Review

GRANULOMA ANNULARE C. ROBERT CHARLES, M.D., CDR, MC USN, BERNETT L. JOHNSON, M.D., CAPT, MC USN, AND STEPHEN R. DAMM, M.D., LCDR, MC USN

Granuloma annulare is a disease familiar to most clinicians; however, controversy still exists after more than 80 years about its pathogenesis, significant clinical behavior, histopathological presentations and association with underlying diseases such as diabetes. We shall review the current information on this disease and discuss the pathogenesis in view of our recent studyi at the fine structural level. Clinical Presentations Since its initial description in 1895 by T. Colcott Fox,2 granuloma annulare has been classified in a variety of ways. Originally, it was subdivided in the French literature^' '^ into 3 basic categories: (1) lesions which are typical clinically and histologically; (2) lesions which are clinically typical of the disease but which show atypical histologic features; (3) lesions with atypical clinical presentations but with a typical histologic presentation, such as giant, nodular, deep, gummaceous, nonannular, tuberculoid, lichen obtusus-like and erythematous. Lesions in the second category are now probably best considered separate from the spectrum of this disease and may, in retroThe opinions expressed herein are those of the authors and cannot be construed as reflecting the views of the Navy Department or of the Naval Service at large. Address for reprints: CDR C. Robert Charles, MC USN, Dermatology Service, Naval Regional Medical Center, Philadelphia, PA 19145.

From the Department of Dermafo/ogy, ,

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Naval f-iospital Medical Center, Philadelphia, Pennsylvania

spoct, have represented actinic granuloma'' or other recently described entities. The typical presentation of granuloma annulare consists of groups of 1-2 mm papules, usually in a circular arrangement and located over the distal upper and lower extremities. It is most commonly seen during the first 2 decades of life. The lesions are asymptomatic, heal spontaneously over 12-24 months, but have some tendency to recur after months or years.'' There is some seasonal variation with improvement usually in the summer.^ Females are affected twice as often as males.** Despite statements that mucous membranes are never affected in this disease,^ there is at least one case report to the contrary.^" Interesting clinical variations of typical granuloma annulare include presentation as target lesions suggestive of erythema multiforme.^1 In contrast, the generalized type tends to affect an older age group, usually between the fourth and seventh decade of life.12. 13 Further, it is characterized by multiple small papules (usually not in an annular configuration) which rarely may coalesce to form erythematous plaques (the so-called erythematous variety).^^ Not infrequently, generalized granuloma annulare has been reported confined to 655

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sun-exposed areas of the extremities, but sparing the face." This observation has led to speculation that this type might represent a photosensitive dermatosis. However, subsequent light testing has failed to reproduce lesions in several series.''*'^'' Other interesting hypotheses concerning the etiology of the generalized type have implicated the gnat, Culicoides furans. Three children from the Canal Zone who had both generalized granuloma annulare and an associated eosinophilia^^ were bitten by the insect, but the association has not been confirmed. The generalized type may be associated with diabetes mellitus. Such speculation in all varieties of the disease is interesting because of the close histologic similarity between it and necrobiosis lipoidica diabeticorum, the association of the 2 diseases in at least 2 cases^** and the finding of PAS-positive diastase resistant material in blood vessel walls as well as of granuloma annulare and diabetic angiography"' 20 (although this finding is apparently not now considered by some specific for diabetes.)2^ While at least some recent investigations have found an increased incidence of diabetes or the prediabetic state in all types of granuloma annulare,20' 22 others have found no association,''' 23. 24 while still others have found an association only with the generalized variety.^^' 25-27 Jhus, while this association is still tenuous, many would agree with Blohme,28 who states that: ". . . generalized granuloma annulare has been associated with the diabetic state and it has been reported that this disease in diabetic subjects often presents with atypical or unusual forms. It is attractive to speculate that all stages of the diabetic syndrome, including the prediabetic state, may cause the disease to become generalized or atypical."

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If this hypothesis is correct, then at least all patients with the generalized type should be studied for associated diabetes. Still another interesting association with the generalized type includes a recent report of this entity in 2 patients who also had circulating antibodies to thyroglobulin.^'' Although this association provides for speculation regarding the etiology of the disease, it has not been subsequently confirmed." Another variant of granuloma annulare is the deep nodular type. This variety is seen as deep nodules close to the bone but without adherence to periostium. Lesions are located most commonly on the legs, scalp, buttocks and palms.^ They may occur in association with the more typical cutaneous lesions of the disease, particularly if carefully searched for.29-3i They are seen most commonly in children.^ Because of the close histologic similarity between this variety and the rheumatoid nodule, some have raised the question as to whether this variant predisposes to the development of arthritis.-^2 However, 2 recent series have found no such association in long-term follow-up.^^' 2'* A more recently described but equally interesting variant is the generalized perforating type. This type was first described by Owens and Freeman in 1971.3'' Since that time, at least 5 additional cases have been reported.^''^^^ Clinically, this entity is seen as small, umbilicated nodules located over the distal extremities or, in some instances, generalized in distribution. Histologically, as will be detailed later, the lesions are characterized by epidermal perforations communicating with necrobiotic connective tissue. Unlike the other variants of granuloma annulare, these lesions tend to worsen in summer and improve during the winter months.^^ This type most closely resembles perforating collageno-

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sis clinically,-^'^ but differs from this latter entity by not producing a Koebner phenomenon and by its longer clinical duration. Finally, granuloma multiforme is a disease which has, on occasion, been considered to be yet another variant of granuloma annulare.^O' '•i This disease is found almost exclusively within Nigeria and involves primarily the middle aged and the elderly with an equal sex ratio. The disease consists of multiple annular lesions up to 15 cm in diameter with borders composed of confluent papules. These lesions are typically confined to exposed skin and have a total average duration of 1-5 years. Histologically, the disease closely resembles granuloma annulare, although giant cells are more frequently observed. Recently, it has been suggested that this disease might better be considered a variant of actinic granuloma.5

Histopathology The histologic features of granuloma annulare can be subtle and easily overlooked. The pattern of its presentation in the dermis is important in detecting its presence (Fig. 1). As Pinkus'*^ states, "the histological diagnosis is best made under low power, because it is the peculiar configuration that counts rather than details of the lesion. An ovoid infiltrate in the mid-dermis should arouse suspicion." As we have often been taught, if one is using high power and has not made the diagnosis, the chances of doing so rapidly approach zero. The epidermal changes are minimal and usually confined to moderate hyperkeratosis and focal areas of parakeratosis. Acanthosis, although not a usual occurrence, may be present in some specimens. Necrobiotic areas are present in the upper and mid-corium and are characterized by focal areas of degenerated or par-

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tially degenerating collagen surrounded by a cellular reaction. Smaller foci usually show less severe collagen involvement, whereas large areas show complete collagen degeneration."-^ Between these degenerative collagen bundles or connective tissue remnants, a basophilic granular-tostringy material is almost always noted.'*'* Surrounding the necrobiotic collagen, distinct collections of fibroblasts, histiocytes and epitheloid cells are observed which may show degenerative changes or lysis the closer they are to the necrobiotic focus (Fig. 2). These cells are often arranged with the long axis perpendicular to the necrobiotic collagen, giving a palisade arrangement. Within this granulomatous zone or wall, giant cells occur in over onehalf of the cases studied.'''* Lymphocytes are frequently observed and these are usually intermixed with and surround the granulomatous reaction. A fairly brisk and often dense perivascular lymphocytic reaction extends outward in the tissue away from the foci of necrobiosis (Fig. 3). Capillary endothelial proliferation and increased numbers of capillaries may be noted in the mid and lower corium. The vascular reaction and response in granuloma annulare is less intense and severe than reported in necrobiosis lipoidica. Elastic tissue may be diminished or often absent in the areas of necrobiosis.'*-*-"' However, Pinkus has observed preservation of the elastic fibers in the necrobiotic areas with loss or absence of the elastica in the granulomatous wall with Orcein Giemsa staining (Fig. 4).'^Histochemistry

The histochemical changes noted in granuloma annulare are not specific for this condition and similar changes can be seen in other necrobiotic processes with only slight variations. PAS-positive, diastase-resistant material

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Fig. 1. Top, gianuloma annulare, with central necrobiotic focus (X100). Fig. 2. Bottom, necrobiotic focus, with necrobiotic center at right, granulomatous wall with lymphocytes at left (X400).

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material is noted within the necrobiotic areas. This probably represents a complex protein, carbohydrate, mucosaccharide material.'*'*' •*' The basophilic granules and somewhat stringy material observed on routine hematoxylin and eosin sections is colloidal iron positive, hyaluronidase labile, toiuidine blue positive at pH 3.0 and negative at pH 2.0, alcian blue positive at pH 3.0 and negative at pH 0.4; this probably represents hyaluronic acid, since the reactions for hyaluronic acid are identical.'•7. ^s Elastic fibers as demonstrated by the aldehyde-fuchsin reaction are usually diminished to absent in the area of necrobiosis. A network of argyrophilic fibers may be noted in the areas of inflammation. Fat may be demonstrated in the areas of necrobiosis with the oil-red O fat stain on frozen sections.'^^ Curiously, it is not doubly refractile. In addition to the other cells noted, mast cells may be seen in the areas of inflammation as demonstrated by the aldehyde-fuchsin reaction. Histologic Variations

Perforating Granuloma Annulare This form has the same necrobiotic involvement of the dermal collagen, but the histologic features vary depending on the type of lesion studied by biopsy. The histology can range from that of the usual granuloma annulare to the typical histologic change for this variety. The focus of necrobiosis is located close to an atrophic or ulcerated epidermis and may protrude through the epidermis. Parakeratosis and exocytosis are prominent features of the epidermal response. The inflammatory response is greater than in the nonperforating variety of granuloma annulare and many more lymphocytes are noted. Multinucleated giant cells can be found with some fre-



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quency. The clinical central core of the umbilicated papules is composed of parakeratotic debris and protruding necrobiotic collagen.36.39 Subcutaneous Cranuloma Annulare The epidermis is usually uninvolved or may show thinning. The area of involvement is at the dermal subcutaneous junction or in the subcutis. Usually, the areas of necrobiosis are larger, with more central necrosis. The granulomatous wall is thicker and may contain eosinophils, as well as nuclear dusting from degenerated eosinophils.7'42 This lesion must be differentiated histologically from the rheumatoid nodule, but may show more angiomatous proliferation around the necrobiotic focus than the latter entity. The clinical history is also important in helping make this distinction. Granuloma annulare is one of the family of necrobiotic processes, the others being necrobiosis lipoidica, associated or not with diabetes, rheumatoid and rheumatic nodules and the juxta-articular nodes of syphilis. These all show essentially the same basic histologic features with differences in the size, location and severity of the necrobiotic or necrotic process and in the vascular and cellular responses (Table 1). The common denominator for all is necrobiosis; granuloma annulare has the most consistent findings histologically of this group of necrobiotic processes. Etiology

The etiology of granuloma annulare is unknown. In the early part of the century, latent tuberculosis was thought to be a cause.-''0 More recently, metabolic disturbances such as forme fruste sarcoid,5' diabetes^O' 22 or antigen-antibody reactionsifi have been implicated. Drugs such as calciferol have been suggested as a cause of generalized granuloma an-

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Fig. 3. Top, vascular reaction in granuloma annulare, the predominant cell, the lymphocyte (X450). Fig. 4. Bottom, granuloma annulare in an area of necrobiosis (X400).

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Table 1. Comparative Histologic Changes

Histologic changes Epidermal change

Perforation of epidermis Location of involvement

Foreign body giant cells Prominence of lymphocytes Eosinophils Fibrinoid necrosis Significant vascular involvement Lipids Mucin

Perforating granuloma annulare

Cranuloma annulare Minimal may have acanthosis None Mid-upper Corium

Atrophy, ulceration common Yes Superficial corium

Rare Yes No No No May be present Yes Yes

Frequent Yes No No No May be present Yes Yes

nulare.52. 53 Trauma/' insect or sunlight exposure^^ have also been thought significant as etiologic factors but have not been conclusively proven factors.I'f-i'^ A familial predisposition has been suggested, with some 15 case reports of granuloma annulare involving multiple family members now in the literature."-57 From a histologic standpoint, some observers have theorized a hematogenous origin for the disease, believing that granuloma annulare emanates from the blood vessels' (a hypothesis originally suggested by Jacobi-''^ and Stillians^'), but there have been no studies to substantiate this theory. It was for this reason that we studied granuloma annulare at the fine structural level in the hope of resolving at least this question,' as will be detailed. In order to understand this disease at the ultrastructural level, 6 patients with granuloma annulare were studied, 4 having the localized annular variety and 1 each with the papular disseminated and deep nodular variants. All sections were •"''*

Subcutaneous granuloma annulare

Necrobiosis Lipoidica

None

Atrophy

None Dermalsubcutaneous junction Frequent No Yes Yes Yes May be present Yes Yes

None Middle and lower portions of dermis Frequent No Rare Rare Yes Consistent Yes Variable

correlated with toluidine blue stained thick sections so that localization within incipient foci, large acellular necrobiotic zones or peripheral palisaded cellular zones could be determined. Using this frame of reference, our results indicate that the necrobiosis of granuloma annulare originates not around vessels but secondary to disruption of histiocytes with release of contained lysosomal enzymes. When small incipient foci were studied, the histiocytes showed changes which included dilation of mitochondria, lysis of cytoplasm and extrusion of lysosomal granules into the interstitium. Similar changes were noted among histiocytes at the proximal margin of peripheral palisaded cellular layers. Within the central, acellular necrobiotic foci, the cells showed complete disruption (Fig. 5) with cytoplasmic remnants and cell organelles scattered among abnormal collagen fibrils. The collagen in these areas was characterized by a spectrum of change which ranged from swelling of individual fibrils to dissolution into constituent filaments.*"

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Fig. 5. An overview of a large, well established focus of necrobiosis which illustrates degenerative cells, cytoplasmic debris and swollen collagen. Uranyl acetate and lead citrate (X4900).

In addition, many of the intact but swollen collagen fibrils were coated by cellular debris which seemed to serve as a protective matrix and protect this collagen from further disruption. The vessels associated with necrobiotic foci were characterized by multiple layers of basal lamina and narrowed lumens suggestive of endothelial collapse but without evidence of vasculitis. These observations lead to interesting speculation. If necrobiosis in granuloma annulare results from the release of lyso-

somal enzymes into the interstitium, then one must consider both the enzymatic content of histiocytes (which is necessary to explain the disruption of collagen) and the stimulus responsible for this phenomenon. In answer to the former point, collagenase, in addition to other known enzymes, has been identified in cell cultures of histiocytes harvested from several disease states.^^' ^2 The stimulus responsible for the cellular disintegration is unknown but we would suggest that it originates with the lymphocyte.

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An analogous situation to our discussion of the lymphocyte in granuloma annulare has recently been described in contact dermatitis to explain the epidermal alterations in this condition.'^^ In that study, the authors postulated that the Langerhans cell, a modified epidermal histiocyte, perhaps after ingestion or coating by antigen, released contained lysosomal enzymes in response to liberated lymphokines. Not only are lymphocytes prominent around the foci of necrobiosis as we have already pointed out, but necrobiotic collagen has also been described in diseases thought to arise on the basis of delayed hypersensitivity.'^'*-'^'' Differential Diagnosis

The typical case of granuloma annulare presents little problem, either clinically or histologically. The generalized form of the disease is most often confused with sarcoidosis, lichen planus and papular mucinosis (lichen myxedematosus). Dicken'-^ reported 2 patients in whom granuloma annulare was considered clinically and histologically, but liver and lung biopsies proved the presence of sarcoidosis. Lichen planus, with its violaceous hue, pruritus and typical histology, should not prove a major differential diagnostic problem. Lichen myxedematosus can be manifested by papules on the dorsae of the hands and ears; however, special stains reveal the dense accumulation of acid mucopolysaccharide which is hyaluronidase labile. Occasionally, cutaneous papules can be seen in rheumatic fever which can be confused clinically and histologically with generalized granuloma annulare.f'^ However, these patients are all systemically i l l ; this is not a feature of granuloma annulare. "" • -' > The large subcutaneous nodular variety of granuloma annulare may simulate rheumatoid nodules. As we have pre-

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viously pointed out, however, there appears to be no association with arthritis in this variant. The perforating variety of granuloma annulare resembles perforating collagenosis clinically; histologically, there is some similarity to papulonecrotic tuberculid''^ but the degree of vasculitis in this entity should serve as a differential feature. Treatment The natural history of granuloma annulare makes treatment unnecessary in many cases. In the 80 years since its original description, many modalities of treatment have been tried but none has proven completely successful. Gold injections and antihistamlnes have not influenced the course of the disease.''^-" X-ray therapy may produce temporary improvement or may have no effect. Improvement has been reported with systemic corticosteroids, penicillin, calciferol, antimalarials, bismuth and secondary to punch biopsies.12 However, Wells, in his series of 208 patients, concluded that trauma in the form of punch biopsies was not helpfuK' and others have reported that calciferol may disseminate the disease."' ^3. 72 Diethylstilbesterol, liquid nitrogen, dry ice and dichlorotetrafluorethane have also been tried with minimal success. Ravits^-^ recommends Cordran tape renewed daily for several weeks or intralesional triamcinolone suspension diluted with 1 % lidocaine (2.5 mg/ml). If treatment with any or all of these modalities fail, reassurance and tincture of time will usually be ef"fective. References 1.

:

• •

•-'

,'•

Charles, C. R., Cooper, P. H., a n d H e l w i g , E. B., The fine structure of granuloma a n n u lare. Manuscript in preparation. 2. Fox, T. C , Ringed eruption of t h e fingers. Br. J. D e r m a t o l . Syphilol. 7 : 9 1 , 1895.

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3. Vissian, L., Formes atypiques et etiologiques de granulome annulaire. Ann. Dermatol. Syphilol. 8:363, 1948. 4. Gougerot, H., Revision de la nosologie due granulome annulaire. Bull. Soc. Franc. Dermatol. Syphilol. 56:153, 1949. 5. O'Brien, J. P., Actinic granuloma. Arch. Dermatol. 111:460, 1975. 6. Wells, R. S., and Smith, M. A., The natural history of granuloma annulare. Br. J. Der. matol. 75:199, 1963. 7. Rubin, M., and Lynch, F. W., Subcutaneous granuloma annulare. Arch. Dermatol. 93: 416, 1966. 8. Gleitz, T., and Heite, H. J., Das krankheitsbild des granuloma annulare in haufigkeitsanalytischer betrachtungsweise. Arch. Dermatol. Syphilol. 199:92, 1954. 9. Van Der Lugt, L., About the limitation of the clinical picture of granuloma annulare. Dermatologica 139:374, 1969. 10. Zangel, V., Cranuloma annulare den mundschleimhaut. Dermatol. Vi^ochenschr. 148: 581, 1963. 11. Brown, C. R., Target lesions In granuloma annulare. Arch. Dermatol. 105:928, 1972. 12. Stankler, L., and Leslie, C , Generalized granuloma annulare: a report of a case and review of the literature. Arch. Dermatol. 95: 509, 1967. 13. Dicken, C. H., Carrington, S. G., and Winkelmann, R. K., Generalized granuloma annulare. Arch. Dermatol. 99:556, 1969. 14. Selmanowitz, V. J., VanDow, J. E., and Director, W., Atypical granuloma annulare. Arch. Dermatol. 93:454, 1966. 15. Leppard, B., and Black, M. M., Disseminated granuloma annulare. Trans. St. John's Hosp. Dermatol. Soc. 58:166, 1972. 16. Gross, P. R., and Shelley, W. B., The association of generalized granuloma annulare with antithyroid antibodies. Acta Derm. Venerol. 51:59, 1971. 17. Moyer, D. G., Papular granuloma annulare. Arch. Dermatol. 89:41, 1964. 18. Feldman, F. F., Granuloma annulare and necrobiosis lipoidica in the same patient. Arch. Dermatol. 98:677, 1968. 19. Haim, S., Shafrir, A., Haim, N., and Lichtig, G., Micro angiopathy in cases of granuloma annulare. Dermatologica 147:261, 1973. 20. Rhodes, E. L. et al., Granuloma annulare; prednisone glycosuria tests in a non-diabetic group. Br. j . Dermatol. 78:532, 1966. 21. Braverman, I. M., Personal communication, 1975. 22. Castro, A., Hammond, R., and Potts, J., Glucose, insulin, HGH, and cortisol plasma

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levels in granuloma annulare patients during glucose tolerance and cortisone glucose tolerance test. Glin. Biochem. 7:150, 1974. 23. Mobacken, H., Gisslen, H., and Johannisson, G., Granuloma annulare; cortisone glucose tolerance test in a non-diabetic group. Acta Derm. Venerol. 50:440, 1970. 24. Williamson, D. M., and Dykes, J. R., Carbohydrate metabolism in granuloma annulare. J. Invest. Dermatol. 58:400, 1972. 25. Haim, S., Friedman-Birnbaum, R., Haim, N., Shafrir, A., and Ravina, A., Carbohydrate tolerance in patients with granuloma annulare. Br. J. Dermatol. 88:447, 1973. 26. Romaine, R., Rudner, E. J., and Altman, J., Papular granuloma annulare and diabetes mellitus. Arch. Dermatol. 98:152, 1968. 27. Haim, S., Friedman-Birnbaum, R., and Shafrir, A., Generalized granuloma annulare and relationship to diabetes mellitus as revealed in eight cases. Br. J. Dermatol. 83:302, 1970. 28. Blohme, G., Mobacken, H., and Waldenstrom, J., Early insulin response to glucose injected intravenously in patients with localized granuloma annulare. Act Derm. Venereol. 54:259, 1974. 29. Little, E. G., Granuloma annulare. Br. J. Dermatol. Syphilol. 20:213, 1908. 30. Draheim, J. H., Johnson, W. C., and Helwig, E. B., A clinicopathologic analysis of "rheumatoid" nodules occurring in 54 children. Am. J. Pathol. 35:678, 1959. 31. Graver, F. H., Granuloma annulare. Arch. Dermatol. Syphilol. 30:785, 1934. 32. Tizard, J., and Moncrieff, A.: Subcutaneous nodules: For diagnosis? Granuloma annulare. Proc. Roy. Soc. Med. 41:115, 1948. 33. Zaphiropoulos, G., and Grahme, R., A study of joint disease in granuloma annulare. Rheumatol. Rehabil. 13:42, 1974. 34. Eichmann, T. H., Granuloma annulare and rheumatismus. Dermatologica 147:25, 1973. 35. Owens, D. W., and Freeman, R. G., Perforating granuloma annulare. Arch. Dermatol. 103:64, 1971. 36. Izumi, A. K., Generalized perforating granuloma annulare. Arch. Dermatol. 107:708, 1973. 37. Jacyk, W. K., and Birecka, I., Generalized perforating granuloma annulare. Arch. Dermatol. 809:110, 1974. 38. DeLaney, T. J., Gold, S. G., and Leppard, B., Disseminated perforating granuloma annulare. Br. J. Dermatol. 89:523, 1973. 39. Duncan, W. C., Smith, J. D., and Knox, J. M., Generalized perforating granuloma annulare. Arch. Dermatol. 108:570, 1973. 40. Marshall, J., Weber, H. W., and Kok, S. H.,

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Cranuloma multiforme. Dermatologica 134: 193, 1967. Meyers, W. M., Connor, D. H., and Shannon, R., Histologic characteristics of granuloma multiforme. Int. J. Lepr. 38:241, 1970. PInkus, H., and Mehregan, A. H.: A Cuide to Dermatohistopathology. New York, Appleton-Century-Crofts, 1969, p. 257. Lever, W., and Lever, C. S., Histopathology of the Skin. 5th edition. Philadelphia, J. B. Lippincott Co., 1975, pp. 214-217. Craham, J. H., Johnson, W. C , and Helwig, E. B., Dermatopathology. New York, Harper & Row, 1972, pp. 417-422. Ellis, F. A., and Smith, H. K., Necroblosis lipoidica and granuloma annulare. Arch. Dermatol. 45:55, 1942. Layman, C. W., and Fisher, 1., Necrobiosis lipoidica. Arch. Dermatol. 59:150, 1949. Johnson, W. C , and Helwig, E. B., Histochemistry of the acid mucopolysaccharides of skin in normal and in certain pathologic conditions. Am. J. Clin. Pathol. 40:123,1963. Cray, H. R., Craham, J. H., and Johnson, W. C , Necrobiosis Lipoidica: A histopathological and histochemical study. J. Invest. Dermatol. 44:369, 1965. Wood, M. C , and Beerman, H., Necrobiosis lipoidica, granuloma annulare and rheumatoid nodule. J. Invest. Dermatol. 34:139, 1960.

50. Cray, A. M. H., Cranuloma Annulare (case presentation). Brit. J. Dermatol Syphilol. 26: 157, 1914. 51. MacCormac, H., Case of granuloma annulare. Proc. Roy. Soc. Med. 18:60, 1925. 52. Lawichy, H. H., and Kanof, N. B., Cranuloma annulare; dissemination following administration of calciferol, clinical notes. Arch. Dermatol. 64:58, 1951. 53. Braun, O., Uber einen atypischen fall von granuloma annulare. Arch. Dermatol. Syphilol. 190:438, 1950. 54. Curwen, W., Cranuloma annulare, multiple, suggesting insect-bite reaction. Arch. Dermatol. 88:355, 1963. 55. Schiff, B. L., and Cohen, W. B., Granuloma annulare in identical twins. Arch. Dermatol. Syphilol. 68:205, 1953. 56. Coolamall, S. K., and Stevenson, C, Cranuloma annulare in identical twins. Br. J. Dermatol. 86:636, 1972. 57. Amer, S., and Aspegren, N., Familial granuloma annulare. Acta Derm. Venereol. 48: 253, 1968.

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58. Jacobi, F., "Cranuloma annuiare." In Handbuch der Haut-und Ceschlechts Krankeiten. Edited by jadassohn, J. Berlin, Julius Springer, volume 10, part 1, 1931, p. 796. 59. Stilllans, A. W., An unusual case of granuloma annulare. J. Cutan. Dis. 3:580, 1919. 60. Bouteille, M., and Pease, D. C , The tridimensional structure of native collagenous fibrils, their proteinaceous filaments. J. Ultrastruct. Res. 35:314, 1971. 61. Salthouse, T. N., and Matlaga, B. F., Collagenase associated with macrophage and giant cell activity. Experientia 28:326, 1972. 62. Wall, L. M., Martin, C. R., and Mergenhagen, S. E., Production of collagenase by endotoxin activated macrophages (Abstr. 104). Presented at the annual meeting of the reticulo-endothelial Society, Willlamsburg, VA, 1973. 63. Sllberberg, I., Baer, R. L., and Rosenthal, S. A., Role of langerhans' cells in contact allergy. I. Ultrastructural study in actively induced contact dermatitis in guinea pigs. Acta Derm. Venereol. 54:321, 1974. 64. Glaisher, I. L., A case of necrobiosis of apparently fungal origin. Br. J. Dermatol. 78: 497, 1966. 65. Johnson, W. T., and Helwig, E. B., Cat scratch disease. Histopathologic changes in skin. Arch. Dermatol. 100:148, 1969. 66. Lever, W. F., and Schaumburg-Lever, C , Histopathology of the Skin, 5th edition. Philadelphia, J. B. Lippincott Co., 1975, p. 205. 67. Burns, R. E., Boyer, P., and Fine C , Cutaneous papules heralding rheumatic carditis. Arch. Dermatol. 89:334, 1964. 68. Pinkus, H., and Mehregan, A. H., A guide to dermatohistopathology. New York, Appleton-Century-Crofts, 1969, pp. 257-260. 69. Monash, S., Cranuloma annulare disseminatum. Arch. Dermatol. Syphilol. 25:122, 1932. 70. LIndgren, !., Cranuloma annulare in a 67year-old woman with small cutaneous nodules. Acta Derm. Venereol. 31:458, 1951. 71. Haxthausen, H., Cranuloma annulare of unusually large extent. Acta Derm. Venereol. 36:200, 1956. 72. Hall, F. H., Cranuloma annulare with dissemination following calciferol therapy. Arch. Dermatol. Syphilol. 61:145, 1950. 73. Ravits, H. C , How I treat granuloma annulare. Postgrad. Med. 48:176, 1970.

Granuloma annulare.

Review GRANULOMA ANNULARE C. ROBERT CHARLES, M.D., CDR, MC USN, BERNETT L. JOHNSON, M.D., CAPT, MC USN, AND STEPHEN R. DAMM, M.D., LCDR, MC USN Gran...
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