Bronchial MALT lymphoma in longstanding rheumatoid arthritis

K. M. J. Douglas, K. Raza1, R. Stevens2, N. Erb, E. L. Jones3 and G. D. Kitas

Department of Rheumatology, The Guest Hospital, Dudley Group of Hospitals, Tipton Road, Dudley DY1 4SE, 1 MRC Centre for Immune Regulation, Division of Immunity and Infection, The University of Birmingham, Birmingham, B15 2TT, 2 Department of Rheumatology, The City Hospital, Dudley Road, Birmingham B18 7QH and 3 Department of Pathology, The University of Birmingham, Birmingham B15 2TT, UK

Correspondence to: K. M. J. Douglas, Department of Rheumatology, The Guest Hospital, Dudley Group of Hospitals, Tipton Road, Dudley, West Midlands DY1 4SE, UK. E-mail: Karen.Douglas{at}dgoh.nhs.uk

SIR, A 64-yr-old female non-smoker with a 30-yr history of erosive RA previously treated with penicillamine, gold and sulphasalazine presented with weight loss, fatigue and night sweats. Examination revealed rheumatoid deformities without active synovitis. Investigations showed erythrocyte sedimentation rate (ESR) 130 mm/h (normal range 0–20), C-reactive protein (CRP) 115 mg/l (normal range 0–6), normochromic anaemia with haemoglobin 8.9 g/dl (normal range 11.5–16), normal biochemistry, positive rheumatoid factor but negative antinuclear antibodies, anti-Ro and anti-La antibodies; no evidence of Sjögren's syndrome (SS) on labial biopsy and sialography; very raised serum IL-6 (1316 U/l; normal range 0–50) and normal peripheral blood lymphocyte markers. Chest radiograph showed a left lower zone opacity; computed tomography (CT) revealed several left lobe masses (Fig. 1) without evidence of fibrosing alveolitis. Histology (from thoracoscopic biopsy) suggested Castleman's disease of the hyaline vascular type, a form of Castleman's disease in which only a minority of patients are symptomatic. Treatment with oral prednisolone (40 mg/day) improved the constitutional symptoms, but the inflammatory markers and IL-6 remained raised. Oral methotrexate (MTX) (15 mg/week) gave no further benefit. Ciclosporin was not tolerated. After 6 months the left lower lobe mass had enlarged. Left lower lobectomy was performed and within 2 weeks constitutional symptoms resolved and ESR, CRP and IL-6 normalized. Blood results at pre-op, and 2 weeks, 3 months, 12 months and 36 months post-op were: Hb (g/dl): 8.0, 10.1, 12.2, 12.8, 13.1; ESR (mm/h): 124, 32, 27, 29, 19; CRP (mg/l): 118, 12, <8, 11, <8; IL-6 (U/l): 1128, 62, 40, undetectable, undetectable. Histology revealed a low-grade mucosa-associated lymphoid tissue (MALT) B-cell lymphoma with focal areas of activation and Epstein–Barr virus (EBV) latent membrane protein-1 (LMP-1) expression. The patient's RA flared 3 months later and after counselling MTX 7.5 mg/week with folic acid 5 mg/week were recommenced with regular surveillance (monthly clinical review of weight and constitutional symptoms for the first year, then 3 monthly; monthly CRP and ESR; annual chest X-rays; yearly chest CT, for the first 5 yr). The patient remains well without evidence of recurrence at 8 yr follow-up.



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FIG. 1. CT scan showing soft tissue masses in the left lower lobe.

 
This report contributes three novel findings: (1) pulmonary MALT lymphoma can exist in RA without SS; (2) it may be associated with very high serum IL-6, which could be useful for surveillance; (3) control of inflammatory activity may be more important than avoidance of MTX therapy in such cases.

Primary pulmonary lymphoma represents 3–4% of extra-nodal lymphomas and only 0.5% of primary lung malignancies [1]. It is usually of the MALT type, which is normally found in intestinal Peyer's patches. Chronic inflammation associates with development of MALT in ectopic areas: this is thought to be important in the development of MALT lymphomas in salivary glands in SS [2], thyroid in Hashimoto's thyroiditis [3], and the stomach in chronic Helicobacter pylori infection [4]. MALT lymphomas are of B-cell type, and are usually indolent, though they may cause local effects or constitutional upset. Surgery, radiotherapy and chemotherapy have all been used but there is no consensus regarding optimal therapy.

MALT lymphomas have only been described in RA patients with SS [5], which was excluded in this case. Lymphomas are commoner in RA than the general population [6], and associations have been found between MTX therapy and lymphoma development [7]. A recent survey of lymphomas in patients with RA, however, did not find this association and suggested that disease activity was the risk factor [8]. EBV has also been implicated in the pathogenesis of several lymphomas, including those in RA [9] and the expression of LMP-1, the protein identified in this patient's tumour, may be important in B-cell transformation [10]. Cases thought to be related to EBV have regressed on withdrawal of MTX [9, 11]. It remains unclear whether such mechanisms or chronic uncontrolled inflammation are more important for the development of lymphomas in RA. The risk of MTX therapy may be counterbalanced by beneficial suppression of the inflammatory response. This patient had not been exposed to MTX prior to the identification of the tumour. Post-operative deterioration of her RA required the use of disease-modifying drugs and, in view of previous therapeutic failures, options were limited. Treatment with MTX after counselling has proved successful and continuous long-term surveillance has not revealed tumour recurrence.

The authors have declared no conflicts of interest.

References

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  5. Sutcliffe N, Smith C, Speight PM et al. Mucosa-associated lymphoid tissue lymphomas in two patients with rheumatoid arthritis on second-line agents, and secondary Sjögren's syndrome. Rheumatology 2000;39:185–8.[Abstract/Free Full Text]
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  9. Starkebaum G. Rheumatoid arthritis, methotrexate, and lymphoma: risk substitution, or cat and mouse with Epstein-Barr virus? J Rheumatol 2001;28:2573–4.[ISI][Medline]
  10. Devergne O, Hatzivassiliou E, Izmui KM et al. Association of TRAF1, TRAF2 and TRAF3 with Epstein-Barr virus LMP1 domain important for B lymphocyte transformation: role in NF-kB activation. Mol Cell Biol 1996;16:7098–108.[Abstract]
  11. Kamel OW, van de Rijn M, Weiss LM et al. Brief report: reversible lymphomas associated with Epstein-Barr virus occurring during methotrexate therapy for rheumatoid arthritis and dermatomyositis. N Engl J Med 1993;328:1317–21.[Free Full Text]
Accepted 14 December 2004





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