INIFR--:" I ION.o\ .. JOI' M:'\AI. 0'- I .F.I'KO.'" Volume :,l6, N umher : ~ ' )1';,,11'(1;11 III.,. U .S.A . INTERNA TIONAl JOURNAL OF lEPROSY And Other Mycobacterial Diseases

\'OLUtll E 38, N UMBI·:rt :3 .] lJLy-SI': I'TI':N1 BErt, 1970

Histologic Characteristics of Multiforme (Mkar Disease) Including a Comparison with Leprosy and Report of First Case from Congo (Kinshasa) 1

Wayne M. Meyers, Daniel H. Connor and Ralph Shannon!!·3

Granuloma mu)tiformc is a skin disease Clinicall y granuloma multiformc, tuber­ of unknown cause that clinically resembles culoid leprosy, and granuloma annulare tuberculoid leprosy and granuloma annu­ have a number of similarities: (1) the lare. Until now the disease has been repoli­ lesions are usually few; (2) they develop ed only from Nigeria and Kenya. H ere we slowly, and (3 ) plaques expand peripher­ present clinical and histopathologic findin gs ally while theiT centers become hard and in a patient with granuloma l1lultiforme resolve, producing a circinate pattern. His­ from Congo (Kin shasa). topathologically, granuloma annulare and The disease was first described by Leiker granuloma multiforme are similar, but tu­ et a1. (4) in 1964 after a dctailed study of berculoid leprosy has distinctive features. several hundred patients detected in vari­ Histologic characteristics of the three dis. ous leprosaria in the Mkar area of nOlthern eases are listed in Table 1. Nigeria. Subsequently Browne (2) discov­ ered 20 patients with granuloma l1lulti­ REPORT OF A CASE forme among 400 being treated for leprosy A 45 year old Congolese man of the in neighboring eastern Nigeria. More re­ Baluba tribe was examined in May 1967 cently Leiker and Ziedses des Plantes (3) during a survey of 200 patients under treat­ and Verhagen et aZ. (7) have observed ment for leprosy at the Kellersberger Mem­ granuloma multiforme in Kenya. orial Hospital, Bibanga, Kasai Province, Congo. He stated that his deceased father 1 R eceived for publication 28 May 1970. 2 W. M. Meyers, \I.D., Ph.D. , Institll t Medical had had leprosy. He was a lifelong resident Evangelique, Kimpese. Democratic Repllblic of of this area, which is about 60 mil es east of Congo; D. H. Connor, M.D., Geographic Pathology the town of Mbuji Mayi. The region is hilly Di vision , Armed Forces Institute of Pathology, Washington, D.C. 2030.5; R. Shannon. M.D., Kell crs· savannah, with sandy soil, and has distinct berger ;Vl emorial Hospital , Bibanga, Lllluabourg, wet and dry seasons. Democratic R epllblic of Congo. Clinical findings. In 1960 the patient :! Dr. Meyers was a Leonard ' ,Vood Memorial· I'\'ational Institlltes of Hea lth fellow in Research noted pruritic papules where well­ Pa thology in Leprosy at the time this work was d veloped les ions were found on examina­ done. R f'qllesl for r(!f>rints shollid be addressed to Or. tion-left deltoid, right forearm, right lum­ D. H. (;onnor. bar, and sacral areas. These papules had 242 International Jou.rnal of Leprosy 1970

TA BI,E L. Dist£u{Juishill{J characteristics of (Jra'lIuloma muil'IJOl'nle, gralltliol1ta allllulare, and luberculm'd leprosy.

Granuloma multiforme Granuloma annulare 'fuberculoid leprosy ------_._------_._--_. Clinical A diBease of adults. A disease of children. r\ di:;ease of children and finding;; Upper body u ~ u a ll y tn ­ Us u a ll~ ' hands and feet adults. No itching. Sen­ volved. Le;;ions itch. No in volved, No sensory loss sory los,o; 111 lesions and sensory lo s,.; or nervr en­ or nerve en la rgemen t. frequrnt nerve enla rg('­ largement.. ment , ------_._------_._-- Histopathologic Random di,.;tri bution of Foci of coll agen d~'gen e r ­ may in volve findings granuloma" tn dermi,.; , at ion ,.; urround('d by a all layers of dermis. No but papillary la.ver gran ul omatous zon('. co llagen degeneration, spa red. Plasma ce ll ,.;, Nerve" in tact. Plasma Nerves damaged, Acid­ mast ce ll s, and eo"in o­ cclb, mast ('e ll s, and fast baeilli pre"ent within phils sometim e~ present. eOsin ophil" som(' times nerves. Nerves in tact. Focal co l­ present. Ly mphocytic in ­ lagen degeneration (3) , as fil trate around \'essels. well as fragmentation and No etiologic agent phagocytosis of ela,.;tica, known. No etiologic agent kn own. ------_·------1-----·_------

Re .~ ponse t (> No re"ponse to diamino !\ifa~ ' resolve spontane­ T end to be se lf-healing, therapy diphenyl ," ulfone, Lesions ously or ma.\' I'('spond to but healing hastened b.v per,.; i"t fo r year" and local steroid". DDS. even tuall~ ' heal spon­ taneousl.\·. graduall y progressed to form the present Mitsuda-Hayashi lepromin ) produced an lesions, which ranged from 4 to 8 cm. in area 4 mm. wide after 48 hours (Fernandez greatest diameter and had circinate, ele­ reaction ) and 7 mm. wide after 30 days vated borders ( Figs. 1 and 2). The central ( Mitsuda reaction ). areas were slightly indurated but not ele­ The patient had taken DDS by mouth vated. Most of the lesions were uniformly (300 mgm. twice a week) for 30 months, hypopigmented but two lesions had a few without improvement. areas of hyperpigmentation, 2 to 3 mm. A biopsy specim en was taken from the wide. In none of the lesions was there loss elevated edge of a lesion in the lumbar of sensitivity to light touch nor to discrimi­ region and fix ed in cold 10 per cent nation between heat and cold. No cutane­ formalin. The specimen included a margin ous nerves were palpable and there was no of normal skin. tenderness of nerves. The remainder of the Histopathologic findings. The fix ed bi­ findings on examination \-"ere normal. opsy specimen was blocked in paraffin, cut Skin smears revealed no acid-fast bacilli at 5 microns, and stained by a combined and skin scrapings revealed no fungi. He­ trichrome-Fite-Faraco ( TRIFF ) method moglobin was 13.5 gm.j 100 ml., and the ( 8). Later, additional sections were cut, white blood cell count was 8,300/ cmm., and a vari ety of other stains were made. with a distribution of 71 per cent polymor­ These included hematoxylin-eosin; Fite­ phonuclear neutrophils, 28 per cent lym­ Faraco for acid-fast bacilli; Movat's pen­ phocytes, and 1 per cent eosinophils. tachrome for elastica, mucin, and coll agen; Routine urine and stool examinations and a periodic acid-Schiff; Giemsa; reticulum; chest roentgenogram revealed no abnor­ Brown and Brenn for bacteri a; and Warth­ malities. The intracutaneous injection of 0.1 in-Starry for spirochetes. ml. lepromin (Wade modification of the Granulomas were prominent within the 38, 3 Me!J ers et 01 .: Histologic Characteristics of Granuloma .\1I1.ltiforme 243

Flc . 1. Lcsions of th e left deltoid and right lumbar regions are shown. The lesions have raised serpiginous margins which surround a hroad sli gh tl y indurated and sli ghtly hypopigmcnted central zOlle. ( AFIP neg. 69-3643).

Flc. 2. Lesion on the left arm. It has a smooth lo\\'er margin and a seripiginous margin ahovt'. ( AFIP Ilcg. 69-8G-L5). 244 International Journal of Leprosy 1970 dermis. They were most conspicuous at the here described is the first reported from margin of the lesion beneath a slight eleva­ south of the equatorial forest of central tion of the epidermis and were present in Africa. Personal experience (W.M.M.) in­ all layers of the dermis, except for a narrow dicates that granuloma multiforme is "free" zone beneath the basal layer (Fig. 3, uncommon in Congo. No case has yet been top and Fig. 4 ). The granulomas were not found in the lower Congo or North Kivu circumscribed, and merged with surroun­ areas ( in the Ituri fores t ) among patients ding dermal collagen. They were composed bein g treated for leprosy, and our patient of epithelioid cells, histiocytes, and was the only one found among 200 patients Langhans' giant cells and contained a few at a single location in the Kasai Province. plasma cells, mast cell s eosinophilic leu­ Additional surveys are essential ·to deter­ kocytes, and lymphocytes ( Fig. 5). Reticu­ mine the prevalence and distribution of lum and collagen fibers traversed the gran­ granuloma multiforme in Congo. ulomas. No definite evidence of degener­ The cause of granuloma multiforme is ation of collagen fibers was seen. The col­ not known. No mi croorganisms have been lagen fi.bers were not tinctorially altered, seen in the lesions, but cultures for bacteria nor had they lost their normal bire­ and viruses have not been done. An inA am­ fringence. Between the granulomas, and matory or allergic response to insect bites distinct from them, were scaHered collec­ or stings has been suggested ( l . ~ ). Ver­ tions of plasma cells, especially in the loose hagen et al. (7) believe that granuloma connective tissue around the dermal ap­ multiforme may be a variant of granuloma pendages, vessels, and nerves ( Fig. 6 ). annulare, atypical forms of which have Dermal elasti ca was strikingly reduced been described following bites by the gnat within the lesion, and each of the granulo­ Culicoides furan s in the Canal Zone (G) . mas contained minute fragments of phago­ Culicoides sp, are w ide ly distribute d cytosed elastic fibers. Both histiocytes and throughout central Africa, but there is at giant cells contained fragments of elastica present no direct evidence to implicate this ( Fig 3, bottom left and right), and some of or any other insect. the phagocytosed fragments were sur­ Marshall et al. (5) in a detailed study of rounded by acid mucosaccharide. Surviving the clinical, pathologic, and geographic as­ elastic fibers were few, as there were only pects of 50 patients, noted a conspicuous scattered fragments between bundles of degeneration of connective tissue, especial­ dermal collagen, and these were surrounded ly the col·lagen. Allenby and Wilson Jones by histiocytes. None of the granulomas con­ ( 1 ), however, found reduced elastica in tain ed areas of necrosis, foreign bodies, or four of 15 biopsy specim ens and noted microorganisms. giant cell s that appeared to be engaged in phagocytosis of elastic remnants. They sug­ COMMENT gest that granuloma multiforme is identical Granuloma mu\.tiforme has been report­ with lipoidica diabeticorum. cd only from central Africa, and the patient In our patient, the granulomas appear to

F IG. 3. Top. This is through the margin of the lesion. The inA ammatory cell infil­ trate in the dermis has raised the overl yin g epidermis. Elastic fib ers, stain ed black, have a normal distribution in the uninvolved dermis seen at the bottom and at the right side of the picture. Elastic fib ers are greatly reduced within the lesion and most of those th at remain are fragmented and lie within his tiocytes and giant cells. (Movat stain X70, AFIP photo No. 70-3231). Bottom left. At the margin of the lesion there is acti ve phagocytosis of elas tica. Elastic fib ers are fragmented and here three strands of elas tica are within a giant cell. (Movat stain X485, AFIP photo No. 70-3233 ). Bottom ri ght. This granuloma is composed of epithelioid cells and two giant cells, both of which contain fragments of elastica. ( Movat stain X350, AFIP photo No. 70-3232) .

246 International Journal of Leprosy 1970

;

. " , .. ~'

4 .f " .. -

FIG. 4. Section through the area of maximum cellular reaction. There are granulomas in the upper, middle, and lower dermis. Chronic inHammatory cells, mainly plasma cells, are scattered throughout the dermal collagen, especially around the small vessels. The granuloma in the outlined area is enlarged in Figure 5. (TRIFF, X42, AFIP neg. 69-4974). FIG. 5. A granuloma in the lower dermis. It shows a giant cell surrounded by a mix­ ture of epithelioid cells and fibroblasts. It contains a few strands of collagen. (TRIFF, X350, AFIP neg. 69-4138-1). 38,3 Meyers et al.: Histologic Characteristics of Granuloma Multiforme 247

I

0- • • r , •I , ' .. , - I - .-

FIG. 6. There is an intact nerve (arrow) in the deep corium which, although sur­ rounded by plasma cells, is not structurally altered. Langhans' giant cells are evident in a near-by gran uloma. (TRIFF, X304, AFIP neg. 69-2678) . be a manifes tation of the phagocytosis of lesion, and histopathologic study has failed dermal elastica because the giant cells and to reveal inflammatory changes of dermal histi ocytes in each granuloma contained nerves and fail ed also to reveal acid-fast elastic fibers. Whether this reflects a pri­ bacilli within nerves. The demonstration of mary degeneration of elastica, or is second­ fragmentation and phagocytosis of elastica ary to an obscure process, cannot be deter­ is another feature which may be helpful in mined, but the fo cal nature of the disease, the diagnosis of granuloma multiforme. its tendency to spontaneous resolution, and Clarification of the cause and pathogenesis the fact that phagocytosis of elastica was of granuloma multi forme awaits further not a constant feature in the study by clinica I and pathologic studies. All enby and Wilson Jones (1), all argue against granuloma mu].tiforme bein g a pri­ SUMMARY mary degeneration of elas ti ca. This is the first report of a Congolese The diagnosis of granuloma multiforme with granuloma multiforme, a disease enti­ requires an evaluation of the clinical and· ty which has been recognized only in tropi­ histopathologic findin gs, as well as a careful cal Africa. The patient described is a 45 search for microorganisms to exclude the year old man from Kasai Provin ce of Congo common infectious granulomas of the skin. (Kinshasa), who had gradually enlarging Tuberculoid leprosy, in particul ar, can be macules of the forearm, as well as an the excluded on Iy after clinical evaluation has lumbar, deltoid and sacral regions. The fail ed to demonstrate anesthes ia of the lesions had elevated circinate borders, in- 248 International !oumaJ of Leprosy 1970 duratcd centers, and were not anesthetic. demostrado que no hay ca mbios inf1amatorios At the time of diagnosis the paticnt was o bacilos alcohol-ac ido resistentes en los nervios under treatment for leprosy at a leprosari­ dermicos. um. Histopathologically there was marked reduction of elastica within the lesion and RESUME active phagocytosis of dermal elastica at Ceci constitue Ie premier rapport, chez un the margin of the lesion. Granulomas were Congolais, de granulome multiforme, une entite conspicuous throughout the dermis. They morbide qui n'a ete reconnue qu'en Afrique were comprised of giant cells, histiocytes tropicale. Le malade que I'on decrit est un homme age de 45 ans, originaire de la Province and epithelioid cells, containing phagocy­ du Kasai, en Republique Democratique du Congo tosed elastic fib ers. The cause of the frag­ (Kinshasa). Ce malade presentait des macules mentation and phagocytosis of elastica is qui s'etendaient progressivement sur I'avant-bras, unknown. It may be a reaction to a primary de me me qu'au niveau des regions lombaire, degeneration of elastica or it may b e secon­ deltoide, et sacree. Les lesions presentaient des dary to an obscure antecedent injury. bords circines surleves, un centre indure, sa ns The diagnosis of granuloma multiforme anesthesie concomi ttante. Au moment du diag­ depcnds on a careful clinical and histopath­ nost ic, Ie malade etait en traitment pour la ologic evaluation. Tuberculoid leprosy can lepre dans une leproserie. Du point de vue histopathologique, on a note une reduction be excluded only after clinical studies have notable des fibres ela stiq ues a I'interieur de la failed to reveal anesthesia of the lesions lesion, ainsi qu'une phagocytose ac ti ve des and histopathologic studies have failed to fibres elastiques du derme a la peripherie de la reveal inflammatory changes of dermal lesion. Les granulomes pouvaient facilement nerves or acid-fast bacilli in dermal nerves. etre vus a travers Ie derme. lis etaient con­ stitues de cellules gea ntes, d'histiocytes et de cellules epithelioides, contenant des fibres elas­ RESUMEN tiques phagocytees. La cause de cette fragmenta­ tion, de meme que la cause de la phagocytose des Esta es la primera vez que se describe un caso fibres elastiques, reste non elucidee. II peut de un Congoles con granuloma multi forme, s'agir d'une reaction a une d~ge nere sce n ce enfermedad que ha sido diagnosticada sola mente primitive des fibres elastiques, ou bien ces en Africa tropical. EI paciente es un hombre de lesions peuvent etre secondaires a un trauma­ 45 anos de la Provincia de Kasai del Congo tisme anterieur meconnu. (Kinshasa), que presentaba maculas que aumenta­ Le diagnostic du granulome multiforme pro­ ban gradualmente de tamano, en el antebrazo cede d'une evaluation clinique et histopatholo­ y en las regiones lumbar, deltoidea y sacra. gique soigne use. La lepre tuberculo"ide ne peut Las lesiones tenian bordes circinados elevados, etre exclue qu'apres que les etudes cliniques centros indurados y no eran anestesicas. En el n'aient pas permis de mettre en evidence une momenta del diagn6stico el paciente estaba en anesthesie au niveau des lesions, et a la condi­ tratamiento antileproso en un leprocomio. tion que les etudes histopathologiques n'ont Histopatol6gicamente, habia una marcada re­ pas reussi a reveler des modifications inf1am­ ducci6n de la elastica dentro de la lesi6n y una matoires au niveau des nerfs du derme ou la fagocitosis act iva de las fibras ehisticas en el presence de bacilles acido-resistants chez les margen de la lesi6n. Los granulomas eran con­ nerveux du derme. spicuos en todo el dermis. Estaban formados de celulas gigantes, histiocitos y celulas epitelioides, que contenian fibras elasticas fagocitadas. La Acknowledgments. A histopathologic diag­ causa de la fragmentaci6n y fagocitosis de la nosis of granuloma multiforme in this case was elastica es desconocida. Puede ser una reacci6n made on a biopsy specimen by Dr. E. Wilson a una degeneraci6n primaria de la elastica 0 Jones of St. John's Hospital, London, and Dr. puede ser secundaria a un antecedente de injuria D. J. Harman of the Leprosy Study Centre, no determinado. London. Dr. D. L. Leiker reviewed histopatho­ EI diagn6stico de granuloma multiforme logic sections, and Dr. C. H. Binford made depende de una cuidadosa evaluaci6n clinica e helpful suggestions. Figures 4-6 illustrate areas histopatol6gica. La lepra tuberculoide se puede in a section prepared by the Leprosy Study excluir solamente despues que los estudios cli­ Centre (their Lab. No . 8621). nicos han demostrado que no hay anestesia en This study was supported in part by Ameri­ las lesiones y los estudios histopatol6gicos han can Leprosy Missions, Inc., New York; in part 38, 3 Meyers et at.: Histologic Chamcteristics of Cmnuloma Multiforme 249 by Grant AI-220 from the National Institute 4. LEJKEH , D. L., KOK, S. H . and SPAAS, of Allergy and Infectious Diseases, National J. A. J. Granuloma multiforme, a new skin Institutes of H ealth, Bethesda, Maryland; and disease resembling leprosy. Internat. J. Lep­ in part by a research contract, Project 3A014- rosy 32 (1964) 368-376. 501B71Q, from the Medical Research and De­ 5. MARSHALL, J., WEBER, H. W. and KOK, velopment Command, U.S. Army, Washington, S. H. Granuloma multiforme (Leiker). Der­ D.C. matologica (Basel) 134 (1967) 193-207. 6. MOYER, D. C. Papular granuloma annulare. REFERENCES Arch: Dermal. 89 ( 1964) 41-45. 7. VEIUJAGEN, A. R. H. B., KOTEN, J. W., 1. ALLEN BY, C. F. and VVILSON JONES, E. CHADDAH, V. K. and PATEL, R. 1. Skin dis­ Granuloma mu ltiforme. Trans. St. John eases in Kenya. A clinical and histopatho­ Hosp. D ermat. Soc. SS (1969) 88-98. logic study of 3,168 pati ents, Arch Dermat. 2. BROWNE , S. G. Granuloma multiforme in 98 (1968) 577-585. Eastern Nigeri a. Internal. J. Leprosy 34 8. WHEELER, E. A. , HAM ILTON, E. C. and (1966) 27-29. HARMAN, D. S. An improved technique for 3. LEIKER, D. L. and ZlEDSES DES PLANTES, the histopathological diagnosis and classifI­ M. Granuloma multiforme in Kenya. East cation of leprosy. Leprosy Rev. 36 (1965) African Med. J. 44 (1967) 429-436. 37-39.