggest an investigation for pSS in patients presenting with MALT lymphoma in salivary glands.

We compared the distribution of lymphoma subtypes with a general population reference. Both diffuse large B-cell lymphoma (DLBCL) (32%) and marginal zone lymphoma (MZL) (31%) were common, but only MZL (MALT lymphomas) occurred at an increased relative frequency compared to the general population.

Men constituted 15% of 105 pSS patients with lymphoma. Men had a shorter time between the pSS and lymphoma diagnoses and more often had lymphoma in the salivary glands compared with women. Increased awareness of signs of lymphoma in salivary glands already during the first years after pSS diagnosis is justified in men with pSS.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2017. , 94 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1331
Keyword [en]
Sjögren's syndrome, primary Sjögren's syndrome, lymphoma, IgG4-related disease
National Category
Rheumatology and Autoimmunity
Research subject
Medical Science
Identifiers
URN: urn:nbn:se:uu:diva-320220ISBN: 978-91-554-9912-9 (print)OAI: oai:DiVA.org:uu-320220DiVA: diva2:1088920
Public defence
2017-06-07, Enghoffsalen, Ingång 50 bv, Akademiska sjukhuset, Uppsala, 13:00 (Swedish)
Opponent
Supervisors
Available from: 2017-05-17 Created: 2017-04-18 Last updated: 2017-06-07
List of papers
1. Lymphoid organisation in labial salivary gland biopsies is a possible predictor for the development of malignant lymphoma in primary Sjogren's syndrome
Open this publication in new window or tab >>Lymphoid organisation in labial salivary gland biopsies is a possible predictor for the development of malignant lymphoma in primary Sjogren's syndrome
Show others...
2011 (English)In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 70, no 8, 1363-1368 p.Article in journal (Refereed) Published
Abstract [en]

OBJECTIVE:

The development of non-Hodgkin's lymphoma (NHL) confers a high risk of mortality in primary Sjögren's syndrome (pSS) patients, but the sensitivity and specificity of proposed lymphoma predictors are insufficient for practical use. The performance of lymphoid organisation in the form of germinal centre (GC)-like lesions was evaluated in labial salivary gland biopsies taken at pSS diagnosis as a potential lymphoma-predicting biomarker.

METHODS:

Labial salivary gland tissue biopsies available from two Swedish pSS research cohorts (n=175) were re-evaluated by light microscopy in a blind study in order to identify GC-like structures as a sign of ectopic lymphoid tissue formation and organisation. A linkage study was performed with the Swedish Cancer Registry for lymphoma identification. The risk of developing NHL in GC-positive patients in comparison with GC-negative patients was evaluated using Kaplan-Meier statistics and log-rank test. Associations between GC-like structures and clinical and/or laboratory disease markers were also determined using χ(2) or Fisher's exact tests.

RESULTS:

At diagnosis, 25% of pSS patients had GC-like structures in their salivary glands. Seven of the 175 patients studied (14% GC+ and 0.8% GC-) developed NHL during 1855 patient-years at risk, with a median onset of 7 years following the initial diagnostic salivary gland biopsy. Six of the seven patients had GC-like structures at diagnosis; the remaining patient was GC negative at the time of diagnosis (p=0.001).

CONCLUSIONS:

The detection of GC-like structures by light microscopy in pSS diagnostic salivary biopsies is proposed as a highly predictive and easy-to-obtain marker for NHL development. This allows for risk stratification of patients and the possibility to initiate preventive B-cell-directed therapy.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-156261 (URN)10.1136/ard.2010.144782 (DOI)000292188100004 ()
Available from: 2011-07-18 Created: 2011-07-18 Last updated: 2017-04-20
2. Sporadic occurrence of non-diagnosed IgG4-related disease in lymphoma patients with a previous Sjögren's syndrome diagnosis.
Open this publication in new window or tab >>Sporadic occurrence of non-diagnosed IgG4-related disease in lymphoma patients with a previous Sjögren's syndrome diagnosis.
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2016 (English)In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 55, no 9-10, 1139-1144 p.Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: IgG4-related disease (IgG4-RD) is a recently recognized fibro-inflammatory disorder, which may affect many organs, and often comes to clinical attention due to tumor-like organ swelling or is identified incidentally by specific biopsy findings. Typical histopathology of IgG4-RD is lymphoplasmacytic infiltration rich in IgG4 + plasma cells (PCs), storiform fibrosis, and obliterative phlebitis. Patients with sicca symptoms can be misdiagnosed as primary Sjögren's syndrome (pSS) instead of IgG4-RD because of clinical and histopathological similarities. Moreover, an association with lymphoma development is described in both diseases. This study investigated signs of IgG4-RD in a population-based cohort of patients diagnosed with pSS complicated by lymphoma.

METHODS: Patients with pSS and lymphoma diagnoses and available lymphoma specimens were identified by linkage with the Swedish Patient Register 1964-2007 and the Cancer Register 1990-2007 (n = 79). Clinical data and lymphomas were reviewed and the diagnoses evaluated. All lymphoma tissues and available minor salivary gland biopsies (n = 11) were immunostained for IgG4 + PCs and evaluated for other histopathological signs of IgG4-RD. In a case with specific findings of IgG4-RD, other available tissue specimens of the same patient were investigated for IgG4-RD.

RESULTS: Only one patient of 79 (1.3%) had >10 IgG4 + PCs/high power field (HPF) in the lymphoma tissue, an unspecified low-grade B-cell lymphoma localized in the submandibular gland. This patient also had other histopathological features of IgG4-RD in the lymphoma and a surgical lung biopsy taken five years before lymphoma diagnosis and, therefore, fulfilled the criteria for IgG4-RD. Occasional IgG4 + PCs (<10/HPF) without signs of IgG4-RD were observed in another six lymphomas. No IgG4 + PCs were identified in the minor salivary gland biopsies.

CONCLUSION: Histopathological findings of IgG4-RD may co-exist with low malignant B-cell lymphoma in patients with initially suspected pSS and may be associated with an underlying IgG4-RD.

National Category
Rheumatology and Autoimmunity
Research subject
Medical Science
Identifiers
urn:nbn:se:uu:diva-300373 (URN)10.1080/0284186X.2016.1182644 (DOI)000385554200012 ()27196149 (PubMedID)
Funder
Swedish Rheumatism AssociationSwedish Society of Medicine
Available from: 2016-08-08 Created: 2016-08-08 Last updated: 2017-04-20Bibliographically approved
3. Support for removal of lymphoma as an exclusion criterion in classification criteria for primary Sjögren’ s syndrome
Open this publication in new window or tab >>Support for removal of lymphoma as an exclusion criterion in classification criteria for primary Sjögren’ s syndrome
(English)Manuscript (preprint) (Other academic)
Abstract [en]

Objective. Classification criteria for primary Sjögren’s syndrome (pSS) have previously included pre-existing lymphoma as an exclusion criterion for a pSS diagnosis, but the rationale for this exclusion criterion has not been formally studied.

We, therefore, aimed to explore if there were differences between pSS patients with and without pre-existing lymphoma.

Methods. Patients registered with ICD-7-10 codes for SS (which capture all reasons for sicca symptoms) and a diagnosis of malignant lymphoma before or after the SS diagnosis were identified by linking the Swedish Patient Register 1964-2007 with the Cancer Register 1990-2007 (n=224). Clinical data was collected from medical records and the underlying cause of the SS diagnosis code was investigated. Lymphoma diagnoses were evaluated by tissue review. Patient characteristics in pSS patients with and without pre-existing lymphoma were compared by Mann-Whitney and Fisher’s tests.

Results. A total of 207 SS-lymphoma patients remained after lymphoma tissue review. 107 (52%) of these had pSS according to the treating physician. 18 (17%) had a pre-existing lymphoma at pSS diagnosis. The pSS characteristics were similar in patients with and without pre-existing lymphoma, also in analyses restricted to patients fulfilling the 2002 AECG criteria for pSS. Mucosa-associated lymphoid tissue (MALT) lymphoma (50% vs. 22%, p=0.02), and lymphoma in the salivary glands, (61% vs. 26%, p=0.006) were more common in patients with pre-existing lymphoma.

Conclusions. Our results support the removal of pre-existing lymphoma as a general exclusion criterion for a pSS diagnosis. The results also suggest that patients with MALT lymphoma or lymphoma in the salivary glands should be investigated for the presence of pSS.

Keyword
Sjögren’s syndrome, pre-existing lymphoma, lymphoma, International Classification of Diseases, classification criteria
National Category
Rheumatology and Autoimmunity
Research subject
Medical Science
Identifiers
urn:nbn:se:uu:diva-320441 (URN)
Available from: 2017-04-20 Created: 2017-04-20 Last updated: 2017-04-20
4. Population-based study of primary Sjögren’s syndrome and lymphoma: lymphoma subtypes, clinical characteristics, and sex differences
Open this publication in new window or tab >>Population-based study of primary Sjögren’s syndrome and lymphoma: lymphoma subtypes, clinical characteristics, and sex differences
(English)Manuscript (preprint) (Other academic)
Abstract [en]

Objective. To examine lymphoma subtypes, clinical characteristics and sex differences of primary Sjögren’s syndrome (pSS) patients with lymphoma in a population-based setting.

 Methods. We identified 224 patients with both Sjögren’s syndrome and lymphoma diagnoses by linking the Swedish Patient Register 1964-2007 with the Cancer Register 1990-2007. Clinical data was collected from medical records and diagnoses validated. Lymphoma specimens were classified using the WHO classification and Epstein-Barr virus (EBV) was searched for by EBER in situ hybridization. The lymphoma subtype distribution was compared with the Swedish Lymphoma Register as a reference.  After exclusions (where pSS or lymphoma diagnoses could not be confirmed) 105 patients remained in the study.

Results. Diffuse large B-cell lymphoma (DLBCL) (32%) and marginal zone lymphoma (MZL) (31%) were the two most common lymphoma subtypes. The proportion of DLBCL was not increased compared to the general population reference (32%, p=1), in contrast to MZL (general population 5%, p<0.0001). Similar proportions were found of the germinal center B-cell-like and activated B-cell-like subtypes of DLBCL. EBV was found in 22% of DLBCLs and in 80% of Hodgkin lymphomas but was not detected in the MZL tissues.

Compared to DLBCL, MALT lymphoma (28/31 of all MZLs) was diagnosed at a younger age (55 vs. 67 years, p=0.0001), and earlier after patient-reported sicca onset (seven vs. 18 years, p=0.0001) and pSS diagnosis (two vs. nine years, p=0.0005).

Sixteen of the pSS-lymphoma cases were men (15%), twice the proportion in general pSS populations. Compared to women, men had a shorter median time from pSS diagnosis to lymphoma diagnosis (one vs. eight years, p=0.0003) and more often had lymphoma in the salivary glands (56% vs. 29%, p=0.04).

Conclusion. Both DLBCL and MZL are common in pSS patients, but only MZL/MALT lymphoma occurs at an increased relative frequency in pSS compared to the general population. The identified sex differences support an increased awareness of signs of lymphoma in men already the first years after pSS diagnosis. 

Keyword
Sjögren’s syndrome, lymphoma, MALT lymphoma, diffuse large B-cell lymphoma, sex differences
National Category
Rheumatology and Autoimmunity
Research subject
Medical Science
Identifiers
urn:nbn:se:uu:diva-320444 (URN)
Available from: 2017-04-20 Created: 2017-04-20 Last updated: 2017-04-20

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