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The granuloma annulare phenotype and tuberculosis
The granuloma annulare phenotype and tuberculosis Richard K. Winkelmann, MD, PhD Scottsdale, Arizona At one time it was believed that granuloma annulare was associated with or even caused by tuberculosis. In the past 50 years, that idea has seemed to be of little more than historic importance. A case is reported of chronic, inadequately treated tuberculosis with erythema induratum in which clinical and histologic lesions compatible with granuloma annulare occurred. Specific antituberculosis therapy caused clearing of the skin lesions. The previous reported cases of granuloma annulare and tuberculosis are summarized. Other systemic diseases reportedly associated with granuloma annulare are noted to emphasize the many possible etiologic relationships. Granuloma annulare may be viewed not as a disease sui generis but as a phenotypic macrophage– granulomatous response to multiple etiologic disease patterns. (J Am Acad Dermatol 2002;46:948-52.)
P
autrier1 in 1936 stated that most dermatologists considered that tuberculosis was a possible etiologic factor in granuloma annulare (GA) on the basis of the coincidental occurrence, granulomatous histologic features, positive tuberculin skin tests, and cures with tuberculin injections. GA had also been associated with papulonecrotic tuberculid. However, Pautrier also recognized that many cases of GA were unrelated to tuberculosis, had nontuberculous pathology, and could be associated with negative tuberculin tests. Schuppli2 in 1965 and Braun-Falco et al3 in 1991 pointed out that GA was appropriately viewed as a polyetiologic syndrome for which focal infection, rheumatic disease, and toxicity, as well as tuberculosis, might be considered causative factors. The concurrence of GA with tuberculosis was emphasized by a series of cases reported in the 1920s by Hauser,4 Gru¨tz,5 Horowitz,6 Hirschfeld,7 and Sokolew.8 Papulonecrotic tuberculid occurred in one of Hauser’s cases. The decline in the number of cases of chronic, relapsing tuberculosis has resulted in diminishing experience with associated disease states of the skin for physicians in developed countries, and it has been recognized that the problem of tuberculosis and tuberculids has been oversimplified in the literature of recent decades. This Emeritus member, Department of Dermatology, Mayo Clinic, Scottsdale. Reprints not available from author. Correspondence: R. K. Winkelmann, MD, PhD, Emeritus Office, Mayo Clinic Scottsdale, 13400 E Shea Blvd, Scottsdale, AZ 85259. Copyright © 2002 by the American Academy of Dermatology, Inc. 0190-9622/2002/$35.00 ⫹ 0 16/91/120925 doi:10.1067/mjd.2002.120925
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report presents a case similar to those observed by dermatologists of earlier years and points to the recognition of the GA phenomenon as a macrophage phenotype skin reaction that can have multiple etiologies.
CASE REPORT A 59-year-old woman visited Mayo Clinic Scottsdale in 1992 because of skin eruptions of some duration. Deep red subcutaneous masses and scars had been present on her legs for some years, and annular yellow to flesh-colored papular lesions of shorter duration appeared on her upper back, shoulders, and arms. Her significant medical history began with her emigration from Italy to the United States in 1974. At that time, a chest x-ray showed tuberculosis, and she had a positive tuberculin skin test. No culture information was available from this medical evaluation. She was given 1 drug orally for 1 week, presumably isonicotinic acid hydrazide (INH). The medication was stopped because a generalized erythematous pruritic rash appeared on the trunk and extremities, which lasted 2 months. There was no further diagnosis or treatment. She had erythematous deep nodules of the legs for the first time while still living in Italy 20 years before, and shortly after her arrival in New York, symmetric red nodular eruptions of the lower legs occurred, which lasted 1 month. The patient arrived in Arizona in 1985 and soon after found a sore, painful nodule on her left thigh. Subsequently red lesions have recurred and have led to scarring on the thighs, lower legs, and calves. Irregular masses have constantly been present. She has had no fever, cough, malaise, or general sense of illness.
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Fig 2. Annular plaque of upper back.
Fig 1. Erythematous dermal and subcutaneous lesions of left thigh. Erythema induratum.
A second, asymptomatic eruption had occurred on the back and upper arms, and she was, in fact, unaware of it until our examination. Eight years ago, the patient was found to have abnormally elevated liver function tests. After 2 liver biopsies, she was informed that she had cirrhosis and hepatitis C. Her husband had died of hepatitis. The patient has always been anemic and has been diagnosed as having thalassemia. Results of a general physical examination were satisfactory except for the skin lesions. Deep nodular lesions were present on the thighs and legs. Biopsy and other scars were present (Fig 1). The lesions were a deep red to brown-red, and several showed focal surface crusting. On the upper back, arms, and shoulders were yellow to flesh-colored, infiltrated papules in annular rings (Figs 2-4). On pathologic study, excision biopsy of the right knee lesion revealed a lobular, granulomatous pathologic picture consistent with erythema induratum. Biopsy performed elsewhere was also diagnosed as showing erythema induratum. Immunofluorescence demonstrated C3 and fibrinogen consistent with vasculitis of the dermal vessels. Culture of the biopsy specimen was negative for organisms, including fungus and mycobacteria. A polymerase chain reaction (PCR) study of the leg biopsy tissue was positive for mycobacterial DNA. The biopsy specimens of the annular plaques were interpreted as showing GA, with pathologic features con-
Fig 3. Annular lesion of right upper arm.
sistent with the infiltrative stage of that process (Fig 5). The PCR of all of these lesions was negative. At laboratory examination, a chest x-ray showed bilateral, apical fibrocalcific disease consistent with tuberculosis. Induced sputum, urine, and gastric washings were negative for acid-fast bacteria by smear and culture. The hemogram revealed a mild anemia— hemoglobin 11 g/dL, with 5.57 ⫻ 1012 red blood cells per liter. Special smear showed marked microcytosis, moderate poikilocytosis, and hypochromia. Moderate numbers of elliptocytes and a small number of target cells were seen. The smear was interpreted as showing iron deficiency consistent with thalassemia. Blood chemistries were normal except for elevated liver function enzymes: as-
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Table I. Granuloma annulare–associated diseases28,34,38-46 Genetic Physical Infections
Drug Systemic diseases Fig 4. Closer view of lesion in Fig 2, showing coalescing papules that compose border. Lymphoma
Familial Twins Trauma Ultraviolet Virus: varicella-zoster, Epstein-Barr, human immunodeficiency Bacteria Mycobacteria Fungus Gold Diabetes, necrobiosis lipoidica Hashimoto’s thyroiditis Sarcoid Vasculitis Hodgkin’s disease T- and B-cell lymphoma
have continued to form on the extremities and then heal spontaneously with time. The annular lesions have never recurred.
DISCUSSION
Fig 5. Granulomatous histologic features of upper back lesion, showing macrophage and giant cell histologic characteristics. (Hematoxylin-eosin stain; original magnification ⫻400.)
partate aminotransferase, 73 U/L (normal 12-31 U/L); alanine aminotransferase, 67 U/L (normal 9-29 U/L); gamma glutamyl-transferase, 42 U/L (normal 6-29 U/L). Bilirubin values were normal. Prothrombin time was 13 seconds (normal, up to 12 seconds). The hepatitis C test was positive. Ultrasound of the liver demonstrated a diffusely coarse echo consistent with cirrhosis, and splenomegaly was also noted. In treatment, the patient was given rifampin, 300 mg twice a day for 2 months and then 300 mg/d for 6 months, together with rubber-filled Ace bandages for the leg lesions. After 8 months, all the lesions had healed. The upper back GA lesions healed in 3 months. While she was receiving therapy, 2 new separate, tender red lesions of 1 to 2 cm occurred below the knee, and 1 such lesion appeared on the upper arm. One month later, these had involuted. Over the past 5 years, occasional tender red nodules
This patient had clinical and laboratory findings of tuberculosis, including response to antituberculosis therapy. The associated erythema induratum was confirmed histologically and by PCR for mycobacterial DNA in skin tissue. The PCR has been demonstrated to be positive for myocobacterial DNA in erythema induratum, papulonecrotic tuberculid, and lichen scrofulosorum.9-12 The yellow annular lesions on the back and upper arms did not contain Mycobacterium tuberculosis DNA by PCR performed at the same time. These lesions disappeared in a shorter time after treatment was started and could have involuted for other reasons. The lesions were compatible with GA by clinical and histologic study, and GA lesions can disappear after biopsy. The question of GA versus an unusual annular tuberculid has to be considered. Annular tuberculids were not discussed in recent reports on tuberculosis of the skin.13-16 It is difficult to find any lesions in the literature comparable to those described here. Oppenheim17 discussed a case of lichen scrofulosorum (LS) in which some yellow plaques showed central scaling. Tappeiner and Wolff18 also mentioned that in LS yellow papules show a tendency to coalesce. Gawkrodger19 discussed LS presenting as yellow papules with patchy evolution. Schidachi,20 reviewing J. Jadassohn’s cases of erythema induratum and the literature, found 5 cases of associated LS in a total of 156 patients, but none resembled the lesions in the current case. LS lesions are typically follicular, a feature
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not seen in this patient. Other series have shown that erythema induratum and papulonecrotic tuberculids are often associated with each other.21-24 Reported cases of lichenoid tuberculid were not similar to the case reported here.25,26 Civatte27 reported a case (case 2) of tuberculosis with GA in 1952; however, despite the presence of necrosis, the lesion was not considered to be a tuberculid. GA is an infiltrative and often palisading macrophage granuloma.28,29 It is considered an immunologic granuloma and has a population of T lymphocytes.30,31 This histopathologic picture can occur with tuberculin skin tests and also with delayed hypersensitivity skin tests of other types, such as histoplasmin32,33 (Winkelmann RK, unpublished observations). GA occurs in a variety of clinical presentations—papules, plaques, or annular lesions; dermal, subcutaneous, tendon, and soft tissue locations; and localized and generalized forms, some of which may perforate the skin surface.28,34-37 The multiplicity of presentations reflects multiple etiologic relationships, as shown in Table I. The validity of this correlation in a given clinical association is based on the finding of causative DNA in the GA lesions. Varicella-zoster virus DNA has been demonstrated by the PCR method in GA cutaneous lesions that appeared after the healing of herpes zoster skin lesions.47 Varicella-zoster virus has been associated with the evolution of granulomatous vasculitis, and it seems likely that this could be the mechanism of onset of some GA-type lesions described as having multiple causes. GA has been discussed as a form of vasculitis, and though most cases do not show overt inflammatory vessel disease, this remains a recognized path of immunologic granuloma formation.48 This case emphasizes again that GA may be a phenotypic clinicopathologic reaction to multiple etiologic agents and various forms of therapy, at times aimed at related etiologic factors. The recognition of this feature of GA will alert clinicians to the possibility that other diseases are involved and to consider various approaches to therapy. It is useful to understand that granulomatous disease can occur with vascular lesions, and because this phenomenon has been recognized with varicella-zoster virus, it is not a great leap to consider it in the setting of active tuberculosis and the vascular tuberculid, erythema induratum. I believe that the reported case is an index case for the recognition that a focal granuloma type of skin reaction can occur in many kinds of infectious and active immunologic states.
2.
3. 4. 5. 6. 7. 8.
9. 10.
11.
12.
13.
14. 15. 16. 17. 18.
19.
20. 21. 22.
23. 24.
REFERENCES 1. Pautrier L-M. Dermatoses dont les rapports avec la tuberculose sont incertains et discutables. In: Darier, Sabouraud, Gougerot,
25.
Milian, Pautrier, Ravaut, et al, editors. Nouvelle pratique dermatologique. Vol 3. Paris: Masson et Cie; 1936. p. 825-35. Schuppli R. Granuloma annulare–necrobiosis lipoidica diabeticorum– granulomatosis disciformis–necrobiosis maculosa. In: Jadassohn J, editor. Handbuch der Haut und Geschlechtskrankheiten. Vol 2, pt. 2, Supplement. Entzu¨ndliche Dermatosen. Miescher G, Storck H, editors. Berlin: Springer-Verlag; 1965. p. 141-55. Braun-Falco O, Plewig G, Wolff HH, Winkelmann RK. Dermatology. Berlin: Springer-Verlag; 1991. Hauser A. Ueber ungewohnliche tuberkuliformen. Arch Dermatol Syphilis 1922;128:149-72. Gru¨tz O. [Relations between granuloma annulare and tuberculids.] Arch Dermatol Syphilis 1924;147:590-8. German. Horowitz. Granulomas annulare bei einer tuberkulosen patientin. Z Haut Geschlechtskr 1925;17:271. Hirschfeld. Granulomea annulare-ahnliches tuberkulid. Z Haut Geschlechtskr 1926;20:740. Sokolew. Zur Frage des granuloma annulare und dessen beziehungen zu den tuberkuliden. Dermatol Wochenschr 1927;85: 1466. Degitz K, Steidl M, Thomas P, Plewig G, Volkenandt M. Aetiology of tuberculids [letter]. Lancet 1993;341:239-40. Schneider JW, Geiger DH, Rossouw DJ, Jordaan HF, Victor T, van Helden PD. Mycobacterium tuberculosis DNA in erythema induratum of Bazin [letter]. Lancet 1993;342:747-8. Baselga E, Margall N, Barnadas MA, Coll P, de Moragas JM. Detection of Mycobacterium tuberculosis DNA in lobular granulomatous panniculitis (erythema induratum-nodular vasculitis). Arch Dermatol 1997;133:457-62. Yen A, Rady PL, Cortes-Franco R, Tyring SK. Detection of Mycobacterium tuberculosis in erythema induratum of Bazin using polymerase chain reaction [letter]. Arch Dermatol 1997;133:532-3. Beyt BE Jr, Ortbals DW, Santa Cruz DJ, Kobayashi GS, Eisen AZ, Medoff G. Cutaneous mycobacteriosis: analysis of 34 cases with a new classification of the disease. Medicine (Baltimore) 1981; 60:95-109. Sehgal VN, Bhattacharya SN, Jain S, Logani K. Cutaneous tuberculosis: the evolving scenario. Int J Dermatol 1994;33:97-104. Philit F, Cordier JF. [New findings in tuberculosis.] Ann Dermatol Venereol 1995;122:45-9. French. MacGregor RR. Cutaneous tuberculosis. Clin Dermatol 1995;13: 245-55. Oppenheim H. Lichen scrofulosorum. Arch Dermatol Syphilis 1920;125:661-2. Tappeiner G, Wolff K. Tuberculosis and other mycobacterial infections. In: Fitzpatrick TB, Eisen AZ, Wolff K, Freedberg IM, Austen KF, editors. Dermatology in general medicine. Vol. 2. 4th ed. New York: McGraw-Hill; 1993. p. 2370-95. Gawkrodger DJ. Mycobacterial infections. In: Champion RH, Burton JL, Burns DA, Breathnach SM, editors. Rook/Wilkinson/ Ebling textbook of dermatology. Vol. 2. 6th ed. Oxford: Blackwell Science; 1998. p. 1181-214. Schidachi T. Ueber das erythema induratum. Arch Dermatol Syphilis 1908;371-414. Morrison JG, Fourie ED. The papulonecrotic tuberculide: from Arthus reaction to lupus vulgaris. Br J Dermatol 1974;91:263-70. Wilson-Jones E, Winkelmann RK. Papulonecrotic tuberculid: a neglected disease in Western countries. J Am Acad Dermatol 1986;14:815-26. Visser AJ, Heyl T. Skin tuberculosis as seen at Ga-Rankuwa Hospital. Clin Exp Dermatol 1993;18:507-15. Rademaker M, Lowe DG, Munro DD. Erythema induratum (Bazin’s disease). J Am Acad Dermatol 1989;21:740-5. Ockuly OE, Montgomery H. Lichenoid tuberculid: clinical and histopathologic study. J Invest Dermatol 1950;14:415-26.
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26. Schuhmachers R. Zwei fa¨lle eines lichenoiden tuberkulids (⫽lichen scrophulosorum). Hautarzt 1967;18:81-4. 27. Civatte A. Les formes tuberculo-ulce´rueˆses et tuberculo-gommeuses du granulome annulaire. Ann Dermatol Syphiligraphie 1952;79:387-97. 28. Muhlbauer JE. Granuloma annulare. J Am Acad Dermatol 1980; 3:217-30. 29. Umbert P, Winkelmann RK. Histologic, ultrastructural and histochemical studies of granuloma annulare. Arch Dermatol 1977; 113:1681-6. 30. Winkelmann RK. Immunologic granulomas. In: Stone J, editor. Dermatologic immunology and allergy. St. Louis: CV Mosby; 1985. p. 711-33. 31. Buechner SA, Winkelmann RK, Banks PM. Identification of T-cell subpopulations in granuloma annulare. Arch Dermatol 1983; 119:125-8. 32. Beer WE, Wilson-Jones E. Granuloma annulare following tuberculin Heaf tests. Trans St Johns Hosp Dermatol Soc 1966;52:68. 33. Fisher I. Unusual late histologic change seen in intracutaneous tuberculin reaction. J Invest Dermatol 1954;23:233-5. 34. Dabski K, Winkelmann RK. Generalized granuloma annulare: histopathology and immunopathology: systematic review of 100 cases and comparison with localized granuloma annulare. J Am Acad Dermatol 1989;20:28-39. 35. Dabski C, Winkelmann RK. [Granuloma annulare and carpal tunnel syndrome.] Ann Dermatol Venereol 1993;120:375-7. French. 36. Dabski K, Winkelmann RK. Destructive granuloma annulare of the skin and underlying soft tissues—report of two cases. Clin Exp Dermatol 1991;16:218-21. 37. Rubin M, Lynch FW. Subcutaneous granuloma annulare: comment on familial granuloma annulare. Arch Dermatol 1966;93: 416-20. 38. Magro CM, Crowson AN, Regauer S. Granuloma annulare and
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39.
40.
41. 42.
43.
44. 45.
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necrobiosis lipoidica tissue reactions as a manifestation of systemic disease. Hum Pathol 1996;27:50-6. Friedman SJ, Winkelmann RK. Familial granuloma annulare: report of two cases and review of the literature. J Am Acad Dermatol 1987;16:600-5. Willemsen MJ, de Coninck AL, Jonckheer MH, Roseeuw DI. Autoimmune thyroiditis and generalized granuloma annulare: remission of the skin lesions after thyroxine therapy. Dermatologica 1987;175:239-43. Umbert P, Winkelmann RK. Granuloma annulare and sarcoidosis. Br J Dermatol 1977;97:481-6. Spencer SA, Fenske NA, Espinoza CG, Hamill JR, Cohen LE, Espinoza LR. Granuloma annulare-like eruption due to chronic Epstein-Barr virus infection. Arch Dermatol 1988;124:250-5. Ghadially R, Sibbald RG, Walter JB, Haberman HF. Granuloma annulare in patients with human immunodeficiency virus infections. J Am Acad Dermatol 1989;20:232-5. Kleber R, Landthaler M, Burg G. [Post-zoster granuloma annulare.] Hautarzt 1989;40:110-1. German. Pujol RM, Matias-Guiu X, Planaguma M, de Moragas JM. Chronic lymphocytic leukemia and cutaneous granulomas at sites of herpes zoster scars. Int J Dermatol 1990;29:652-4. Barksdale SK, Perniciaro C, Halling KC, Strickler JG. Granuloma annulare in patients with malignant lymphoma: clinicopathologic study of thirteen new cases. J Am Acad Dermatol 1994;31: 42-8. Serfling U, Penneys NS, Zhu WY, Sisto M, Leonardi C. Varicellazoster virus DNA in granulomatous skin lesions following herpes zoster: a study by the polymerase chain reaction. J Cutan Pathol 1993;20:28-33. Dahl MV, Ullman S, Goltz RW. Vasculitis in granuloma annulare: histopathology and direct immunofluorescence. Arch Dermatol 1977;113:463-7.
P
autrier1 in 1936 stated that most dermatologists considered that tuberculosis was a possible etiologic factor in granuloma annulare (GA) on the basis of the coincidental occurrence, granulomatous histologic features, positive tuberculin skin tests, and cures with tuberculin injections. GA had also been associated with papulonecrotic tuberculid. However, Pautrier also recognized that many cases of GA were unrelated to tuberculosis, had nontuberculous pathology, and could be associated with negative tuberculin tests. Schuppli2 in 1965 and Braun-Falco et al3 in 1991 pointed out that GA was appropriately viewed as a polyetiologic syndrome for which focal infection, rheumatic disease, and toxicity, as well as tuberculosis, might be considered causative factors. The concurrence of GA with tuberculosis was emphasized by a series of cases reported in the 1920s by Hauser,4 Gru¨tz,5 Horowitz,6 Hirschfeld,7 and Sokolew.8 Papulonecrotic tuberculid occurred in one of Hauser’s cases. The decline in the number of cases of chronic, relapsing tuberculosis has resulted in diminishing experience with associated disease states of the skin for physicians in developed countries, and it has been recognized that the problem of tuberculosis and tuberculids has been oversimplified in the literature of recent decades. This Emeritus member, Department of Dermatology, Mayo Clinic, Scottsdale. Reprints not available from author. Correspondence: R. K. Winkelmann, MD, PhD, Emeritus Office, Mayo Clinic Scottsdale, 13400 E Shea Blvd, Scottsdale, AZ 85259. Copyright © 2002 by the American Academy of Dermatology, Inc. 0190-9622/2002/$35.00 ⫹ 0 16/91/120925 doi:10.1067/mjd.2002.120925
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report presents a case similar to those observed by dermatologists of earlier years and points to the recognition of the GA phenomenon as a macrophage phenotype skin reaction that can have multiple etiologies.
CASE REPORT A 59-year-old woman visited Mayo Clinic Scottsdale in 1992 because of skin eruptions of some duration. Deep red subcutaneous masses and scars had been present on her legs for some years, and annular yellow to flesh-colored papular lesions of shorter duration appeared on her upper back, shoulders, and arms. Her significant medical history began with her emigration from Italy to the United States in 1974. At that time, a chest x-ray showed tuberculosis, and she had a positive tuberculin skin test. No culture information was available from this medical evaluation. She was given 1 drug orally for 1 week, presumably isonicotinic acid hydrazide (INH). The medication was stopped because a generalized erythematous pruritic rash appeared on the trunk and extremities, which lasted 2 months. There was no further diagnosis or treatment. She had erythematous deep nodules of the legs for the first time while still living in Italy 20 years before, and shortly after her arrival in New York, symmetric red nodular eruptions of the lower legs occurred, which lasted 1 month. The patient arrived in Arizona in 1985 and soon after found a sore, painful nodule on her left thigh. Subsequently red lesions have recurred and have led to scarring on the thighs, lower legs, and calves. Irregular masses have constantly been present. She has had no fever, cough, malaise, or general sense of illness.
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Fig 2. Annular plaque of upper back.
Fig 1. Erythematous dermal and subcutaneous lesions of left thigh. Erythema induratum.
A second, asymptomatic eruption had occurred on the back and upper arms, and she was, in fact, unaware of it until our examination. Eight years ago, the patient was found to have abnormally elevated liver function tests. After 2 liver biopsies, she was informed that she had cirrhosis and hepatitis C. Her husband had died of hepatitis. The patient has always been anemic and has been diagnosed as having thalassemia. Results of a general physical examination were satisfactory except for the skin lesions. Deep nodular lesions were present on the thighs and legs. Biopsy and other scars were present (Fig 1). The lesions were a deep red to brown-red, and several showed focal surface crusting. On the upper back, arms, and shoulders were yellow to flesh-colored, infiltrated papules in annular rings (Figs 2-4). On pathologic study, excision biopsy of the right knee lesion revealed a lobular, granulomatous pathologic picture consistent with erythema induratum. Biopsy performed elsewhere was also diagnosed as showing erythema induratum. Immunofluorescence demonstrated C3 and fibrinogen consistent with vasculitis of the dermal vessels. Culture of the biopsy specimen was negative for organisms, including fungus and mycobacteria. A polymerase chain reaction (PCR) study of the leg biopsy tissue was positive for mycobacterial DNA. The biopsy specimens of the annular plaques were interpreted as showing GA, with pathologic features con-
Fig 3. Annular lesion of right upper arm.
sistent with the infiltrative stage of that process (Fig 5). The PCR of all of these lesions was negative. At laboratory examination, a chest x-ray showed bilateral, apical fibrocalcific disease consistent with tuberculosis. Induced sputum, urine, and gastric washings were negative for acid-fast bacteria by smear and culture. The hemogram revealed a mild anemia— hemoglobin 11 g/dL, with 5.57 ⫻ 1012 red blood cells per liter. Special smear showed marked microcytosis, moderate poikilocytosis, and hypochromia. Moderate numbers of elliptocytes and a small number of target cells were seen. The smear was interpreted as showing iron deficiency consistent with thalassemia. Blood chemistries were normal except for elevated liver function enzymes: as-
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Table I. Granuloma annulare–associated diseases28,34,38-46 Genetic Physical Infections
Drug Systemic diseases Fig 4. Closer view of lesion in Fig 2, showing coalescing papules that compose border. Lymphoma
Familial Twins Trauma Ultraviolet Virus: varicella-zoster, Epstein-Barr, human immunodeficiency Bacteria Mycobacteria Fungus Gold Diabetes, necrobiosis lipoidica Hashimoto’s thyroiditis Sarcoid Vasculitis Hodgkin’s disease T- and B-cell lymphoma
have continued to form on the extremities and then heal spontaneously with time. The annular lesions have never recurred.
DISCUSSION
Fig 5. Granulomatous histologic features of upper back lesion, showing macrophage and giant cell histologic characteristics. (Hematoxylin-eosin stain; original magnification ⫻400.)
partate aminotransferase, 73 U/L (normal 12-31 U/L); alanine aminotransferase, 67 U/L (normal 9-29 U/L); gamma glutamyl-transferase, 42 U/L (normal 6-29 U/L). Bilirubin values were normal. Prothrombin time was 13 seconds (normal, up to 12 seconds). The hepatitis C test was positive. Ultrasound of the liver demonstrated a diffusely coarse echo consistent with cirrhosis, and splenomegaly was also noted. In treatment, the patient was given rifampin, 300 mg twice a day for 2 months and then 300 mg/d for 6 months, together with rubber-filled Ace bandages for the leg lesions. After 8 months, all the lesions had healed. The upper back GA lesions healed in 3 months. While she was receiving therapy, 2 new separate, tender red lesions of 1 to 2 cm occurred below the knee, and 1 such lesion appeared on the upper arm. One month later, these had involuted. Over the past 5 years, occasional tender red nodules
This patient had clinical and laboratory findings of tuberculosis, including response to antituberculosis therapy. The associated erythema induratum was confirmed histologically and by PCR for mycobacterial DNA in skin tissue. The PCR has been demonstrated to be positive for myocobacterial DNA in erythema induratum, papulonecrotic tuberculid, and lichen scrofulosorum.9-12 The yellow annular lesions on the back and upper arms did not contain Mycobacterium tuberculosis DNA by PCR performed at the same time. These lesions disappeared in a shorter time after treatment was started and could have involuted for other reasons. The lesions were compatible with GA by clinical and histologic study, and GA lesions can disappear after biopsy. The question of GA versus an unusual annular tuberculid has to be considered. Annular tuberculids were not discussed in recent reports on tuberculosis of the skin.13-16 It is difficult to find any lesions in the literature comparable to those described here. Oppenheim17 discussed a case of lichen scrofulosorum (LS) in which some yellow plaques showed central scaling. Tappeiner and Wolff18 also mentioned that in LS yellow papules show a tendency to coalesce. Gawkrodger19 discussed LS presenting as yellow papules with patchy evolution. Schidachi,20 reviewing J. Jadassohn’s cases of erythema induratum and the literature, found 5 cases of associated LS in a total of 156 patients, but none resembled the lesions in the current case. LS lesions are typically follicular, a feature
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not seen in this patient. Other series have shown that erythema induratum and papulonecrotic tuberculids are often associated with each other.21-24 Reported cases of lichenoid tuberculid were not similar to the case reported here.25,26 Civatte27 reported a case (case 2) of tuberculosis with GA in 1952; however, despite the presence of necrosis, the lesion was not considered to be a tuberculid. GA is an infiltrative and often palisading macrophage granuloma.28,29 It is considered an immunologic granuloma and has a population of T lymphocytes.30,31 This histopathologic picture can occur with tuberculin skin tests and also with delayed hypersensitivity skin tests of other types, such as histoplasmin32,33 (Winkelmann RK, unpublished observations). GA occurs in a variety of clinical presentations—papules, plaques, or annular lesions; dermal, subcutaneous, tendon, and soft tissue locations; and localized and generalized forms, some of which may perforate the skin surface.28,34-37 The multiplicity of presentations reflects multiple etiologic relationships, as shown in Table I. The validity of this correlation in a given clinical association is based on the finding of causative DNA in the GA lesions. Varicella-zoster virus DNA has been demonstrated by the PCR method in GA cutaneous lesions that appeared after the healing of herpes zoster skin lesions.47 Varicella-zoster virus has been associated with the evolution of granulomatous vasculitis, and it seems likely that this could be the mechanism of onset of some GA-type lesions described as having multiple causes. GA has been discussed as a form of vasculitis, and though most cases do not show overt inflammatory vessel disease, this remains a recognized path of immunologic granuloma formation.48 This case emphasizes again that GA may be a phenotypic clinicopathologic reaction to multiple etiologic agents and various forms of therapy, at times aimed at related etiologic factors. The recognition of this feature of GA will alert clinicians to the possibility that other diseases are involved and to consider various approaches to therapy. It is useful to understand that granulomatous disease can occur with vascular lesions, and because this phenomenon has been recognized with varicella-zoster virus, it is not a great leap to consider it in the setting of active tuberculosis and the vascular tuberculid, erythema induratum. I believe that the reported case is an index case for the recognition that a focal granuloma type of skin reaction can occur in many kinds of infectious and active immunologic states.
2.
3. 4. 5. 6. 7. 8.
9. 10.
11.
12.
13.
14. 15. 16. 17. 18.
19.
20. 21. 22.
23. 24.
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