Perineural granulomas in cutaneous sarcoidosis may be associated with sarcoidosis small‐fiber neuropathy

Perineural granulomas in cutaneous sarcoidosis have been rarely reported and their clinical significance has yet to be evaluated. Recently, a 27‐year‐old male presented with multiple pink papules on the flank and lower back, accompanied by a painful, burning sensation. Biopsies revealed well‐defined granulomas, consistent with sarcoidosis, in the dermis and involving small cutaneous nerves. We hypothesized that perineural granulomas may be an under‐recognized feature of cutaneous sarcoidosis and may be responsible for sensory disturbances. We reviewed cases from 29 consecutive patients with cutaneous sarcoidosis. Perineural granulomas were identified in 18/29 (62%) patients and in 22/40 (55%) biopsies. Perineural granulomas were identified in 7/9 biopsies from the proximal upper extremity, 1/3 from the distal upper extremity, 7/12 from the head and the neck, including 4/4 from the nose, 5/9 from the back, 1/2 from the flank and 1/1 from the proximal lower extremity and 0/4 from the distal lower extremity. The anatomical distribution is similar to sarcoidosis small‐fiber neuropathy (SSFN), in which sarcoidosis patients without evident skin lesions experience sensory disturbances of unknown etiology involving the face, the proximal extremities and the trunk. Our results indicate perineural granulomas in cutaneous sarcoidosis are more common than previously appreciated, primarily involve the head, the proximal upper extremities and the back, and may be responsible for neurological manifestations.     

Clinical spectrum and histological analysis of 32 cases of specific cutaneous sarcoidosis

BACKGROUND: Sarcoidosis is a multisystem granulomatous disorder of unknown aetiology in which skin involvement is frequent. OBJECTIVE: To review histological characteristics of biopsies of specific cutaneous lesions of sarcoidosis and their relationship with clinical course. PATIENTS AND METHODS: Biopsies from 32 patients with specific cutaneous sarcoidosis were reviewed. Histological findings and clinical characteristics of these patients were analysed. RESULTS: The initial clinical lesions of the patients were ten infiltrated nodule-plaques, eight papules, four maculopapular eruptions, five scar sarcoidosis, four subcutaneous nodules and one lupus pernio. Sarcoidal granulomas were located at dermis in 31 cases (74%) and at subcutaneous fat in 12 (28%) but only four were subcutaneous exclusively. Perivascular or periannexial distribution of granulomas was observed in eight cases (19%) and they had coalescence in 29 samples. The presence of foreign material was demonstrated in 11 cases (26%). CONCLUSIONS: Clinical spectrum of specific lesions of cutaneous sarcoidosis showed a good correlation with granulomas localization in the biopsies. However, traditional classification of specific cutaneous sarcoidosis is often overlapping. On the other hand, foreign bodies and other atypical histological findings were more common than initially expected.     

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.     

Cutaneous sarcoidosis in black South Africans

BACKGROUND: It has been observed that, in the USA, sarcoidosis is more common in African-Americans than in other races. It has also been noted that sarcoidosis in African-Americans is characterized by more severe extrapulmonary involvement and more exuberant skin lesions. There is little information on sarcoidosis in black Africans. METHODS: Fifty-four black South African patients with cutaneous lesions of sarcoidosis proven by biopsy were prospectively studied. Dermatologic and ophthalmologic examinations and chest X-rays were performed in all patients. Other investigations relevant in the diagnosis of extracutaneous sarcoidosis were also performed in a variable number of patients. RESULTS: In 40 patients (71%), systemic sarcoidosis was found with lung, eye, and acral bone involvement being most common. Great variations in the morphology of skin lesions were observed. In one-quarter of patients, atypical cutaneous lesions (hypopigmented, ichthyosiform, lymphedematous, mutilating, ulcerative, verrucous) were found. Lupus pernio, once thought to be confined to Northern Europe, was observed in five patients in the subtropical milieu of South African Transvaal. Sarcoidal dactylitis with nail changes was seen in eight patients. Fibrinoid necrosis was found in 12% of the biopsies. CONCLUSIONS: Sarcoidosis in black South Africans is characterized by extensive cutaneous involvement. The lesions are morphologically extremely variable, frequently atypical, and often demonstrate fibrinoid necrosis on histology.     

Sarcoidosis associated with pegylated interferon alfa and ribavirin treatment for chronic hepatitis C: a case report and review of the literature

BACKGROUND: At least 2.7 million Americans are infected with chronic hepatitis C. An increasing number are treated with interferon alfa plus ribavirin regimens. Not surprisingly, this immune stimulation is associated with the development of autoimmune and cutaneous diseases. Several cases of sarcoidosis have been reported with hepatitis C treatment, most recently in association with pegylated interferon alfa plus ribavirin. Systemic manifestations of sarcoidosis are usually treated with oral steroids, which unfortunately often increase the hepatitis C viral load. Thus, it is important to ascertain whether systemic corticosteroids are required to treat interferon alfa-associated sarcoidosis. OBSERVATIONS: We report the third case of cutaneous sarcoidosis in association with pegylated interferon alfa plus ribavirin treatment. Our patient had both cutaneous and pulmonary involvement, which has been spontaneously resolving since his treatment regimen was completed. In addition, we review the 12 previously reported cases of cutaneous sarcoidosis that occurred in patients undergoing hepatitis C treatment with interferon alfa. CONCLUSIONS: As the number of patients being treated with interferon alfa and ribavirin for hepatitis C increases, it is essential that dermatologists recognize the association of this treatment with sarcoidosis, because skin lesions may provide the first clue to diagnosis. Development of sarcoidosis may relate to hepatitis C as a possible antigenic trigger in the presence of an enhanced helper T cells type 1 response from treatment. Sarcoidosis with skin lesions in patients undergoing hepatitis C treatment often follows a benign course, and interferon alfa therapy may sometimes be continued with resolution of sarcoidosis occurring spontaneously or within a few months of completing treatment. Cautious use of systemic corticosteroids is warranted given their adverse effects on hepatitis C viral loads.     

Where does the antigen of cutaneous sarcoidosis come from?

Background: The antigen pathway of cutaneous sarcoidosis remains obscure. We have investigated topographic involvement of inflammatory cells and lymphatic vessels. Methods: Eleven cutaneous biopsies from eight patients were studied, along with controls from other granulomatous disorders and various skin lesions. Markers for lymphocytes, dendritic cells (DCs), and lymphatic vessel endothelial cells were detected using immunohistochemistry. Results: S100⁺ and CD1a⁺ immature DCs (Langerhans cells) occurred more frequently within the epidermis, whereas S100⁺, fascin⁺, or CD83⁺ maturing DCs occurred more frequently beneath the epithelium in cutaneous sarcoidosis cases than in controls (e.g. CD83, cutaneous sarcoidosis vs. other granulomatous disorders: r = 0.557, p = 0.011). Fascin⁺ and CD83⁺ mature DCs were often closely attached to CD3⁺ T‐lymphocytes around dermal granulomas. D2‐40⁺ lymphatic vessels were often found surrounding dermal granulomas, especially those located in the deeper dermis, in contrast to fascin⁺ blood vessels. Conclusions: Antigen‐capturing by immature DCs seems to take place initially in the epidermis, followed by maturation of DCs. These mature DCs may present the processed antigen to T‐lymphocytes that cause dermal granulomas either in the interstitium of the upper dermis, or in or around lymphatic vessels of the lower dermis. Environmental antigen could be verified by skin test. Kurata A, Terado Y, Izumi M, Fujioka Y, and Franke FE. Where does the antigen of cutaneous sarcoidosis come from?     

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.     

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.     

Cutaneous sarcoidosis: Prognosis and treatment

The physician who has made a diagnosis of cutaneous sarcoidosis is faced with three basic questions: (1) Are there lesions in organs other than the skin? (2) Should the patient be given treatment? (3) What will the final outcome of the disease be?

Cutaneous sarcoidosis can be a great imitator of other skin diseases with a wide spectrum of clinical manifestations ranging from small asymptomatic cutaneous lesions that fade spontaneously without scarring, to widespread skin lesions and disease in many organ systems. The latter may be associated with severe symptoms such as pulmonary insufficiency or life-threatening biochemical abnormalities. Approximately two thirds of all patients recover completely or with a minimum of residual changes, while 2–5% of sarcoidosis patients die from the disease.^1,2

It is therefore of interest to review the literature that deals with the course and prognosis of sarcoidosis. It is also important to deal with the association of cutaneous sarcoidosis and other types of sarcoidosis in order to provide the dermatologist with a basis for his or her decision about whether treatment should, in fact, be instituted.     

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.     

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.     

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.     

Thalidomid in der Behandlung der kutanen und systemischen Sarkoidose

The clinical courses of two patients suffering from generalized or disseminated cutaneous sarcoidosis are described. Both were treated with thalidomide 2×100 mg/day, later 100 mg/day. After 8 to 12 months of treatment the skin and systemic lesions had resolved almost completely.     

Successful treatment of lichen planus with sulfasalazine in 20 patients

BACKGROUND: Lichen planus (LP) is a disturbing pruritic cutaneous disease that may have an spontaneous resolution or exhibit a more chronic course during some weeks or months. OBJECTIVE: Our objective was to demonstrate that sulfasalazine is effective in the treatment of LP. METHODS: Twenty patients were diagnosed in our department with LP of the skin and/or mucosa between 1985 and 2001 on the basis of clinical and histologic findings. RESULTS: All patients were treated with sulfasalzine at initial doses of 1.5 g/day, increasing by 0.5 g/week to 3 g/day for 4-16 weeks. Some patients also received descendent doses for 2-12 months. Complete responses were observed in 13 patients and partial responses in seven patients. All patients reported an early resolution of the pruritus. No changes were detected in mucosal LP. Most of the patients tolerated the treatment well and only eight patients presented some minor side-effects. CONCLUSION: Sulfasalazine is a successful therapeutic option for cutaneous LP, constituting an alternative to corticosteroids and retinoids.     

Subcutaneous sarcoidosis--clinicopathological study of 10 cases

BACKGROUND: Subcutaneous sarcoidosis is a specific cutaneous lesion of sarcoidosis that is rarely reported. OBJECTIVE: Our purpose was to analyse the clinicopathological features of 10 patients with subcutaneous sarcoidosis and its relationship with the systemic features of the disease. PATIENTS AND METHODS: The patients with systemic sarcoidosis, diagnosed from 1974 to 2002 at a university hospital in Barcelona, Spain, who developed subcutaneous involvement, were included in the study. The diagnosis of systemic sarcoidosis was made according to conventional criteria. All the patients were monitored prospectively at the sarcoidosis clinic of the hospital. Skin biopsies were performed when granulomatous cutaneous involvement was suspected clinically. RESULTS: Granulomatous cutaneous involvement was demonstrated in 85 of 480 patients with systemic sarcoidosis. In 10 of these 85 patients subcutaneous sarcoidosis was diagnosed (11.8%). The lesions were most frequently located in the extremities, involving the forearms in nine patients. Indurated linear bands from the elbow to the hand were observed in five patients. In all of our patients the subcutaneous nodules appeared at the beginning of the disease. In six patients, the nodules remitted spontaneously in less than 2 years. In two cases foreign particles were detected under polarized light. CONCLUSIONS: Subcutaneous sarcoidosis is a quite uniform clinicopathological entity usually appearing at the beginning of the disease. It usually heralds forms of sarcoidosis with nonsevere systemic involvement and is not associated with chronic fibrotic 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.     

2%酮康唑制剂治疗小儿念珠菌皮炎110例临床观察

目的：为选择治疗小儿念珠菌皮炎适当而有效的药物和剂型，并了解其疗效。方法：用酮康唑片2g加入锌氧油或炉甘石洗剂中，配成2％酮康唑油剂或洗剂。外涂患处，每日3次，治疗1周观察。结果：1周治疗后，治愈98例（89.09%)，显效9例（8.18%)，好转3例（2．72％），总有效率为97．27％。结论：外涂2％酮康唑油剂、洗剂治疗小儿念珠菌皮炎无刺激性是目前安全有效理想的外用药。     

Foreign bodies in granulomatous cutaneous lesions of patients with systemic sarcoidosis

OBJECTIVE: To assess the presence of foreign material in the granulomatous cutaneous lesions of patients with systemic sarcoidosis. DESIGN AND SETTING: Observational study reevaluating histological specimens at a university referral hospital. PATIENTS: Sixty-five patients diagnosed as having sarcoidosis who developed granulomatous cutaneous involvement. MAIN OUTCOME MEASURES: To detect the presence of polarizable foreign particles in cutaneous biopsy specimens and to evaluate the association with clinical features of the patients. RESULTS: Granulomatous cutaneous involvement was demonstrated in 65 (15.3%) of 425 patients with systemic sarcoidosis. In 14 (22%) of the 65 patients, the cutaneous biopsy specimen showed foreign particles in polarized light. The skin lesions corresponded to 3 different clinical patterns: an admixture of papules and infiltration of previously undetected minute scars (n = 6); scar sarcoidosis (n = 4); and subcutaneous nodules (n = 4). The lesions were located most frequently in the extremities, involving the knees in 10 patients. CONCLUSIONS: The presence of polarizable foreign body material in granulomatous cutaneous lesions is not infrequent in patients with systemic sarcoidosis. Inoculation of foreign matter from a previous inapparent minor trauma may induce granuloma formation in individuals with sarcoidosis.