Granuloma annulare: Epidemiology, clinical manifestations, and diagnosis

INTRODUCTION — Granuloma annulare (GA) is an often self-limited disorder that can affect both children and adults. Localized GA, which classically presents as an erythematous or skin-colored, annular plaque without scale, is the most common form of GA (picture 1A-F). The generalized form of GA, which accounts for approximately 15 percent of cases, typically presents with numerous papules and plaques on the trunk and extremities (picture 2A-G). Less common forms of GA include subcutaneous, perforating, and patch variants. Many cases of GA resolve spontaneously within a few years. (See "Granuloma annulare: Management", section on 'Prognosis'.)

The epidemiology, pathogenesis, clinical manifestations, and diagnosis of GA will be reviewed here. The management and prognosis of GA is discussed separately.

●(See "Granuloma annulare: Management".)

EPIDEMIOLOGY — The exact prevalence of GA is unknown. In a United States, cross-sectional study that analyzed patient data from a medical claims database obtained from 2017 to 2018, the annualized incidence and prevalence of GA were 0.04 percent (38 per 100,000) and 0.06 percent (58 per 100,000), respectively [1].

Localized GA is considered the most common form of GA, with generalized GA as the second most common variant. In one retrospective study of 407 patients with GA, 303 had localized GA and 104 had generalized GA [2]. Localized and generalized GA occur in both adults and children [2-4]. Generalized GA appears to occur more frequently in adults than in children [2,3].

Subcutaneous GA, patch GA, and perforating GA are less common presentations. Subcutaneous GA is most common in children, while the patch type has primarily been reported in adults [5]. Perforating GA is a rare variant that may occur in both adults and children [6,7].

In general, females appear to be at increased risk for GA [1-3]. A cross-sectional study from the United States found a female-to-male prevalence ratio of 3:1 [1]. A retrospective study of 100 patients with generalized GA suggests there may be differences related to clinical presentation; the female-to-male ratio was 2.9:1 among patients with predominantly annular lesions and 1.4:1 among patients with generalized, papular GA [3].

PATHOGENESIS — The cause of GA is unknown. A variety of potential inciting factors have been reported, including drug exposure [8], viral infections [9-11], herpes zoster-related scarring [12-16], trauma, insect bites, tuberculin skin testing, vaccinations [17], sun exposure, and subcutaneous immunotherapy for allergic disease [18]. A causative relationship between these factors and GA has not been confirmed. (See 'Drug exposure' below.)

It is uncertain whether genetic factors influence susceptibility to GA. Familial cases have been documented, but studies investigating associations of the disease with human leukocyte antigen (HLA) genes have yielded inconsistent results [19,20]. Increased frequency of HLA-B35 in patients with generalized GA has been reported [21,22].

The histopathologic findings in GA may offer clues to the pathogenesis of this disorder. A dermal, lymphohistiocytic infiltrate and degenerated collagen are typical histopathologic findings [23]. A delayed-type hypersensitivity reaction, in which T helper type 1 (Th1) lymphocytes stimulate macrophages to express proinflammatory cytokines and collagen-degrading enzymes, may play a role [24]. Injury to dermal elastic fibers has also been proposed as an inciting factor [25]. Vasculitis does not appear to be a prominent feature in GA, suggesting immune-mediated vasculitis is not involved [23].

CLINICAL FEATURES — GA can present with a variety of clinical findings. Shared histopathologic features support the classification of these clinical variants into a single disorder.

Localized granuloma annulare — As the most common form of GA, localized GA classically presents as an asymptomatic, erythematous or skin-colored, annular or arciform plaque with a moderately firm, rope-like border and central clearing (picture 1A-F). Discrete, 1 to 2 mm papules may be noted at the periphery of lesions that have not developed a continuous border. In a minority of cases, papules may also be present centrally (picture 3). In patients with moderately to highly pigmented skin, lesions of GA may also exhibit hypopigmentation or hyperpigmentation (picture 1D).

Lesions of localized GA typically grow slowly in a centrifugal pattern; most lesions are less than 5 cm in size [7]. Infrequently, localized GA may also present as clusters of small papules without an annular or arcuate configuration (picture 4).

The most frequent locations for localized GA are the wrists, ankles, dorsal hands, and dorsal feet. Involvement of the palms is rare [26]. The presence of multiple lesions is common.

Generalized granuloma annulare — Generalized GA presents with widespread, erythematous or skin-colored papules and plaques, ranging from millimeters to a few centimeters in diameter (picture 2A-G). Annular plaques are present in up to two-thirds of patients [3,4]. In patients with moderately to highly pigmented skin, lesions of GA may also exhibit hypopigmentation or hyperpigmentation.

The trunk and extremities are prominent sites of involvement in generalized GA, while the head, neck, palms, soles, and mucous membranes are generally spared. Involved skin may be asymptomatic or pruritic.

Subcutaneous granuloma annulare — Single or multiple, deep dermal or subcutaneous, painless nodules on the scalp or extremities are the hallmark of subcutaneous GA (picture 5). The skin overlying the nodules appears normal. Lesions of subcutaneous GA are usually less than 4 cm in size and are most commonly located on the anterior lower legs, hands, head, and buttocks of children [27,28].

Perforating granuloma annulare — Perforating GA is a variant in which damaged collagen from the dermis is extruded onto the skin surface. This variant, which is most commonly seen in children and young adults, is characterized by asymptomatic, erythematous or skin-colored papules that evolve into umbilicated papules that discharge clear or white fluid [6]. Some lesions may resemble pustules. Perforating GA may be localized (usually on the extremities) or widespread [7,29-31]. Pruritus or pain is present in a minority of patients. Lesions heal with scarring.

Patch granuloma annulare — Patients with the patch type of GA present with annular or nonannular patches without scale (picture 6) [5,32,33]. The patches may be localized or generalized and commonly involve the proximal extremities.

Other variants — In addition to the established variants, GA has been reported to occur with other presentations:

●Papular, umbilicated granuloma annulare – Papular, umbilicated GA is a rare variant reported to occur in children. The cutaneous findings include skin-colored or erythematous, umbilicated papules on the extensor surfaces [34-36].

●Linear granuloma annulare – Linear presentations of GA have been documented in a few patients (picture 7) [37-39]. In one patient, the lesion appeared following venectomy [37].

●Acute, painful, acral granuloma annulare – Acute, painful, erythematous papules or plaques on the hands and feet with histopathologic findings consistent with GA have been reported [40]. Arthralgias accompanied symptoms in some patients.

POTENTIAL ASSOCIATIONS

Diabetes mellitus — There are data suggesting a relationship between GA and diabetes mellitus. Additional study is necessary to confirm an association.

Examples of studies supporting an association include:

●A retrospective study of 557 patients with GA found a higher incidence of insulin-dependent diabetes than expected when compared with data from an age-matched population (16 actual cases versus 0.9 expected cases) [41].

●A retrospective, cohort study of 5137 patients with a diagnosis of GA and over 51,000 control patients from a commercial claims database in the United States supports an association between diabetes and GA. Patients with GA were more likely to have diabetes than patients in the control group (21 versus 13 percent, adjusted odds ratio 1.67, 95% CI 1.55-1.80) [42].

The strength and type of an association with diabetes may vary based upon the clinical presentation. A retrospective study reported a higher incidence of diabetes (type unspecified) among 100 patients with generalized GA than among 1350 patients with localized GA (21 versus 10 percent had diabetes) [3]. In addition, a retrospective study of 84 patients with GA suggests an association between the course of GA and diabetes; patients with diabetes (n = 10) appeared to have more chronic, relapsing courses of disease [43].

Dyslipidemia — GA may be associated with dyslipidemia. A retrospective, cohort study that included data from 5137 individuals with a recorded diagnosis of GA and over 51,000 controls supports an association between GA and hyperlipidemia. Patients with GA were more likely to have hyperlipidemia (33 versus 28 percent, adjusted odds ratio 1.15, 95% CI 1.08-1.23). Moreover, in a case-control study of 140 adults with idiopathic GA and 420 controls, dyslipidemia was more prevalent among adults with GA (79 versus 52 percent, adjusted odds ratio 4.04, 95% CI 2.53-6.46) [44]. The highest rates of dyslipidemia were seen with generalized GA (all of 23 patients) and GA with annular lesions (65 of 76 patients [86 percent]).

The rationale for an association between GA and dyslipidemia is unclear. Theories on the mechanism of the association include the possibility of an effect of chronic inflammation related to GA on the development of lipid abnormalities and the possibility that microvascular inflammation and dysfunction due to dyslipidemia contribute to GA [44]. Additional studies on the relationship between GA and dyslipidemia are needed.

Drug exposure — A wide variety of drug exposures have been linked to the development of GA [8]. Examples of reported associations include allopurinol, amlodipine, diclofenac, gold, levetiracetam, intranasal calcitonin, paroxetine, secukinumab, thalidomide, topiramate, tumor necrosis factor (TNF)-alpha inhibitors, and tocilizumab [45-53].

Malignancy — Although there are reports of GA occurring in patients with malignancy, particularly in patients with atypical presentations of GA, a relationship between GA and malignancy has not been proven [54,55]. Retrospective analyses of data from a claims database that included 5137 patients with GA and over 51,000 matched controls in the United States did not find an increased risk for solid organ or hematologic malignancy among patients with GA [42,56]. Other studies also suggest that patients with GA may not have increased risk for malignancy [3,54,57].

Some cases of GA that have been associated with malignancy may have been cases of interstitial granulomatous dermatitis (IGD) that were misdiagnosed. IGD can clinically and histologically resemble GA and has been associated with the development of malignancy [58]. (See "Neutrophilic dermatoses", section on 'Palisaded neutrophilic granulomatous dermatitis and interstitial granulomatous dermatitis'.)

Other — Retrospective studies and case reports have linked GA to thyroid disease [42,59-62]. There have also been multiple reports of GA in the setting of HIV infection [63-66]. In a series of 34 patients with both HIV and GA, the generalized variant of GA was most common, occurring in approximately 60 percent of patients [63].

HISTOPATHOLOGY

●General features – A lymphohistiocytic infiltrate, degeneration of collagen, and mucin deposition are characteristic histopathologic features of GA; these findings often present in an interstitial or palisaded pattern [23,67]. Mucin deposition can be highlighted with Alcian blue or colloidal iron stains:

•Interstitial pattern – The interstitial pattern is characterized by histiocytes embedded in basophilic mucin infiltrating between collagen bundles in the mid to upper dermis [68]. Incomplete degeneration of collagen fibers is present (picture 8).

•Palisading pattern – The palisading pattern is characterized by lymphohistiocytic, inflammatory infiltrates that palisade around foci of collagen and elastin degeneration in the mid to upper dermis [68]. Areas of collagen degeneration appear as eosinophilic, fibrillar material separated by basophilic mucin deposits (picture 9A-C). Eosinophils may also be present.

Rarely, epithelioid, histiocytic nodules resembling findings in sarcoidosis can be seen in GA. (See "Cutaneous manifestations of sarcoidosis".)

The interstitial pattern can be subtle and challenging to diagnose. Staining for CD163, a histiocyte marker, has been suggested as a method to help with distinguishing the interstitial pattern of GA from other entities. In a series of 69 cases of GA demonstrating an interstitial pattern, strong staining for CD163 in small mononuclear cells was demonstrated in all cases [69].

●Features of specific variants – Both the interstitial and palisading patterns can occur in localized and generalized GA. The interstitial pattern is typically associated with patch type GA. Subcutaneous GA frequently presents with large, histiocytic palisades surrounding degenerated collagen and mucin in the connective tissue septae within the subcutis [28]. Perforating GA shows transepidermal elimination of mucinous, degenerating collagen fibers surrounded by palisading, lymphohistiocytic granulomas (picture 10) [6].

●Features suggestive of other disorders – Necrobiosis lipoidica diabeticorum and rheumatoid nodules can present with histopathologic features similar to the palisading, necrobiotic granulomas of GA.

Histopathologic features that can assist with distinguishing these disorders from GA include:

•Necrobiosis lipoidica diabeticorum – Broad areas of necrobiosis that sometimes extend into the subcutis are present within the superficial and deep dermis (picture 11). Lipid deposits are visible within areas of necrobiosis, and mucin deposition is absent. (See "Necrobiosis lipoidica".)

•Rheumatoid nodules – Rheumatoid nodules are difficult to distinguish from GA histopathologically. Sharp, irregular areas of necrobiosis are present within the subcutis and deep reticular dermis. Acute or chronic endoarteritis adjacent to the necrobiotic foci is evident in some cases. Unlike GA, mucin is usually absent. (See "Rheumatoid nodules".)

DIAGNOSIS — The approach to diagnosis differs based upon the clinical presentation:

●Clinical assessment – Recognition of the classic clinical features of localized GA is usually sufficient for diagnosis. The presence of an asymptomatic, erythematous or skin-colored, annular or arcuate plaque with peripheral papules, central clearing, and absent scale is characteristic of localized GA. Performance of a potassium hydroxide (KOH) preparation to rule out tinea corporis is helpful when the differential diagnosis includes tinea corporis. A skin biopsy is helpful for atypical presentations or other scenarios in which the diagnosis is in question. (See 'Differential diagnosis' below and "Office-based dermatologic diagnostic procedures", section on 'Potassium hydroxide preparation'.)

Clinicians experienced with the diagnosis of subcutaneous GA may be able to make the diagnosis based upon clinical examination. However, the lack of overlying cutaneous changes can make a clinical diagnosis of subcutaneous GA difficult. A biopsy should be performed when the diagnosis is in question.

Given the variable lesion morphology and overlap with other skin conditions, a skin biopsy is often necessary to confirm a diagnosis of generalized, patch, or perforating GA.

●Skin biopsy – Skin biopsies are performed to confirm the diagnosis and rule out other disorders. In patients with suspected localized, generalized, patch, or perforating GA, a 4 mm punch biopsy is sufficient. Performance of more than one punch biopsy may be helpful in the presence of multiple lesion morphologies. An incisional biopsy is preferred for the histopathologic assessment of suspected subcutaneous GA. (See "Skin biopsy techniques", section on 'Biopsy techniques'.)

ADDITIONAL TESTS — Additional testing is based upon potential associations between GA and dyslipidemia, HIV infection, and malignancy. Given that relationships with GA have not been confirmed, we take a conservative approach to additional testing. (See 'Potential associations' above.)

Our typical approach for adults with GA consists of:

●Lipid profile. (See "Screening for lipid disorders in adults", section on 'Choice of tests'.)

●Performance of a review of systems to identify patients with signs or symptoms of diabetes mellitus, and subsequent testing for diabetes mellitus, if indicated. (See "Screening for type 2 diabetes mellitus", section on 'Screening tests'.)

●Performance of a history and review of systems to identify patients with risk factors or symptoms suggestive of HIV infection, and subsequent HIV testing, if indicated. (See "The natural history and clinical features of HIV infection in adults and adolescents" and "Screening and diagnostic testing for HIV infection", section on 'Testing algorithm'.)

●Completion of age-appropriate cancer screening for older adults is always appropriate. For adults up-to-date on age-appropriate screening, no additional work-up for malignancy is generally required in the absence of suggestive signs or symptoms. (See "Overview of preventive care in adults", section on 'Cancer screening'.)

We do not routinely screen children with GA for other diseases.

DIFFERENTIAL DIAGNOSIS — A variety of other skin conditions may mimic the clinical findings in GA. The differential diagnosis differs based upon the clinical presentation.

Annular lesions — Annular lesions similar to those seen in localized or generalized GA may also occur in other disorders (see "Approach to the patient with annular skin lesions"):

●Tinea corporis – Tinea corporis typically presents as an annular plaque with peripheral scale. Absence of scale is a key feature of GA that distinguishes it from tinea corporis on clinical examination (picture 12). A potassium hydroxide (KOH) preparation or fungal culture can be used to confirm tinea infection. (See "Dermatophyte (tinea) infections", section on 'Tinea corporis'.)

●Annular lichen planus – The detection of characteristic violaceous, polygonal, pruritic papules at the periphery of annular lesions of lichen planus can help to distinguish this disorder from GA. Rounded, erythematous, nonpruritic papules are more consistent with GA. The penis and scrotum are common sites of involvement in annular lichen planus (picture 13A-B). (See "Lichen planus".)

●Cutaneous sarcoidosis – Sarcoidosis may present with widespread, skin-colored papules and annular plaques (picture 14). Histopathology revealing naked granulomas will distinguish sarcoidosis from GA. (See "Cutaneous manifestations of sarcoidosis".)

●Annular elastolytic giant cell granuloma (actinic granuloma) – Lesions of annular elastolytic giant cell granuloma (AEGCG) appear as annular, erythematous patches on sun-exposed skin (picture 15A-B). A biopsy of AEGCG reveals giant cells phagocytizing elastic fibers in the dermis; necrobiosis and palisading granulomas may be present. Loss and fragmentation of elastic fibers in the dermis and the absence of mucin are characteristic histopathologic features that distinguish this disorder from GA.

●Erythema annulare centrifugum – Superficial or deep erythema annulare centrifugum (EAC) usually presents with multiple annular, erythematous plaques (picture 16A-B). The characteristic rim of scale along the inner margin of the lesion that occurs in superficial EAC ("trailing scale") is not present in GA. However, scale is often absent in deep EAC. Histopathologic findings distinguish this disorder from GA; a distinctive, dense, lymphocytic infiltrate surrounding blood vessels is present in EAC.

●Interstitial granulomatous dermatitis – Interstitial granulomatous dermatitis (IGD) has been associated with autoimmune disease, malignancy, and medications. This disorder often presents with erythematous, annular plaques favoring the lateral trunk and skin folds (picture 17). Like GA, degenerated collagen and palisading histiocytes are histopathologic features of IGD. The presence of neutrophils and an absence of mucin are useful for distinguishing this disorder from GA. (See "Neutrophilic dermatoses", section on 'Palisaded neutrophilic granulomatous dermatitis and interstitial granulomatous dermatitis'.)

●Nodular tertiary syphilis – Rarely, cutaneous tertiary syphilis may present as annular plaques [70]. Plasma cells and granulomas on biopsy suggest this diagnosis. (See "Syphilis: Treatment and monitoring".)

Other lesions — A variety of cutaneous diseases may resemble the other manifestations of GA. Biopsy is often helpful for distinguishing GA from these disorders.

Lesions of generalized, papular GA may resemble:

●Secondary syphilis (picture 18) (see "Syphilis: Epidemiology, pathophysiology, and clinical manifestations in patients without HIV", section on 'Clinical manifestations')

●Id (autoeczematous) reactions (see "Dermatophyte (tinea) infections", section on 'Id reactions')

●Arthropod bites (see "Insect and other arthropod bites", section on 'Types of reactions')

●Eruptive xanthomas (picture 19A-B) (see "Cutaneous xanthomas", section on 'Eruptive xanthomas')

●Eruptive histiocytomas

●Eruptive syringomas (picture 20A-B) (see "Cutaneous adnexal tumors", section on 'Syringoma')

Subcutaneous GA has a broad clinical differential diagnosis, including:

●Rheumatoid nodules (histopathology may closely resemble GA) (picture 21) (see "Rheumatoid nodules")

●Epithelioid sarcoma (see "Clinical presentation, histopathology, diagnostic evaluation, and staging of soft tissue sarcoma", section on 'Introduction')

●Subcutaneous sarcoidosis (see "Cutaneous manifestations of sarcoidosis", section on 'Subcutaneous sarcoidosis')

●Deep fungal or bacterial infections

Perforating GA may mimic other disorders in which dermal contents are eliminated through the epidermis. Examples include:

●Perforating dermatoses, including reactive perforating collagenosis, perforating folliculitis (picture 22A-B), and elastosis perforans serpiginosa (picture 23) (see "Perforating dermatoses")

●Perforating cutaneous sarcoidosis (histopathologic features may closely resemble GA) [6] (see "Cutaneous manifestations of sarcoidosis", section on 'Perforating sarcoidosis')

The umbilicated shape and white, central core noted in some lesions of molluscum contagiosum may also resemble perforating GA (picture 24). (See "Molluscum contagiosum", section on 'Clinical features'.)

Patch GA may resemble parapsoriasis, which presents with large, erythematous patches on the trunk and proximal extremities (picture 25) [33]. Fine scale, when present, suggests a diagnosis of parapsoriasis. Biopsy confirms the diagnosis. (See "Parapsoriasis (small plaque and large plaque parapsoriasis)".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topic (see "Patient education: Granuloma annulare (The Basics)")

SUMMARY AND RECOMMENDATIONS

●Overview – Granuloma annulare (GA) is a benign, cutaneous, granulomatous disorder with multiple clinical variants that share histopathologic features. Multiple factors have been proposed to contribute to the development of GA; however, the pathogenesis of GA is unknown. (See 'Epidemiology' above and 'Pathogenesis' above.)

●Clinical features:

•Localized granuloma annulare – Localized GA is the most common variant of GA. The classic presentation is an asymptomatic, erythematous or skin-colored, annular or arcuate plaque with a moderately firm, rope-like border and central clearing (picture 1A-F). Scale is absent. The wrists, ankles, dorsal hands, and dorsal feet are among the most common sites for localized GA. Affected patients may have more than one lesion. (See 'Localized granuloma annulare' above.)

•Generalized granuloma annulare – Generalized GA is the second most common variant of GA. Characteristic features include widespread, erythematous or skin-colored papules and plaques (picture 2A-G). Annular plaques are common. The trunk and extremities are typical sites of involvement. The head, neck, palms, soles, and mucous membranes are generally spared. Pruritus may be present. (See 'Generalized granuloma annulare' above.)

•Other variants – Examples of other variants of GA include subcutaneous, perforating, and patch GA:

-Subcutaneous GA typically presents as single or multiple painless, subcutaneous nodules (picture 5). The most common sites of involvement are the scalp and extremities. (See 'Subcutaneous granuloma annulare' above.)

-Perforating GA typically presents with asymptomatic, erythematous papules that evolve into umbilicated papules that discharge clear or white fluid. Pruritus or pain may be present. Lesions typically heal with scarring. (See 'Perforating granuloma annulare' above.)

-Patch GA typically presents with annular or nonannular patches without scale (picture 6). The patches commonly occur on the proximal extremities. (See 'Patch granuloma annulare' above.)

●Potential associations – Conditions proposed to occur in association with GA include diabetes mellitus, dyslipidemia, exposure to certain drugs, and malignancy. Additional study is necessary to confirm associations between GA and these disorders and to confirm appropriate indications for screening. (See 'Potential associations' above.)

●Diagnosis – The diagnostic approach to GA is based upon the clinical presentation. Localized GA can often be diagnosed based solely on the physical examination. A skin biopsy is often helpful for the diagnosis of other variants of GA. Characteristic histopathologic findings include a lymphohistiocytic infiltrate, degeneration of collagen, and mucin deposition in an interstitial or palisaded pattern. (See 'Diagnosis' above.)