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Familial Waldenstrom's macroglobulinemia and relation to immune defects, autoimmune diseases, and haematological malignancies: a population-based study from northern Sweden
Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology. (Arcum)
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2016 (English)In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 55, no 1, p. 91-98Article in journal (Refereed) Published
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Abstract [en]

Background: Waldenstrom's macroglobulinemia (WM) is a rare lymphoprolipherative disorder with geographic and ethnic disparities in incidence. The cause of WM remains mostly unknown although a role for genetic, immune-related, and environmental factors has been suggested. Most cases of WM are sporadic although familial cases occur. Aim: This study estimated the incidence of WM in northern Sweden and identified and described patients with familial WM in this area. Patients and methods: The Swedish and Northern Lymphoma Registry, the Swedish Cancer Registry (1997-2011), and medical records were used to identify patients with WM in two counties (Norrbotten and Västerbotten) in northern Sweden and to calculate the overall age-adjusted incidence (2000-2012). We identified 12 families with a family history of WM, IgM monoclonal gammophathy (MGUS), and/or multiple myeloma (MM). Results: In Norrbotten and Västerbotten, the age-adjusted incidence of WM/LPL is 1.75 and 1.48 per 100 000 persons per year, respectively (2000-2012), rates that are higher than the overall incidence of WM/LPL in Sweden (1.05 per 100 000 persons per year; 2000-2012). Autoimmune diseases and other haematological malignancies in the medical history (their own or in relatives) were reported in 9/12 and 5/12 families, respectively. A high proportion of abnormal serum protein electrophoresis was found in the relatives; 12/56 (21%) had a MGUS and 13/56 (25%) showed abnormalities in the immunoglobulin levels (i.e. subnormal levels and poly/oligoclonality). Conclusion: The incidence of WM in Norrbotten and Västerbotten counties was higher than expected. We found a strong correlation between autoimmune/inflammatory diseases, other haematological malignancies, and familial WM and a high frequency of serum immunoglobulin abnormalities in the relatives of the WM patients, findings that strengthen the hypothesis that the aetiology of WM depends on both immune-related and genetic factors.

Place, publisher, year, edition, pages
Taylor & Francis, 2016. Vol. 55, no 1, p. 91-98
National Category
Cancer and Oncology
Identifiers
URN: urn:nbn:se:umu:diva-114606DOI: 10.3109/0284186X.2015.1096019ISI: 000367007700013PubMedID: 26559865OAI: oai:DiVA.org:umu-114606DiVA, id: diva2:902585
Note

Published online: 11 Nov 2015

Available from: 2016-02-11 Created: 2016-01-25 Last updated: 2020-01-07Bibliographically approved
In thesis
1. Waldenstrom's macroglobulinemia: population based studies of familial aggregation and prognostic factors
Open this publication in new window or tab >>Waldenstrom's macroglobulinemia: population based studies of familial aggregation and prognostic factors
2020 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Background

Waldenstrom’s macroglobulinemia (WM) is a rare lymphoproliferative disorder with a world-wide incidence of 3-4 patients per million persons per year. In Sweden, the incidence was about three times higher, and approximately 100 patients per year are reported to the Swedish Lymphoma Registry (SLR). Our aim was to study the WM population with focus on incidence and survival in relation to clinical prognostic factors and primary therapies (Paper I-II). We also discussed the diagnostic difficulties in patients with non-WM lymphoplasmacytic lymphoma (LPL). In Paper III-IV, we study familial WM from different aspects to better understand underlying pathogenetic factors.

Patients and methods

The patients in all four studies were collected from SLR. In papers I and II, a total of 1511 patients with WM and non-WM LPL were registered between 2000 and 2014, and medical records were retrieved for 1139 patients (75%). A retrospective review showed that 981 and 33 (after review by haematopathologist) of these patients fulfilled the World Health Organization (WHO) diagnostic criteria for WM and non-WM LPL, respectively. In Paper III and IV, we used SLR and the Northern Lymphoma Registry (NLR) for the years 1997- 2011. We identified 12 families with a family history of WM, IgM monoclonal gammopathy of undetermined significance (MGUS) and/or multiple myeloma (MM).

Results

In paper I, the overall survival (OS) for WM improved between the two time periods, 2000-2006 and 2007-2014, with a five-year OS of 61% and 70%, respectively. Significant prognostic factors for OS at the time of diagnosis in asymptomatic patients in no need of therapy were age, poor performance status (PS), haemoglobin ≤115 g/l, and female sex. Elevated lactate dehydrogenase (LDH) level and haemoglobin ≤115 g/l were significant prognostic factors for patients receiving therapy 0-3 months after diagnosis. The level of the IgM monoclonal immunoglobulin (MI) had no significant prognostic value. Rituximab included in first-line therapy was associated with improved survival. Paper II describes the differential diagnostic difficulties in non-WM LPL, especially with Marginal Zone Lymphoma (MZL). The non-WM LPL patients had more adverse prognostic factors as elevated LDH, anaemia, and lymphocytosis at diagnosis compared to the patients with WM. Despite this, the OS did not significantly differ between the groups (P = 0.249). The median OS for non-WM LPL was 71 months and the three-year and five-year survival was 71 % and 55%, respectively. The OS and RS were worse for males than females. In Paper III, we showed that age-adjusted incidence in Norrbotten and Västerbotten for WM and non-WM LPL was higher than expected – 17.5 and 14.8 per million person and year, respectively. The corresponding figure for Sweden was 10.5 per million persons per year. Autoimmune diseases or haematological malignancies in the medical history in patients or in their relatives were reported in nine and five of the 12 families, respectively. The relatives showed a high proportion abnormal serum protein electrophoresis (SPE): 12/56 (21%) showed MGUS and 13/56 (25%) showed abnormalities in the immunoglobulin levels (i.e., subnormal levels and poly/oligoclonality). Paper IV describes hyperphosphorylated paratarg 7 (pP-7), a target of 11% of the monoclonal immunoglobulin M (IgM) in WM and MGUS of IgM type, and distribution in Sweden and in familial WM. The frequency of pP-7 seems to be in line or lower in non-familial WM (7.1%) and higher in familial WM (16.7%) in the counties of Norrbotten and Västerbotten than in earlier published studies. Positive analysis for pP-7 was shown up to 10 years before diagnosis of WM.

Conclusion

We show that in a rare disease such as WM registry studies might bring new knowledge about incidence, disease characteristic, prognostic factors, treatments, and outcome. We also identified aggregation of families with WM in an effort to better understand the underlying pathogenesis

Place, publisher, year, edition, pages
Umeå: Umeå universitet, 2020. p. 85
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 2064
Keywords
Waldenstrom’s macroglobulinemia, lymphoplasmacytic lymphoma, monoclonal gammopathy of undetermined significance, Swedish Lymphoma Registry, incidence, overall survival, prognostic factors, familial Waldenstrom’s macroglobulinemia, hyperphosphorylated paratarg 7
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:umu:diva-166875 (URN)978-91-7855-142-2 (ISBN)
Public defence
2020-01-30, Aulan, Sunderby sjukhus, Sunderbyn/Luleå, 09:00 (Swedish)
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Available from: 2020-01-09 Created: 2020-01-06 Last updated: 2020-01-09Bibliographically approved

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