17 Clin Pathol 1994;47:138-142

Lymph node hyalinisation in rheumatoid arthritisand systemic sclerosis

W G McCluggage, H Bharucha

Department ofPathology, RoyalVictoria Hospital,BelfastW G McCluggageQueen's University,BelfastH BharuchaCorrespondence to:DrW G McCluggage,Department of Pathology,Royal Victoria Hospital,Grosvenor Road,Belfast BT12 6BA,Northern IrelandAccepted for publication7 September 1993

AbstractAims-To review the histological fea-tures of lymph nodes excised from seven

patients with rheumatoid arthritis andone with systemic sclerosis.Methods-Lymph nodes excised fromseven patients with rheumatoid arthritisand one patient with systemic sclerosisover a 10 year period were examinedusing the stains haematoxylin and eosin,periodic acid Schiff (PAS), Masson-trichrome, and Congo red for amyloid.Results-Of the seven nodes examinedfrom the cases of rheumatoid arthritis,three showed definite reactive follicularhyperplasia with a prominence of plasmacells in the interfollicular areas, twoshowed subtotal replacement of the nodeby numerous sarcoid like granulomata,and one contained a large central area ofnecrosis with a surrounding palisade ofhistiocytes. In all six cases, focal areas

of PAS positive eosinophilic hyalinematerial were present, which did notstain with Congo red. In some cases thishyaline material was focally calcified. Inthe seventh patient with rheumatoidarthritis the excised lymph node was

almost totally replaced by similar PASpositive hyaline material which showedextensive areas of calcification. Thelymph node removed from the patientwith systemic sclerosis similarly showedalmost total replacement by PAS positivehyaline material.Conclusion-In all cases the nodes con-

tained PAS positive extracellular hyalinematerial to a greater or lesser degree.The lymph nodes from two of thepatients with rheumatoid arthritis con-

tained numerous sarcoid like granulo-mata, further indicating a possibleassociation between sarcoidosis andrheumatoid arthritis. Pathologists andclinicans should include rheumatoidarthritis and systemic sclerosis in theirdifferential diagnosis of lymph nodehyalinisation ofunknown aetiology.

(J Clin Pathol 1994;47:138-142)

Local or generalised lymphadenopathy mayoccur in up to 75% of patients with rheuma-toid arthritis.' Most commonly the axillary,supraclavicular, and cervical lymph nodes are

enlarged, but other lymph node groups maybe affected.'2 Lymphadenopathy in systemic

sclerosis has not been so well documented. Inboth these conditions malignant lymphomamay supervene and lymph node biopsy maybe undertaken to exclude this.35 Previouspublications on node changes in rheumatoidarthritis have commented on the extremereactive follicular hyperplasia and prominentplasma cell infiltration of the interfollicularareas.' 2 As far as we are aware, lymph nodechanges have only been reported in one previ-ous necropsy case of systemic sclerosis andthe histological findings were of obliterationof the nodal architecture by extensive hyalinefibrosis.6

MethodsThe clinical summaries stated on the requestforms of all lymph nodes submitted to theRoyal Victoria Hospital, Belfast, since 1984were reviewed. Seven patients with rheuma-toid arthritis and one with systemic sclerosiswere identified.

Sections from each node were routinelyprocessed and stained with haematoxylin andeosin, periodic acid Schiff (PAS), Massontrichrome, and the Congo red stain for amy-loid. The clinical notes of all eight patientswere reviewed.

ResultsCASE REPORTSCases 1-3Cases 1, 2, and 3 were a 50 year old man, a59 year old woman, and a 71 year oldwoman, respectively. Each had had a fiveyear, 10 year, and long history of seropositiverheumatoid arthritis, respectively. All hadmultiple joint disease. Case 1 developed bilat-eral axillary lymphadenopathy and anenlarged lymph node was removed from hisright axilla. In case 2 an enlarged node wasremoved from the right groin, and in case 3(a patient who developed bilateral axillaryand inguinal lymphadenopathy) a node wasremoved from the right axilla.

Histological examination of the excisednodes in all three cases showed essentiallysimilar features. There was a noticeabledegree of reactive follicular hyperplasia withlymphoid follicles and germinal centres situ-ated throughout the cortex and medulla ofthe nodes. Many of these lymphoid folliclesshowed a "starry-sky" appearance of tingiblebody macrophages in their germinal centres.In the interfollicular areas there was a mixtureof small lymphoid cells, among which were

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Lymph node hyalinisation in rheumatoid arthritis and systemic sclerosis

Figure 1 Node showing follicular hyperplasia with eosinophilic hyaline material ininterfollicular areas (haematoxylin and eosin).

Figure 2 Node from case 4 showing extensive replacement by focally calcified eosinophilichyaline material (haematoxylin and eosin).

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Figure 3 Node replaced by numerous sarcoid like granulomata with interveningeosinophilic hyaline material (haematoxylin and eosin).

plasma cells in considerable numbers. Theinterfollicular areas contained focal depositsof eosinophilic hyaline material which werecalcified in case 2 (fig 1). This material gave apositive reaction with the PAS stain andstained green with the Masson trichromestain. In all three cases the material did notstain with Congo red.

Case 4The patient was a 78 year old man with along history of rheumatoid arthritis andFelty's syndrome. He had an enlargedlymph node in his right axilla. This wasremoved.

Histological examination showed the nodeto be extensively replaced by eosinophilichyaline material which was focally calcified(fig 2). A small amount of residual lymphoidtissue was identified, particularly around theperiphery of the node. This was composedmainly of small lymphocytes with occasionalscattered plasma cells. No follicular struc-tures were identified. The staining reactionsof the eosinophilic hyaline material wereidentical with those of the above group (cases1-3).

Cases 5 and 6These comprised a 50 year old man with a 10year history of seropositive rheumatoid arthri-tis, and a 67 year old woman with a long his-tory of seropositive rheumatoid arthritis. Bothhad multiple joint disease. The patient in case6 also had autoimmune hypothyroidism, per-nicious anaemia, and liver cirrhosis of pre-sumed autoimmune aetiology. In case 5 anenlarged lymph node was removed from theright side of the neck, and in case 6 anenlarged node was removed from the leftaxilla.

Histological examination of the excisednodes in cases 5 and 6 showed similar fea-tures. There was extensive replacement of thelymph nodes by numerous well formed sar-coid-like granulomata. These granulomatawere composed of epithelioid histiocytes andLanghans' type giant cells. Small centralareas of necrosis were present in a few of thegranulomata. Plasma cells were identifiedadmixed with small lymphocytes surroundingthe granulomata. Between the granulomata,deposits of eosinophilic hyaline material werepresent, similar to those described in the pre-vious cases (fig 3). This hyaline material wasalso PAS positive, stained a green colour withthe Masson-trichrome stain, and was Congored negative. The Ziehl-Neelsen stain for acidfast bacilli was negative in both cases, andfungal organisms were not identified with thePAS stain.A chest x ray picture of case 5 showed

bilateral hilar lymphadenopathy, and follow-ing the results of the lymph node pathology,the patient underwent a Kveim test whichproved positive.

After a node biopsy and before furtherinvestigation could be undertaken, case 6died as a result of liver failure. A post mortemexamination was not carried out.

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Figure 4 Nodefrom case 8 showing extensive replacement by eosinophilic hyalinematerial (haematoxylin and eosin).

Case 7This was a 62 year old woman with a fouryear history of seropositive rheumatoidarthritis, mainly affecting her hands. Shedeveloped an enlarged lymph node inher right axilla, and the lymph node was

biopsied. She also had bilateral subcutaneousswellings on the extensor surfaces of bothforearms, which clinically indicated rheuma-toid nodules.

Histological examination showed a largearea of coagulative necrosis within the centre

Summary of clinicalfeatures and lymph node histology

Case No AgelSex Clinicalfindings Lymph node histology

1 50/M Five year history of rheumatoid Pronounced reactive folliculararthritis. Bilateral axillary hyperplasia. Plasma cells inlymphadenopathy interfollicular areas. Focal

deposition of PAS positiveeosinophilic hyaline material

2 59/F 10 year history of rheumatoid Pronounced reactive folliculararthritis. Enlarged node right hyperplasia. Plasma cells ingroin interfollicular areas. Focal

deposition of calcified PASpositive eosinophilic hyalinematerial

3 71 /F Long history of rheumatoid Pronounced reactive folliculararthritis. Bilateral axillary and hyperplasia. Plasma cells ininguinal lymphadenopathy interfollicular areas. Focal

deposition of PAS positiveeosinophilic hyaline material

4 78 /M Long history of rheumatoid Extensive replacement of nodearthritis with Felty's syndrome. by focally calcified PASEnlarged node right axilla positive eosinophilic hyaline

material

5 50/M 10 year history of rheumatoid Numerous well formed sarcoidartritis. Enlarged right like granulomata. PAScervical node positive eosinophilic hyaline

material betweengranulomata

6 67/F Long history of rheumatoid Numerous well formed sarcoidarthritis, autoimmune like granulomata. PAShypothyroidism, pernicious positive eosinophilic hyalineanaemia, cirrhosis. Left axillary material betweenlymphadenopathy granulomata

7 62 /F Four year history of rheumatoid Large central area of necrosisarthritis. Enlarged nodes right with surrounding palisade ofaxilla histiocytes. PAS positive

eosinophilic hyaline material

8 39/M Five year history of systemic Extensive replacement of nodesclerosis by PAS positive eosinophilic

hyaline material

of the lymph node, with a surrounding pal-isade of histiocytes. The remaining lymphnode contained a few inactive lymphoid folli-cles, together with plasma cells and smalllymphocytes. Deposits of eosinophillic hya-line material were also identified in interfollic-ular areas. This material was PAS positive,Congo red negative, and stained a greencolour with the Masson-trichrome stain.The Ziehl-Neelsen stain was negative, as

was the Warthin-Starry stain for cat scratchbacilli. Fungal organisms were not identified.

Investigations performed following thebiopsy included serology for toxoplasmosis,Q-fever and infectious mononucleosis. Alltests yielded negative results. The lympha-denopathy disappeared and no infective causewas ever found.

Case 8A 39 year old man with a five year history ofsystemic sclerosis was found to have mediasti-nal lymphadenopathy on chest x ray. One ofthese nodes was removed for histologicalexamination.

Histological examination showed that thelymph node had been extensively replaced byeosinophilic hyaline material similar to case 4(fig 4). Occasional inactive lymphoid follicleswere present in parts of the node which werenot hyalinised. In contrast to case 4, calcifica-tion was not identified in the hyalinised areas.The staining reactions of the hyalinised mate-rial were similar to those in the previous cases.The clinical features and histological find-

ings of the excised lymph nodes are sum-marised in the table.

DiscussionLocalised or generalised lymphadenopathymay be found in up to 75% of patients withrheumatoid arthritis at some stage during thedisease process.' In rheumatoid arthritis lym-phadenopathy is most common when thesymptoms in the joint are active. The mostcommon nodes affected are the axillary, cer-vical, and supraclavicular groups,' 2 althoughother lymph nodes may also be enlarged.Lymphadenopathy may be particularly severein Felty's syndrome (rheumatoid arthritis,splenomegaly, and autoimmune neutropenia)and in juvenile rheumatoid arthritis (Still'sdisease). As well as lymphadenopathy,patients with rheumatoid arthritis may haveassociated systemic features such as fever,weight loss, and anaemia. These clinicalsymptoms may raise the question of a malig-nant lymphoma, and lymph node biopsy maybe undertaken to exclude this diagnosis. Theclinical suspicion may be further heightenedby the increased incidence of malignant lym-phoma previously reported in patients withrheumatoid arthritis.'5The histological findings reported in

excised nodes comprise pronounced follicularhyperplasia with large active germinalcentres.' 2 Increased numbers of plasma cellsare generally found in interfollicular areas inthe medullary cords.

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Lymph node hyalinisation in rheumatoid arthitis and systemic sclerosis

Lymph node changes have been describedrarely in patients with systemic sclerosis. Asfar as we are aware, only one necropsy casehas been reported, and the findings were ofextensive nodal replacement by hyaline fibro-sis.6 Malignant lymphomas have also beendescribed arising in association with systemicsclerosis and so lymph node biopsy may beundertaken to exclude this.4The histological findings in cases 1, 2, and

3 were of pronounced reactive follicularhyperplasia and prominent plasma cell infil-tration of interfollicular areas. These findingswere similar to those reported before.' 2 In allthree cases there were focal deposits of PASpositive eosinophilic hyaline material (focallycalcified in case 2) in interfollicular areas.Hyaline material may be seen in burnt-outgerminal centres in rheumatoid arthritis, andin other conditions where reactive follicularhyperplasia has been followed by involutionof lymphoid follicles. As far as we are aware,however, the presence of such material withininterfollicular areas in association with reac-tive follicular hyperplasia has not been com-mented on in other reviews of lymph nodehistology in patients with rheumatoid arthri-tis. In 1946 Poursines and Rochu7 mentionedlymphoid aplasia with pronounced sclerosisof the lymph nodes accompanying longstand-ing rheumatoid arthritis. They called this"lymph node cirrhosis". The changes theydescribed are similar to those in case 4 inwhich the excised lymph node was almosttotally replaced by focally calcified hyalinematerial. Similar hyaline material was alsoseen in cases 5, 6, and 7. In cases 5 and 6,numerous well formed sarcoid-like granulo-mata were present throughout the substanceof the node. There is no doubt that in case 5the patient also had active sarcoid disease asthere was extensive bilateral hilar lym-phadenopathy and the patient exhibited apositive Kveim reaction. In case 6 the patientdied from hepatic failure soon after the lymphnode biopsy and before it could be deter-mined whether he had sarcoidosis. The histo-logical findings of well formed granulomata,however, were certainly suggestive of thisdiagnosis.

Sarcoidosis has many features in commonwith various autoimmune disease. Severalstudies have commented on a possible associ-ation between sarcoidosis and rheumatoidarthritis.89 The findings in cases 5 and 6 lendfurther support to the existence of such anassociation.

In case 7, a large central area of necrosiswas present in the node, with a surroundingpalisade of histiocytes. The histological find-ings were suggestive of an infective process,but no infective cause was found despitedetailed investigation following the lymphnode biopsy. The findings also raised thequestion of a rheumatoid nodule arising inthe lymph node, a phenomenon which hasbeen described.'0 The pattern of coagulativenecrosis found in this case, however, was nottypical of that found in rheumatoid noduleswere the necrosis generally has a more

basophilic appearance, typical of necrobioticcollagen. In the area of the node which wasnot affected by this necrotising process thesame PAS positive eosinophilic hyaline mate-rial seen in cases 1 to 6 was also present.

In all seven cases of rheumatoid arthritisthis eosinophilic hyaline material was negativewith Congo red stain for amyloid. Amyloid,of course, may complicate the course ofrheumatoid arthritis and has been describedin lymph nodes in patients with this condi-tion." The nature of the hyaline material inour cases was unclear. It may representimmunoglobulin which does not have a /B-pleated structure when deposited in tissues,and therefore does not have the stainingproperties of amyloid. This material mighthave been produced by the plasma cells,commonly seen in nodes in rheumatoidarthritis and present to a greater or lesserdegree in all of our cases examined.Interestingly, similar PAS positive amorphouseosinophilic material may also be seenin lymph nodes in angioimmunoblasticlymphadenopathy with dysproteinaemia(AILD)"2-'4 and in nodes affected by lympho-plasmacytoid lymphomas."5 Again this mater-ial may represent immunoglobulin productsproduced by plasma cells in AILD, and bythe lymphoplasmacytoid cells in lymphoplas-macytoid lymphomas. Plasma cells may, ofcourse, be present in large numbers in AILD.Amyloid has also been reported in lymphnodes in occasional cases of AILD.16 Somepatients with AILD have a history of anautoimmune disease such as rheumatoidarthritis, although most cases arise de novo.We suggest that this characteristic hyaline

material is produced in lymph nodes in casesof rheumatoid arthritis. Plasma cells, whichare present in appreciable numbers in inter-follicular areas in association with the pro-nounced reactive follicular hyperplasia seen incases 1 to 3, were probably responsible. Wehave not seen such hyaline material in inter-follicular areas of nodes showing reactive fol-licular hyperplasia in association with otherconditions. More pronounced changes ofextensive fibrosis and calcification (case 4)may occur in later stages of the diseaseprocess, in nodes where the reactive hyperpla-sia has subsided. These changes may lead to aconfusing picture which the pathologist couldfind difficult to interpret.

Hyaline material, similar to that which wehave described, has been referred to as para-amyloid, and it is not uncommon in advancedstages of inflammatory or neoplastic condi-tions affecting nodes.'7 The hyaline materialfound in cases 5 and 6 may simply representhealed sarcoid granulomata, and in case 7may represent the sequela of a healed infec-tive process which has subsequently becomereactivated. Alternatively, the material mayhave resulted from previous reactive changesand plasmacytosis secondary to the associatedrheumatoid arthritis.

Extensive lymph node fibrosis has beenreported in one previous necropsy case ofsystemic sclerosis.6 Four visceral nodes

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were examined histologically (one tracheo-bronchial, two bronchopulmonary, and onemesenteric) and all showed similar features.The findings described are similar to thoseseen in the mediastinal lymph node in case 8.The aetiology of this fibrosis is unknown, butfibrosis may be found in various other organsin systemic sclerosis.

Extensive lymph node hyalinisation is par-ticularly common in the inguinal and iliacgroup of nodes. These changes may resultfrom longstanding non-specific low gradeinflammation. Hyalinisation is also commonfollowing inflammatory conditions such assarcoidosis and tuberculosis, and in associa-tion with certain neoplastic diseases such asnodular sclerosing Hodgkin's disease.Occasionally extensive lymph node hyalini-sation may be found with no clue as to itspossible aetiology. This hyaline material maycalcify, in time. We suggest that rheumatoidarthritis and systemic sclerosis should beadded to the list of causes of lymph nodehyalinisation and calcification, and thatpathologists and clinicians should considerthese conditions in their differential diagnosisof nodal sclerosis.

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