Granuloma annulare (GA) is a benign inflammatory dermatosis. T. Colcott Fox first described granuloma annulare in 1895; however, not until 1902 did Radcliffe-Crocker label it as granuloma annulare.
Granuloma annulare is relatively common disease that occurs in all age groups, but it is rare in infancy. Granuloma annulare is characterized clinically by dermal papules and annular plaques. The precise cause of granuloma annulare is unknown. Histological examination reveals foci of degenerative collagen associated with palisaded granulomatous inflammation.
The following clinical variants are recognized:
Some authorities consider actinic granuloma (AG) to be a subset of granuloma annulare, but others view actinic annulare as a separate, but related, entity.
Proposed pathogenic mechanisms for granuloma annulare include cell-mediated immunity (type IV), immune complex vasculitis, and an abnormality of tissue monocytes. Some other possible mechanisms include primary degeneration of connective tissue leading to granulomatous inflammation, lymphocyte-mediated immune reaction with macrophage activation, and cytokine-mediated degradation of connective tissue.
The frequency of granuloma annulare is in the general population is unknown. Granuloma annulare does not favor a particular race, ethnic group, or geographical area.
Localized granuloma annulare is the most common among the various subtypes. Of all patients with granuloma annulare, 9-15% have the generalized variant. Perforating granuloma annulare has been reported to have a prevalence of 5% among granuloma annulare subtypes; further, reports suggest that this variant may be more common in the Hawaiian Islands.
Women are affected by granuloma annulare twice as often as men.
Localized granuloma annulare is most commonly found in children and in adults younger than 30 years. Generalized granuloma annulare demonstrates a bimodal age distribution, occurring in patients younger than 10 years and in patients aged 30-60 years. Although subcutaneous granuloma annulare can occur in adults, it is predominantly a disease of otherwise healthy children, who are typically aged 2-10 years. Similarly, perforating granuloma annulare most often affects children.
Both localized and generalized granuloma annulare lesions usually manifest as asymptomatic cutaneous lesions. Lesions may improve in winter and worsen in summer.
Subcutaneous granuloma annulare most often manifests as a large, asymptomatic soft tissue mass. Although nodules are usually stable for months, they may rapidly enlarge over the course of weeks.
Patients with localized granuloma annulare commonly present with groups of 1- to 2-mm papules that range in color from flesh-toned to erythematous, often in an annular arrangement over distal extremities. Grouped lesions may expand into arciform or annular plaques measuring 1-5 cm in diameter. Centers of lesions may be slightly hyperpigmented and depressed relative to their borders, which may be solid or composed of numerous dermal papules. Lesions most commonly manifest on the dorsal surfaces of the feet, hands, and fingers, and on the extensor aspects of the arms and legs. Rarely, lesions appear on the face, scalp, or penis.
Patients with generalized granuloma annulare characteristically present with a few to thousands of 1- to 2-mm papules or nodules that range in color from flesh-toned to erythematous and involve multiple body regions. Lesions may coalesce into annular plaques, which measure 3-6 cm in diameter and which may enlarge centrifugally over weeks to months. Although any part of the cutaneous surface may be involved, lesions tend to be symmetrically disposed over acral areas and the trunk. Rarely, the head, palms, soles, and mucous membranes are involved.
Patients with subcutaneous granuloma annulare present with a firm, nontender, flesh-colored or pinkish nodule without overlying epidermal alteration. Lesions are typically solitary but may occur in clusters. The most commonly reported site of involvement is the lower extremities (65% of cases), often on the pretibial surface. Other typical sites include the fingers and palms and the dorsa of the feet. The buttocks, forehead, and scalp are less commonly affected. Deep dermal or subcutaneous nodules on the extremities are attached to fascia and are often therefore mobile, whereas lesions on the scalp are attached to underlying periosteum and are therefore fixed or only slightly mobile.
Patients with perforating granuloma annulare present with 1 to hundreds of grouped 1- to 4-mm papules that range in color from flesh-toned to erythematous. Papules often coalesce to form annular plaques. In some patients, the erythematous papules may evolve into yellowish pustular lesions that subsequently exude a thick and creamy or clear and viscous fluid, forming umbilicating, crusting, or scaling papular lesions that heal, leaving atrophic hypopigmented or hyperpigmented scars. Larger and more ulcerated plaques are common in middle-aged and elderly patients. Lesions affect all areas of the body but have a predilection for the extensor surfaces of extremities and the dorsa of hands and fingers.
Arcuate dermal erythema is an uncommon form of granuloma annulare that manifests as infiltrated erythematous patches that may form large, hyperpigmented rings with central clearing. Papules are a less prominent feature in this variant. Patches typically appear on the trunk and may spread centrifugally over weeks to months.
Patients with actinic annulare present with 1-10 plaques, which tend to be annular or serpiginous areas with raised erythematous borders. Lesions may be hypopigmented centrally; the epidermis is otherwise spared. Plaques are typically distributed over sun-exposed areas, such as the arms, neck, face, and dorsa of the hands. Other than by their location on heat- or sun-damaged skin, actinic annulare lesions are difficult to distinguish clinically from eruptions of granuloma annulare.
The etiology of granuloma annulare is usually unknown, and the pathogenetic mechanisms are poorly understood, with a vast majority of granuloma annulare cases occurring in patients who are otherwise healthy. The range of predisposing events and associated diseases is diverse, and granuloma annulare is thought to represent a reaction pattern with many different initiating factors.
Granuloma annulare has been hypothesized to be associated with tuberculosis, insect bites, trauma, sun exposure, thyroiditis, vaccinations, and viral infections, including HIV, Epstein-Barr virus, hepatitis B virus, hepatitis C virus, and herpes zoster virus. However, these suggested etiologic factors remain unproven.
Familial cases of granuloma annulare observed in identical twins and siblings in several generations, along with an association of granuloma annulare with HLA phenotypes, suggest the possibility of a hereditary component in some cases. The HLA-B8 level has been reported to be increased in localized granuloma annulare; HLA-A29 and HLA-BW35 levels are reported to be increased in generalized granuloma annulare.
Some reports associate chronic stress with granuloma annulare as a trigger of the disease. Granuloma annulare also has some predilection for the sun-exposed areas and photodamaged skin. Photosensitive granuloma annulare has been found in association with HIV infection. Finally, some cases of granuloma annulare or granuloma annulare–like reactions have been reported after gold therapy and treatment with allopurinol, diclofenac, quinidine, calcitonin, amlodipine, ACE inhibitors, daclizumab, and calcium channel blockers.
Granuloma annulare has been associated primarily with type I diabetes mellitus, but it is only rarely associated with type II diabetes mellitus and thyroid disease, based on an increased number of granuloma annulare patients with these diseases in small case series.
Small case series have reported granuloma annulare to occur in association with malignancy, AIDS, and herpes zoster lesions. Although no definite patterns relating granuloma annulare and systemic disease have been thoroughly established, it has been suggested that an atypical histologic (vasculopathy or extravascular neutrophilia) or clinical presentation (unusual appearance or location) may indicate an associated disease. In the case of malignancy, a 2003 study by Li et al reviewed classic cases in the literature and could find no definite relationship between granuloma annulare and malignant neoplasms.
Certain malignancies are accompanied by different mucocutaneous paraneoplastic syndromes. Lesions that mimic granuloma annulare or are histologically confirmed as granuloma annulare have occurred in association with the following:
Laboratory studies are largely noncontributory in patients with granuloma annulare (GA). With a classic history and unremarkable physical examination findings (other than the presenting lesion[s]), no additional workup is necessary.
If, however, a thorough history is not available or systemic disease is considered likely, appropriate laboratory evaluations should be performed to exclude other diagnostic possibilities. For example, in subcutaneous granuloma annulare, a CBC count, an erythrocyte sedimentation rate, and a rheumatoid factor study may assist in excluding other possible causes for nodules.
Imaging studies are not generally necessary in diagnosing granuloma annulare. However, radiographs, CT scans, or MRIs may be helpful in the evaluation of atypical subcutaneous lesions.
Radiographs of subcutaneous granuloma annulare show a nonspecific soft tissue mass without calcification. On CT scans, subcutaneous granuloma annulare appears as a poorly defined mass with variable attenuation and variable contrast enhancement. On MRIs, subcutaneous granuloma annulare appears as a mass with poorly defined margins that is limited to subcutaneous tissue. MRI findings may be suggestive of, but not diagnostic of, subcutaneous granuloma annulare.[9, 10]
Biopsy is recommended for a subcutaneous lesion and for an atypical presentation with respect to history (ie, rapid enlargement, pain) or location of lesion.
Early interstitial or incomplete granuloma annulare lesions show an interstitial pattern characterized by lymphocytes around vessels of the superficial and deep plexuses and by macrophages scattered between reticular dermal collagen bundles that are separated by mucin within which mast cells may be found. Mucin in granuloma annulare is hyaluronic acid and is visible in sections stained with hematoxylin and eosin as faintly basophilic stringy material. Its presence can be confirmed by staining with colloidal iron or Alcian blue at pH 2.5.
Fully evolved granuloma annulare lesions and deep subcutaneous granuloma annulare nodules demonstrate palisaded granulomatous dermatitis or a septal and lobular panniculitis, respectively. Macrophages surround acellular necrobiotic areas in which collagen bundles are thinned, or they sometimes have a pale, homogeneous, light-blue appearance, the latter of which is due to the presence of mucin.
In many cases of subcutaneous granuloma annulare, and in some dermal infiltrates, the centers of granulomas contain degenerated, homogeneous-appearing collagen and are deeply eosinophilic. In some sections, necrotic small vessels in the centers of palisaded foci are surrounded by nuclear dust. Presence of fibrinogen can be shown by direct immunofluorescence in the centers of palisaded granulomas. In perforating lesions, necrobiotic material is extruded through focal perforations. Epidermal hyperplasia at the edge of the perforation forms a pseudochannel communicating with an underlying necrobiotic granuloma.
Rare cases of nonnecrobiotic, sarcoidal, or tuberculoid granuloma annulare are also described.
Actinic annulare, also known as annular elastolytic giant cell granuloma, may lack the classic palisaded arrangement observed in granuloma annulare. Although elastosis is abundant in the mid dermis outside the granuloma, elastic tissue is absent from the center of the annulus. Giant cells frequently abut elastotic tissue, and phagocytosed elastotic fibers are noted in histiocytic cells at the advancing edge. Collagen has a normal appearance outside the lesion but a finely fibrillar pattern within the annulus. Mucin deposition is not increased as it is in granuloma annulare. Thus, actinic annulare can be distinguished histologically from granuloma annulare by a preponderance of giant cells in relation to elastotic tissue, by absence of mucin, and, occasionally, by absence of palisading histiocytes around granulomas.
Localized granuloma annulare (GA) is not often symptomatic and it has a tendency towards spontaneous resolution. Reassurance is often all that is necessary. Painful or disfiguring lesions have been treated by various methods, although the level of evidence supporting these methods is low.
Localized lesions have been treated with potent topical corticosteroids with or without occlusion for 4-6 weeks, as well as with intralesional corticosteroids with varying total doses of steroid.
Cryotherapy using liquid nitrogen or nitrous oxide as refrigerants has been shown in a prospective, uncontrolled trial to be an effective treatment for localized granuloma annulare. Secondary dyschromia may be a complication of cryotherapy.
Other anecdotes of therapeutic efficacy in both localized and generalized granuloma annulare involve tacrolimus and pimecrolimus[12, 13, 14] and imiquimod cream.[15, 16]
Generalized granuloma annulare tends to be more persistent and unsightly. Treatment of the generalized disease is unfortunately fraught with a lack of consistently effective options. While the treatment of choice remains to be defined, the available literature supports the use of isotretinoin or phototherapy with oral psoralen and UV-A (PUVA) as first-line options for generalized granuloma annulare.[17, 18, 19]
Piaserico et al report successful therapy for long-standing generalized granuloma annulare using methyl aminolevulinate photodynamic therapy. Weisenseel et al reported moderate success with photodynamic therapy using 20% 5-aminolevulinic acid (ALA) gel.
Marcus et al report on 6 patients with granuloma annulare that was refractory to standard treatment. The patients were treated with monthly combination therapy including rifampin at 600 mg, ofloxacin at 400 mg, and minocycline hydrochloride at 100 mg monthly for 3 months. Three to 5 months after the initiation of treatment, the plaques were cleared completely. Postinflammatory hyperpigmentation was reported by some patients. Although the treatment was successful, the authors suggested further studies may be needed to confirm this combination therapy as a successful option for recalcitrant granuloma annulare.
Other anecdotal reports and small series describe successful treatment with dapsone, narrow-band UVB, systemic steroids, pentoxifylline, hydroxychloroquine, cyclosporine, fumaric esters, interferon-gamma, potassium iodide, nicotinamide, etanercept, infliximab, adalimumab, and efalizumab.[23, 24, 25]
A clinical guideline, the 2012 Infectious Diseases Society of America Clinical Practice Guideline for the Diagnosis and Treatment of Diabetic Foot Infections, may be helpful.
Therapies that may be considered as initial approaches for patients seeking therapy for localized granuloma annulare include intralesional corticosteroids, potent topical corticosteroids alone or under occlusion, and cryotherapy.
Patients with generalized granuloma annulare may accept more aggressive treatment because of the chronicity or pronounced cosmetic disfigurement associated with the disease. Generalized granuloma annulare may be treated initially with isotretinoin or PUVA, if not otherwise contraindicated.
Clinical Context: Clobetasol is used for inflammatory dermatoses responsive to steroids. It decreases inflammation by suppressing the migration of PMN leukocytes and reversing capillary permeability. Clobetasol affects the production of lymphokines and has inhibitory effects on Langerhans cells.
Clinical Context: Triamcinolone is used for inflammatory dermatoses responsive to steroids. It decreases inflammation by suppressing the migration of PMN leukocytes and reversing capillary permeability. Triamcinolone affects production of lymphokines and has inhibitory effects on Langerhans cells.
Clinical Context: Prednisone is a synthetic corticosteroid, strong immunosuppressant, and anti-inflammatory drug with proven effects in cutaneous inflammatory disorders.
Corticosteroids have anti-inflammatory properties and cause profound and varied metabolic effects. Corticosteroids modify the body's immune response to diverse stimuli.
Clinical Context: Isotretinoin is an oral agent that treats serious dermatologic conditions. It is a synthetic 13-cis isomer of the naturally occurring tretinoin (trans -retinoic acid). Both agents are structurally related to vitamin A. Isotretinoin should be prescribed only by physicians experienced and/or trained in its use.
A US Food and Drug Administration–mandated registry is now in place for all individuals prescribing, dispensing, or taking isotretinoin. For more information on this registry, see iPLEDGE. This registry aims to further decrease the risk of pregnancy and other unwanted and potentially dangerous adverse effects during a course of isotretinoin therapy.
Vitamin A derivatives have many roles. They encourage cellular differentiation, are antiproliferative, and serve as immunomodulators.
Clinical Context: Methoxsalen plus UVA inhibits mitosis by binding covalently to pyrimidine bases in DNA when photoactivated by UVA. It may have a direct cytotoxic effect on activated histiocytes, fibroblasts, and lymphocytes in the dermal infiltrate of lesions. Methoxsalen plus UVA may control lymphokine production through modulation of activated lymphocytes.
These agents inhibit cell proliferation.
Gass et al report a 70-year-old man with disseminated granuloma annulare (GA) in a photosensitive distribution, who, after successful systemic and topical treatment, developed milia and scarring. This is purported to be the first report of scarring and milia formation after successful treatment of granuloma annulare.
Spontaneous resolution of localized granuloma annulare has occurred within 2 years in 50% of cases, although lesions may last weeks to decades. Recurrence, often at the same site, is noted in 40% of cases.
Generalized granuloma annulare has a more chronic course, with rare spontaneous resolution, poor response to treatment, and frequent relapses.
Subcutaneous granuloma annulare lesions often spontaneously regress. Local or distant recurrences have been reported in 20-75% of cases in different studies.
Patients and families should be reassured about the typically benign nature and course of granuloma annulare.