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.     

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.     

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.     

Correlation between cutaneous sarcoidosis and systemic sarcoidosis.

Twenty patients with cutaneous sarcoidosis and 21 patients carrying isolated skin sarcoids were studied. (We use the term 'sarcoid' to emphasize that exclusively skin was altered.) Both groups were compared by clinical and histological patterns and certain data concerning the state of the mononuclear phagocyte system (MPS). It was found that skin lesions in sarcoids and sarcoidosis do not differ regarding either in clinical or histological manifestations. The changes in the functional activity of monocytes and macrophages were the same. The data obtained allow us to suggest that sarcoids should be regarded as a systemic disease connected with changes in the MPS reaction.     

Langhans-type and foreign-body-type multinucleated giant cells in cutaneous lesions of sarcoidosis

Multinucleated giant cells are characteristic of a monocyte-macrophage lineage in sarcoidosis and consist of two types of cells: Langhans-type with an arcuate arrangement of nuclei and a foreign-body type with random arrangement of nuclei. To compare these cells in the cutaneous lesions of sarcoidosis, we histologically and immunohistologically examined multinucleated giant cells in 25 scar infiltrations (cutaneous sarcoidosis with foreign bodies) and 30 cutaneous lesions of sarcoidosis without foreign bodies. Regardless of the presence or absence of foreign bodies, the cutaneous lesions had both types of multinucleated giant cells, usually with a predominance of the Langhans-type, although the numbers of total multinucleated giant cells were higher in scar infiltrations than in cutaneous sarcoidosis without foreign bodies, suggesting that their frequency is influenced by the microenvironment in sarcoidal lesions such as the presence of foreign bodies. Immunohistochemical studies using surface antigens of monocyte-macrophage lineage cells and adhesion molecules indicated that both types of multinucleated giant cells are formed from monocytes rather than tissue macrophages and are phenotypically the same cells with different distributions of nuclei.     

Lupus erythematosus: systemic and cutaneous manifestations

Skin and joint involvements are the most commonly occurring manifestations of systemic lupus erythematosus. There are 3 forms of cutaneous lupus: chronic cutaneous (discoid) lupus, subacute cutaneous lupus, and acute cutaneous lupus. Joint manifestations are usually not associated with warmth of the joints and may be only associated with pain and swelling. Painful or swollen joints respond rapidly to small or moderate doses of corticosteroids, whereas cutaneous manifestations usually respond to antimalarial drugs. Anti-Ro is associated closely with a photosensitive rash and with subacute lupus.     

Immunopathological studies on the cutaneous lesions in sarcoidosis

We examined the immunohistology of the cutaneous granulomas in sarcoidosis. By direct immunofluorescence immunoglobulin deposits were found in the skin lesions of 5 to 8 patients. These consisted of IgM within blood vessel wall (5 patients), IgM at the epidermal-dermal junction (2 patients) and IgG within and around the granuloma (2 patients). A fibrin network was present within the granulomas. Biopsy of a Kveim test site but not of uninvolved skin or of an erythema nodosum lesion showed similar immunofluorescence findings. Sheep erythrocytes sensitized with IgG antibody adhered to epithelioid cells within the granuloma indicating the presence of surface Fc receptors. At the periphery of the granulomas were B-lymphocytes. These findings are similar to those described in nodal and pulmonary sarcoid granulomas, and suggest that humoral antibodies may be important in the pathogenesis of the sarcoid granuloma.     

Immunologic studies on cutaneous lesions in sarcoidosis

To gain some understanding of the pathogenesis of sarcoid granuloma, several investigators have examined the immunohistology of the cutaneous lesions. Two general types of experimental approaches have been taken. First, skin biopsies have been examined by direct immunofluorescence for the presence of immunoreactants. Biopsy specimens taken from skin lesions, Kveim skin reaction, and clinically uninvolved skin of sarcoid patients have been examined. Second, the cellular composition and the architecture of the cutaneous granuloma have been studied by cytoadherence of cellular reagents and by cytochemistry and, more recently, with monoclonal antibodies of defined specificity to lymphocytes and other mononuclear cell populations.     

Epidermal changes in cutaneous lesions of sarcoidosis.

The essential histologic finding of cutaneous sarcoidosis is a noncaseating epithelioid cell granuloma in the dermis or, infrequently, in the subcutaneous tissues. However, there have been cases of cutaneous sarcoidosis with clinical appearances altered by epidermal changes such as ulcers, the formation of psoriasiform or verrucous plaques, and by hypopigmentation. In this study, histologic examinations of the epidermis were performed in cutaneous lesions of 62 cases of sarcoidosis. Seventy-nine percent (49/62) showed epidermal changes including hyperkeratosis (8/49), parakeratosis (10/49), acanthosis (6/49), and epidermal atrophy (35/49). Lymphoid cells extended into the epidermis in 50 of 62 cases. The infiltration patterns were in the forms of a spongiotic reaction (21/50), lichenoid tissue reaction (9/50), and simple exocytosis without epidermal vesiculation (20/50). Immunohistochemical studies showed that the lymphoid cells in the epidermis expressed CD3, 8, 45RO, and 11a. The epidermal changes overlying the granulomatous lesions contribute to the variety of clinical manifestations and are in part associated with the pathogenesis of cutaneous sarcoidosis.     

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.     

Annular lesions of cutaneous sarcoidosis with granulomatous vasculitis

Sarcoidosis is known to be involved in diseases with vasculitis as sarcoid vasculitis. However, vasculitis in cutaneous sarcoidal lesions is extremely rare. Here we describe a case of sarcoidosis with multiple annular skin lesions with granulomatous vasculitis. A 62‐year‐old female was diagnosed with sarcoidosis by chest‐abdominal computed tomographic examination and laboratory tests. The skin lesions had appeared on her lower limbs 2 years before. Physical examination showed multiple infiltrated annular eruptions on the lower extremities. A skin biopsy of an area of erythema showed multiple non‐caseating epithelioid cell granulomas in the dermis and subcutaneous fat and granulomatous vasculitis with fibrinoid degeneration in the subcutaneous fat. There are two types of vasculitis in sarcoidosis: leukocytoclastic and granulomatous vasculitis. Ulcers and livedo were more common in granulomatous vasculitis than in leukocytoclastic vasculitis. The present case had unique annular skin lesions of sarcoidosis with granulomatous vasculitis.     

Mast cells in leprosy skin lesions

The density and distribution of mast cells was assessed in skin biopsies of 118 untreated leprosy cases and 20 healthy individuals taken as controls. Mast cells were present in only small numbers in the skin biopsies of healthy individuals. Significantly higher mast cell counts were obtained in the skin lesions of indeterminate leprosy (P < 0.01). The mast cell count in the tuberculoid group was significantly lower than that in the lepromatous group (P < 0.05). The lepromatous group also showed increased mast cell degranulation and altered morphology. The mast cell distribution in the skin biopsies of the two groups was, however, similar. The mast cell count in leprosy is probably determined by the pattern of cytokines released by the T lymphocytes. However, the influence of mast cells on the outcome of the disease needs to be evaluated further.     

Mast cells in histoid lepromatous lesions

Ten patients with histoid lesions among the lepromatous leprosy cases, of both sexes in the age group of 35-65 years, were included in this study. Skin biopsy from the nodule with surrounding healthy skin of histoid lesion was taken. The biopsies were fixed in susa solution and processed for light microscopy. 5-7 mu thick sections were cut and stained with haematoxylin and eosin, Toludine blue and Fite faraco. Observations were made on the dermis to locate the mast cells and bacilli. Proliferation of mast cells and their degranulation was seen in the histoid nodule as compared to surrounding normal healthy skin where the cells were mainly intact. The study further investigates the role of mast cells in the histopathogenesis of the disease.     

Keratitis-ichthyosis-deafness syndrome: A comprehensive review of cutaneous and systemic manifestations

Keratitis-ichthyosis-deafness syndrome is a rare genetic disease presenting with cutaneous, ocular, and otic defects. This comprehensive review provides insight into the clinical presentations, highlighting the cutaneous manifestations including histopathology and treatment options.     

Treatment options for the cutaneous manifestations of systemic sclerosis

Systemic Sclerosis is a multisystem disorder with vascular instability as a clinical hallmark. Treatment currently consists of recognition and management of end-organ damage. Dermatologists can assist in the management of these patients by facilitating early diagnosis, and treating cutaneous manifestations such as Raynaud's phenomenon, cutaneous calcinosis, and digital ulceration. New potentially disease-modifying therapies are now undergoing clinical trials.