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Generalized granuloma annulare

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Generalized granuloma annulare
Martha P Arroyo MD PhD
Dermatology Online Journal 9(4): 13

From the Ronald O. Perelman Department of Dermatology, New York University


Granuloma annulare is an inflammatory condition that is primarily idiopathic, but it has been associated with certain diseases, most notably diabetes mellitus. Lesions usually resolve, but resolution is less likely to occur with diffuse disease. This case report presents a patient with diffuse granuloma annulare. Recent advances in pathogenesis and treatment options are discussed.

Clinical summary

History.—A 61-year-old woman presented with a 3-year history of a dermatosis involving the face, neck, arms, trunk, and legs. The patient first noted a few lesions 3 years ago. After a diagnosis of breast cancer was made, she states that the lesions became diffuse, with occasional pruritus. She had no improvement with either the application of topical glucocorticoids or a short course of pentoxifylline but had some improvement with intralesional glucocorticoids. A trial of isotretinoin improved the lesions, but she did not wish to continue therapy because of the side-effect profile. Past medical history includes breast cancer with lumpectomy. Medications include tamoxifen and loratadine. Risk factors include tobacco use.

Physical Examination.—There were numerous, widely distributed, annular and arcuate plaques with a raised, erythematous border and central clearing.

Figure 1 Figure 2

Laboratory data.—Blood glucose was < 50 mg/dL, lactic dehydrogenase 262 IU/L, and thyroid stimulating hormone 1.5 µIU/ml. Hepatitis C antibody was negative.

Histopathology.—The dermis has a granulomatous inflammation of mono- and multinucleated epithelioid histiocytes, some with blue-gray phagocytized, degenerated elastic fibers within their cytoplasm. There is a perivascular lymphocytic infiltrate and increased connective-tissue mucin in the dermis.

Diagnosis.—Generalized granuloma annulare.


Granuloma annulare has a slight female predilection and can present as localized, generalized, subcutaneous, or perforating lesions. The localized type tends to occur primarily in young people, whereas the generalized type has a bimodal distribution and presents in patients less than 10 or older than 40 years of age. Other types include arcuate dermal erythema and actinic granuloma. Blau syndrome is an autosomal dominantly inherited syndrome that includes granulomatous arthritis, iritis, and skin granulomas, such as granuloma annulare [1]. Clinically, granuloma annulare presents as annular plaques that may be skin-colored, erythematous, or violaceous, with a slightly depressed and hyperpigmented center. Histologically, the lesions consists of multiple foci of granulomatous inflammation with a central core of necrobiosis surrounded by palisaded histiocytes. The central area of necrobiosis stains positively for mucin and may contain blood vessels with thick walls. A direct immunofluorescence test shows C3, IgM, and fibrinogen in some dermal blood vessels and at the dermal-epidermal junction.

The pathogenesis of granuloma annulare is unknown. There is some evidence to suggest that it is an immunologic disease. A study has shown that the primary cell types involved are interferon-γ producing Th-1 lymphocytes and macrophages that express TNF-α and matrix metalloproteinases, which possibly contribute to a delayed-type hypersensitivity reaction [2].

Although granuloma annulare tends to be idiopathic, there is an association with diabetes mellitus. There are also weaker associations with Bacillus Calmette-Guerin vaccination, drugs (allopurinol, zalcitabine), viral infections (Epstein Barr virus, human immunodeficiency virus, hepatitis C, parvovirus B19, and herpes simplex virus), autoimmune thyroiditis, and malignant conditions (Hodgkin disease, pulmonary adenocarcinoma, breast carcinoma, and ovarian cancer) [3, 4, 5, 6, 7, 8, 9, 10, 11].

The course is often self-limited, and 50-70 percent of patients with the localized type show resolution after 1-2 years. The generalized type is less likely to clear spontaneously [12, 13]. Treatment is based on anecdotal reports since few large case-controlled studies exist. Topical glucocorticoids, liquid nitrogen cryotherapy, oral and topical PUVA photochemotherapy, UVA1 phototherapy, and cyclosporin have been used with some success [12, 13, 14, 15, 16].


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2. Fayyazi A, et al. Expression of IFN gamma, coexpression of TNF alpha and matrix metalloproteinases and apoptosis of T lymphocytes and macrophages in granuloma annulare. Arch Dermatol Res 2000;292:384.

3. Setoyama M, et al. Granuloma annulare associated with Hodgkin's disease. Int J Dermatol 1997;36:445.

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10. Penas PF, et al. Association between zalcitabine therapy for human immunodeficiency virus and granuloma annulare? Arch Dermatol 2001; 137:964.

11. O'Moore EJ, et al. HIV-associated granuloma annulare (HAGA): A report of six cases. Br J Dermatol 2000;142:1054.

12. Wells RS, Smith MA: The natural history of granuloma annulare. Br J Dermatol 1963;75:199.

13. Tan HH, Goh CL. Granuloma annulare: A review of 41 cases at the National Skin Centre. Ann Acad Med Singapore 2000;29:714.

14. Fiallo P. Cyclosporin for the treatment of granuloma annulare. Br J Dermatol 1998;138:369.

15. Simon JC, et al. Recent advances in phototherapy. Eur J Dermatol 2000; 10:642.

16. Grundmann-Kollmann M, et al. Cream psoralen plus ultraviolet A therapy for granuloma annulare. Br J Dermatol 2001;144:996.

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