Annals of the Rheumatic Diseases, 1987; 46, 224-227

Lymphadenopathy in rheumatic patients

C A KELLY, A J MALCOLM, AND I GRIFFITHS

From the Departments of Rheumatology and Pathology, Royal Victoria Infirmary, Newcastle upon Tyne

SUMMARY Lymph node biopsy specimens from 22 patients with chronic inflammatory jointdisease have been studied. The histology has been reviewed and immunoperoxidase stainingcarried out for the major immunoglobulin heavy and light chains, macrophage markers, andMT1, MB1 surface markers. Although two of these patients had been initially diagnosed andtreated for malignant lymphoma, the clinical course has not substantiated the diagnosis, and on

review malignancy could not be identified in any of the biopsy specimens. Careful attention tospecific histological features, together with adequate clinical information, is therefore essential ifthe true nature of the lymph node enlargement is to be recognised. Clinical review of the 22patients suggested that lymphadenopathy may, in some cases, be an early feature ofinflammatory polyarthritis, and this was supported by the observation that 20% of patients withotherwise unexplained reactive lymphadenopathy developed an inflammatory polyarthropathywithin one year of biopsy.

Key words: lymphoma, rheumatoid arthritis, immunoglobulins.

Lymph node enlargement often causes clinicalconcern, especially when it is associated with sys-temic symptoms such as weight loss, anaemia, andmalaise. The anatomical site, e.g., supraclavicularfossa, may enhance the suspicion of malignancy.Although lymphadenopathy in association withchronic inflammatory joint disease is welldescribed,1 2 there may be a strong indication forbiopsy, especially if lymph node enlargement occursbefore clinical, radiological, or serological stigmataof joint disease are present. These indications maybe further strengthened by the described associationbetween rheumatoid arthritis and malignantlymphoma.3 Resolution of the problem may bedifficult histologically as the lymph node in rheuma-toid disease may mimic lymphoma.4 This reportemphasises the clinical and pathological features oflymphadenopathy in 22 patients with inflammatoryjoint disease.

Patients and methods

Twenty two patients with chronic inflammatoryjoint disease and significant lymphadenopathy wereidentified. Sixteen of these had classical seropositiverheumatoid arthritis.5 Half of these were male, and

Accepted for publication 15 August 1986.Correspondence to Dr A J Malcolm, Dept of Pathology, RoyalVictoria Infirmary, Newcastle upon Tyne NE1 4LP.

the mean age of the group was 54 years (range 38-75years), with a mean disease duration of seven years(range one month to 20 years). Two patients hadadult Still's disease and two had Sjogren's syndromewith a non-destructive polyarthritis. Both thesepatients had a monoclonal gammopathy with anormal bone marrow. One patient had an asymmet-rical seronegative polyarthritis and one was con-sidered to have palindromic rheumatism.Lymph node biopsies were performed on all

patients because various clinical features raised thepossibility of coexistent malignant disease. Indica-tions for biopsy are shown in Table 1.Two patients with rheumatoid arthritis were

considered to have malignant lymphoma from thehistology of their node biopsy. Brief case historiesare presented below:One of the patients was a 47 year old woman with

a 13 year history of classical rheumatoid arthritiswho presented to her family doctor with rightaxillary lymphadenopathy. She was referred to asurgical unit at a hospital not involved in themanagement of her rheumatoid disease. Biopsy wasundertaken, and the histology was initially inter-preted as showing lymphoma, and she consequentlyreceived a course of radiotherapy.The other patient was a 65 year old man with an

11 year history of classical rheumatoid arthritis,admitted with a perforated gastric ulcer. Again the

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Lymphadenopathy in rheumatic patients 225

Table 1 Indications for lymph node biopsy in 22 patients with rheumatic disease

No of Weight Gamtnopathy Organomegaly Markedpatients loss lymphadenopathy

Rheumatoid arthritis 16 4 0 3 9Still's disease 2 0 0 2 0Seronegative arthritis 1 0 0 0 1Sjogren's syndrome 2 0 2 0 0Palindromic rheumatism 1 0 0 0 1

hospital was not involved with the management ofhis rheumatoid disease. He underwent partial gas-trectomy, and at laparotomy mesenteric lym-phadenopathy was noted and a biopsy specimentaken. This was initially interpreted as showinglymphoma, and he received a course of radio-therapy.

The majority of the biopsy specimens were takenfrom the supraclavicular and cervical areas (13patients) and most of the others from the axilla (sixpatients). Five of the patients (23%) underwentbiopsy within one year of the onset of jointsymptoms. Sections from all blocks of the biopsyspecimens were recut from each case and stainedwith haematoxylin and eosin, periodic acid-Schiffreagent after treatment with diastase, and Perls'stain for iron and reticulin silver impregnation. Astandard peroxidase-antiperoxidase technique6 wasperformed to assess the distribution of immunoglo-bulin and macrophages. The distribution of MT1and MB1 positive cells (Eurodiagnostics-T and Bcell antibodies for fixed tissue preparations) was alsoassessed on a representative block for each case. Allsections were examined by two independent obser-vers. The criteria assessed are well standardised.7No fresh tissue was available to allow T cell subsetsto be examined.

ResultsThe commonly encountered histological features ofthe nodes were capsular thickening and marked

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226 Kelly, Malcolm, Griffiths

follicular hyperplasia with large, sometimes irregu-lar follicles but retention of the normal folliculararchitecture of the lymph node (Fig. 1). There weremany mitoses, which were confined to the germinalcentres, and there was a polymorphous cell popula-tion with tingible body macrophages within thecentres. Interfollicular areas showed prominentvascularity with many plasma cells and only occa-sional mitotic figures (Fig. 2). There was no com-pression of reticulin fibres within the node. All theselatter features helped to separate a reactive follicu-lar hyperplasia from a follicular lymphoma becausein lymphoma the follicles have a more uniformpopulation of cells, show mitoses in the interfollicu-lar area in addition to those within the follicles, andplasma cells are scarce.4 The reticulin fibres inlymphoma tend to be compressed.9The distribution of MT1 positive cells (all non-B

lymphoid cells) within the interfollicular areas andMB1 positive cells (B lymphoid cells) in the germi-nal centres with diffuse extrafollicular scatter was asexpected in a reactive node (Figs 3a and b). The

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distribution of light and heavy chains of the majorimmunoglobulin classes was easily shown and had apolyclonal distribution in every case, including thosepatients with gammopathy (Figs 4a and b). This is ahelpful feature in that follicular lymphoma tendseither to have little or no immunoglobulin produc-tion within the follicles and, when present, it isusually monoclonal.'() Malignancy was not identifiedin any of the cases despite the original diagnosis oflymphoma in two patients. The confidence of thisstatement relies to some extent on the immunohis-tochemistry. Clinical follow up for four years aftercompletion of radiotherapy could not substantiatethe original diagnosis of lymphoma. It was dis-appointing that there were no histological or im-munohistochemical features in the lymph nodes thatcould be used to separate the different rheumatolo-gical conditions causing the lymphadenopathy.

Discussion

Clinically detectable lymphadenopathy has beendescribed in the majority of patients with rheuma-

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Lymphadenopathy in rheumatic patients 227

toid arthritis. 1 Robertson et al have shown theobserved incidence of lymphadenopathy in rheuma-toid patients to be significantly higher than that in amatched hospital control group.2 The increasedincidence was almost entirely due to axillary lym-phadenopathy. Therefore clinical concern remainsregarding the aetiology of cervical and supraclavicu-lar lymph node enlargement in patients withrheumatoid arthritis, and this is reflected in the factthat 59% of our patients had their biopsies forlymphadenopathy at these sites.There is conflicting evidence about the association

of rheumatoid arthritis and lymphoma. " 12 Despitethe initial diagnosis of lymphoma in two of ourpatients with rheumatoid arthritis, there was noevidence of malignant disease on review of thehistology. The increased risk of lymphoma inpatients with Sjogren's syndrome is welldocumented,'3 but the histological features of ourpatients with this condition were indistinguishablefrom the other cases. The lymph nodes showed apolyclonal distribution of immunoglobulin which didnot reflect the serum monoclonal gammopathies.Predominance of either x or k light chains wouldsupport the diagnosis of well differentiated malig-nant lymphoma, and this may be a useful means ofdiscrimination between benign and malignant causesof monoclonal gammopathy.The difficulty in distinguishing the histology of

florid reactive hyperplasia in some patients withrheumatoid disease from follicle centre or im-munoblastic lymphoma has been stressedpreviously.4 In both our cases where lymphoma wasoriginally diagnosed the reporting pathologist wasunaware of the rheumatic condition and was pre-sented with a clinical history suggestive of malig-nancy.The situation may be complicated by the develop-

ment of lymphadenopathy before the onset of jointsymptoms. A complementary study was set up tostudy 72 patients who had previously had lymphnode biopsies for unexplained lymphadenopathy,the histology of which had shown pure reactivehyperplasia. Spontaneous remission occurred inseven patients and no cause was determined for thelymphadenopathy in another 11. Of the 54 patientswho did develop a related disease, 16 had or

developed an inflammatory polyarthropathy, thisbeing classical rheumatoid arthritis in nine and aninflammatory polyarthropathy in another four.Although the diagnosis of arthropathy had beenpreviously established in half the patients with jointdisease, there remained sufficient clinical concern tojustify node biopsy. In the cases where lymphadeno-pathy predated other symptoms the arthropathybecame apparent within one year of biopsy.

It is important that the clinician appreciates therelation between lymphadenopathy and early jointdisease, and it is clearly mandatory that the report-ing pathologist is made aware of any coexistentrheumatic disease so that detailed attention to thehistological features already noted may prevent aserious misdiagnosis of lymphoma.

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4 Motulsky A G. Wcinburg S. Saphir 0. Rosenburg E. Lymphnodcs in rhcumatoid arthritis. Arch ltiterti Med 1952; 90: 66(0.

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12 Nosanchuk J S, Schnitzer B. Follicular hyperplasia in lymphnodes from paticnts with rheumatoid arthritis: a clinico-pathological study. Catncer 1969; 24: 343-54.

13 Azzopardi J D, Evans D J. Malignant lymphoma of parotidassociatcd with Mikulicz disease (benign lymphoepitheliallesion). J Clin Pathol 1971; 24: 744-52.

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