Cutaneous Sarcoidosis: The ‘Great Imitator’

Sarcoidosis is a multisystem disease that can involve almost any organ system. The underlying cause of the disease remains unknown. Immunopathologically and histologically, cutaneous sarcoidosis is characterized by a macrophage/T helper-1 cell-mediated, non-caseating, granulomatous inflammation process. An imbalance between proinflammatory and anti-inflammatory cytokines plays an important role in the development of cutaneous granulomas. Recognition of cutaneous sarcoidosis lesions is very important because they provide a visible clue to the diagnosis and are an easily accessible source of tissue for histologic examination. Because skin lesions of patients with the disease can exhibit many different morphologies, cutaneous sarcoidosis is known as one of the "great imitators" in dermatology. Specific manifestations can include patches (sometimes hypopigmented), papules, scar sarcoidosis, ulcers, ichthyosis, and alopecia. The treatment of cutaneous sarcoidosis is often frustrating because some of the skin lesions may be refractory to treatment or may recur following successful treatment. Systemic and topical corticosteroids are the most effective treatments for cutaneous sarcoidosis. This article focuses on the dermatologic aspects of sarcoidosis and includes a review of the most recent literature, which includes new data on the diagnosis, differential diagnosis, pathogenesis, and treatment of the disease.     

Cutaneous sarcoidosis treated with levamisole.

16 patients with cutaneous sarcoidosis were treated intermittently over a period of 6 months with levamisole in an open study. The skin lesions cleared in 2 of 13 patients completing the course of treatment. Aggravation of the sarcoidosis was noted in 2 other patients after a few weeks of treatment. Tuberculin sensitivity did not increase during the treatment period. Dinitrochlorobenzene sensitivity increased in 5 patients but the lesions did not clear in any of these patients. It is concluded that levamisole is not useful in the treatment of cutaneous sarcoidosis.     

Relationship of cutaneous sarcoidosis to systemic disease

Cutaneous sarcoidosis can be represented by an acute, nonspecific process (eg, erythema nodosum) or by a more chronic process represented histologically by the noncaseating granuloma. These manifestations have adequately been documented in other sections of this issue (see chapters 4 and 9). It is the purpose of this section to relate those skin lesions to the potential for internal organ involvement, and the correlation of a particular cutaneous variant with a specific type of organ involvement.

In preparing this section, I began to review the data generated by our practice; then I compared and contrasted it to data reported in the literature. Much of the data is difficult to analyze for a number of reasons. Many of the studies (including ours) have an inclusion bias. For example, patients seen in a pulmonary clinic necessarily have a higher incidence of lung involvement in contrast to those studies seen by dermatologists who may have milder systemic disease. Another problem relates to the inability of a pulmonary specialist to describe the exact nature of the skin lesions or a dermatologist to adequately and thoroughly evaluate the systemic nature of the patient. Despite these biases, this section will deal with studies of systemic disease in patients with cutaneous disease, specifically, lupus pernio, subcutaneous lesions, and the miscellaneous cutaneous manifestations.     

Foreign bodies in sarcoidosis

Sarcoidosis is a multisystem disease of unknown etiology. The demonstration of polarizable foreign bodies in cutaneous granulomas is generally thought to exclude a diagnosis of sarcoidosis. Nevertheless. some investigators have reported systemic sarcoidosis with cutaneous manifestations in which polarizable particles were associated with granuloma formation in the skin. We searched the biopsy specimens of granulomatous lesions from 50 patients with cutaneous sarcoidosis using polarization microscopy to estimate the frequency of polarizable foreign bodies in cutaneous lesions of sarcoidosis. Using electron probe microanalysis, we sought to determine what elements compose these foreign bodies. Polarizable foreign bodies were found in the granulomatous skin lesions of 12 of 50 patients with cutaneous sarcoidosis. All 12 patients also had at least one other granulomatous systemic lesion, and 4 had biopsy specimens of a systemic lesion available for review. Polarizable foreign bodies were found in two cases. The elements identified were calcium, phosphorus, silicon, and aluminum. Polarizable foreign bodies were found in cutaneous sarcoidosis far more often than expected. Foreign bodies were also found in granulomatous systemic lesions. The foreign body may serve as an inciting stimulus for granuloma formation in selected cases of sarcoidosis.     

Subcutaneous sarcoidosis in a melanoma scar

Cutaneous sarcoidosis often has been referred to. as the great imitator because skin lesions can present with various morphologies. Skin lesions may be the only site of involvement or may accompany systemic disease. Occasionally, sarcoidosis also may infiltrate scars from prior trauma, tattoos, or surgery. We report a case of subcutaneous sarcoidosis limited to a melanoma scar without any other cutaneous or systemic involvement. Familiarity with and proper diagnosis of cutaneous sarcoidosis can allow for appropriate systemic screening and timely management of the disease.     

Clinicopathologic features of ulcerative-atrophic sarcoidosis

BACKGROUND: Sarcoidosis is a chronic granulomatous disease of unknown etiology. Cutaneous disease is common and includes two clinicopathologic categories: granulomatous infiltration or a reactive phenomenon. In the granulomatous infiltrative group, clinical manifestations can be variable. Ulcers in sarcoidosis are uncommonly recognized and have been categorized previously under the rubric of atrophic, necrobiosis-like, or ulcerative sarcoidosis. PATIENTS AND METHODS: We evaluated retrospectively sarcoidosis patients presenting to the Johns Hopkins Department of Dermatology between June 1989 and May 2002. Multiple skin biopsies were performed for histopathologic evaluation. Investigation for extracutaneous manifestations, including routine serologic assays, chest radiography, pulmonary function tests, electrocardiogram, and angiotensin-converting enzyme level, and referral for ophthalmologic examination were performed in all patients. RESULTS: Of 147 consecutive patients presenting with cutaneous sarcoidosis, seven demonstrated ulcerative-atrophic sarcoidosis lesions. All patients were African-American (five females and two males). All patients had ulcers surrounded by atrophic necrobiosis lipoidica-like plaques on the pretibial areas. All patients had other mucocutaneous manifestations of sarcoidosis, with the majority having evidence of internal disease. Combined immunosuppressive and immunomodulatory therapy was effective in controlling the cutaneous manifestations of all patients with ulcerative sarcoidosis. CONCLUSIONS: The ulcerative variant is a poorly defined subset of cutaneous sarcoidosis. Trauma, superimposed on atrophic plaques, appears to be the principal mechanism of this rare variant of cutaneous sarcoidosis.     

The use of tetracyclines for the treatment of sarcoidosis

BACKGROUND: To evaluate the safety and efficacy of minocycline in the treatment of sarcoidosis, a nonrandomized, open study was performed in patients with cutaneous sarcoidosis. OBSERVATIONS: Twelve patients with cutaneous sarcoidosis were treated with minocycline, 200 mg/d, for a median duration of 12 months. Three patients had extracutaneous lesions at the time of the study. The median follow-up was 26 months. A clinical response was observed in 10 patients, consisting of complete responses in 8 patients and partial responses in 2 patients. A progression of skin lesions was observed in 1 patient, and lesions remained stable in another patient. Adverse effects were minimal, except in 1 patient, who developed hypersensitivity syndrome. A slight hyperpigmentation occurred in 2 patients at the site of previous lesions, which completely disappeared after minocycline use was discontinued. A relapse of skin symptoms occurred after minocycline withdrawal in 3 patients, who further received doxycycline, 200 mg/d, allowing a complete remission of lesions. CONCLUSIONS: These results support that minocycline and doxycycline may be beneficial for the treatment of cutaneous sarcoidosis. Randomized controlled studies are warranted for the evaluation of the true efficacy of tetracyclines in these patients.     

Sarcoidosis: Are there differences in your skin of color patients?

The skin of color population is growing at an astronomical rate, making it critically important to recognize diseases, such as sarcoidosis, in patients with skin of color. Sarcoidosis is a multisystem, granulomatous disease, which manifests in a variety of organs and is found more frequently in Blacks as compared with Caucasians. In addition, Blacks have a poorer prognosis and often present with more advanced disease. Sarcoidal lesions can present with multiple morphologic features, some more common in patients with skin of color. We offer a review of the cutaneous presentations of sarcoid lesions in patients with skin of color, an overview of extracutaneous sarcoidosis, the cutaneous signs that may impact overall disease prognosis, and treatment options.     

Sarcoidosis presenting with erythema multiforme-like cutaneous lesions

Sarcoidosis is a systemic disease that involves the skin in approximately 35 percent of cases. Typical cutaneous lesions are violaceous or hyperpigmented papules, plaques, or nodules. Less commonly, cutaneous lesions of sarcoidosis simulate the lesions of other cutaneous diseases such as psoriasis, ichthyosis, and erythroderma. We report on a patient who presented with cutaneous sarcoidal lesions resembling the target lesions of erythema multiforme (EM).     

Cutaneous sarcoidosis treated with methotrexate

Sixteen patients with cutaneous sarcoidosis, 15 of whom also had involvement of other organs, were treated with methotrexate (MTX) orally once a week in an open study. The treatment period was from 1 to 72 months (mean 23 months). In 12 patients the skin lesions cleared, and in 3 of 4 patients who had sarcoid uveitis this cleared as well. The chest X-ray of 6 patients showed no corresponding improvement in pulmonary changes or in hilar adenopathy. Ten patients suffered side effects, usually nausea on the day MTX was taken. Two had transiently increased transaminase levels. Treatment was discontinued in 2 patients due to nausea. It is concluded that MTX is a useful alternative to systemically administered glucocorticoids in the treatment of disfiguring cutaneous sarcoidosis and sarcoid uveitis. The effect of MTX on hilar adenopathy and pulmonary sarcoidosis is uncertain.     

Serum angiotensin-converting enzyme in sarcoidosis and psoriasis

Untreated pulmonary sarcoidosis is associated with an increased level of serum angiotensin-converting enzyme (SACE), which is regarded as a valuable method of diagnosing sarcoidosis and measuring the activity of the disease. The level of SACE in cutaneous sarcoidosis or other skin diseases has not been clearly established. We therefore examined SACE in 31 patients with systemic sarcoidosis, including cutaneous manifestations, and 12 patients with isolated cutaneous sarcoidosis. Also, 23 patients with psoriasis were studied. The level of SACE was generally elevated only in patients with untreated systemic sarcoidosis, whereas it was normal in cutaneous sarcoidosis and psoriasis. If the level of SACE is elevated in "isolated" cutaneous sarcoidosis, systemic disease must be strongly suspected.     

Three cases of cutaneous sarcoidosis: search for bacterial agent by the 16S RNA gene analysis and treatment with antibiotics

BACKGROUND: The aetiology of sarcoidosis remains controversial. An infectious origin is often discussed, but only anti-inflammatory or immunosuppressive treatment is recommended. OBJECTIVES: To investigate the hypothesis of bacterial origin by treating cutaneous sarcoidosis with antibiotics. METHODS: Patients with chronic cutaneous sarcoidosis, unresponsive to the usual treatment and not requiring systemic corticotherapy, were given combined antibiotherapy for 6 months. Search for bacterial DNA by amplification and sequencing of the 16S ribosomal RNA gene in skin biopsies of lesions before and after antibiotherapy was done. RESULTS: Three patients received a combined treatment with clarithromycin 1 g/day and ciprofloxacin 1 g/day. No clinical changes occurred in 2 cases and transient worsening in 1. Amplification for bacterial DNA was positive in all skin biopsies. The sequencing of this DNA could not identify a unique bacterial species. CONCLUSION: No evident bacterial origin could be demonstrated; however, this approach should be extended to more patients.     

Ocular sarcoidosis

Ocular involvement in sarcoidosis is the second most common manifestation of the disease, preceded only by pulmonary abnormalities with hilar adenopathy. Ocular disease is the presenting manifestation in 9% of cases,¹ and 25–50% of patients with systemic sarcoidosis will at some time show ocular involvement.^1–3 Chronic ocular sarcoidosis may correlate with cutaneous lesions in 38% of cases. All patients with suspected sarcoidosis should have a thorough ophthalmologic examination.     

Serum angiotensin-converting enzyme in sarcoidosis and psoriasis

Summary Untreated pulmonary sarcoidosis is associated with an increased level of serum angiotensin-converting enzyme (SACE), which is regarded as a valuable method of diagnosing sarcoidosis and measuring the activity of the disease. The level of SACE in cutaneous sarcoidosis or other skin diseases has not been clearly established. We therefore examined SACE in 31 patients with systemic sarcoidosis, including cutaneous manifestations, and 12 patients with isolated cutaneous sarcoidosis. Also, 23 patients with psoriasis were studied. The level of SACE was generally elevated only in patients with untreated systemic sarcoidosis, whereas it was normal in cutaneous sarcoidosis and psoriasis. If the level of SACE is elevated in isolated cutaneous sarcoidosis, systemic disease must be strongly suspected.     

Quantitation of cutaneous Langerhans cells of sarcoidosis patients

Langerhans cells play a role in cell-mediated immune reactions which are often depressed in sarcoidosis. We examined the epidermis of 17 anergic patients with sarcoidosis (Kveim-reactive and/or biopsy-proved) for the number of Langerhans cells in noninvolved skin and in any cutaneous sarcoidal lesions. Skin biopsies of 10 healthy volunteers served as controls. In comparison to controls, the epidermis overlying noninvolved (p less than 0.05), sarcoidal (p less than 0.0005), and Kveim-reactive (p less than 0.005) skin contained significantly fewer detectable Ia and T6 antigen-bearing Langerhans cells. The reductions within noninvolved skin were most pronounced in patients with multisystem disease. Lower epidermal Langerhans cell densities, in comparison to controls, were detected in both prednisone-treated and untreated patients. Epidermis overlying sarcoidal skin of untreated patients contained significantly fewer Ia and T6 antigen-bearing Langerhans cells (p less than 0.05, p less than 0.0025, respectively) than epidermis from noninvolved skin. Whether reduced numbers of cutaneous Langerhans cells are due to either a local and/or systemic effect of sarcoidosis, or reflect the anergic state of these patients is unknown.     

Specific cutaneous lesions in patients with systemic sarcoidosis: relationship to severity and chronicity of disease

Background. Specific (granulomatous) cutaneous lesions are seen in 9–37% of cases of systemic sarcoidosis, and are usually classified into maculopapules, plaques, lupus pernio (LP), scar sarcoidosis, and subcutaneous sarcoidosis. Their prognostic significance has not been fully established. Aim. To analyse the relationship between the clinical type of granulomatous cutaneous lesions and the systemic features and prognosis of systemic sarcoidosis. Methods. The clinical charts of 86 patients (19 men, 67 women, mean age 46.82 years) with systemic sarcoidosis and granulomatous cutaneous involvement followed up for > 2 years at Bellvitge University Hospital were reviewed. Results. Cutaneous lesions developed before or at the time of diagnosis of systemic sarcoidosis in 80.23% of patients. The main cutaneous lesions were classified as maculopapules (28 patients), plaques (31), LP (6), scar sarcoidosis (7) and subcutaneous sarcoidosis (14). Erythema nodosum (EN) was seen in 30 patients. Radiological stage was 0 for 8 patients, I for 48, II for 24, III for 5 and IV for 1. Systemic sarcoidosis activity persisted for > 2 years in 47 patients, and 42 received systemic corticosteroid treatment for their disease. Maculopapular and subcutaneous sarcoidosis were mainly seen in patients with EN and radiological stage I. Plaques and LP were associated with chronic disease and requirement for systemic corticosteroids. Conclusions. Cutaneous granulomatous lesions are usually present at the diagnosis of systemic sarcoidosis, and the type of cutaneous involvement may have prognostic significance.     

Photodynamic therapy as an alternative treatment for cutaneous sarcoidosis

Sarcoidosis is a systemic granulomatous disease. In more than 90% of the cases, sarcoidosis affects the lung with bilateral hilar adenopathy, while skin involvement occurs in about 25% of the cases. Whereas sarcoidosis of the lung is often successfully treated with oral corticosteroids, therapy of cutaneous sarcoidosis is frequently frustrating because some of the lesions may be refractory to treatment or recur quickly after resolution. We report two cases of cutaneous sarcoidosis successfully treated with photodynamic therapy, which represents an effective alternative therapy with fewer side effects.     

Cutaneous manifestations of sarcoidosis in blacks

The diverse patterns of skin lesions occurring in black patients with sarcoidosis are described. Shiny, somewhat waxy papular lesions are the most frequent cutaneous manifestation of sarcoidosis in blacks. Erythema nodosum remains an infrequent finding when compared with the frequency of other cutaneous lesions. Because of its protean cutaneous manifestations, sarcoidosis should be included in the differential diagnosis of all chronic dermatoses in blacks.     

Papular sarcoidosis of the knees: a clue for the diagnosis of erythema nodosum-associated sarcoidosis

BACKGROUND: In recent years we have systematically explored the skin whenever sarcoidosis was suggested and we have observed with increasing frequency the presence of granulomatous cutaneous lesions of sarcoidosis involving the knees. OBJECTIVE: We sought to evaluate the specific cutaneous lesions of sarcoidosis involving the knees. METHODS: A total of 18 patients with biopsy-proven specific cutaneous sarcoidosis predominantly involving the knees were included in the study. Biopsy specimens were evaluated under polarized light. RESULTS: Of these cases, 4 corresponded to scar-sarcoidosis, 1 to plaque-type sarcoidosis, and 13 were an admixture of papules and minute scars frequently associated with erythema nodosum (papular sarcoidosis of the knees). Foreign particles were observed in 10 of 13 patients with papular sarcoidosis. CONCLUSION: Papular sarcoidosis of the knees can be considered a frequent form of cutaneous sarcoidosis, mainly observed in acute forms of the disease, and frequently associated with erythema nodosum.     

Identification of mycobacterial DNA in cutaneous lesions of sarcoidosis

Sarcoidosis is a multisystemic granulomatous disease of uncertain etiology. Recently, mycobacterial DNA especially Mycobacterium tuberculosis and Mycobacterium avium complex were detected in lung tissue and bronchial lavage fluid from patients with sarcoidosis by polymerase chain reaction (PCR) assays in 30% to 50% cases. Moreover, cell wall-defective form (CWDF) acid-fast bacteria have been isolated from skin lesions of patients with sarcoidosis which were later confirmed as M. avium complex by PCR assays. CWDF acid-fast bacteria were also found to grow from the blood of 95% patients with active sarcoidosis demonstrating a mycobacterial origin similar to M. tuberculosis. In view of these reports, we investigated 20 cases of cutaneous sarcoidosis using PCR/restriction enzyme pattern analysis (PCR/REPA) to detect mycobacterial DNA from paraffin-embedded skin biopsy samples. The method involves restriction enzyme analysis of nested PCR products obtained with primers encoding for the 65-KDa protein common to all mycobacteria. Using three restriction enzymes, the mycobacterial DNA from PCR product was differentiated to the species level. All the 20 cases had clinical and histologic evidence of sarcoidosis. Special stains for fungi (PAS) and mycobacteria (Fite) were negative and no foreign body was identified on polaroscopic examination in any of the cases. The cell lysates of M. tuberculosis, Mycobacterium bovis, Mycobacterium avium-intracellulare, Mycobacterium kansasii and Mycobacterium marinum from Centers for Disease Control (CDC) were used as standard control for PCR/REPA. Eight cases of foreign body granuloma, seven normal skin samples from the margin of surgical excisions and 5 cases of dermatitis were used as negative controls, and 4 cases of cutaneous tuberculosis were used as positive controls. Mycobacterial DNA was detected by PCR in 16 of the 20 cases of sarcoidosis. PCR/REPA subtyped 8 of these to M. tuberculosis complex (2 cases), M. avium-intracellulare (4 cases), M. kansasii (2 cases) while the other 8 cases were non-tuberculous mycobacteria. All four cases of cutaneous tuberculosis were positive by PCR and had a typical M. tuberculosis PCR/REPA pattern. Mycobacterial DNA was not detected in any of the negative controls. Our results demonstrated that mycobacterial DNA is present in 80% of cutaneous lesions of sarcoidosis and these mycobacteria may play a role in the pathogenesis of sarcoidosis.