Mucosa-associated lymphoid tissue lymphomas in two patients with rheumatoid arthritis on second-line agents, and secondary Sjögren's syndrome

N. Sutcliffe4, C. Smith1, P. M. Speight2 and D. A. Isenberg

Centre for Rheumatology/Bloomsbury Rheumatology Unit, Department of Medicine, University College London,
1 Department of Rheumatology, Barnet Hospital, Hertfordshire and
2 Department of Oral Pathology, Eastman Dental Institute for Oral Health Care Sciences, University of London, London, UK

Abstract

We report two patients with rheumatoid arthritis and secondary Sjögren's syndrome whose disease was complicated by a mucosa-associated lymphoid tissue (MALT) lymphoma. Although this particular type of lymphoma is associated with primary Sjögren's syndrome, it has not been described, to our knowledge, in the context of rheumatoid arthritis and Sjögren's syndrome. The potential causative factors are discussed.

KEY WORDS: Rheumatoid arthritis, Second-line agents, Sjögren's syndrome, Mucosa-associated lymphoid tissue lymphoma

The presence of rheumatoid arthritis (RA) and Sjögren's syndrome (SS), and the use of some second-line agents have been linked to lymphoma development [13]. However, a particular type of non-Hodgkin's lymphoma (NHL), mucosa-associated lymphoid tissue (MALT) lymphoma, while described in association with primary SS [4], has not as far as we are aware, been reported in the context of RA or second-line agents. We report two patients with RA treated with second-line agents and secondary SS, who developed MALT lymphomas.

Case 1

A 59-yr-old man first presented at the age of 35 yr with symmetrical, peripheral arthritis involving his hands, feet and shoulders. He developed erosions in his hands and feet compatible with RA. He was negative for rheumatoid factor (slide latex) and his antinuclear antibody was only 1/10 with a speckled pattern, but his anti-Ro and La antibodies were absent (Shield Diagnostics, Dundee, UK). He was diagnosed as having seronegative, erosive RA and treated first with D-penicillamine (for 8 yr) and subsequently with azathioprine (alone for 7 yr and then in combination with sulphasalazine for 2 yr). In response to failing these treatments, he had a combination of sulphasalazine, methotrexate and prednisolone (for 1 yr), then methotrexate and sulphasalazine (for 1 yr). He subsequently had triple treatment with oral gold, methotrexate and sulphasalazine for 3 yr. His arthritis has thus been difficult to control over the years despite the above regimens and occasional intra-articular and intramuscular steroid treatment. He had replacement of both elbows and the right elbow was revised later.

He developed severe, persistent dry eyes and mouth at the age of 47 yr. This was treated with tear supplements. Apart from these features he complained of dry skin, dry nose and fatigue. He did not have any systemic involvement with the exception of an ulnar nerve palsy following his left elbow replacement. He had a positive Schirmer's test. Although a labial biopsy was performed, unfortunately no salivary tissue was found on the sample taken.

He had an acute gastrointestinal tract bleed aged 57 yr in 1995. Endoscopy revealed a gastric ulcer and histology showed a low grade B cell lymphoma of MALT type. The tumour was localized to the stomach with no nodal or bone marrow involvement. In view of coexisting helicobacter infection on endoscopy, he was first treated with helicobacter eradication therapy and omeprazole, but after failing to respond he was given chlorambucil 10 mg/day for 12 weeks. When endoscopy was repeated after chemotherapy, it showed persistence of lymphoma. He then had a total gastrectomy with Roux-en-Y anastomosis (1996). His lymphoma remains in remission following his surgery, but his arthritis is still relatively active being treated with methotrexate.

Case 2

A 35-yr-old Caucasian man developed a symmetrical non-erosive synovitis affecting the wrists, small hand joints, shoulders and forefeet. A latex test for rheumatoid factor was positive (1:40). Rheumatoid arthritis was diagnosed. He was treated with non-steroidal anti-inflammatory drugs alone for 6 yr. Although his symptoms improved a little, the erythrocyte sedimentation rate remained elevated, he became more strongly seropositive, and by 6 yr of disease he had extensive radiological erosions and a rheumatoid nodule.

Treatment with sulphasalazine 2 g/day was prescribed for 1 yr with significant improvement in disease control, but his disease flared again and he commenced methotrexate, increased to a weekly dose of 12.5 mg, which he continues to date (3 yr). After 9 months of treatment with methotrexate his disease was greatly improved with a normal sedimentation rate and haemoglobin. New nodules, and occasional digital infarcts, were noted at this time.

Fifteen months after starting methotrexate treatment, and 8 yr after the diagnosis of RA, he noted a left parotid swelling. There was no lymphadenopathy, no other salivary gland swelling, and he had no systemic symptoms. He denied dryness of the eyes or mouth at this time, but a Schirmer test was completely dry bilaterally, and over the ensuing months he developed mild sicca symptoms. The serum immunoglobulin levels, blood count, sedimentation rate, and renal and hepatic function were normal, as was a chest radiograph. The antinuclear antibodies were positive at a titre of 1:1280 with a speckled pattern, and he had a low titre of anti-Ro antibodies. He had no gastrointestinal symptoms. A left parotidectomy was carried out, with complete excision of a 6 x 5 cm mass. Histology showed low grade MALT lymphoma arising on a background of extensive lymphoid infiltration of the gland with lymphoepithelial lesions compatible with SS. He was well for 6 months after surgery. His lymphoma then recurred in the right parotid gland and enlarged para-aortic nodes were found on staging investigations (stage 3). He is currently being followed up without any specific treatment. His RA is well controlled with methotrexate 12.5 mg weekly.

Discussion

Both patients had long-standing erosive RA, seropositive and nodular in case 2. Both had treatment with several second-line agents.

Role of RA in the development of lymphoma
The evidence that the risk of malignancy is increased in RA has been conflicting [57]. Both population- and hospital-based studies have shown a significant association between RA and the subsequent development of lymphoproliferative malignancy, namely NHL, Hodgkin's disease, multiple myeloma and leukaemia [612]. However, other studies failed to show any major increase in the frequency of cancer, distribution of neoplasm, or any important increase in death due to malignancy in patients with RA [13, 14]. Overall, however, there is an impression that NHL are more common than expected in RA [1, 15].

Is the risk of lymphoma higher in patients treated with second-line agents? Which second-line agents?
It is often difficult to separate the effects of treatment, especially of cytotoxic drugs, from that of the disease itself. Although some studies clearly indicate that therapy was not the cause of malignancy [1, 6, 8, 10, 13], this has not been confirmed by all. Both our patients had been on sulphasalazine, case 1 also had D-penicillamine. Neither drug has been associated with malignancy in RA. Although it has been suggested that sulphasalazine may affect the lymphocyte traffic pathways of cells emerging from the gut-associated lymphoid tissue of the small intestine, there have been no case reports of lymphoma attributed to sulphasalazine [16]. Case 1 also had gold and azathioprine treatment. Although an increased risk of lymphoma and leukaemia was found in a study of patients treated with parenteral gold, the authors felt that this was probably not related to the drugs but was due to generally increased risk in patients with RA. Others failed to confirm a relationship between gold and the development of such tumours [17, 18]. Azathioprine has been shown to be associated with the development of lymphomas [2] and the increased lymphoproliferative risk from high-dose azathioprine in patients with RA has been shown to be twice that due to RA alone [19].

Both our patients were also taking methotrexate at the time of their lymphoma diagnosis (duration of treatment was 5 yr in case 1 and 15 months in case 2). Low-dose methotrexate is commonly used for treatment of RA. It is an anti-folate anti-metabolite drug and there have been several case reports of lymphoma development in patients with RA treated with it [2025]. These appear to be NHL of mainly B cell origin. It is of interest that in some cases, there has been a spontaneous and complete regression of lymphoproliferative disease after methotrexate withdrawal. This is a rare event in NHL. It is also interesting that in some of these cases evidence of Epstein–Barr virus (EBV) was provided which supports the idea that methotrexate-induced immunosuppression in RA can promote EBV-associated lymphoproliferative disease [23, 25]. This is similar to EBV-related lymphoproliferative disease seen in post-transplant patients in whom withdrawal of immunosuppressive therapy may result in partial or complete tumour reduction [23].

In contrast, in a recent study of patients with RA from the Mayo clinic, it was shown that although NHL was the most frequently observed haematological malignancy, neither its occurrence nor that of other haematological malignancies was particularly associated with the use of methotrexate as an anti-rheumatic agent. The authors concluded that haematological malignancies are uncommon in patients with RA treated with disease-modifying drugs including methotrexate and their occurrence is not related to cumulative or peak dose or duration of treatment [26].

Role of SS in the development of lymphoma
It seems very likely that both patients had secondary SS. In case 1, it started 10 yr prior to the onset of lymphoma, in case 2, it presented concurrently. An association between primary SS and NHL is well known [27]. SS is a lymphoproliferative disorder, characterized by lymphoid infiltrates in exocrine glands. The classic histopathological lesion of SS is salivary lymphoepithelial lesion of the parotid gland [28]. This shows replacement of the salivary tissue by dense focal or diffuse lymphocytic infiltrates associated with islands of proliferating ductal epithelium. The infiltrating lymphocytes are segregated and form normal lymphoid follicles which are found adjacent to the epithelium. Between the follicle and the epithelium is a zone of B cells, and the epithelium itself is infiltrated by B cells to form the typical lymphoepithelial lesions which gives the disorder its name. The overall organization of the lymphoid tissue is similar to that found in MALT which is typified by the Peyer's patches of the gut. Thus, salivary lymphoepithelial lesion is an acquired MALT which is most probably a result of persistent antigenic challenge.

The risk of NHL development in SS has been shown to be 40 times the incidence expected from a comparable normal population [3]. The incidence is between 5 and 10% of patients [4]. In a recent multicentre European study, Voulgarelis and colleagues showed that malignant NHL seen in patients with primary SS are most often extranodal marginal zone lymphomas, and are usually found in the salivary glands. Lymphadenopathy, skin vasculitis, peripheral nerve involvement, low grade fever, anaemia and lymphopenia were seen more frequently than in the general SS population. Survival depended on the grade, presence of B symptoms and the size of tumour [29]. Of the two patients reported here, case 1 had lymphopenia as low as 7% with an absolute count of 0.5 prior to the onset of lymphoma. His total white cell counts had been normal. Case 2 did not have any significant leucopenia or lymphopenia.

Both our patients developed extranodal marginal zone lymphomas which have been well characterized as lymphomas of MALT, originally by Isaacson and Wright in 1983 [30]. MALT lymphomas appear to arise from the B lymphocytes within the epithelial islands and are first seen as focal proliferations of small to medium lymphocytes. These proliferations are monoclonal on the basis of light chain or heavy chain restriction. Reactive follicles almost always accompany a MALT lymphoma, which lends weight to the concept that these lesions are antigen driven. This is supported by the findings of restricted idiotypes and of a restricted repertoire of VH and CDR3 genes [31]. Even stronger evidence comes from reports that MALT lymphomas of the gut may resolve after treatment of Helicobacter pylori infection. Although H. pylori is not found in parotid lesions [32], salivary lymphoepithelial lesions may resolve after anti-H. pylori therapy [33]. This raises the possibility that the malignant clones found in salivary MALT lymphomas may, in some cases, arise in the gut. Of the two patients reported here, case 2 had some evidence of H. pylori infection, but his lymphoma did not respond to helicobacter eradication treatment.

Salivary MALT lymphomas appear to be low grade and indolent. Many patients survive for years with no evidence of systemic disease after diagnosis, and many salivary lymphoepithelial lesions, even with evidence of monoclonality, do not progress to clinically definable lymphomas. Studies have shown that between 40 and 80% of salivary lymphoepithelial lesions may have monoclonal proliferations [34]. Recent molecular studies, however, have shown that multiple clones may be present and that metachronous or synchronous lesions may contain two or more dominant clones [35]. These are seen even in clinically and histologically benign lesions. This suggests that these clones may be reactive, antigen driven in nature. Sensitive methods of detection therefore may identify clonality in a large number of cases and lead to over-diagnosis of lymphoma. This is still a strongly debated issue, but it has implications for the diagnosis of all lymphomas.

Current views, therefore, suggest that salivary lymphoepithelial lesion is an antigen-driven lymphoproliferation which may contain oligoclonal or monoclonal B cell populations. Lymphomas may develop within these proliferating populations as a result of further molecular events. Because of the indolent nature of the lesions and doubt about the criteria for the identification of the malignant transition, management remains empirical. It seems appropriate to instigate treatment for lymphoma only in those cases where there is histological evidence of lymphoma associated with monoclonality and supportive clinical findings.

Recently we have described a cohort of 72 patients with primary SS of whom 7% developed MALT lymphomas. History of swollen glands, lymphadenopathy and skin ulcers predicted the lymphoma development in that cohort [4]. However, neither of the two patients described here had these features.

Conclusion

Our patients had several risk factors for lymphoma development, including RA, the use of several second-line agents and SS. MALT lymphoma, to our knowledge, has not been described in association with RA or second-line agents before. We feel that the development of secondary SS was likely to be the main cause of MALT lymphoma development in these patients. We recommend that those patients with RA treated with second-line agents, especially those who also develop secondary SS, are followed up carefully for the presence of upper gastrointestinal tract symptoms and swollen salivary glands, since they may be at particular risk of MALT lymphoma development.

Notes

4 Correspondence to: N. Sutcliffe, Centre For Rheumatology/Bloomsbury Rheumatology Unit, Arthur Stanley House, 4th floor, 40–50 Tottenham Street, London W1P 9PG, UK. Back

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Submitted 28 January 1999; revised version accepted 20 September 1999.