Granuloma Annulare

Granuloma annulare is an idiopathic, palisaded, granulomatous condition that is frequently encountered by dermatopathologists. It occurs most commonly in children and young adults but may affect all age groups. Females are affected somewhat more commonly than males. The lesions of granuloma annulare consist of small, firm, asymptomatic papules that are flesh colored or pale red and are often grouped in an annular or circinate fashion . There usually are several lesions, but there may be just one, or there may be many. The lesions are found most commonly on the arms, hands, legs, and feet. The trunk may also be involved, and rare sites of involvement include the palms, penis, ear, and periocular regions . Although chronic, the lesions usually subside after a number of years. Unusual variants of granuloma annulare include  a generalized form,

consisting of hundreds of papules that are either discrete or confluent but only rarely show an annular arrangement  perforating granuloma annulare, with umbilicated lesions occurring usually in a localized distribution  and, rarely, in a generalized distribution  erythematous or patch granuloma annulare, showing large, slightly infiltrated erythematous patches, with a palpable border, on which scattered papules may subsequently arise , and (d) subcutaneous/deep granuloma annulare, in which subcutaneous nodules occur, especially in children, either alone or in association with intradermal lesions . The subcutaneous nodules have a clinical appearance similar to that of rheumatoid nodules, although there is no history of arthritis, and there is a greater tendency to occur on the legs, feet, and, occasionally, the head

. In adults, similar lesions may be found near the small joints of the hands . A very rare, deep, destructive form of granuloma annulare has also been described .

A correlation between generalized papular granuloma annulare and diabetes mellitus has been observed by several authors . Granuloma annulare has been reported in at least 60 patients with HIV or AIDS, with a greater incidence of generalized disease in this population . Granuloma annulare-like lesions have also been reported to develop at sites of resolved herpes zoster  and occasionally in association with tattoos , necrobiosis lipoidica , and sarcoidosis .

Histopathology.

Histologically, granuloma annulare shows an infiltrate of histiocytes and a perivascular infiltrate of lymphocytes that is usually sparse. The histiocytes may be present in an interstitial pattern without apparent organization or in palisades surrounding areas with prominent mucin .Patterns between these two extremes occur, and typically a single biopsy will show histiocytes that are not palisaded, are slightly palisaded, and are well palisaded. Although degenerated collagen or small quantities of fibrin may be present , increased mucin is the hallmark of granuloma annulare. Increased mucin is almost always apparent on routinely stained sections as faint blue material with a stringy, finely granular appearance. Stains such as colloidal iron and Alcian blue can be used to highlight mucin if it is not clearly apparent. Occasionally, sections will not reveal increased mucin, particularly those lacking a palisaded arrangement of histiocytes. In biopsies with well-developed palisades, the central mucinous area is commonly accompanied by a few nuclear fragments or neutrophils. Plasma cells are present rarely. A sparse infiltrate of eosinophils is seen in approximately half of cases, and occasional biopsies show abundant eosinophils . Multinucleated histiocytes are present more often than not, but they are usually few and often subtle. They can occasionally be seen to have engulfed short, thick, blue-gray elastic fibers . The histiocytic infiltrate is usually present throughout the full thickness of the dermis or the middle and upper dermis, but occasionally just the superficial or the deep dermis is involved . Mitotic figures are usually rare (fewer than 1 per 10 high-power fields) but may be as frequent as 7 per 10 high­power fields in rare examples .

Rare examples of granuloma annulare show aggregates of epithelioid histiocytes, usually with some giant cells and a rim of lymphoid cells, which resemble the granulomas of sarcoidosis . These usually differ from sarcoidal granulomas, however, by showing poorer circumscription and by lacking asteroid bodies. Vascular changes in granuloma annulare are variable but generally inconspicuous . In some instances, however, there are fibrinoid deposits in vessel walls and occlusion of vascular lumina .

Among the variants of granuloma annulare mentioned, the usual histologic picture of palisaded and interstitial pattern is found in the generalized form . An interstitial pattern predominates in the erythematous and patch variants .

In perforating granuloma annulare, at least part of the palisading granulomatous process is located superficially and is associated with disruption of the epidermis

The subcutaneous nodules of deep granuloma annulare usually show large histiocytic palisades surrounding mucin and degenerated collagen . These central, degenerated foci exhibit a pale appearance ; however, examples in which mucin was not apparent or in which the central area appeared more fibrinoid have also been reported . Thus, subcutaneous granuloma annulare may be histologically indistinguishable from rheumatoid nodule, an appearance that has led to the term pseudorheumatoid nodule.

Pathogenesis.

 The cause of granuloma annulare is unknown. Possible precipitating events in small subsets of patients have included insect bites, warts, erythema multiforme, herpes zoster, exposure to sunlight, hepatitis B vaccine, andtuberculin skin tests . There is likely an increased incidence and increased disease severity in patients with diabetes mellitus. Thrombi or vasculitic changes have been noted in some examples, and it is possible that what we term granuloma annulare may represent a variety of disease processes.

Electron microscopic examination reveals degeneration of both collagen and elastic fibers in granuloma annulare . The macrophages (histiocytes) show a high content of primary Iysosomes and considerable cytoplasmic activity with release of lysosomal enzymes into the extracellular space . Synthesis of types I and III collagen also occurs, probably as a reparative response . A cell-mediated immune response also appears to be involved, marked by prominent activated helper T cells . One immunoperoxidase study of the histiocytic population showed staining for lysozyme but not for other macrophage markers such as HAM 56 or CD­6B . Another demonstrated positivity for these two markers .

Differential Diagnosis. Granuloma annulare and necrobiosis lipoidica may resemble one another histologically.

Although much has been written about the difficulty of separating these disorders histologically (43), the distinction can be easily accomplished clinically in most circumstances (58). Furthermore, although it is true that histologic distinction may be impossible, usually it can be accomplished by using the following criteria: (a) Although either disease may involve the dermis diffusely, necrobiosis lipoidica rarely involves just one focus of the dermis or predominantly the upper half of the dermis, whereas granuloma annulare often does. (b) Histiocytes in palisades that completely encircle altered connective tissue are more common in granuloma annulare, whereas histiocytes in linear array that are horizontally oriented in a somewhat tiered fashion are more typical of necrobiosis lipoidica. (c) Abundant mucin is typical of granuloma annulare and distinctly uncommon in necrobiosis lipoidica. (d) Necrobiosis lipoidica often shows dermal sclerosis and thickened subcutaneous septa, whereas granuloma annulare does not (the sclerosis often produces a straight edge to the sides of a punch biopsy, in contrast to the inward retraction and/or more irregular edge seen in biopsies without sclerosis). Other features that are more characteristic of necrobiosis lipoidica include the presence of a larger number of giant cells, prominent deep dermal plasma cells, and more pronounced vascular changes, including thickened blood vessel walls. Furthermore, necrobiosis lipoidica is more likely to show extensive deposits of lipids or nodular lymphocytic infiltrates in the deep dermis or subcutis (59), although neither feature is commonly seen.

The interstitial type of granuloma annulare, in which palisades of histiocytes are not well developed, is less likely to be confused with necrobiosis lipoidica. This pattern is more likely to be mistaken for a process that can also show a superficial and deep lymphocytic infiltrate, such as the inflammatory stage of morphea, but the subtle presence of histiocytes in an interstitial pattern usually allows a definitive diagnosis of granuloma annulare. Mycosis fungoides can have a granulomatous infiltrate with a granuloma annulare-like pattern (60,61). Such examples of this cutaneous T-cell lymphoma can usually be recognized by the presence of at least some intraepidermal lymphocytes, a dermal lymphocytic infiltrate that is more dense around the superficial plexus than the deep one, and/or a lichenoid component to the infiltrate. The interstitial type of granuloma annulare may also resemble a xanthoma. Distinction is usually possible because in granuloma annulare a foamy appearance to the histiocytes is either completely lacking or very subtle; in xanthoma, at least some of the histiocytes are obviously foamy. In addition, granuloma annulare tends to show an obvious perivascular lymphocytic infiltrate, whereas most xanthomas do not (62). Drug reactions may also mimic granuloma annulare, but these usually show interface changes that allow for their distinction (63). Rarely, infection with Mycobacterium marinum may have few neutrophils and may produce a histologic picture resembling interstitial granuloma annulare (64).

Differentiation of subcutaneous granuloma annulare from a rheumatoid nodule is not always possible on histologic grounds, but subcutaneous granuloma annulare is more likely than rheumatoid nodule to show prominent mucin and less likely to show foreign-body giant cells or prominent stromal fibrosis (45).