Granuloma Annulare Clinical Presentation

• 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,^[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