AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

T. Colcott Fox first described granuloma annulare (GA) in 1895; however, it was not until 1902 that Radcliffe-Crocker labeled it as GA.

GA is a benign inflammatory dermatosis characterized clinically by dermal papules and annular plaques. Its precise cause is unknown. Histological examination reveals foci of degenerative collagen associated with palisaded granulomatous inflammation.

The following clinical variants are recognized:

• Localized GA
• Generalized GA
• Subcutaneous GA
• Perforating GA
• Arcuate dermal erythema

Some authorities consider actinic granuloma (AG) to be a subset of GA, but others view it as a separate but related entity.

Pathophysiology

Proposed pathogenic mechanisms include cell-mediated immunity (type IV), immune complex vasculitis, and an abnormality of tissue monocytes. None has convincing supporting evidence.

Frequency

International

GA is an uncommon dermatosis whose frequency in the general population is unknown. Localized GA is the most common among the various subtypes. Of all patients with GA, 9-15% have the generalized variant. Perforating GA has been reported to have a prevalence of 5% among GA subtypes, although reports suggest that this variant may be more common in the Hawaiian Islands. The other subtypes are uncommon variants.

Mortality/Morbidity

Most cases resolve without adverse medical sequelae.

Sex

Women are affected twice as often as men.

Age

• Localized GA is most commonly found in children and in adults younger than 30 years.
• Generalized GA demonstrates a bimodal age distribution, occurring in patients younger than 10 years and in patients aged 30-60 years.
• Although subcutaneous GA can occur in adults, it is predominantly a disease of otherwise healthy children, who are typically aged 2-10 years. Similarly, perforating GA most often affects children.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

• Both localized and generalized GA lesions usually manifest as asymptomatic cutaneous lesions. Lesions may improve in winter and worsen in summer.
• Subcutaneous GA 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.

Physical

• Patients with localized GA 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 GA 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 GA 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 GA 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 GA 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 AG 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, AG lesions are difficult to distinguish clinically from eruptions of GA.

Causes

• GA has traditionally been hypothesized to be associated with tuberculosis, insect bites, trauma, sun exposure, thyroiditis, and viral infections, including HIV, Epstein-Barr virus, and herpes zoster virus. However, these suggested etiologic factors remain unproven.
• Familial cases of GA observed in identical twins and siblings in several generations, along with an association of GA 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 GA; HLA-A29 and HLA-BW35 levels are reported to be increased in generalized GA.
• Relationship to systemic diseases
• • GA has been associated with diabetes mellitus and thyroid disease based on an increased number of GA patients with these diseases in small case series. The evidence for a relationship with GA is weak.
  • Small case series have reported GA to occur in association with malignancy, AIDS, and herpes zoster lesions. Although no definite patterns relating GA 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 recent study by Li et al (2003) reviewed classic cases in the literature and could find no definite relationship between GA and malignant neoplasms.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Localized GA
Annular lichen planus
Erythema annulare centrifugum
Erythema elevatum diutinum
Erythema migrans of Lyme disease
Hansen disease (leprosy)
Necrobiosis lipoidica diabeticorum

Generalized GA
Cutaneous metastases
Cutaneous paraneoplastic syndrome
Lichen myxedematous
Lichen planus
Sarcoidosis

Subcutaneous GA
Epithelioid sarcoma
Rheumatoid nodule

Perforating GA
Elastosis perforans serpiginosa
Molluscum contagiosum
Perforating collagenosis

Actinic granuloma
Erythema annulare centrifugum
Necrobiosis lipoidica diabeticorum
Sarcoidosis

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• Laboratory studies are largely noncontributory in patients with 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 GA, a CBC count, an erythrocyte sedimentation rate, and a rheumatoid factor study may assist in excluding other possible causes for nodules.

Imaging Studies

• Imaging studies are not generally necessary in diagnosing GA. However, radiographs, CT scans, or MRIs may be helpful in the evaluation of atypical subcutaneous lesions.
• • Radiographs of subcutaneous GA show a nonspecific soft tissue mass without calcification.
  • On CT scans, subcutaneous GA appears as a poorly defined mass with variable attenuation and variable contrast enhancement.
  • On MRIs, subcutaneous GA 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 GA.

Procedures

• Biopsy is recommended for a subcutaneous lesion and for an atypical presentation with respect to history (ie, rapid enlargement, pain) or location of lesion.

Histologic Findings

Early interstitial or incomplete GA 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 GA 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 GA lesions and deep subcutaneous GA 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 GA, 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 GA are also described.

AG, also known as annular elastolytic giant cell granuloma, may lack the classic palisaded arrangement observed in GA. 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 GA. Thus, AG can be distinguished histologically from GA by a preponderance of giant cells in relation to elastotic tissue, by absence of mucin, and, occasionally, by absence of palisading histiocytes around granulomas.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

Localized 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 GA. Secondary dyschromia may be a complication of cryotherapy. Other anecdotes of therapeutic efficacy in both localized and generalized GA involve tacrolimus and pimecrolimus (Harth, 2004; Jain, 2004; Rigopoulos, 2005) and imiquimod cream (Kuwahara, 2003; Badavanis, 2005).

Generalized GA 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 GA. Other anecdotal reports and small series describe successful treatment with dapsone, systemic steroids, pentoxifylline, hydroxychloroquine, cyclosporine, fumaric esters, interferon-gamma, potassium iodide, and nicotinamide.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Therapies that may be considered as initial approaches for patients seeking therapy for localized GA include intralesional corticosteroids, potent topical corticosteroids alone or under occlusion, and cryotherapy.

Patients with generalized GA may accept more aggressive treatment because of the chronicity or pronounced cosmetic disfigurement associated with the disease. Generalized GA may be treated initially with isotretinoin or PUVA, if not otherwise contraindicated.

Drug Category: Corticosteroids

Have anti-inflammatory properties and cause profound and varied metabolic effects. Corticosteroids modify the body's immune response to diverse stimuli.

Drug Name	Triamcinolone acetonide
Description	For inflammatory dermatoses responsive to steroids. Decreases inflammation by suppressing migration of polymorphonuclear leukocytes and reversing capillary permeability. Affects production of lymphokines and has inhibitory effect on Langerhans cells.
Adult Dose	0.1-1 mL of 3- to 5-mg/mL concentration injected intralesionally; lesions may be re-treated in 4-6 wk
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; bacterial, viral, or fungal skin infections
Interactions	None reported
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Multiple complications (eg, severe infections, hyperglycemia, edema, atrophy and thinning of nearby skin, telangiectasia, pigmentary changes, delayed pain, scarring, osteonecrosis, myopathy, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, myasthenia gravis, growth suppression) may occur; abrupt discontinuation of glucocorticoids may cause adrenal crisis

Drug Category: Retinoids

Vitamin A derivatives have many roles. They encourage cellular differentiation, are antiproliferative, and serve as immunomodulators.

Drug Category: Psoralen phototherapy agents

These agents inhibit cell proliferation.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Prognosis

• Spontaneous resolution of localized GA 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 GA has a more chronic course, with rare spontaneous resolution, poor response to treatment, and frequent relapses.
• Subcutaneous GA lesions often spontaneously regress. Local or distant recurrences have been reported in 20-75% of cases in different studies.

Patient Education

• Patients and families should be reassured about the typically benign nature and course of GA.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Since most cases of GA resolve without adverse medical sequelae, the risk of medical/legal liability is minimal. Complications resulting from treatment may be a more likely cause of litigation.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

• Argent JD, Fairhurst JJ, Clarke NM. Subcutaneous granuloma annulare: four cases and review of the literature. Pediatr Radiol. 1994;24(7):527-9. [Medline].
• Badavanis G, Monastirli A, Pasmatzi E, Tsambaos D. Successful treatment of granuloma annulare with imiquimod cream 5%: a report of four cases. Acta Derm Venereol. 2005;85(6):547-8. [Medline].
• Blume-Peytavi U, Zouboulis CC, Jacobi H, et al. Successful outcome of cryosurgery in patients with granuloma annulare. Br J Dermatol. Apr 1994;130(4):494-7. [Medline].
• De Maeseneer M, Vande Walle H, Lenchik L, et al. Subcutaneous granuloma annulare: MR imaging findings. Skeletal Radiol. Apr 1998;27(4):215-7. [Medline].
• Felner EI, Steinberg JB, Weinberg AG. Subcutaneous granuloma annulare: a review of 47 cases. Pediatrics. Dec 1997;100(6):965-7. [Medline].
• Ghadially R. Granuloma annulare, actinic granuloma. In: Arndt K, et al, eds. Cutaneous Medicine and Surgery. WB Saunders Co;1996:438-443.
• Harth W, Linse R. Topical tacrolimus in granuloma annulare and necrobiosis lipoidica. Br J Dermatol. Apr 2004;150(4):792-4. [Medline].
• Jain S, Stephens CJ. Successful treatment of disseminated granuloma annulare with topical tacrolimus. Br J Dermatol. May 2004;150(5):1042-3. [Medline].
• Kakourou T, Psychou F, Voutetakis A, et al. Low serum insulin values in children with multiple lesions of granuloma annulare: a prospective study. J Eur Acad Dermatol Venereol. Jan 2005;19(1):30-4. [Medline].
• Kerker BJ, Huang CP, Morison WL. Phototherapy of generalized granuloma annulare. Arch Dermatol. 1990;126:359-61. [Medline].
• Kuwahara RT, Naylor MF, Skinner RB. Treatment of granuloma annulare with topical 5% imiquimod cream. Pediatr Dermatol. Jan-Feb 2003;20(1):90. [Medline].
• Li A, Hogan DJ, Sanusi ID, Smoller BR. Granuloma annulare and malignant neoplasms. Am J Dermatopathol. Apr 2003;25(2):113-6. [Medline].
• Looney M, Smith KM. Isotretinoin in the treatment of granuloma annulare. Annals of Pharmacotherapy. 2004;38(3):494-7. [Medline].
• O''Brien JP, Regan W. Actinically degenerate elastic tissue is the likely antigenic basis of actinic granuloma of the skin and of temporal arteritis [published erratum appears in J Am Acad Dermatol 2000 Jan;42(1 Pt 1):148]. J Am Acad Dermatol. Feb 1999;40(2 Pt 1):214-22. [Medline].
• Penas PF, Jones-Caballero M, Fraga J, et al. Perforating granuloma annulare. Int J Dermatol. May 1997;36(5):340-8. [Medline].
• Rigopoulos D, Prantsidis A, Christofidou E, et al. Pimecrolimus 1% cream in the treatment of disseminated granuloma annulare. Br J Dermatol. Jun 2005;152(6):1364-5. [Medline].
• Shehan JM, El-Azhary RA. Magnetic resonance imaging features of subcutaneous granuloma annulare. Pediatr Dermatol. Jul-Aug 2005;22(4):377-8. [Medline].
• Smith MD, Downie JB, DiCostanzo D. Granuloma annulare. Int J Dermatol. May 1997;36(5):326-33. [Medline].

Article Last Updated: Mar 14, 2007