British Journal ofOphthalmology 1992; 76: 755-757

Bilateral Kimura's disease of the eyelids

S M Kennedy, J F Pitts, W R Lee, D C Gibbons

Tennent Institute ofOphthalmology, WesternInfirmary, GlasgowS M KennedyJ F PittsW R Lee

Queen ElizabethHospital, St Michael,Barbados, West IndiesD C GibbonsCorrespondence to:SusanM Kennedy,Department of Pathology,Royal Victoria Eye & EarHospital, Adelaide Road,Dublin, Ireland

Accepted for publication22 July 1992

Figure 1 Clinicalphotograph ofthe patientshowing bilateral swolleneyelids, more severe on theleft.

AbstractA case ofKimura's disease affecting the eyelidsbilaterally is reported in a 5-year-old boy ofAfro-Caribbean extraction who has beenfollowed for 12 years with repeat biopsies. Heinitialiy presented at 5 years ofage with swellingof the left upper eyelid, left cervical lymph-adenopathy, and eosinophilia. One year laterhe developed swelling ofthe right upper eyelid.There has been no change in the clinicalappearance over the next 12 years. Repeatedbiopsies of the eyelids showed a diffuseinflammatory infiltrate with many eosinophilsand lymphocytes. A lymph node biopsy showedreactive lymphoid hyperplasia. Immuno-histochemistry using lymphoid markersshowed a polyclonal pattern. Kimura's diseaseis a rare cause of eyelid swelling, particularly atsuch a young age and with bilateral involve-ment. This case demonstrates that bilateralorbital lymphoid lesions with cervical nodeinvolvement do not always imply lymphoma,but may have a benign pathogenesis. Theunusually long follow up in this case confirmsan excellent prognosis for Kimura's diseasewith conservative management. Accuratediagnosis in small orbital biopsies may sparethe patient unnecessary radical surgery.(BrJ Ophthalmol 1992; 76: 755-757)

Kimura's disease is a chronic inflammatorycondition occurring predominantly in orientals,with occasional cases reported in Caucasians,and rarely in blacks.`'5 To our knowledge it hasnot been reported previously in a person ofCaribbean extraction. The first descriptionappeared in the Chinese literature in 1937' as'eosinophilic hyperplastic lymphadenopathy',but the disorder became popularly known asKimura's disease following the report of

Kimura et al in the Japanese literature.2Kimura's disease has a predilection for the headand neck region, but orbital involvement hasbeen reported in only 14 cases.5-" Four of thesepatients had eyelid involvement.56 In only onepatient5 was the disease bilateral. In the publishedliterature on orbital disease there is little infor-mation on the long-term clinical behaviour or ofthe progressive histopathological changes whichmight occur. We had the opportunity to studyrepeat biopsies in the Afro-Caribbean boy over aperiod of 12 years and the findings are reportedhere.

Case reportA 5-year-old boy presented with swelling of theleft upper lid and bilateral cervical lymphadeno-pathy. He was otherwise in good health and noother abnormalities were detected on ocular andgeneral physical examination. Laboratoryinvestigations included an ESR of 23 mm/hour,WBC of 10 6x 109/ml with a differential ofneutrophils 42%, lymphocytes 41%, monocytes3%, eosinophils 13%, and basophils 1%. Thehaemoglobin and platelet counts were normal. Abiochemical profile, thyroid function tests, andserum calcium and albumin were normal. Serumelectrophoresis showed a diffuse hypergamma-globulinaemia. HTLV 1 antibody titre wasnegative. An orbital computed tomographic(CT) scan showed diffuse swelling of the leftlateral rectus muscle. A biopsy of the cervicallymph node showed a prominent eosinophilicinfiltrate of follicles and interfollicular areas.This was interpreted as a benign inflammatoryprocess. One year later swelling of the righteyelid became apparent. At that time both lidswere almost symmetrically enlarged. The lefteyelid was biopsied but there was no othersurgical intervention. The child achieved normalgrowth and remained well despite the cosmetichandicap of grossly swollen eyelids. He noticed avariation in the size of his eyelids from day today. At the age of 17, the patient was re-evaluated at his annual clinical examination. Hewas a healthy looking black male with massivelyswollen upper and lower eyelids (Fig 1). Therewas generalised swelling of the subcutaneoustissues of the eyelids, and firm discrete noduleswere palpable, three on the right and two on theleft (approximate maximal diameter 1 cm). Allwere freely mobile and non tender. One of theright upper lid nodules was biopsied. Physicalexamination revealed no lymphadenopathy ororganomegaly.

Histopathologic findingsBiopsy of the left upper eyelid was performed atthe age of 6 years. An inflammatory infiltratecomposed of eosinophilic polymorphonuclear

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Figure 2 Extensive inflammatory infiltrate ofstriatedmuscle andfibroconnective tissue ofthe eyelid.

leucocytes, small lymphocytes, mast cells, andplasma cells was scattered throughout fibroustissue and striated muscle (Fig 2). A few reactivelymphoid follicles were present. Degranulatingeosinophils were particularly prominent aroundsmall blood vessels but there was no evidence offibrinoid necrosis. The vessels had a slightlyhyperplastic endothelial lining, but theepithelioid change and intracellular luminawhich are typical of angioimmunoblasticlymphadenopathy were not seen (Fig 3). Clustersof eosinophils were present in the mantle zone ofsome follicles and occasional eosinophilic micro-abscesses were seen in the germinal centres(eosinophilic folliculolysis). The cervical lymphnode showed follicular hyperplasia with multi-nuclear giant cells and eosinophils in germinalcentres. Some eosinophils were degranulating.There was no evidence of atypia and Reed-Stemnberg cells were not seen. Mitoses wereconfined to the germinal centres.

Biopsy ofthe right upper eyelid was performed11 years later. It showed hyperplastic lymphoidfollicles embedded in sclerotic fibroconnectivetissue. The follicles were oval with a well definedeccentric mantle zone and prominent germinalcentres. Polykaryocytes resembling Warthin-Finkeldy type giant cells were conspicuous (Fig4) both in germinal centres and mantle zones.These giant cells contained up to 25 nucleiclustered together. Numerous eosinophils werepresent in the soft tissue and lymphoid follicles.Sheets of eosinophils, many degranulating, and

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ml,

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Figure 3 High power photomicrograph showing thepredominance ofthe bilobed eosinophils (arrows) in theinflammatory infiltrate. A vessel with a hyperplasticendothelial lining is shown.

small lymphocytes infiltrated striated muscleand fibrous tissues.

Immunohistochemical studies usingmonoclonal antibodies to B and T cell markers(L26 and UCHL1) and immunoglobulin (Ig)heavy and light chains (Dakopatts, Copen-hagen, Denmark), the avidin-biotin-peroxidasecomplex (ABC) method of Hsu'2 and the VectorABC kit (Vector Labs, Burlingame, CA, USA)revealed a polymorphic lymphoid infiltrate withthe usual distribution of B and T cells. IgEstaining was seen in lymphoid follicles and someplasma cells and mast cells. IgM and IgGpositivity was also seen.

DiscussionKimura's disease is an inflammatory processwith a predilection for the head and neck regionin young men histologically characterised by anangiolymphoid proliferation with eosinophiliaand elevated serum immunoglobulin IgE. '- Theaetiology is unknown and controversy exists as towhether it represents a benign lymphoidneoplastic process or is an allergic reaction.Evidence concerning the long-term behaviour ofthe disease is scanty. Although some authors usethe terms Kimura's disease and angiofollicularlymphoid hyperplasia interchangeably, recentstudies suggest that they may be differententities."25 Kimura's disease presents as a largesolitary lump or multiple lumps, with aninsidious onset, long duration, and a frequentoccurrence of peripheral blood hyper-eosinophilia. Regional lymph node involvementoccurs in up to 75% of cases. Systemic associ-ations include asthma and the nephroticsyndrome.6 14 Recurrence is common, estimatedbetween 15% and 40% of cases,'5 but fatalitieshave not beein reported. By contrast, angio-lymphoid hyperplasia is said to present withsmall papules or nodules on the face and scalp.On histological examination prominent hyper-trophic vessels with swollen endothelial cellsproliferating around arterioles and venules areseen; lymphoid proliferation is less apparent.Systemic abnormalities are not frequent.Although Kimura's disease is most often

periauricular or submandibular, a small numberof orbital lesions have been reported on the basisof an isolated biopsy and very few cases have

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Figure 4 Haematoxylin and eosin stained section oftheeyelid showing a hyperplastic lymphoidfollicle, with a welldelineated mantle zone. Warthin-Finkeldey type giant cells orpolykaryocytes are shown in the inset.

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Bilateral Kimura's disease ofthe eyelids

been followed over prolonged time interval. Thefirst orbital cases were recorded in 1976,4 1979,5and 198210. In 1983, a series of five orbital andthree adnexal cases was published,6 including apreviously reported case.'0 The mean age was 51years (range 38-72), which is older than themean age at other sites. Neither lid nor orbitaldisease have been reported in a child. The lesionswere uniformly solitary and affected the eye-brow, superior orbital ridge, and roof of theorbit. The orbital nodules varied in size from 1-2to 2-7 cm in maximal diameter. Those with anadnexal location comprised a solitary nodule atthe inner canthus in one patient and the upper lidin two. These nodules were smaller (7-8 mm)than the orbital cases. Four orbital cases havebeen reported subsequently.79 11 In one of these8the lesion arose in a patient who had undergoneenucleation for malignant melanoma of thechoroid, followed by an Iowa (polymethyl-methacrylate) implant. The occurrence ofKimura's disease in this situation led the authorsto suggest that the disease was a probablereaction to the implant. There have been nosubsequent reports of Kimura's disease followingorbital implants. The histopathological featuresdescribed in the literature are similar to thoseseen in the present case - for example, eosino-philic infiltration of soft tissue, florid germinalcentres, apparently increased postcapillaryvenules, and fibrous sclerosis. Giant cells ofWarthin-Finkeldy type, which are more oftenassociated with viral lymphadenopathies such asmeasles, were prominent in the germinal centresand the paracortex of our case. These cells havebeen noted by others in lymph nodes and salivaryglands but not in the orbital cases affected byKimura's disease."'8Ocular adnexal lymphoid proliferations can

present clinical and histopathological problemsand are well documented although there is muchto learn. The finding of a mixed lesion composedof an eosinophilic and lymphocytic infiltrate,follicular hyperplasia, and fibrosis brings bothorbital pseudotumour and Hodgkin's disease tomind. Inflammatory pseudotumours have apolymorphous inflammatory infiltrate composedof lymphocytes, plasma cells, and histiocyteswith a hyalinised or oedematous stroma. Endo-thelial cells are hypertrophied and prominent.Eosinophils may be present but are not usuallysuch a conspicuous feature as in this case.Although lymphoid aggregates may be seen,reactive germinal centres are a relativelyuncommon feature. 920 Hodgkin's disease is ruledout by the lack of the diagnostic Reed-Stemnbergcells and atypical mononuclear cells. Vessels areprominent, but there is no true vasculitis nor arethere malignant cytologic features, so thatsystemic vascular disease is unlikely.

Previously reported cases of periorbitalKimura's disease were successfully treated withexcisional biopsy. Hidayat et a16 reportedexcessivebleeding duringsurgery in onepatient.Radiotherapy and intralesional steroids have notbeen tried in orbital disease. There has beensome success with radiotherapy in skin disease.6In our patient the untreated lesions slowlyincreased in size and there was continuingeosinophilia but no other haematological abnor-

mality. Despite the CT evidence of lateral rectusinvolvement eye movement was normal. Thispattern suggests a low grade, possibly aberrant,hypersensitivity or allergic response to acontinuing antigenic stimulus. We have com-pared the early and late pathological features inthe eyelid over a 12 year period and found acontinuing active inflammatory reaction but noevidence of neoplasia. Eosinophils were just asnumerous in the late biopsy.

Surgical treatment oflarge eyelid nodules maypresent difficult technical problems. In onereport an orbital lesion underwent severehaemorrhage on resection.6 In such cases conser-vative management may be the best option, butshould include biopsy and histopathologicalexamination to rule out lymphoma.

In a large study of orbital and conjunctivallymphoid infiltrates, Medeiros and Harris2' statethat bilateral involvement and dissemination,such as cervical lymphadenopathy, at the time ofpresentation, occur only in lymphomas. Ourcase disproves this statement, showing theimportance of histopathological examination.

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4 Takenaka T, Okuda M, Usami A, Kawabori S, Ogami Y,Kubo K, et al. Histochemical and immunological studies oneosinophilic granuloma of soft tissue called Kimura's disease.Clin Allergy 1976; 6:27-35.

5 Dhermy P, Haye C, Dufier JL, Regnault F. L' Hyperplasieangio-lymphoide avec d'une localisation palpebral. J FrOphtalmol 1979; 2:247-52.

6 Hidayat AA, Cameron JD, Font RL, Zimmerman LE.Angiolymphoid hyperplasia with eosinophilia (Kimura'sdisease) of the orbit and ocular adnexa. Am J Ophthalmol1983; %: 176-89.

7 Francis IC, Kappagoda ME, Smith J, Kneale K. Kimura'sdisease of the orbit. Ophthalmic Plast Reconst Surg 1988; 4:235-9.

8 Smith DL, Kincaid MC, Nicolitz E. Angiolymphoid hyper-plasia with eosinophilia (Kimura's disease) of the orbit. ArchOphthalmol 1988; 106: 793-5.

9 Shields CL, Shields JA, Glass RN. Bilateral orbital involve-ment with angiolymphoid hyperplasia with eosinophilia(Kimura's disease). Orbit 1990; 9: 89-95.

10 Bostad L, Pettersen W. Angiolymphoid hyperplasia witheosinophilia involving the orbit: a case report. Acta Ophthal-mol 1982; 60: 419-26.

11 Conrads H, Bosse U. Angiofolliculare Hyperplasie mitEosinophilie (Kimura's disease). Fortschr Ophthalmol 1987;84:489-90.

12 Hsu SM, Raine L, Fanger H. The use of avidin-biotin-peroxidase complex (ABC) in immunoperoxidase technics: acomparison between ABC and unlabeled antibody (PAP)procedures.JHistochemCytochem 1981; 29: 577-80.

13 Rosai J, Gold J, Landy R. The histiocytoid hemangioma.Human Path 1979; 10: 707-30.

14 Kung ITM, Gibson JB, Bannatyne PM. Kimura's disease: aclinicopathologic study of 21 cases and its distinction fromangiolymphoid hyperplasia with eosinophilia. Pathology1984; 16: 39-44.

15 Kuo TT, Shih HY, Chan HL. Kimura's disease: involvementof regional lymph nodes and its distinction from angio-lymphoid hyperplasia with eosinophilia. Am J Surg Path1988; 12:843-54.

16 Chan JKC, Hui PK, Ng CS, Yuen NWF, Kung ITM, Gwi E.Epithelioid haemangioma (angiolymphoid hyperplasia witheosinophilia) and Kimura's disease in Chinese. Histopatho-logy 1989;15: 557-74.

17 Hui PK, Ng CS, Kung ITM, Gwi E. Lymphadenopathy ofKimura's disease. Am7Surg Path 1989;13: 177-86.

18 Tham KT, Leung PC, Saw D, Gwi E. Kimura's disease withsalivary gland involvement. BrJSurg 1981; 68:495-7.

19 Knowles DM, Jakobiec FA. Ocular adnexal lymphoidneoplasms: clinical, histopathologic, electron microscopic,and immunologic characteristics. Hum Pathol 1982; 13:148-62.

20 Lee WR, McGhee CNJ. Pseudotumours in the orbit. RecentAdvHistopathol 1989; 14: 123-37.

21 MedeirosLJ, Harris NL. Lymphoid infiltrates of the orbit andconjunctiva. A morphologic and immunophenotypic studyof 99 cases. AmJSurg 1989; 13: 459-71.

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