Introduction

Sarcoidosis is a systemic granulomatous disease of unclear origin that commonly affects the lungs, lymph nodes, eyes and the skin [1]. Cutaneous involvement is seen in about 25% of cases. Skin lesions are heterogeneous and may be specific, as maculopapular eruptions, plaques, infiltrated scars and lupus pernio, or nonspecific, as erythema nodosum, on the basis of the presence or the absence of the typical sarcoidal granulomas, respectively [2]. Subcutaneous sarcoidosis is a specific subset of cutaneous sarcoidosis, first described by Darier and Roussy in 1904, and is known also as Darier–Roussy sarcoid [3]. This variant represents sarcoidosis limited to the subcutaneous tissue and it is clinically characterized by multiple, firm, asymptomatic to slightly tender, mobile, round to oval, skin-colored nodules commonly located on the extremities (forearms and legs), commonly in a bilateral and asymmetric fashion. Other sites, such as the trunk, face, buttocks, head and neck, can also be affected. In contrast with erythema nodosum, the lesions in subcutaneous sarcoidosis are not tender, flesh coloured and may persist for much longer periods of time. Ahmed and Harshad have recently suggested a strong association between subcutaneous sarcoidosis and mild systemic involvement [4]. We describe here two cases of subcutaneous sarcoidosis with systemic involvement and review the literature about this condition.

Case 1

An 81-year-old man presented with a 6-month history of multiple, firm and asymptomatic, skin-coloured nodules on the lateral and extensor surface of both forearms and gradually increased in size and number to involve the thighs, buttocks and the dorsal surface of the hands (Fig. 1a). The overlying skin was normal. Biopsy examination of a subcutaneous nodule of forearm revealed non-caseating granulomas within subcutaneous tissue and deep dermis. Special stains for acid-fast bacilli and fungi were negative (Fig. 1b and c). The patient had a previous history of myocardial infarction. There was no palpable lymphadenopathy or hepatosplenomegaly. Results of cardiac and ophthalmological examination were normal. The complete blood count and routine biochemistry were normal. Erythrocyte sedimentation rate (ESR), C-reactive protein (PCR), rheumatoid factor, Waaler-Rose and antinuclear antibodies (ANA) were within normal range. Laboratory studies revealed an angiotensin-converting enzyme (ACE) level of 135 U/L (normal 8–54 U/L). Chest radiograph and skin tuberculin test were negative. Computed tomography disclosed multiple enlarged mediastinal lymph nodes. Gallium-67 scintigraphy showed diffuse hot spots in the upper mediastinum, intrapulmonary parahilar, axillary and collarbone lymph node groups and in submandibular glands. Lung function tests were normal. Patient was treated with oral prednisone at a dosage of 0.3 mg/kg daily, and the subcutaneous nodules gradually diminished in size with a complete resolution in 3 months.

Fig. 1
figure 1

Case 1: Subcutaneous nodules covered by normal-looking skin on the right forearm (a). Histology confirmed the presence of subcutaneous nodular infiltrates (×4, haematoxylin and eosin) (b), showing the typical features of sarcoid granuloma (×200, haematoxylin and eosin) (c)

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Case 2

A 69-year-old woman was referred because of multiple slightly tender, erythematous plum-sized lumps on the extensor surface of the upper and lower limbs of about 2 months duration (Fig. 2a). A biopsy revealed a normal epidermis and dermis. Subcutaneous fat tissue contained noncaseating epithelioid granulomas without acid-fast bacilli, fungi, other organisms or foreign-body particles (Fig. 2b and c). There was no palpable lymphadenopathy. The patient had a 10-year history of bilateral uveitis, treated with systemic corticosteroids that the patient had stopped by herself 1 year before. Other comorbidities included diabetes and hypercholesterolemia. Routine haematological and biochemical profiles were normal. ESR, rheumatoid factor, Waaler-Rose and ANA were normal. PCR level was 21 mg/L (normal range <5 mg/L). Serum ACE level was 99 U/L (normal range 8–54 U/L). The skin tuberculin test was negative. Chest radiograph was normal, but a high-resolution computed tomography of the chest revealed mediastinal lymphadenopathy with diffuse interstitial lung infiltrates. The ratio of diffusing capacity of the lung for carbon monoxide over alveolar ventilation was reduced. Gallium-67 scintigraphy showed increased uptake in the upper mediastinum, in both hila, in mayor salivary glands, knees and tibio-tarsic joints. Patient was treated with oral prednisone at a dosage of 0.4 mg/kg daily and the nodules completely resolved within 4 months.

Fig. 2
figure 2

Case 2: Subcutaneous nodules on the left arm (a). Histology showed the presence of subcutaneous nodular infiltrates (×4, haematoxylin and eosin) (b), with numerous giant cells characteristics of old sarcoid granuloma (×90, haematoxylin and eosin) (c)

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Discussion

Subcutaneous sarcoidosis is the less frequent of the specific cutaneous lesions of sarcoidosis [5]. In a recent series by Marcoval et al., it was observed in only 2% of patients with systemic sarcoidosis and represented about 12% of specific cutaneous lesions [6]. It typically affects middle-age subjects with a peak incidence during the fourth decade. It is slightly more frequent in females than in males and in caucasian than in Africans [7]. Fewer than 100 cases of subcutaneous sarcoidosis have been reported to date. The largest reported series published included 21 patients (15 women and 6 men) with a mean age of 46.3 years [4]. With the use of Vainsencher and Winkelmann’s histological criteria, we identified 85 cases of subcutaneous sarcoidosis reported in the literature through PubMed search (August 1, 1984 to November 30, 2010; terms: sarcoidosis, subcutaneous sarcoidosis, subcutaneous nodules) including our two cases (Table 1) [8]. Of these patients, 56 were female and 29 were male, with a mean age of 47 years. The nodules were distributed over the upper extremities in 69 patients and over the lower extremities in 54 patients. Other sites of involvement included the trunk in 27 patients, the face, head and neck in 12 patients and the buttock and groins in 9 patients. MRI appears to be the most useful diagnostic imaging modality. Gallium-67 scintigraphy is useful in detecting sarcoidosis lesions that are not apparent on clinical examination and it is also convenient for following the course during treatment. Recently Chen et al. have described the sonographic appearance of subcutaneous sarcoidosis, characterized by hyperechoic plaquelike lesions with irregular contours in the thickened subcutaneous tissue. The hypoechoic part corresponds to the noncaseating granulomas, and the hyperechoic part corresponds to the surrounding inflammatory infiltrates [9]. These findings are not specific but they might be helpful for early diagnosis of subcutaneous sarcoidosis.

Table 1 Features of 85 cases of subcutaneous sarcoidosis
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In the vast majority of patients, subcutaneous nodules were the principal manifestation that allowed the diagnosis of systemic sarcoidosis [4]. Evidence of systemic involvement was seen in 66 of the 85 patients (77.6%). Lymphadenopathy was identified in 56 patients (hilar in 38, hilar plus other in 14 and other in 4). Other systemic involvements in subcutaneous sarcoidosis were lung infiltrates in 17 patients, parotitis and uveitis in 7 patients each, arthritis/arthralgia in 6, mucositis in 5, dactylitis in 4, neurological and renal involvement in 3 patients each, hepatosplenomegaly in 2. Neurological involvement associated with subcutaneous lesions is rare, mainly characterized by cranial neuropathies as facial palsy and a favorable response to oral corticosteroid [10]. Serum ACE levels were elevated in 25 patients. Coexistence of subcutaneous lesions and other cutaneous lesions was found in 31 patients: papules, plaques and erythema nodosum in 9 patients each, scars sarcoid in 4 patients. An association between subcutaneous lesions and autoimmune diseases including thyroiditis, vitiligo, pernicious anaemia, rheumatoid arthritis, ulcerative colitis, systemic lupus erythematosus, sicca syndrome and Cushing syndrome was observed in 12 patients. Subcutaneous sarcoidosis occurring after interferon-α therapy for chronic hepatitis C was observed in six cases [11–16].

Because of the limited number of cases reported, it is difficult to assess the prognostic value of subcutaneous sarcoidosis in the evolution of the systemic disease, but in one study of ten cases, no patients developed chronic or severe complications [6]. These findings suggest that subcutaneous sarcoidosis has a relatively good prognosis. For patients with systemic involvement or disfiguring skin lesions, the mainstay of treatment is systemic corticosteroids. Traditional dosages range from 0.3 to 0.5 mg/Kg/day of prednisone, with responses noted within 4–8 weeks after initiation of therapy. Methotrexate, allopurinol, minocycline and potassium iodide have also been used with various responses [4, 17, 18].