Annals of the Rheumatic Diseases, 1989; 48, 326-330

Case report

Multicentric Castleman's disease associated withrheumatoid arthritis: a possible role of hepatitis BantigenELDAD BEN-CHETRIT,1 DANIEL FLUSSER,1 ELIMELECH OKON,2ZVI ACKERMAN,1 AND ALAN RUBINOW1

From the 'Department of Medicine A, Rheumatology Unit and the 2Department of Pathology, HebrewUniversity-Hadassah Medical Center, Jerusalem, Israel

SUMMARY A patient with seropositive rheumatoid arthritis and a carrier of hepatitis B surfaceantigen developed angiofollicular hyperplasia (multicentric Castleman's disease). The hepatitis Bvirus and the rheumatoid factor may have had a role in the aetiology of this lymphatic disorder.The development of Castleman's disease in association with these factors may provide anotherclue supporting the reactive nature of this disease.

Castleman's disease (angiofollicular lymph nodehyperplasia), first described as a localised hyper-plastic lymphoid process of the mediastinum, is alymphoproliferative disorder of unknown cause.1Later, multicentric giant lymph node hyperplasiainvolving extramediastinal lymphoid tissues wasdescribed.2 Whether it is an autoimmune disorder, areaction to an unidentified infectious agent, animmunodeficiency disease, or an autonomouslympho3proliferative disorder has not been deter-mined.Lymphadenopathy, usually adjacent to areas of

active synovitis, is found in 29-82% of patients withrheumatoid arthritis.4 Characteristic, although notpathognomonic, histological features of lymph nodesfrom patients with rheumatoid arthritis show reactivefollicular hyperplasia throughout both cortex andmedulla, with prominent plasmacytosis in the inter-follicular region.5We report a patient with seropositive rheumatoid

arthritis and a carrier of hepatitis B surface antigen(HBsAg) who developed huge axillary and cervicallymphadenopathy. Serial lymph node biopsies dis-closed the classical morphological features of multi-

Accepted for publication 30 August 1988.Correspondence to Dr Alan Rubinow, Department of Medicine A,Hadassah University Hospital, PO Box 12000, Jerusalem 91120,Israel.

centric Castleman's disease of the hyaline vascularand plasmacytic type.

Case report

CLINICAL SUMMARYA 45 year old man was seen in our rheumatologyclinic with right axillary lymphadenopathy. Twoyears previously rheumatoid arthritis had beendiagnosed based on symmetrical pain and swellingof the proximal interphalangeal joints, morningstiffness of one hour's duration, rheumatoid noduleson the left forearm, and positive rheumatoid factor.For nine months he was treated with ibuprofen andhydroxychloroquine. Thereafter, aurothioglucoseand tetracosactrin in weekly intramuscular injectionswere added. Four months later he developednausea, anorexia, abdominal pain, and jaundice. Aliver biopsy specimen was characteristic of infectioushepatitis with positive immunoperoxidase stainingfor HBsAg. Despite the causal relation betweenthe hepatitis and HBsAg the aurothioglucose andtetracosactrin injections were discontinued, andtreatment was maintained with ibuprofen andhydroxychloroquine.

Physical examination showed synovial thickening,tenderness of the proximal interphalangeal joints, acyst in the right popliteal fossa, and rheumatoidnodules along the extensor aspect of the left

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Castleman's disease associated with rheumatoid arthritis 327

forearm. Non-tender, huge lymph nodes, 8 cmdiameter, were palpated in his right axilla. The liverand spleen were palpable.

Relevant laboratory studies showed an erythrocytesedimentation rate of 40 mm/lst h (Westergren),haemoglobin 140 g/l, white blood cells 7-5x1O/1with a normal differentiation count, and positivelatex fixation and sheep red cell agglutination tests(1/640 and 1/128 respectively). Hepatitis B surfaceantigen, anti-HBc, and anti-HBe were found in theserum. Antibodies to nuclear antigens, Epstein-Barrvirus, and cytomegalovirus were not detected. AVenereal Disease Research Laboratory test was

Fig. I Patient showing axillary lymphadenopathy. Notealso the enlarged cervical lymph nodes.

negative and an electrocardiogram and chest radio-gram were normal. An axillary lymph node wasbiopsied. Six months later, during which time hisrheumatic disease was completely asymptomatic, hedeveloped enlarged lymph nodes in both axillae,and another biopsy specimen was taken from the leftaxilla. Four months later, following persistent fever,weakness, night sweats, and cervical lymphadeno-pathy, a chest radiogram showed mediastinallymphadenopathy (Fig. 1), and abdominal computedtomography disclosed enlarged para-aortic andretroperitoneal lymph nodes. Bone marrow aspira-tion showed normal red cell line and plasmacytosisof 5%. A third biopsy specimen was obtained from acervical node.

PATHOLOGICAL STUDIESAll three lymph nodes examined from this patientshowed the characteristic features of angiofollicularlymph node hyperplasia. The first biopsy specimenshowed many large hyperplastic follicles and rela-tively few hyaline vascular centres (Fig. 2). Theinterfollicular areas showed extensive vascularitywith many sheets of plasma cell infiltrating thewhole node. Immature large and intermediate sizedlymphoid cells were also seen between the plasmacells. This histopathological pattern corresponds tomulticentric Castleman's disease, proliferative orhyperplastic type.6 The histological features of thetwo lymph nodes excised later during the patient's

Fig. 2 Biopsy specimen from thefirst lymph node showinghyperplastic follicle. Note theconcentric arrangement ofthesmall lymphocytic cells around the

>,=*wjtsB centre. (Haematoxylin and eosin.)

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328 Ben-Chetrit, Flusser, Okon, Ackerman, Rubinow

Fig. 3 Biopsy specimenfrom thesecond lymph node showing ahyaline vascular centre. Note theblood vessel at the left enteringperpendicularly into the smallcentre. (Haematoxylin and eosin.)

Fig. 4 Biopsy specimenfrom thecervical lymph node showinginterfollicular areas infiltratedheavily by sheets ofplasma cells.(Haematoxylin and eosin.)

treatment were of the hyaline vascular type (Fig. 3).Specifically, these follicles showed vessels enteringperpendicularly to their centre and their arrangementwas more concentric, bound by small lymphocytes.The interfollicular areas contained many bloodvessels together with sheets of mature plasma cells(Fig. 4). Immunoperoxidase staining with antibodies

against light and heavy chains showed that thelymphoid cells exhibited a polyclonal pattern.Immunoperoxidase staining with anti-HBs antibodywas negative.

IMMUNOLOGICAL STUDIESPertinent immunological studies included a total

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Castleman's disease associated with rheumatoid arthritis 329

serum protein of 91 g/l, of which 65 g/l were globulinfractions. A protein electrophoresis showed noparaprotein, albumin 30%, a, globulins 4%,a2 globulins 8-0%, globulins 7-1%, andy globulins 51%. On quantitative immunoelectro-phoresis the IgG was 30 g/l (normal 8-17), IgM4.5 g/l (0-65-2-8), and IgA 4.7 g/l (0.9-4-5). Totalwhite blood cell count was 7-5 x 109/l with 40%lymphocytes. The T lymphocytes comprised 55%and B cells 15%. When OKT antibodies were usedthe ratio OKT4/OKT8 was 2-1 (2-3). Serum anti-bodies to HIV were not detected (Elavia, DiagnosticPasteur, France).

Isolation of HBs-anti-HBs complexes was per-formed using the methods described by Gazitt et al.7Briefly, the patient's serum was passed through aClq affinity column containing agarose polyacroleinmicrospheres of 100-200 iim diameter. The effluentwas then passed through an anti-HBs affinitycolumn (2 mg monoclonal anti-HBs coupled to 1 mlmicrosphere beads). The titres of HBsAg were

determined in the effluents before and after passagethrough the anti-HBs affinity column by solid phaseradioimmunoassay (Ausria, Abbott, Chicago, IL).Material absorbed to the two affinity columns waseluted by 10 ml of 1 M glycine-HCl buffer pH 2-5,dialysed against phosphate buffered saline, andconcentrated by diquat dibromide. The proteincontent was determined according to Lowry7a andsamples were analysed by sodium dodecyl sulphate-polyacrylamide gel electrophoresis (not shown).The patient's serum contained 33 ,ug/ml HBsAg inimmune complexes and 3 [ig/ml in its free state.

Discussion

Castleman's disease was first described as a localisedhyperplastic lymphoid process of the mediastinumcharacterised histologically by peculiar Hassall-body-like germinal centres and marked vascularproliferation.' Gaba et al described the multicentricgiant lymph node hyperplasia, which involvedaxillary, retroperitoneal, and other lymph nodes aswell as the spleen.2 Subsequently, Castleman addedthe plasma cell type to his original hyaline vascular

8type. Frizzera et al described 15 patients withmulticentric Castleman's disease of plasmacytictype, two of whom had arthralgias and two othersxerostomia and xerophthalmia. None of them fittedcompletely the syndrome of rheumatoid arthritis,Sjogren's syndrome, or systemic lupus erythe-matosus.3 9 Recently, Weisenburger et al added aclinicopathological description of 16 more cases withangiofollicular lymph node hyperplasia, and none ofthem had rheumatoid arthritis. 10

At some time during their illness 50-70% ofpatients with rheumatoid arthritis may developlymphadenopathy.5 Histologically, lymph nodes ofpatients with rheumatoid arthritis are difficult todistinguish from those in Castleman's disease of theplasma cell type. Despite these similarities Kelleret al found no case of rheumatoid arthritis among 81patients with plasma cell type Castleman's disease.8On the other hand, recurrent biopsies of enlargedlymph nodes from patients with rheumatid arthritisover a 14 year period failed to detect the hyalinevascular type of Castleman's disease.5The development of multicentric Castleman's

disease in our patient with rheumatoid arthritisdeserves comment. Firstly, such an association maybe coincidental. Alternatively, lymphadenopathymay be associated with ingestion of drugs, suchas phenytoin,11 ibuprofen, hydroxychloroquine,aurothioglucose, and tetracosactrin, however, havenot been implicated in the development of lymph-adenopathy resembling Castleman's disease.Features suggesting that Castleman's disease maybe an immunological disorder included lymphoiddepletion in the T area of the spleen, an associationwith Kaposi's sarcoma, and the presence of auto-antibodies in the sera of some patients.612 Adefined immunological stimulus accounting forthese features has not been identified, however.Conceivably, the hepatitis B virus may have playedan important part in the development of Castleman'sdisease in our patient. Besides being a chroniccarrier of hepatitis B virus, the patient had receivedweekly injections of aurothioglucose and syntheticcorticotrophin for four months before the develop-ment of hepatitis. Synthetic corticotrophin may haveenhanced replication of hepatitis B virus which,modified by the gold salt treatment, caused infectioushepatitis and the increase of HBsAg in the serum.13The production of anti-HBs antibodies may have inturn resulted in a large amount of immune complexescontaining these two components. Thus the presenceof at least three independent stimulating factors-that is, immune complexes, hepatitis B virus antigen,and rheumatoid factor, caused continuous stimu-lation of the lymphatic system and the developmentof angiofollicular hyperplasia (Castleman's disease).No data are available regarding the presence ofHBsAg in the blood of patients with Castleman'sdisease.9 10 Patients with chronic liver dysfunctionand bile duct damage, however, have been reportedto develop nodal lesions identical to Castleman'sdisease of plasma cell type.9 The HBsAg carrierstate of these patients is unknown. The possible roleof HBsAg in Castleman's disease needs to beconfirmed by epidemiological studies in largergroups of patients.

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This study was supported by the Adolfo and Evelyn Blum researchfund for arthritis.

References

1 Frizzera G. Castleman's disease: more questions than answers.Hum Pathol 1985; 16: 202-5.

2 Gaba A R, Stein R S, Sweet D L, Variakojis D. Multicentricgiant lymph node hyperplasia. Am J Clin Pathol 1979; 69:86-90.

3 Hallett M, Landis M D, Harris N L, Richardson E P. Anelderly man with progressive neuropathy and elevated gammaglobulins. N Engl J Med 1984; 311: 388-98.

4 Meyers D L, Klemp P. Lymph node enlargement in rheumatoidarthritis: a case of angio-immunoblastic lymphadenopathy.S Afr Med J 1982; 62: 1038-9.

5 Nosanchuk J S, Schnitzer B. Follicular hyperplasia in lymphnodes from patients with rheumatoid arthritis. Cancer 1969; 24:343-54.

6 Frizzera G, Banks P M, Massarelli G, Rosai J. A systemiclymphoproliferative disorder with morphologic features ofCastleman's disease. Am J Surg Pathol 1983; 7: 211-3.

7 Gazitt Y, Margel L, Lerner A, Wands J R, Shouval D.Development of a novel Clq immunoadsorbent for removal of

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7a Lowry 0 H, Rosebrough N J, Farr A L. Randall R J. Proteinmeasurement with the folin-phenol reagent. J Biol Chemn 1951:193: 265-75.

8 Keller A R, Hochholzer L, Castleman B. Hyaline-vascular andplasma-cell types of giant lymph node hyperplasia of themediastinum and other locations. Cancer 1972; 29: 670-83.

9 Frizzera G, Peterson B A, Bayrd E D, Goldman A. A systemiclymphoproliferative disorder with morphologic features ofCastleman's disease: clinical findings and clinicopathologiccorrelations in 15 patients. J Clin Oncol 1985; 3: 1202-16.

10 Weisenburger D D, Nathwani B N, Winberg C D, RappaportH. Multicentric angiofollicular lymph node hyperplasia: aclinicopathological study of 16 cases. Hum Pathol 1985; 16:162-72.

11 Schroer K R, Fransilla K 0. Atypical hyperplasia of lymphnodes: a follow up study. Cancer 1979; 44: 1155-63.

12 Chen K T K. Multicentric Castleman's disease and Kaposi'ssarcoma. Am J Surg Pathol 1984; 8: 287-93.

13 Sagnelli E, Manzillo G, Maio G, et al. Serum levels of hepatitisB surface and core antigens during immunosuppressive treat-ment of HBsAg-positive chronic active hepatitis. Lancet 1980;ii: 395-7.

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