eMedicine Specialties > Dermatology > Reactive & Inflammatory Dermatoses

Granuloma Annulare

Author: Ruby Ghadially, MBChB, FRCP(C)Derm, Professor, Department of Dermatology, University of California, San Francisco, School of Medicine
Coauthor(s): Akos Z Szabo, MD, Resident Physician, Department of Plastic and Hand Surgery, Freiburg University Medical Center; Amit Garg, MD, Director of Clinical Elective in Dermatology, Assistant Professor, Department of Internal Medicine, Division of Dermatology, University of Massachusetts Medical School
Contributor Information and Disclosures

Updated: Aug 26, 2009

Introduction

Background

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:

• Localized granuloma annulare: This is the most common form. Localized granuloma annulare is characterized by skin-colored to violaceous lesions up to 5 cm in diameter. Usually, the epidermis has attenuated surface markings. Annular rings with solitary firm papules or nodules may be present. Localized granuloma annulare has a predilection for the feet, ankles, lower limbs, and wrists.
• Generalized granuloma annulare: This form occurs predominantly in adults. The trunk is usually involved, as well as the neck, extremities, face, scalp, palms, and soles. Lesions range from widespread papules to annular plaques to large, discolored patches with a variety of coloration from yellow to violaceous.
• Subcutaneous granuloma annulare^1,2 : This form occurs predominantly in children. Subcutaneous granuloma annulare is characterized by firm or hard asymptomatic nodules in the deep dermis or subcutaneous tissues, with individual lesions measuring from 5 mm to 4 cm in diameter. They are prevalent on the anterotibial plateau, ankles, dorsal feet, buttocks, hands, scalp, and eyelids.
• Perforating granuloma annulare³ : This form is very rare. Perforating granuloma annulare is usually localized to the dorsal hands and fingers or may be generalized on the trunk and extremities. A variety of superficial umbilicated papules develop, with or without a discharge, that heal with scarring.
• Arcuate dermal erythema: This is an uncommon form of granuloma annulare that manifests as infiltrated erythematous patches that may form large, hyperpigmented rings with central clearing.

Pathophysiology

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.

Frequency

International

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.

Mortality/Morbidity

Most cases of granuloma annulare resolve without adverse medical sequelae.

Sex

Women are affected by granuloma annulare twice as often as men.

Age

• 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.

Clinical

History

• 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.

Physical

• 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.

Causes

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,⁵ and calcium channel blockers.

Relationship to systemic diseases

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.⁶

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.⁷

Relationship with malignant diseases

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:

• Non-Hodgkin lymphoma
• Hodgkin lymphoma
• Acute myelogenous leukemia
• Chronic lymphocytic leukemia
• Myelomonocytic leukemia
• Large granular lymphocytic leukemia
• Myelodysplastic syndrome
• T-cell lymphoma
• Follicular lymphoma
• Lennert lymphoma
• Solid tumors:  
  • Breast tumors
  • Cervical cancer
  • Colon cancer
  • Lung cancer
  • Prostate cancer
  • Testicular tumors
  • Thyroid cancer

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