Chapter 13 Granulomatous diseases of the skin
1. What is meant by “granulomatous diseases of the skin”?
Quite simply, the granulomatous disorders of the skin comprise a broad category of diseases that are characterized by the accumulation of activated macrophages with an epithelioid appearance in the dermis or subcutaneous tissue. A granuloma is a distinct aggregate composed of epithelioid macrophages with or without multinucleated giant cells. These aggregates are typically surrounded by a rim of lymphocytes with plasma cells being variably present. Macrophages develop from bone marrow–derived monocytes that leave the circulation and enter the skin.
2. Explain the role of histiocytes in granulomas.
Many references use the confusing term histiocyte when discussing granulomas. Histiocyte may be used interchangeably with macrophage or monocyte, but the term is not specific and may be applied also to transformed lymphocytes (e.g., histiocytic lymphoma), fibroblasts that demonstrate phagocytosis (e.g., fibrous histiocytoma, reticulohistiocytoma), and antigen-presenting cells (e.g., histiocytosis X). Some authorities eschew the use of this term because it is not specific.
3. What is the difference between an immune granuloma and a foreign body granuloma?
Immune granuloma formation is a local tissue response to a poorly soluble substance that is capable of inducing a cell-mediated immune response (e.g., cutaneous tuberculosis). The persistent presence of a poorly soluble substance in the skin causes the activation of T cells, which secrete cytokines such as interleukin-2 (Il-2) to activate additional T cells and interferon-2 (IFN-2), which transform macrophages into epithelioid macrophages and multinucleated giant cells. In contrast, foreign body granulomas, typically are the result of larger aggregates of inert foreign material that cannot be phagocytized by a single macrophage (e.g., wood splinter). In general, granulomas are produced by infectious agents, foreign bodies, or alterations in the host immune system.
5. Can granulomas be recognized clinically?
Sometimes. Granulomas usually present as dermal nodules, although epidermal changes can be present. Foreign body granulomas may demonstrate a central erosion or ulceration secondary to an attempt by the body to extrude the foreign material through an elimination tract. Granulomas often present as nonspecific erythematous nodules; however, they also may present as dermal nodules with an “apple-jelly hue” that is highly suggestive of an underlying granulomatous process. This apple-jelly hue can frequently be better appreciated by using diascopy (applying pressure to the lesion with a glass slide).
6. How do endogenous “foreign” bodies cause granulomas?
Endogenous substances produce a granulomatous reaction when they come in contact with the dermis or subcutaneous fat. For example, one of the most common foreign body reactions occurs when an epidermoid cyst wall ruptures and its keratin contents come in contact with the dermis. Normally, the keratin within the cyst is protected from the dermis by the cyst’s epithelial lining. However, when a cyst ruptures, the keratin is exposed to the dermis and, being a poorly soluble substance, it produces a granulomatous response.
| Infectious Agents | ||
| Fungi | Bacteria | Miscellaneous Infections |
| Blastomycosis Candidiasis Chromomycosis Coccidioidomycosis Cryptococcosis Histoplasmosis Sporotrichosis |
Actinomycosis Cat scratch fever Granuloma inguinale (donovanosis) Mycobacterial infections Nocardiosis Syphilis Tularemia |
Leishmaniasis Protothecosis (algae infection) |
| Foreign Body Agents | ||
| Exogenous | Endogenous | Miscellaneous Diseases |
| Aluminum Cosmetic fillers Hair Insect parts Paraffin Silica Splinters Starch Sutures Talc Tattoo pigment |
Bone Calcium Cholesterol Keratin Hair Sebum Urate crystals |
Actinic granuloma Crohn’s disease Granuloma annulare Granulomatous cheilitis Granulomatous rosacea Lupus miliaris disseminatus faciei Necrobiosis lipoidica Rheumatoid nodule Sarcoidosis |
8. Do cosmetic fillers ever produce foreign body granulomas?
Yes. Numerous cosmetic fillers, including products made from collagen (Fig. 13-2), silicone, hyaluronic acid, methacrylate, and polyalkylimide, have been reported to produce foreign body granulomas. In some cases the cosmetic results have been very poor and difficult to correct. The number of reported cases is rapidly increasing as the cosmetic filler industry has rapidly expanded in the last decade and larger numbers of patients are receiving injections for cosmetic fillers.
| AGENT | SOURCE |
|---|---|
| Silicone | Breast implants, joint prostheses, soft tissue injections, hemodialysis tubing |
| Silica | Soil and rock (very abundant), glass |
| Paraffin (oils) | Cosmetic injection (historically), factitial injection, grease gun injury |
| Starch | Surgical gloves contaminating wounds |
| Graphite | Pencil lead (see Fig. 13-1A) |
| Thorns | Roses, cactus, yucca (see Fig. 13-1B) |
| Hair | Barbers, dog groomers, sheep shearers |
| Talc | IV drug use, wound contamination |
| Aluminum | Adjuvant in DPT immunizations |
| Zirconium | Deodorant sticks |
| Beryllium | Metal, ceramic, and electronic industries; fluorescent lamp workers (historically, as this ceased in 1951) |
DPT, Diphtheria-pertussis-tetanus, IV, intravenous.
Winslow CP: The management of dermal filler complications, Facial Plast Surg 25:124–128, 2009.
9. Can the cause of a foreign body reaction be diagnosed histologically?
Sometimes. Often, a tattoo granuloma may retain some color or pigment that can help with the diagnosis. Silicone, paraffin, and other oils are often accompanied by fibrosis and a characteristic “Swiss cheese” appearance. The Swiss cheese–like holes are actually cavities formerly filled with the oily material that is lost during tissue processing. Also, some foreign bodies are birefringent under polarized light (e.g., talc, starch, silica, and some types of sutures).
10. What is sarcoidosis?
11. How often is the skin involved in sarcoidosis?
12. Describe the specific cutaneous findings in sarcoidosis.
The most common cutaneous findings are small papules that may be skin-colored, red, violaceous, yellow-brown, brown, or hypopigmented. The surface is typically smooth but variable scale or umbilication may be present. Papules are most commonly found around eyelids, nasal alae and nasolabial folds, and malar and neck regions (Fig. 13-3).
13. What is lupus pernio?
This distinct form of cutaneous sarcoidosis presents as purplish plaques around the nose, ears, lips, face, and fingers (Fig. 13-4). It is usually an insidious process with slow progression that results in scarring, fibrosis, and deformity. It rarely involutes spontaneously and is associated with bony involvement specifically and systemic disease in general.
Spicknall K, English JC 3rd, Elston DM: Lupus pernio, Cutis 79:289–290, 2007.
14. Describe the nonspecific cutaneous lesions of sarcoidosis.
The most common nonspecific cutaneous lesion is erythema nodosum, which may be present in 13% to 20% of patients. Clinically and histologically, it is identical to erythema nodosum associated with other conditions. Less common nonspecific cutaneous lesions include acquired ichthyosis (Fig. 13-5A), calcinosis cutis, erythema multiforme, and nail clubbing.
15. Does sarcoidosis ever present in the skin without extracutaneous involvement?
Yes. Even though sarcoidosis is defined as a multisystem disorder, some patients present with lesions that are clinically and histologically identical to sarcoidosis without any evidence of involvement of other organ systems. It is possible that some of these patients have involvement of other organ systems but it is minimal and asymptomatic. In other cases, the skin lesions predate the discovery of involvement of other organ systems.
16. What is Löfgren’s syndrome?
This is the classic acute presentation of sarcoidosis. It consists of bilateral hilar adenopathy, fever, arthralgias, erythema nodosum, and uveitis (Fig. 13-5B). Sarcoidosis that presents in this manner has an approximately 80% chance of resolving within 2 years.
18. How should cutaneous sarcoidosis be treated?
Treatment of cutaneous sarcoidosis should always be tempered by the fact that 60% to 80% of cases resolve without treatment in 1 to 2 years, especially those patients who present with Löfgren’s syndrome. For patients with mild cutaneous disease, potent topical corticosteroid (e.g., clobetasol) or intralesional corticosteroid is the treatment of choice. For patients with extensive cutaneous involvement or systemic disease, prednisone is the treatment of choice. Antimalarials have also been shown to be effective in the chronic plaque form of cutaneous sarcoidosis, and these can be a useful alternative to prednisone. Miscellaneous treatments reported to be of benefit in select patients include azathioprine, doxycycline, isotretinoin, levamisole, methotrexate, minocycline, thalidomide, tetracycline, adalimumab, and infliximab.
Doherty CB, Rosen T: Evidence-based therapy for cutaneous sarcoidosis, Drugs 68:1361–1383, 2008.
Key Points: Cutaneous Sarcoidosis
3. Lupus pernio is a distinct variant of cutaneous sarcoidosis that presents as purplish plaques around the nose, ears, lips, face, and fingers. It is associated with more severe bony disease.
19. What is the typical presentation of granuloma annulare?
Granuloma annulare (GA) typically presents with violaceous or flesh-colored dermal papules arranged in an annular or semiannular configuration (Fig. 13-6A). The lesions may be solitary or multiple. Most commonly, it affects the dorsum of the hands or feet, but it can also occur on the forearms, arms, legs, or thighs. It tends to affect children or young adults with a 2:1 female preponderance. Several less common variants of granuloma annulare include the macular and erythematous forms, subcutaneous nodules (Fig. 13-6B), actinically induced lesions, perforating type, and disseminated form. Biopsies of GA demonstrate a characteristic palisaded granuloma associated with collagen destruction (necrobiotic granuloma) and increased dermal mucin.
20. Do any systemic associations occur with granuloma annulare?
Patients who present with localized lesions that are few in number have no systemic associations, and no workup needs to be done. However, several studies have suggested an association between the disseminated form of GA and diabetes mellitus. Therefore, an appropriate workup should be done in these patients.
21. What is the typical course of granuloma annulare?
In the classic localized form of GA, the tendency is for spontaneous resolution. Recurrences are fairly common, but the recurrences tend to resolve more quickly than the original lesions. Most studies note that at 2 years postonset of GA, 50% to 80% of patients will be lesion free. However, patients who present with disseminated lesions tend to have a much more protracted course and are frequently less responsive to therapy.
22. How is granuloma annulare treated?
Since GA may spontaneously resolve, expectant observation is certainly a good treatment option. Numerous therapies have been anecdotally reported to be successful, including radiotherapy, cryotherapy, laser, psoralen plus ultraviolet light (type A, [PUVA]), ultraviolet A-1 (UVA-1), niacinamide, isotretinoin, salicylates, potassium iodide, dapsone, antimalarials, cyclosporin, and chlorambucil. None has met with overwhelming success. The treatment of choice at this time is strong topical corticosteroids with or without occlusion or intralesional corticosteroids. Corticosteroid therapy usually makes the lesions resolve, but potent preparations are necessary to get a good response and may produce secondary thinning of the skin.
23. What is actinic granuloma?
Actinic granuloma, also called annular elastolytic giant cell granuloma, is a granulomatous process that tends to occur in older patients on sun-exposed skin of the face, arms, and neck. Clinically, the lesions are annular and resemble GA, although some cases demonstrate subtle atrophy in the center of the lesion (Fig. 13-7). Histologically, it is also similar to GA in that it demonstrates necrobiotic granulomas, but it differs in that it is usually more superficial, demonstrates more foreign body giant cells and prominent elastophagocytosis (macrophages engulfing and breaking down elastic fibers), and mucin is not increased. Some authorities consider it to be a variant of GA but the majority favors it being a disease sui generis. The treatment is the same as for GA but should also include sun protection.
Stein JA, Fangman B, Strober B: Actinic granuloma, Dermatol Online J 13:19, 2007.
24. Are rheumatoid nodules really a granulomatous disorder?
25. Where do rheumatoid nodules typically occur?
These are typically present as asymptomatic, firm, fixed, or mobile subcutaneous nodules adjacent to bony structures. The most common site is the elbow (Fig. 13-8). Other common locations include the extensor aspects of the fingers, flexor sheath tendons in the palms, Achilles tendons, ischial tuberosities, and sacrum. Rheumatoid nodules occur in approximately 25% of patients with rheumatoid arthritis.
Figure 13-8. Unusually large dermal and subcutaneous rheumatoid nodules in a patient with severe rheumatoid arthritis.
(Courtesy of the Fitzsimons Army Medical Center teaching files.)
García-Patos V: Rheumatoid nodule, Semin Cutan Med Surg 26:100–107, 2007.
26. What causes rheumatoid nodules?
The pathogenesis is not understood, but the evidence suggests that rheumatoid arthritis occurs in genetically susceptible patients after an arthritogenic microbial antigen exposure. The identity of the microbial trigger has not been established, although considerable attention has been placed on the Epstein-Barr virus. Once the process is initiated, a complex autoimmune disease develops characterized by increased numbers of CD4+ T cells in the joint, which also activate B cells that produce autoantibodies (primarily IgM) to the Fc portion of autologous IgG. The antigen that provokes the autoimmune response has not been fully established, but research is focusing on type 2 collagen, human cartilage glycoprotein-39, human stress protein BiP, and several different heat shock proteins. How this autoimmune response produces rheumatoid nodules is not clear.
27. What is accelerated nodulosis?
Accelerated nodulosis is the rapid onset of rheumatoid nodules that develops in a small subset of patients treated with methotrexate. The nodules typically regress following discontinuation of the methotrexate and recur with rechallenge. Although several theories have been proposed, the pathogenesis is not understood.
28. Are rheumatoid nodules specific for rheumatoid arthritis?
No. They are not pathognomonic for rheumatoid arthritis. They are seen in 5% to 7% of patients with systemic lupus erythematosus and in a rare condition in children called benign pseudorheumatoid nodules, in which the nodules grow rapidly and then spontaneously involute. These children are usually rheumatoid factor–negative, and some authorities feel that many of these cases represent deep GA. Another rare presentation is rheumatoid nodulosis, in which patients present with multiple rheumatoid nodules about the hands. They are rheumatoid factor-–positive but have a remarkably benign course.
McGrath MH, Fleischer A: The subcutaneous rheumatoid nodule, Hand Clin 5:127–135, 1989.
29. Do patients with lupus miliaris disseminatus faciei have lupus erythematosus?
No. Lupus miliaris disseminatus faciei is a chronic granulomatous disorder of the face of unknown cause. Clinically, it presents as multiple brown to brownish-red to brownish-yellow papules of the face (Fig. 13-9), especially the central face and ears. The cause of this mysterious granulomatous disease is unknown, although some dermatologists consider it to be a variant of granulomatous rosacea. Histologically, it is composed of sarcoidal or, more commonly, caseating granulomas that sometimes demonstrate connections to hair follicles.
Figure 13-9. Lupus miliaris disseminatus faciei. Numerous red to reddish-brown papules of the central face.
(Courtesy of the Walter Reed Army Medical Center teaching files.)
Sehgal VN, Srivastava G, Aggarwal AK, et al: Lupus miliaris disseminatus faciei. Part II: an overview, Skinmed 4:234–238, 2005.
