Table of Contents   This Chapter   All Chapters

GRANULOMATOUS REACTIONS

The granulomatous reaction Granulomatous disorders (Table 11.3)are a difficult diagnostic and therapeutic problem. Many granulomatous lesions are clinically non- specific and pathologically similar. Additionally, some disorders that may cause granulomas in some patients more commonly occur in a non-granulomatous form (e.g. rosacea). A useful clinical clue to a granulomatous process is the brownish ‘apple jelly’ color that can be seen when blood is compressed out of the skin by diascopy.

       Granulomas are formed due to chronic antigen exposure, either due to slow release of antigen or slow degradation of poorly soluble antigens.

        The reaction is characterized by the presence of tissue macrophages (histiocytes) and multinucleated giant cells, which usually group together as intradermal nodules. Depending on the causative process, there may be associated vasculitis (e.g. Wegener granulomatosis), suppuration (e.g. deep fungal infections), necrosis (e.g. tuberculosis), collagen damage known as necrobiosis (e.g. granuloma annulare), or none of these (e.g. sarcoidosis, Crohn disease, and foreign body granuloma). Some disorders may have variable histologic features; for example, some foreign body reactions are necrobiotic, vasculitis has been reported in granulomas of Crohn disease, and so on.

Table 11.3 CAUSES OF GRANULOMATOUS TISSUE REACTIONS

Process	Comments
Sarcoidosis	See text, this chapter
Granuloma annulare	See text, this chapter and Chapter.12
Necrobiosis lipoidica	See Chapter.12
Annular elastolytic giant cell granuloma (Miescher granuloma)	See text, this chapter
Granulomas associated with rheumatologic and collagen vascular disease	Rheumatoid nodules, multicentric reticulohistiocytosis, interstitial granulomatous dermatitis (see Ch.13)
Granulomas associated with vasculitis	Wegener granulomatosis, Churg–Strauss disease, granuloma faciale (see Ch.14)
Granulomas due to infections	Mycobacterial infection (tuberculosis, atypical mycobacteria such as fish tank granuloma, leprosy), deep fungal infections (includes candidal granuloma, Majocchi granuloma, sporotrichosis, blastomycosis, coccidiodomycosis, others), secondary syphilis, granuloma inguinale (donovanosis), leishmaniasis, histoplasmosis, protothecosis
Crohn disease, orofacial granulomatosis	See Chapter.12
Granulomas due to foreign material or keratin	Foreign body granuloma, ruptured epidermoid cyst or follicular rupture (see text, this chapter)
Neoplastic and histiocytoses	Granulomatous slack skin (mycosis fungoides variant), lymphomatoid granulomatosis, necrobiotic xanthogranuloma, eosinophilic granuloma
Miscellaneous	Granulomatous rosacea, tuberculides (see text, this chapter), chronic granulomatous disease, focal Miescher granulomas in erythema nodosum, granuloma gluteale infantum

       Some of these granulomas are illustrated without further discussion, for example rheumatoid nodules (Fig. 11.17), which rarely present to dermatologists unless they occur at unusual sites. Granulomatous vasculitis is discussed in Chapter.14 and Crohn disease and necrobiosis lipoidica are described in Chapter 12; otherwise the more important medical causes of cutaneous granulomas are discussed further here.

Fig. 11.17 A rheumatoid nodule at a typical site on the elbow. Most such lesions occur in patients with well-documented rheumatoid disease, but smaller nodules or those at unusual sites may cause diagnostic problems. Multiple tiny rheumatoid nodules sometimes occur in association with vasculitis.

       Note that the term granuloma is also applied to some lesions that do not have typical granulomatous histology, such as pyogenic granuloma (a benign vascular proliferation) and lethal midline granuloma (now termed nasal NK/T-cell lymphoma), or in which a granulomatous component is either minor or inconsistent, such as granuloma fissuratum (due to friction on the ear from spectacles) or granuloma faciale (a low-grade chronic vasculitis). These are not discussed here.

Granuloma annulare

Etiology and pathogenesis

Granuloma annulare (GA) is a relatively common disorder that has several morphologic variants. Some of these have an association with diabetes mellitus and are discussed in Chapter.12, but this is not now felt to apply to ordinary lesions of GA. Trauma may be involved in the pathogenesis, as lesions are often over bony prominences. Rarely, GA is recurrent on a seasonal basis (spring or summer). Pathologically, GA lesions occur in the mid-dermis and demonstrate necrobiosis (literally, death and life) of collagen, with mucin deposits between the damaged collagen and a surrounding infiltrate of lymphocytes and histiocytes.

Fig. 11.18 Typical annular lesions of granuloma annulare, the appearance being that of multiple semiconfluent papules forming the annular border. Both lesions were also typical in being situated near bony prominences, (a) over the ulna at the elbow and (b) over the knuckles.

Fig. 11.19 Granuloma annulare on the dorsum of the hand, also a common site (in this case in a child). The morphology of the border of the lesion is characteristic.

Clinical

Lesions are most common over bony prominences such as knuckles, elbows, and the dorsum of fingers. The initial lesion is a firm, pink, yellowish, or skin-colored plaque, which gradually expands radially, and has the appearance of coalesced papules producing a cobblestoned morphology (Fig. 11.18 – 11.24). About 50% of GA lesions resolve within 2 years, gradually flattening with some residual purplish staining. In the generalized form, the papules are usually much smaller, but more extensive sheets of superficial GA occur.

       The perforating variety is discussed in Chapter.12. Deep GA presents as a non-specific firm subcutaneous nodule or plaque.

Differential diagnosis

This varies according to the site and pattern.

Fig. 11.20 Granuloma annulare on the foot, again being situated over a bony prominence but showing a more nodular (and less easily diagnosed) morphology.

Fig. 11.21 Multiple small lesions of granuloma annulare is an uncommon pattern.

Fig. 11.22 A small proportion of patients with granuloma annulare describe photoaggravation, as in this case. The lesions are a more extensive sheet of granulomatous appearance.

Fig. 11.23 A characteristic, but often unrecognized, site for granuloma annulare is the antihelix of the ear, as shown here. This variant may occur in isolation, or there may be lesions at other sites. There are usually multiple lesions, and both ears are usually affected (although not necessarily to the same extent).

Fig. 11.24 Resolving lesions of granuloma annulare are often brown or violaceous, and have a flatter border. These seem to cause undue diagnostic confusion, and are often erroneously treated as ringworm infection.

Often, no treatment is required. During the early expanding phase, there may be erythema and itch, in which case topical corticosteroids can be useful. Photochemotherapy (PUVA) can be used, usually for those with more extensive lesions.

Annular elastolytic giant cell granuloma

Annular elastolytic giant cell granuloma (AEGCG) may be a granulomatous reaction to damaged elastic fibers (Fig. 11.25). It occurs in sun-damaged skin and, using appropriate histologic stains, fragments of elastic tissue can be seen within macrophages and giant cells. Like those of GA, lesions are typically annular, but often more serpiginous and without the cobblestoned character of GA. The two disorders are very similar histologically.

Fig. 11.25 Annular elastolytic giant cell granuloma. This entity is felt by some authors to be a variant of granuloma annulare (both have some elastic tissue damage and elastin within tissue macrophages), and by others to be a type of solar damage (lesions occur in sun-exposed skin and resemble O’Brien actinic granuloma). Annular and arciform lesions are typical.

Sarcoidosis

Etiology and pathogenesis

The etiology is uncertain. Some evidence suggests an infective cause, combined with an abnormal degree of humoral and cell-mediated immune response. Polyclonal hypergammaglobulinemia is common in chronic sarcoidosis, and there is an association with a variety of autoimmune disorders and with Sjögren syndrome.

Clinical features and variants

Sarcoid skin lesions are extremely varied (Fig. 11.26 – 11.37). They include erythematous or purplish plaques and nodules, papules (which may be widespread and very numerous in micropapular sarcoid), hypopigmented patches, atrophic lesions, and scar sarcoid. Lesions may mimic psoriasis or morphea, or may be subcutaneous. Atrophic, alopecic, pustular, and ulcerative lesions may occur. Massive granulomatous nodules are uncommon but may resemble lymphedema if a limb is affected. Nails may be affected (usually with underlying osteolysis), as may mucous membranes. Diffuse erythrodermic or ichthyotic presentation causes particular diagnostic difficulty.

       Additionally, non-specific lesions such as erythema nodosum (Ch.22) occur in acute sarcoidosis, usually with hilar lymphadenopathy.

       Other organs that are affected are listed in Table 11.4.

Fig. 11.26 Sarcoidosis, showing multiple, small, papular lesions. The rather purple color is quite frequent, although a range of browns and flesh tones may occur.

Fig. 11.27 Hypopigmented sarcoid is most frequent in black skin, although this may reflect the difficulty of identifying such lesions in white skin.

Fig. 11.28 An individual plaque of sarcoidosis. Patients with chronic cutaneous sarcoid often also show involvement of the lungs and bones.

Fig. 11.29 Multiple nodules of sarcoidosis on the fingers. This is an uncommon pattern resembling multicentric reticulohistiocytosis, which may also be similar histologically.

Fig. 11.30 Annular lesions are relatively common in sarcoidosis, in this case affecting the cheek. This lesion was very atrophic centrally, and responded poorly to a variety of topical and systemic therapies

Fig. 11.31 Sarcoidosis affecting the earlobe, with a prominent purple color. Lymphomas can produce very similar lesions at this site.

Fig. 11.32 Scar sarcoid is a common phenomenon. It differs from a Koebner reaction in that old scars are commonly affected as a gradual process. In this case, a large proportion of an old thoracotomy scar was affected.

Fig. 11.33 Micropapular sarcoidosis is a relatively uncommon variant. It may be difficult to distinguish, both clinically and histologically, from the diffuse form of granuloma annulare.

Fig. 11.34 Ichthyotic sarcoidosis is another uncommon variant that may cause diagnostic difficulty. The combination of acquired ichthyosis and systemic symptoms is also suggestive of lymphoma or other internal malignancy.

Fig. 11.35 Lupus pernio of the nose. This is a chronic variant of sarcoidosis that typically affects the nose and central face, is usually very purple, and may be destructive locally. This type of lesion may also become verrucous, but can respond well to low-dose methotrexate.

Fig. 11.36 Sarcoidosis affecting the nail. This occurs in chronic sarcoidosis, and is a marker of bony involvement of the underlying terminal phalanx (see Fig. 11.37).

Fig. 11.37 Radiograph of the patient shown in Figure 11.36, demonstrating bone cysts in the terminal phalanges.

Fig. 11.38 Erythema induratum (Bazin disease). This disorder is poorly defined, and is best considered as a type of nodular vasculitis in which the proof of a tuberculid process is unconvincing. Most cases occur in relatively stout female lower legs as a recurrent problem in winter or spring, and probably have a vascular etiology.

Lupus pernio

This is a form of chronic cutaneous sarcoidosis that affects predominantly the central face and ears (Fig. 11.35). It is typically purple, but the site on the face may lead to it being confused with LE. It is commonly associated with other features of chronic sarcoidosis, such as restrictive pulmonary disease or bone cysts.

Differential diagnosis

This varies hugely depending on the clinical pattern (Table 11.5).

Treatment

Treatment options for sarcoidosis include strong topical or intralesional corticosteroids, systemic steroids, antimalarials, and methotrexate, depending on the pattern and severity of both the skin disease and other organ involvement. In lupus pernio, physical modalities such as laser, electrocautery, or surgery may be useful. Methotrexate seems to be of particular benefit in verrucous lesions. Allopurinol appears to be beneficial, for uncertain reasons. PUVA may have a role, as does infliximab for severe disease.

Erythema induratum and tuberculides

Etiology and pathogenesis

Direct infection with Mycobacterium tuberculosis (scrofuloderma and lupus vulgaris) and with atypical mycobacteria (e.g. fish tank granuloma) are discussed in Chapter.24.

       The precise pathogenesis of tuberculides is more controversial. Some are felt to represent delayed hypersensitivity to tuberculosis, whereas some evidence favors local reaction to disseminated mycobacteria, or parts of them. Polymerase chain reaction technology has demonstrated mycobacterial DNA sequences in some tuberculide lesions, but also in some cases of sarcoidosis. Lichen scrofulosum and papulonecrotic tuberculid are most convincingly associated with tuberculosis.

Clinical features

Erythema induratum (Bazin disease, Fig. 11.38) is a nodular granulomatous panniculitis that occurs on the lower leg. Clinically, it may be difficult to differentiate from nodular vasculitis, which may occur due to polyarteritis or following phlebitis or chronic perniosis.

       Lupus miliaris disseminatus faciei (Fig. 11.39) is a facial eruption consisting of numerous small papules. Some authorities feel that it is probably a form of granulomatous acne, but it is very refractory to treatment that would normally be used for acne.

       Tuberculin skin tests are positive in many of this group of disorders, but the variable strength of reaction is a reason to suppose that many cases may not be related to tuberculosis. In the true tuberculides, a strong positive skin test reaction is usual.

Differential diagnosis

This varies according to the tuberculide being considered.

    Erythema induratum may resemble ordinary chilblains, venous stasis disease, other types of vasculitis, or panniculitis.

    Lupus miliaris disseminatus faciei is usually diagnosed clinically as acne or rosacea, less commonly as demodecosis. It may resemble the miliary form of lymphocytoma cutis, which also tends to affect the face.

Fig. 11.39 Lupus miliaris disseminatus faciei: multiple papular lesions on the face are typical (see also Ch. 10).

Fig. 11.40 Foreign body granuloma. (a) A nodule at the site of injury from a thorn (from a yucca bush) over 4 years previously. (b) The thorn that caused the damage, after removal from the skin.

Treatment

Cases in which there is evidence to support a true tuberculid should be treated with full antituberculous therapy. Some of the acne- or rosacea-like tuberculides may respond to tetracyclines or to isotretinoin. Nodular vasculitis may respond to steroids, to dapsone, or to vasodilating drugs if there is a perniotic component.

Foreign body reaction

Etiology and pathogenesis

Foreign body granulomas (FBGs) may occur due to numerous agents (Fig. 11.40 –11.43), and the granulomas may be sarcoidal or necrobiotic in type. Examples include the following.

Clinical features

Most foreign body reactions present either as a non-specific inflammatory nodule or in obvious relation to a preceding scar. The features may also vary according to the causative agent and type of injury; for example, granuloma formation due to illicit injection of paraffin for tissue augmentation may produce a broad area of abnormality, whereas a thorn injury is usually very localized. Pathologically, many foreign bodies will be visible by polarized light microscopy, thus confirming the diagnosis.

Fig. 11.41 Granulomatous lesions on the fingers due to spines from a sea urchin.

Fig. 11.42 Vaccination granuloma at a typical site on the upper arm. This is due to aluminum, which is used to absorb the vaccine antigen and improve the production of an immune response. Such individuals usually have positive patch tests to aluminum salts, and the reactions may last for many years. Symptoms, if any, generally settle with intralesional corticosteroid injection. Any further vaccinations should use non-adsorbed agents where these are available, and should use the buttock injection site, where any nodule is less apparent.

Differential diagnosis

Lesions in relation to a preceding scar are usually suspected to be due to foreign material, although keloid scarring and transepidermal elimination of subcutaneous sutures (both early events), and recurrent neoplasms or scar sarcoid (both later events), may be in the differential. In the case of ruptured cysts or follicles, or foreign material in a penetrating wound, the usual differential is from infection or from localized skin nodules such as dermatofibroma. On the sole of the foot, warts or callosities may be suspected.

Treatment

In some cases, it may be possible to extrude a foreign body (e.g. thorns and splinters), or it may be extruded by the skin as a form of transepidermal elimination. In some cases, there may be a good response to intralesional corticosteroids. Some FBGs, such as vaccination granulomas, appear to resolve slowly or to just leave an asymptomatic, deep nodule. Persistently symptomatic localized FBGs may need to be excised.

Multicentric reticulohistiocytosis

Etiology and pathogenesis

This is a granulomatous disorder, usually of unknown etiology but associated with internal malignancy in about 25% of cases.

Clinical

Lesions typically affect skin, bones, and joints, less commonly heart, lungs, eyes, and nervous system. Arthritis is usually manifest in the fingers and knees. The skin lesions usually consist of multiple reddish brown or purple nodules, usually affecting the dorsa of the hands and fingers, and the head and neck (especially around the ears) (Fig. 11.44).

Fig. 11.43 Silica granuloma caused by a penetrating glass injury more than 10 years prior.

Fig. 11.44 Multicentric reticulohistiocytosis: small lesions on the face in a patient with associated malignancy (myelofibrosis).

Differential diagnosis

There is a wide differential, as lesions can be varied. Small papular lesions may suggest sarcoidosis, lymphocytomas, or lupus miliaris disseminata faciei. Larger lesions may resemble rheumatoid nodules.

Treatment

Underlying disorders should be treated. The arthritis may respond to non-steroidal antiinflammatory drugs (NSAIDs). Systemic steroids are of variable benefit, as are antimalarials, cyclophosphamide, and chlorambucil. In some patients, the active disease gradually remits.

PRACTICE POINTS

Previous

Next

White/Cox: Diseases of the Skin, 2ed.(c) 2006, Elsevier Inc. All rights reserved.