J Clin Pathol 1986;39:1209-1216

Acute idiopathic interstitial myocarditis: case reportwith special reference to morphologicalcharacteristics of giant cellsM TANAKA, R ICHINOHASAMA, Y KAWAHARA, Y ESAKI,* K HIROKAWA,tK OKISHIGE,j Y TANAKAtFrom the Pathological Anatomical Services, Tokyo Metropolitan Hiroo General Hospital, and the *TokyoMetropolitan Geriatric Hospital, the tDepartment of Pathology, Tokyo Metropolitan Institute ofGerontology, and the 4Oume Municipal General Hospital, Tokyo, Japan

SUMMARY Necropsy findings of an acute fatal case of idiopathic interstitial myocarditis were

reported. The patient was a 33 year old housewife who had acute cardiac failure on the sixteenthday after the onset of the disease. Necropsy showed important pathological changes confined to theheart. Both ventricles were affected by confluent granulomas with an ill defined patchy appearance.Histologically these lesions consisted of round cells, histiocytes, eosinophils and myogenic giantcells. The findings were compatible with those of interstitial myocarditis associated with a prolif-eration of giant cells. Both atriums were also affected to a minor extent, detectable only byhistological examination. Electron microscopy and cytochemistry showed that most giant cellsnoted in the lesion showed myofibrils and primary lysosomes in the cytoplasm. Giant cells were

positive for myoglobin.Though the macrophage origin of the giant cell in this disorder has been emphasised in a recent

report, these cytological results suggest that giant cells observed in the cardiac granulomatous lesionsof this case were mainly myogenic in origin.

Various infectious disorders are known to inducegranulomatous lesions in the myocardium, which areassociated with the appearance of giant cells. ' 2 Thesedisorders are not necessarily fatal, and some cases canbe cured. An acute idiopathic form of interstitial myo-carditis, a rare primary disorder of the heart, is oftenfatal and is accompanied by extensive degenerationand necrosis of the myocardium and a granuloma likelesion consisting of round cell infiltration,histiocytosis, and eosinophilia. A proliferation ofgiant cells of both histiocytic and myogenic type, witha certain variation in number according to the case, isalso often noted in this disorder.' 2 The importantchange is confined to the heart and has been named aseither isolated or idiopathic interstitial myocarditis.Because of the unique morphology of its myocardialgranulomatous lesion, the disorder is commonlyreferred to as giant cell myocarditis. About 40 cases ofan acute idiopathic form ofgiant cell myocarditis havebeen reported worldwide.3 4

Accepted for publication 27 May 1986

Careful review of these reported cases showed thatnearly half were probably cardiac sarcoidosis.5 Char-acteristic giant cells observed in acute idiopathic inter-stitial myocarditis may originate from degeneratingmyocardial cells and myocardial interstitialhistiocytes,' their origin, however, is still somewhatcontroversial. Filamentous materials resemblingdegenerated myofibrils detectable ultrastructurally inthese cells6 were interpreted either as degeneratingmyofibrils of the myocardial cell7 or phagocytisedmyofibrils of macrophages.8'-I Histochemically, thelysosomal activity of these giant cells did not help todistinguish their origin.10 A recent immuno-histochemical study showed the presence of anti-macrophage and anti-Leu 3a (anti-T cell) antigens ingiant cells and suggested that they originated frommacrophages.'0

This paper adds a further case to the reported casesof acute idiopathic interstitial myocarditis andpresents evidence for the myogenic origin of giantcells, particularly on the basis of their ultrastructuraland immunohistological characteristics.

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Case report

CLINICAL HISTORYA 33 year old Japanese housewife had been healthyand had no history of allergic reaction to commonlyprescribed drugs. She had no history of recent travelabroad. Her husband and two children were allhealthy. In September 1984 she felt discomfort in theespigastric region after breakfast. On a visit to aneighbouring hospital, cardiomegaly and arrhythmiawere pointed out. She then developed syncope for fiveminutes when she went upstairs at home. She wasimmediately taken to a local hospital. Electro-cardiography showed an increase in S-T segment in II,III, aVf and V1-2, premature atrial contraction, andpremature ventricular contraction and sinus tachy-cardia (120/minute). Digitalis and lidocaine wereineffective. She was transferred to Oume MunicipalGeneral Hospital. On admission, her physical condi-tion was as follows: body temperature 36-7°C; cardiacrate 96/minute; respiratory rate 14/minute; bloodpressure 90/70mm Hg. Congestion of both lungs andenlarged cardiothoracic ratio (67%) were found onchest radiography. Central venous pressure wasslightly raised (17cm water). An electron cardiogram

Fig I Cross section of ventricles. Note slight to moderatedilatation of bilateral ventricles with diffuse thinning ofmyocardium. No focal necrosis is observed.

showed first degree A-V block (PQ interval 0-26 sec-onds), disturbance of intraventricular conduction(QRS 009 seconds), and low voltage. Changes inserum enzyme activities were unimportant: creatinephosphokinase 107 IU/i (normal range = 24-170),glutamic-oxaloacetic transaminase 28 IU/I (normalrange: 0-40), glutamic pyruvic transaminase 16 IU/I(normal range: 0-35), except for slightly raised lactatedehydrogenase activities (751 Wroblewski units, nor-mal range: 100-450). Data on peripheral bloodshowed (red blood cells 481 x 104, white cells 7600,haemoglobin concentration 11-2 g/dl, haematocrit33-5%, platelets 16-1 x 104) and serum (rheumaticfactor test negative, Treporema pullidum hae-magglutination test negative, C-reactive protein 1+)showed no clinically important changes. Tests fortuberculin and Kveim reactions and estimations ofantibody titres for viruses were not performed. Pri-mary myocardial disease was suspected clinically, andthe patient was conservatively treated by furosemide(80 mg/day) and dopamine (4-5 ug/kg/minute). Rightpneumothorax occurred and a continuous drainagewas carried out. The pneumothorax improved fourdays later. Ventricular tachycardia (150/minute) thenappeared and bradycardia followed (40/minute). Her

Fig 2 Low power view ofpart of left ventricle showingdifusely distributed patchy granulomas (*). Changes areimportant at external myocardial layer adjacent toepicardialfatty tissue. Endocardial side is at the bottom.(Azan stain.) x 8.

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Case report of acute idiopathic interstitial myocarditis

blood pressure became unmeasurable. A transientpacemaker was inserted but she died on September 21,1984, 16 days after the onset of the disease.

Pathology

Necropsy was carried out two and a half hours afterdeath. Notable pathological changes were confined tothe heart. No clinically important changes wereobserved in other viscera.The heart weighed 320 g. There was a small amount

of pericardial effusion (60 ml) without apparent signsof pericarditis. Both ventricles were moderatelydilated. The volume of the cardiac chambers was mea-sured by a clay moulding method, and the dataobtained were as follows: left ventricle 57 8 ml; rightventricle 72-9 ml; left atrium 28-1 ml; right atrium49-7 ml. The wall thickness of the heart was at the lowlimit of the normal range: left ventricle 8-0 mm; rightventricle 2 0-2-5 mm. The circumference of the val-vula annuli was within the normal range. No abnor-mality was found in any cardiac valve. Both coronaryarteries showed minimal sclerosis. A bean sized freshthrombus was attached to the endocardium of the leftventricular apex. On the cut surface, patchy lesions of

40

(D'V * ;7t w 4'8+

Fig 3 General view ofgranulomatous changes observedadjacent. to degenerating myocardial cells (right uppercorner). Details of cellular reaction in marked area of thispicture are shown in fig4. (Haematoxylin and eosin.)x 155.

1211up to a rice grain size, which were vaguely borderedand appeared greyish-white in colour, were spreaddiffusely and occupied about one third to a half ofbilateral ventricle volumes (figs 1 and 2). Overall,neither scars nor necrotic foci were detectable in themyocardium.

Histologically patchy lesions were noted through-out the myocardium and consisted of granulomas ofvarious sizes spread extensively through both ventri-cles (figs 2-4), the left atrium slightly, and the rightatrium only at the appendage. The disease in bothventricles manifested itself more noticeably in themyocardium of the epicardial side; the epicardial fattissue was only partially affected (fig2). Papillarymuscles of both ventricles were affected. No granu-lomatous lesions were noted in the chorda tendinaeand cardiac valves. Major cellular Clements found inthe granulomatous lesions were small to medium sizedlymphocytes and histiocytes (figs 3 and 4). A mod-erate number of eosinophils and plasma cells werealso noted, but almost no neutrophils. Multinucleatedgiant cells of 25-90 x 10-20gm in size, having up to20 nuclei were found throughout the granulomatousfoci, particularly at the periphery where a close con-tact to undamaged myocardial cells was speculated. In

{~~~P iw ~ &"~. ,-

Fig 4 Granulomatous changes consisted of round cells,fibroblasts, and giant cells (arrow). Giant cells arecommonly seen at parallel to degenerating myocardial cells(*). (Haematoxylin and eosin.) x 185.

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Tanaka, Ichinohasama, Kawahara, Esaki, Hirokawa, Okishige, Tanakagranulomatous foci atrophy, swelling, and degener- Neither granulomatous lesions nor angitis wereation of muscle fibres were common (figs 3 and 4). found in other organs. A 2 x 1 cm sized scar wasProliferation of fibroblasts and capillaries and new found in the right apex of the lung (230:310 g) (weightdeposition of collagen were evident. Neither vasculitis of left lung 230 g, right lung 310 g); focal lympho-nor neuritis was noted. cytosis was also noted. Organising pneumonia of right

*?- v.e

1''~~~~~ kxtp.,g a v b..

Figs 5-7 Three types of multinuclear giant cells distinguished by nuclear position. Figs 5 and 6 were taken fromhaematoxylin and eosin stained sections, andfig 7 was taken from immunohistochemically stained section (PAPmethod, myoglobin.) x 820.

Fig 5 Elongated type which often communicates with degenerating muscle cells.

Fig 6 Giant cell with centrally located multiple nuclei.

Fig 7 Giant cell with circularly arranged multiple nuclei. Myoglobin is weakly positive in upper part of the

cytoplasm ofgiant cell.

Table 1 Immunohistochemical differences of giant cells shown by PAP method

Types ofgiant cells (incidence in %)I 11 III Sarcoidosis Langhans' type Foreign body type Touton type

Myoglobin* (A) 52 24 22 6 () () (-) (-)(B) 32 8 14 10(C) 16 0 10 6

Lysozyme* (A) 8 0 4 4 (+ +) (+ + +) (+)(-)(B) 42 6 26 10(C) 50 20 18 12

IgG** ( + + M( ++ )+ H +)IgA** (++F- (+M- (++ () +F-IgM** (+)-(-) (+M- (+ + () (F-

Sources of reagents: *DakoPatts Inc, **Boehringerwerke. A, B, and C (A =' definitely positive, B = faintly positive, C = negative), stainingintensity = (-) negative, (+) weakly positive, (+ +) moderately positive, (+ + +) strongly positive.

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Fig 8 Low power view of multinucleated giant cell of elongated type. Cell was preserved poorly due tocadaverous change. Parts of cytoplasm, (square) and (arrow) were further enlarged and are shown infigs 9 and 10, respectively. (Lead citrate and uranyl acetate.) x 1960.Fig 9 Higher magnification of cytoplasmic portion of giant cell shown in fig8. Myofibrils (Mf) in cytoplasmare shown. Mb: cell membrane. x 8480.

Fig 10 Dense structure of cytoplasm consisting of condensed (degenerating) myofibrils (Mf).M = mitrochondria. x 17000.

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segment 5 of the lung was also noted. Slighteosinophilia was noted in the muscle layer of the gas-

tric antrum. Numerous fibrin thrombi in the liver(960 g) and a small number of pulmonary vessels sug-

gested that disseminated intravascular coagulationmight have occurred at the final stage.

CHARACTERISTICS OF GIANT CELLSMorphological characteristics in histology Mostgiant cells observed in myocardial granulomas of thiscase resembled either foreign body or myogenic giantcells. Their positions seemed to parallel those of themuscle cells (fig 4). Three types of giant cells weredistinguished in the granulomas: type I-giant cellswith elongated cytoplasm either arranged in parallelor connecting directly with muscle fibres (fig 5); typeII-giant cells with centrally arranged multiple nuclei(fig 6); and type III-giant cells with circularlyarranged multiple nuclei (fig 7). Table 1 shows a roughestimation of their incidence in 100 giant cells. Withperiodic acid Schiff stain the cytoplasm of giant cellsseemed to be rather pink. Lipofuscin granules, whichcould suggest a myogenic origin for the giant cells,were often noted at the paranuclear area.

Electron microscopy (figs 8-10) The tissue was

poorly preserved due to cadaverous changes. Multi-nucleated giant cells (fig8), however, with elongatedcytoplasm (about 80,um in length) that containedmyofibrils (fig 9) were easily detected. Giant cells werelocated adjacent to degenerating muscle fibres, whichappeared condensed and osmiophilic (fig 10).Myofibrils of degenerating muscle cells extendedoccasionally into the cytoplasm of neighbouring giantcells closely attached to a thin membrane of compli-cated infoldings (an intercalated disc), suggesting a

myogenic origin. Filamentous materials of 12-5 to25 nm in thickness, with a sparse density, were alsoseen in the cytoplasm of the giant cell. Occasionallymore than a pair of centrioles were found in the cyto-plasm near the nuclei, suggesting that the giant cellwas formed either by an impaired cytoplasmicdivision or cell fusion. There were two types of gran-ules, one consisting of highly osmiophilic granules of100 to 200 nm in diameter found in mitochondria, andthe other consisting oflow osmiophilic granules of 200to 500 nm in diameter with a halo in the cytoplasm.The second type may have been the primary lysosome.Most rounded form giant cells showed ultrastructuralcharacteristics similar to those of the elongated form,except that numerous lysosomes, both primary andsecondary types, were found in the cytoplasm of somecells which had a few filamentous materials.Immunohistochemistry (tables 1 and 2) Paraffinembedded tissues were examined by both peroxidase-antiperoxidase (table l) and avidin-biotin-peroxidase

Table 2 Immunohistochemical markers of giant cellsshown by ABC method

Markers Reactions

Antihuman rabbita I -antichymotrypsin' (+ + )( +)a I -antitrypsin' (+ +)-(+)

CEA' (-)Desmin' (-)Factor Vlll' (-)Ferritin' (-)Fibronectin2 (-)Immunoglobulin' (+ (-)Keratin' (-)Lactoferin' (-)

Lysozyme' (+ )( )Myoglobin3S-100 protein4 (-)Actin IgG (chicken)5

Antihuman mouse (monoclonal)Myosin6Vimentin7 (-)

Sources of reagents: 1. DakoPatts Inc; 2. ZYM: Zymed LaboratoryInc, USA; 3. CPL: Cappel Laboratory Inc, USA; 4. Dr Matsuda,Department of Pathology, Yamagata University; 5. BTI: BiologicalTechnologies Inc, USA; 6. Dr Nishikawa, Department of Pathology,Tokyo Women's Medical College, Japan; 7. LBS: Labsystem Oy,Finland.

complex (ABC) methods (table 2). Myoglobin,lysozyme, IgG, IgA and IgM were examined using thePAP method (table 1). For controls, various types ofgiant cells obtained from the following cases wereexamined: cardiac sarcoidosis (woman aged 21) forsarcoid giant cells; tuberculous lymphadenitis (managed 27) for Langhans' giant cells; a tissue adjacent tooesophageal cancer (man aged 48) for foreign bodygiant cells; and a pulmonary cryptococcosis tissue(man aged 56) for giant cells of the Touton type.Myoglobin was definitely positive in over 50% of thegiant cells observed in the present case, in contrast tothe negative reaction of giant cells of the control cases.Half of the giant cells of the present case were negativefor lysozyme. A similar tendency was noted in foreignbody giant cells. Giant cells of both tuberculosis andsarcoidosis were strongly positive for the lysozymereaction. Reactions to IgG, IgA, and IgM scarcelydiffered in giant cells of this case and of the controls.Sixteen cellular markers, including both myoglobinand lysozyme that had been studied by the PAPmethod, were analysed using the ABC method (table2). In this study reactions to both myoglobin andlysozyme showed a similar pattern as had been notedwith the PAP method. Giant cells of the present casewere often equally positive in a l-antichymotrypsinand a l-antitrypsin, suggesting that some of the giantcells of the present case were of the macrophage ori-gin. The importance of the rest of the markers testedwas inconclusive and may serve only for a reference.

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Case report of acute idiopathic interstitial myocarditisDiscussion

Acute idiopathic interstitial myocarditis, a diffusetype of Fiedler's myocarditis,"l 12 has been dis-tinguished from other forms of myocarditis observedin systemic disorders, including sarcoidosis, infec-tious, toxic, and allergic diseases.Because of the pres-ence of occasional multinucleated giant cells in themyocardial lesions of this disease,'3 the term isolatedgiant cell myocarditis is often applied, particularly inwestern reports. As the appearance of giant cells isrelated to non-specific myocardial lesions and is lesscommon in acute idiopathic interstitial myocarditisthe term giant cell myocarditis has not been used inthis report.The pathogenesis of this disease is unknown,'4 but

viral infections have been speculated.'5 The acutefatal course of a case of an isolated cardiac lesion,compatible histologically with interstitial myocarditis,led to the final diagnosis. No granulomatous foci,which would suggest sarcoidosis, were detected in sys-temic organs examined both grossly and histologi-cally. Looking at the available pathologicalanatomical data, our case resembles Friedler's myo-carditis reported by Parrish'6 and giant cell myo-carditis reported by Suganuma et all 7; more extensivemyocardial disease was reported in the former case.

In general, the term "giant cell myocarditis" isloosely applied to granulomatous myocardial lesionsassociated with the appearance of giant cells: anygranulomatous lesion that affects the myocardiumcan expect to form giant cells.'4 18 The appearance ofgiant cells in myocardial ganulomatous lesions is pos-sibly related to a reparatory process ofdamaged myo-cardial cells. Intervention of macrophages of bothlocal (histiocytes) and blood (monocytes) origin, withcertain variations in numbers, reflecting the stage ofthe disease, may occur.

In an earlier stage giant cells originating fromdegenerated or regenerating myocardial cells, or both,may predominate, in contrast to specimens of a laterstage, in which macrophages may be obserVed morecommonly following an advanced reparative process.It is likely that the controversial problem of the originof giant cells in interstitial myocarditis is related, atleast in a part, to morphological differences betweengranulomatous lesions, relating to the repair stage ofthe disease. The presence of giant cells in granu-lomatous lesions of the myocardium thus does notsuggest any definitive pathogenesis. Rather, thetopography ofthe granuloma, which is confined to theheart, may be more reliable and specific to define thedisorder.The origin of giant cells is one of the most popular

topics concerning interstitial myocarditis. Both myo-genic and macrophage origins for giant cells have

1215already been considered.' 214 Although a myogenicorigin for giant cells is favoured, both foreign bodyand Langhans' type giant cells have also been sug-gested.'4 19 The morphological grounds for the myo-genic origin of giant cells are as follows: (i) parallelposition of giant cells and muscle fibres; (ii) a directcontact between giant cells and muscle cells'7 18 20 21.(iii) the presence of a smooth transition from a giantcell to a muscle cell; (iv) myofibrils in the cytoplasm ofgiant cells6 22 23 24; (v) lipofuscin granules in the cyto-plasm of giant cells.'3 These criteria have been drawnfrom data obtained during regeneration of the skeletalmuscle after injury.423 Some argue that the latterthree criteria are related to phagocytosis.'0 18We morphologically classified the giant cell of this

case into three types. The type I giant cell satisfies allmorphological citeria stated above and thus can beregarded as a myogenic type. Though giant cells of thetwo other types also satisfy the criteria for the myo-genic origin, the type II giant cells resemble foreignbody giant cells. Morphological differences were seenbetween the type III giant cell and giant cells observedin tuberculosis and sarcoidosis. The myogenic originof most giant cells observed in our case was furtherconfirmed ultrastructurally and immuno-histochemically. An electron microscopical exam-ination showed a close association betweendegenerated muscle fibres and the cytoplasm of thegiant cell, confirming earlier an observation made byPyun et al.6 The presence of myoglobin was shownimmunohistochemically in over 50% of giant cells inour case, suggesting that most of the giant cells wereof myogenic origin.

Recently immunocytochemical methods have beenapplied to define the macrophage nature of giant cellsobserved in interstitial myocarditis.'0 Although nottested in this study, Theaker etal'0 showed twodifferent antimacrophage antibodies (EMB 11 andKB 90) in giant cells using a monoclonal antibodymethod. They reported that both desmin and Ki 67were negative in giant cells, except for a positive Ki 67reaction in the nuclei of lymphocytes and mono-nuclear phagocytes. Lysozyme activity was nearlyabsent in our case, which agrees with the findings ofmost other cases reported,7 810 except that a positivereaction was noted in one case.9 This case may beregarded as specific, as the giant cells of this caseshowed no elongated forms (type I of our case), notransitional forms to muscle cells, and a negative cyto-chemical reaction to myosin and creatine phos-phokinase. Negative lysozyme activity, however, doesnot completely exclude a histiocytic origin for giantcells, because some macrophages are known to appearnegatively.25 Cellular immunity is required to inducethe lysozyme activity.8 Perhaps the positive lysozymalactivity noted in that case9 was related to underlying

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1216 Tanaka, Ichinohasama, Kawahara, Esaki, Hirokawa, Okishige, Tanaka

immunological abnormality caused by chronic activehepatitis with positive antinuclear antibody.

We express our gratitude for the excellent technicalhelp of the following technologists in the preparationof the histological, immunochemical, and electronmicroscopical specimens used in this study: Y Ootaniand Y Hirahara of the Clinical Pathology Service,Oume Municipal General Hospital; Mr I Sakuma andMrs Y Suzuki, the Pathological Anatomical Service,Tokyo Metropolitan Hiroo Hospital. We alsoacknowledge valuable advice and comments for caseanalysis from Dr S Otsu, Yokufiikai Geriatric Hospi-tal, Tokyo, and Professor Morie Sekiguchi, the HeartInstitute of Tokyo Women's Medical College, and DrY Matsui, Japan Red Cross Medical Center, Tokyo.We are indebted to Professor T Kasajima and Dr TNishikawa, Second Department of Pathology, TokyoWomen's Medical College, for their kind help inimmunohistochemical studies (ABC method) of thegiant cells of this case. We also thank associate Pro-fessor J Patrick Barron of St Marianna UniversitySchool of Medicine for his revision of the manuscript.

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