Are You Confident of the Diagnosis?

What you should be alert for in the history

Granuloma annulare (GA) generally presents as asymptomatic papules that may coalesce to form plaques with an annular configuration. Individual lesions tend to arise insidiously and do not wax or wane. Crops of lesions can arise over the course of weeks to months. Pain and bleeding are not seen, but mild pruritis may be present.

Characteristic findings on physical examination

GA can be skin-colored, but tends toward red or violaceous. There is little overlying epidermal change (Figure 1, Figure 2).

Several subtypes of GA exist:

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LOCALIZED

This is the most common form. It typically occurs on the hands and wrists (60%), feet and ankles (20%), or trunk (5%) of young adults or children, and features stereotypical annular configuration with central clearing.

GENERALIZED

This subtype represents up to 15% of cases. It often begins as individual papules, which may or may not coalesce to form annular lesions. Lesions can number in the hundreds. The trunk is often involved. Patients tend to be adults; it is rare in children.

SUBCUTANEOUS

This form typically presents in childhood. It features painless large firm dermal nodules on the hands and feet; however, the buttocks, scalp, and face can be involved as well.

PATCH

This subtype has a distribution that is similarto the localized variant. It features erythematous patches, which lack the raised annular border.

PERFORATING

This form features papules with central crusting, typically appearing on the fingers and hands. A minority of these patients may have associated pain.

Expected results of diagnostic studies

A diagnosis of GA can be made on clinical grounds alone. Histopathologic examination of a biopsy specimen from a suspected lesion is the only useful diagnostic study for GA and can be pathognomonic.

Routine hematoloxylin and eosin sections show either histocytes splayed in between collagen fibers (interstitial patter) or palisading granulomas with central necrobiosis (palisaded pattern) (Figure 3, Figure 4). Less common is a sarcodial-like granuloma, deeper in the dermis.

Increased mucin is a helpful diagnostic clue and can be visualized with colloidal iron or acian blue stains. IgM, fibrin, and C3 can occasionally be found in vessel walls by using immunofluorescence. Magnetic resonance imaging (MRI) has been reported to be helpful in assessing subcutaneous GA if a diagnosis cannot be made on clinical grounds, but the findings are not entirely specific.

Diagnosis confirmation

The main histological differential diagnosis is necrobiosis lipoidica.

The differential diagnosis includes other granulomatous diseases such as sarcoidosis (which tends to involve the face and is less likely to have an annular configuration), necrobiosis lipoidica (plaques on the shins of diabetics with more telangectasias than GA), and rheumatoid nodules (typically over joints).

Lichen planus can have a similar presentation to the papules of GA, but only rarely assumes an annular configuration.

Subacute cutaneous lupus can have a similar annular appearance, but can be differentiated by a photodistribution, scale-crust, and positive antinuclear antibody (ANA) and anti-Ro antibodies.

Tinea corporis also can assume an annular-plaque-like appearance, but typically has a scaly border, which demonstrates hyphae on potassium hydroxide (KOH) examination. Annular elastolytic giant cell granuloma should be considered when arcifom lesions are observed in photoexposed sites; this diagnosis can be confirmed histologically.

Who is at Risk for Developing this Disease?

A majority of patients with GA are children and young adults (2/3 of cases), although the generalized form tends to favor adults. Historically, GA was thought to be more common in females, although there are conflicting data.

A link to type I diabetes has been shown; from 12% to 21% of patients (especially those with the generalized form) have this disorder. There is little correlation with type II diabetes.

HLA-Bw35 has been associated with generalized GA, and HLA-B8 has been associated with the localized form, suggesting a hereditary component. Indeed, familial cases have been reported.

What is the Cause of the Disease?
Etiology
Pathophysiology

The etiology of GA is largely unknown. A Th1-like reaction with production of IFN gamma and resultant matrix degradation may be involved.

Systemic Implications and Complications

There appears to be no systemic involvement with GA. Patients may have disease that lasts for years without other sequelae. In cases in which other diseases are present (such as diabetes or lymphoma), there is no definite temporal relationship. On rare occasions, granuloma-annulare-like eruptions have been considered to be associated with lymphoproliferative processes such as myelodysplastic syndrome.

With the exception of the perforating subtype, there is no scaring.

Treatment Options

MEDICAL TREATMENT

Topical

  • Topical corticosteroids, with or without occlusion

  • Intralesional corticosteroids

  • Tacrolimus ointment or pimecrolimus cream

  • Imiquimod cream

Systemic

  • Prednisone

  • Isotretinoin

  • Dapsone

  • Antimalarials

  • Cyclosporin

  • Methotrexate

PHYSICAL THERAPY

  • Cryotherapy

  • Photodynamic therapy

  • Psoralen and ultraviolet A therapy (PUVA)

  • Laser therapy (pulsed dye or CO2)

Optimal Therapeutic Approach for this Disease

GA is most often a self-limited disease, typically resolving within 2 years. Therefore, reassurance and explanation of the benign nature of the disease may be all that is necessary.

Initial treatment for localized or limited disease is potent topical corticosteroids such as triamcinolone 0.1% ointment or clobetasol 0.05% ointment. These can be applied to individual lesions twice daily for several weeks. Intralesional corticosteroids can also be very effective at a 2.5mg/ml dosage, and may only require one treatment.

Patients should be advised of the risk for dermal atrophy. Topical tacrolimus 0.1% ointment or pimecrolimus 1% cream for up to 12 weeks may also provide benefit, although the data consists of case reports, and patients must be made aware of the Food and Drug Administration (FDA) black box warnings for these products.

Cryotherapy has been been shown to lead to an 81% resolution rate for localized disease. This is a relatively simple office procedure, but can lead to minor scarring or dyspigmentation.

Generalized GA may require systemic therapy, although application of topical steroids to lesions affecting a broad area may still be possible. Prednisone can be effective, but the need for prolonged treatment, with the associated side effects, may outweigh the utility. Similarly, oral retinoids such as isotretinoin at 40mg daily for 8-12 weeks may lead to a 90% response rate, but is associated with liver and lipid abnormalities.

Photodynamic therapy with 5-aminolevulinic acid or PUVA can be effective, but may not be practical due to the need for frequent treatments.

There have been multiple reports of other modalities being used, , with varying success; however, they consist of small case studies or retrospective reviews with small numbers of patients. Examples of such medications include dapsone and hydroxychloroquine.

Patient Management

Patients undergoing treatment for GA can be monitored clinically for a response; there is no need for laboratory tests or even repeat biopsies.

If a response is achieved, no prophylactic therapy is needed. Recurrences are seen in up to 40% of cases, and can be treated as mentioned above.

All treatments for GA have potential side effects, and therefore the risk must be balanced against the benefit. Since this is generally an asymptomatic self-limited disease, reassurance may be the best option. In general, topical modalities can be effective and should be thought of as first line.

Unusual Clinical Scenarios to Consider in Patient Management

GA can be seen as a paraneoplastic response to a variety of cancers including Hodgkin’s and Non-Hodgkin’s lymphomas. These tend to be more symptomatic (typically painful) and can occur on the palms and soles.

Rarely, GA has been reported to be associated with uveitis.

What is the Evidence?

Ghadially, R, Szabo, AZ. “Granuloma annulare”. eMedicine. (An informative overview of the different clinical presentations and treatment options)

Wallet-Faber, N, Farhi, D, Gorin, I, Carlotti, A, Plantier, F, Dupin, N. “Outcome of granuloma annulare: shorter duration is associated with younger age and recent onset”. J Eur Acad Dermatol Venereol. vol. 24. 2010. pp. 75-114. (A retrospective review that describes demographics and clinical course of sixty-seven patients.)

Chaitra, V, Inchara, YK, Rajalakshmi, T, Antony, M. “Granuloma annulare—histology reconsidered”. Indian J Dermatol Venereol Leprol. vol. 76. 2010. pp. 568-9. (Case series of twenty-one GA biopsy specimens that correlates the clinical subtypes with the histological patterns)

Chung, S, Frush, DP, Prose, NS, Shea, CR, Laor, T, Bisset, GS. “Subcutaneous granuloma annulare: MR imaging features in six children and literature review”. Radiology. vol. 210. 1999. pp. 845-9. (Describes the MRI findings associated with subcutaneous GA.)

Li, A, Hogan, DJ, Sanusi, ID, Smoller, BR. “Granuloma annulare and malignant neoplasms”. Am J Dermatopathol. vol. 25. 2003. pp. 113-6. (A meta analysis reviewing the association of GA with various malignancies)

Cyr, PR. “Diagnosis and management of granuloma annulare”. Am Fam Physician. vol. 74. 2006. pp. 1729-34. (An overview of GA and the different subtypes. This review gives a useful assessment in a chart format of data supporting systemic treatments .)

Howard, A, White, CR, Bolognia, JL, Jorizzio, JL, Rapinni, RP. “Non-infectious granulomas”. Dermatology. 2008. (This, along with Prendiville’s review in Fitzpatrick’s Dermatology in General Medicine, is one of the definitive reviews of GA. It covers the pathophysiology, clinical findings, and treatments.)

Prendiville, JS, Wolff, K, Goldsmith, LA, Katz, SI, Gilchrest, BA, Paller, AS, Leffell, DJ. “Granuloma annulare”. 2008. (This, along with the Howard et al.review in Dermatology, is one of the definitive reviews of GA. It nicely outlines associated risk factors and pathological findings.)

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