INTRODUCTION — Sarcoidosis is a granulomatous disease characterized by the presence of noncaseating granulomas in organs and tissue, such as the skin, lung, lymph nodes, eyes, joints, brain, kidneys, and heart. Cutaneous lesions may present with a variety of morphologies, including papules, nodules, plaques, and infiltrated scars.
The diagnosis of cutaneous sarcoidosis is supported by the recognition of compatible clinical features, the detection of classic histopathologic findings, and the exclusion of other granulomatous disorders. Compared with other sites of sarcoidal involvement, histopathologic sampling of lesions in the skin is a relatively simple and safe procedure. When present, cutaneous lesions can be a valuable asset in the confirmation of a diagnosis of sarcoidosis.
In addition to skin lesions that display noncaseating granulomas on biopsy, cutaneous eruptions that are not specific for sarcoidosis also may occur in patients with sarcoidosis. Erythema nodosum is the most frequent nonspecific cutaneous disorder associated with sarcoidosis.
The clinical manifestations and diagnosis of cutaneous sarcoidosis will be discussed here. The management of cutaneous sarcoidosis, the pathogenesis of sarcoidosis, and the clinical features, diagnosis, and treatment of extracutaneous sarcoidosis are reviewed elsewhere. (See "Cutaneous sarcoidosis: Management" and "Pathology and pathogenesis of sarcoidosis" and "Clinical manifestations and diagnosis of pulmonary sarcoidosis" and "Treatment of pulmonary sarcoidosis: Initial approach to treatment" and "Treatment of pulmonary sarcoidosis refractory to initial therapy".)
EPIDEMIOLOGY AND CLASSIFICATION — Skin manifestations of sarcoidosis are estimated to occur in approximately 25 percent of patients [1-6] and are divided into specific and nonspecific lesions based upon histopathologic features [7]. Specific skin lesions contain noncaseating (sarcoidal) granulomas, which represent the classic histopathologic findings in lesional tissue. All other cutaneous findings associated with sarcoidosis are classified as nonspecific. Patients may have both specific and nonspecific skin findings [8].
Specific lesions are estimated to occur in 9 to as many as 36 percent of patients with sarcoidosis, depending upon the characteristics of the evaluated population and study design [8,9]. Although their histopathologic features are similar, the clinical manifestations of specific lesions vary widely. Papules, nodules, plaques, and infiltrated scars are among the most common presentations; other manifestations also occur [9,10]. (See 'Clinical manifestations' below.)
The nonspecific lesions of sarcoidosis include a wide spectrum of disorders. Erythema nodosum, which typically presents as inflammatory, tender nodules on the lower legs, is the most common nonspecific cutaneous lesion of sarcoidosis. In one study of 516 patients with sarcoidosis, erythema nodosum was present in 20 percent of all patients and in 62 percent of patients with cutaneous disease [9]. Other examples of nonspecific cutaneous manifestations include calcinosis cutis, Sweet syndrome, and nail clubbing [7,11]. Although some authors have considered erythema multiforme a nonspecific manifestation of sarcoidosis [12], there is little evidence to support a definitive link between sarcoidosis and erythema multiforme. (See 'Nonspecific eruptions' below.)
PATHOGENESIS — The factors that lead to the development of sarcoidosis are not well understood. The pathogenesis is thought to involve genetically influenced dysregulation of the Th1 immune response to one or more extrinsic antigens, an event that could lead to the over-activation of inflammatory pathways and subsequent granuloma formation [13,14].
Multiple foreign bodies, infectious agents, and medications have been proposed as potential contributors to the development of sarcoidosis [13,15-18]. Polarizable material may be seen in 20 to 78 percent of skin biopsies of sarcoidosis, most commonly with papular, scar, and subcutaneous nodular types [15,18,19]. It is unknown whether environmental factors that come in contact with the skin serve as a nidus for granuloma formation or stimulate an aberrant immune response through other mechanisms [13,14,20]. Additional studies are necessary to explore the pathogenesis of cutaneous sarcoidosis. (See "Pathology and pathogenesis of sarcoidosis".)
HISTOPATHOLOGY — The characteristic histopathologic finding in specific lesions of cutaneous sarcoidosis is the presence of sarcoidal noncaseating granulomas, which consist of aggregates of epithelioid histiocytes, giant cells, and mature macrophages (picture 1A-B) [21]. These granulomas are surrounded by sparse lymphocytic infiltrates composed primarily of CD4+ T-cell lymphocytes and a few CD8+ lymphocytes. The absence of a dense lymphocytic infiltrate, such as is common in cutaneous lesions of tuberculosis, has led to the use of the term "naked granulomas" to describe this classic histopathologic finding in sarcoidosis.
The giant cells located within sarcoidal granulomas may contain intracytoplasmic inclusions. These structures are found in other granulomas and are not pathognomonic of sarcoidosis [4]:
●Asteroid bodies – Stellate, eosinophilic inclusions made up of complex lipids.
●Schaumann (conchoidal) bodies – Round or oval inclusions consisting of laminated calcium oxalate; these may represent residual bodies of lysosomes.
●Crystalline inclusions – Colorless, round or oval, refractile, nonlaminated inclusion bodies composed of calcium oxalate that may represent precursors of Schaumann bodies.
The histopathologic diagnosis of sarcoidosis is complicated by the fact that not all lesions of sarcoidosis demonstrate classic histopathologic findings [4,18,21-27]. While naked granulomas have been strongly associated with sarcoidosis, they are not always present. It is estimated that 71 to 89 percent of specific lesions of sarcoidosis contain typical sarcoidal granulomas [4,18,28]. Occasional cases of sarcoidosis may exhibit florid lymphocytic infiltrates at the periphery of granulomas, central caseation, vasculitis, or increased dermal mucin [4,18,21-27]. A retrospective European review found that a moderate or severe granulomatous infiltrate in biopsy specimens was associated with a more severe clinical presentation disease and more chronic disease course [29].
Epidermal changes are present in some histopathologic specimens of sarcoidosis and are dependent upon lesion type. Atrophy and parakeratotic scale are the most common epidermal changes detected. Epidermal spongiosis, hyperplasia, and ulceration are present occasionally.
Differential diagnosis — The histopathologic differential diagnosis of specific lesions of cutaneous sarcoidosis includes a variety of other granulomatous disorders. Examples include [30]:
●Foreign body reactions – The identification of refractile material with polariscopic examination of a histopathologic specimen suggests a foreign body reaction. Giant cells with multiple nuclei in a haphazard arrangement (foreign-body giant cells) are often present.
●Tuberculosis (lupus vulgaris variant) – The histopathologic features of lupus vulgaris can closely resemble sarcoidosis. A granulomatous infiltrate located primarily in the upper dermis, a more prominent peripheral lymphocytic inflammatory infiltrate, and the presence of significant central necrosis in granulomas suggest a diagnosis of lupus vulgaris. Lesions of lupus vulgaris also may demonstrate ulceration, acanthosis, and pseudoepitheliomatous hyperplasia. A negative acid-fast stain does not rule out lupus vulgaris.
●Tuberculoid leprosy – Granulomas in tuberculoid leprosy are often elongated and located along the course of nerves. Unlike in sarcoidosis, central caseation is a common feature of granulomas in tuberculoid leprosy. Acid fast stains reveal the presence of acid-fast bacilli in a minority of cases of tuberculoid leprosy.
Deep fungal and atypical mycobacterial infections should also be considered in the histopathologic differential diagnosis of sarcoidosis. Microbial stains and fresh tissue cultures can assist with ruling out these diagnoses.
ASSOCIATION WITH SYSTEMIC DISEASE — Because there are no large, well-designed studies, the risk for the development of systemic involvement in patients who present with disease limited to the skin is unknown [31,32]. Systemic involvement is estimated to occur in 30 to 85 percent of patients with cutaneous sarcoidosis [33].
Patients with the lupus pernio variant of cutaneous sarcoidosis or sarcoidosis manifesting in scars appear to have a high risk for pulmonary disease. In a retrospective study of 516 patients with sarcoidosis, pulmonary parenchymal involvement was present more frequently in patients with lupus pernio or sarcoidosis involving scar tissue (64 and 40 percent, respectively) than in patients with erythema nodosum or other specific lesions of sarcoidosis [9]. (See 'Lupus pernio' below.)
CLINICAL MANIFESTATIONS — Specific eruptions of sarcoidosis are characterized by the presence of sarcoidal granulomas on histopathologic examination. Specific lesions may occur in a variety of morphologies, but most commonly appear as papules or nodules. Lesions are often asymptomatic [34].
Papular sarcoidosis — Papular sarcoidosis is a common specific cutaneous manifestation of sarcoidosis (picture 2A-B) [12]. This variant presents with numerous nonscaly, 1 to 10 mm papules. Lesions can be skin-colored, yellow-brown, red-brown, violaceous, or hypopigmented. In some cases, the papules demonstrate a slight central depression [12]. Although papules can develop in chronic disease, this form of sarcoidosis is more common in patients with acute disease [6].
Papular sarcoidosis most frequently occurs on the face, with a predilection for the eyelids and nasolabial folds [12]. Coalescence of lesions may lead to the formation of annular or nonannular plaques [35]. Upon resolution, faintly discolored, occasionally atrophic macules may remain at previous sites of involvement [36].
A rare, micropapular variant consists of small, 1 to 2 mm, flesh-colored to faintly erythematous, nonfollicular, variably pruritic papules that erupt on the trunk, extremities, and/or face [37].
Papular lesions of sarcoidosis may clinically resemble granulomatous rosacea, appendageal tumors, xanthelasma, or xanthomas [7]. Infrequently, lesions may resemble lichen nitidus or erythema multiforme (picture 3) [38,39].
Nodular sarcoidosis — Nodular sarcoidosis is a relatively common form of cutaneous sarcoidosis that results from large collections of sarcoidal granulomas in the dermis or subcutaneous tissue [9,10]. In one series of patients with skin manifestations of sarcoidosis, nodules were present in 10 out of 28 patients (36 percent) [10]. Nodules tend to be between 1 and 2 cm in diameter and may be single or multiple. On the nose, nodular sarcoidosis can resemble rhinophyma (picture 4) [40,41]. The clinical differential diagnosis includes other types of nodular granulomas, such as foreign body reactions, granuloma annulare, rheumatoid nodules, lymphocytoma cutis, nodular cutaneous primary neoplastic and metastatic lesions, and atypical mycobacterial infections [8].
Subcutaneous sarcoidosis — The terms subcutaneous sarcoidosis and Darier-Roussy sarcoidosis are used to describe nodular sarcoidosis that primarily involves the subcutaneous tissue (picture 5) [4]. Subcutaneous sarcoidosis presents as erythematous, flesh-colored, violaceous, or hyperpigmented nodules. On the forearms, lesions often follow a linear distribution and even coalesce to form bands [42].
Estimates of the frequency of subcutaneous lesions in patients with sarcoidosis vary, ranging from 1 to 12 percent [4,43-45]. Based upon data from one retrospective review of 54 patients with subcutaneous sarcoidosis, the disorder may be more common in females and in middle-aged adults and may be associated with a predisposition to autoimmune disease [42]. Although some reports have suggested that subcutaneous sarcoidosis is a marker for an increased risk for systemic disease, the relationship remains controversial [4,42,44,46].
Patients with sarcoidosis have an increased risk for the development of erythema nodosum, which also can present with erythematous, tender nodules. The possibility of erythema nodosum should be considered in patients with sarcoidosis who present with nodular lesions, particularly when the nodules are located on the lower legs. In contrast to erythema nodosum, nodules of subcutaneous sarcoidosis predominate on the upper extremities and are not usually or only mildly tender [42]. Biopsy is useful for distinguishing between these diagnoses [42]. (See 'Erythema nodosum' below.)
Other lesions that may resemble subcutaneous sarcoidosis on clinical examination include lipomas, cysts, subcutaneous granuloma annulare, foreign body granulomas, or cutaneous manifestations of lymphoproliferative malignancies [7].
Maculopapular sarcoidosis — The prevalence of maculopapular sarcoidosis is difficult to assess due to the fact that some reports in the literature include the papular variant of sarcoidosis in this category [4,9]. This type is reported to be more common in patients with acute disease [8].
Characteristically, lesions are asymptomatic or pruritic, and consist of slightly infiltrated, slightly hyperpigmented patches studded with slightly raised papules that are often around 1 mm in diameter (picture 6). Lesions are usually red, brown, or violaceous. The lesions are occasionally pruritic [8]. Facial skin, especially the periorificial or eyelid area, is the most common site of involvement. Lesions may also occur on the neck, trunk, extremities, or mucous membranes.
Plaque sarcoidosis — Plaque sarcoidosis often presents with oval or annular, indurated, discrete plaques that are flesh-colored, erythematous, or brown (picture 7A-B). Occasionally, scale is present. Frequent sites of involvement include the shoulders and arms, back, and buttocks [7].
A number of other cutaneous disorders share clinical features with plaque sarcoidosis and should be considered in the differential diagnosis. Examples of disorders that may resemble plaque sarcoidosis include psoriasis, lichen planus, discoid lupus, granuloma annulare, cutaneous T cell lymphoma, lymphomatoid granulomatosis, Kaposi's sarcoma, and secondary syphilis. [7]. (See 'Psoriasiform sarcoidosis' below.)
Less common variants of plaque sarcoidosis are reviewed below. (See 'Angiolupoid sarcoidosis' below and 'Psoriasiform sarcoidosis' below and 'Verrucous sarcoidosis' below.)
Lupus pernio — Lupus pernio is characterized by violaceous or erythematous, indurated, infiltrative plaques that are primarily distributed on the central face (picture 8A-B), usually the alar rim, nasal tip, and cheeks. Other frequent sites of involvement include the ears and lips. Less commonly, lesions may affect the dorsal hands, fingers, or toes. Lupus pernio is less responsive to treatment than other sarcoidosis lesions [8]. Without treatment, the lesions progressively infiltrate and indurate, eventually resulting in erosion into the underlying cartilage and bone, causing considerable destruction and disfigurement [34]. The lesions heal with scarring, which is often left after healing [47]. Of note, all sarcoidosis lesions on the nose are not lupus pernio [48].
Lupus pernio disproportionally affects Black persons and women [49]. The presence of lupus pernio appears to be associated with an increased risk for extracutaneous disease, particularly sarcoidosis involving the respiratory tract [4,6,48,50,51]. Among 35 patients with lupus pernio in one case series, intrathoracic disease (lymphadenopathy or pulmonary abnormalities), upper respiratory disease, reticuloendothelial involvement, and ocular lesions were present in 74, 54, 54, and 37 percent, respectively [49]. When severe, granulomatous inflammation of the upper respiratory tract can result in airway obstruction [48].
Lytic and cystic bone lesions, especially in the hands and feet, can be present in bone underlying lesions of lupus pernio [50]. Among the 35 patients with lupus pernio in the case series described above, bone cysts were found in 50 percent of the patients who were radiographed, and in half of these cases, cysts were present in both the hands and feet [49].
Hypopigmented sarcoidosis — Hypopigmented sarcoidosis affects almost exclusively dark-skinned persons of African descent. Lesions manifest as hypopigmented, well-demarcated, round to oval patches or barely raised plaques (picture 9A-B) [12,52]. Skin colored or erythematous papules can be found in the center of some lesions of hypopigmented sarcoidosis, leading to an appearance that resembles a fried egg.
Atrophic and ulcerative sarcoidosis — Atrophic sarcoidosis is a form of plaque sarcoidosis that presents with depressed rather than elevated plaques. Ulceration may accompany the clinical findings. The term ulcerative-atrophic sarcoidosis may be used to describe lesions that are both atrophic and ulcerated (picture 10) [53].
Ulcerative-atrophic lesions occur in a minority of patients with sarcoidosis. In one retrospective series, ulcerative-atrophic sarcoidosis was detected in 7 out of 147 cases of cutaneous sarcoidosis (5 percent) [54]. All patients with ulcerative-atrophic lesions presented with other mucocutaneous manifestations of sarcoidosis and the majority also had internal disease. Ulcerative sarcoidosis may be more common in women and Black patients [53,54]. Ulcerated sarcoidosis is more common in the Black population and women than in the White population or in men [53].
Lesions of atrophic sarcoidosis may share features with morphea. In addition, atrophic sarcoidosis can share clinical features with necrobiosis lipoidica or lipodermatosclerosis; these variants often ulcerate. Similar to other specific lesions of sarcoidosis, histopathologic examination of atrophic types of sarcoidosis reveals noncaseating granulomas:
●Morpheaform – In the morpheaform variant, lesions begin as firm, sclerotic, flesh-colored or hyperpigmented plaques that evolve into depressed lesions over time [7]. The lesions occur more frequently on the lower extremities than on the upper extremities [55]. Histopathologic examination of the dermis reveals markedly thickened collagen bundles and obliteration of the subcutaneous tissue. Rarely, lesions occur in a linear distribution, a clinical presentation that closely resembles linear morphea [56].
●Necrobiosis-lipoidica-like – In a rare subtype of atrophic sarcoidosis, the necrobiosis-lipoidica variant, pink to violaceous plaques with depressed centers develop on the shins. Necrobiotic changes in collagen bundles surrounded by epithelioid histiocytes and foreign-body giant cells are present histologically.
●Lipodermatosclerosis-like – Lipodermatosclerosis-like atrophic sarcoidosis presents on the lower extremities as brown, indurated, circumferential, progressively fibrotic plaques. This variant of sarcoidosis should be considered in cases of lipodermatosclerosis (sclerosing panniculitis) that do not respond to compression and standard treatments. A feature that favors sarcoidosis is a unilateral distribution [57].
Rare variants — Angiolymphoid, psoriasiform, and verrucous sarcoidosis are rare variants of plaque sarcoidosis. Ichthyosiform and erythrodermic sarcoidosis are additional uncommon variants that present with extensive cutaneous involvement [34].
Angiolupoid sarcoidosis — Angiolupoid sarcoidosis (also called Brocq-Pautrier angiolupoid) is a variant of plaque sarcoidosis characterized by the presence of prominent large telangiectasias. Usually a single, minimally raised plaque develops on the central face, ears, or scalp; women are most frequently affected (picture 11A-B) [58]. The center of the lesion may be relatively lighter in color than the periphery, and in some cases, the plaque may possess an annular configuration. Angiolupoid sarcoidosis may be mistaken for rosacea or a large basal cell carcinoma.
Psoriasiform sarcoidosis — Psoriasiform sarcoidosis is a type of plaque sarcoidosis that presents with well-demarcated, erythematous, scaly plaques that may be indistinguishable from psoriasis (picture 12). In contrast to psoriatic lesions, sarcoidal plaques may resolve with scarring or atrophy.
Despite sharing a Th1 and Th17 pathogenesis, the association of psoriasis with sarcoidosis is rare, with the largest reported series consisting of seven cases. The authors suggested that uveitis may be less common in these patients, but the series is too small for conclusions [59].
Verrucous sarcoidosis — Lesions of verrucous sarcoidosis consist of well-demarcated, exophytic, hyperkeratotic, plaques or discrete, papillomatous, skin-colored papules (picture 13) or plaques [60]. Most cases involve the lower extremities. Lesions may resemble warts, prurigo nodularis, or hypertrophic lichen planus [60]. Patients usually have systemic involvement, frequently manifesting as significant pulmonary disease [61].
Disseminated lichenoid sarcoidosis — Disseminated lichenoid sarcoidosis is a very rare type characterized by multiple discrete miliary and lichenoid papules over patches of erythema in a distribution that may be so widespread as to resemble erythroderma [62].
Ichthyosiform sarcoidosis — Less than 35 cases of ichthyosiform sarcoidosis have been reported since 1981 [63]. The findings consist of adherent, irregular, polygonal, dry, gray or brown scales varying in size from 0.1 to 1 cm. Ichthyosiform sarcoidosis most commonly involves the pretibial area of the lower extremities (picture 14) [64].
The skin lesions appear concurrently with or precede the diagnosis of systemic sarcoidosis in approximately 75 percent of cases [63]; lesions occur in the setting of established systemic disease in the remainder. It is estimated that 95 percent of patients eventually develop systemic involvement [50].
The patient's history and the detection of dermal noncaseating granulomas in a biopsy specimen from affected tissue distinguish sarcoidal ichthyosis from other forms of ichthyosis [65]. Rarely, sarcoidosis manifests as ichthyosiform erythroderma, with sudden development of diffuse erythema and ichthyotic scale [66]. (See 'Erythrodermic sarcoidosis' below.)
Erythrodermic sarcoidosis — Erythrodermic sarcoidosis typically begins with slightly infiltrated, erythematous to yellow-brown plaques that subsequently coalesce over large areas of the skin (picture 15A-B) [67-70]. Desquamation is common. In contrast to classic exfoliative erythroderma, some areas of skin are usually spared. Patients with erythrodermic sarcoidosis may have symptoms or signs of concomitant systemic involvement, such as fever, weight loss, arthralgias, uveitis, and dyspnea [68].
The absence of large, thick, polygonal scales differentiates erythrodermic sarcoidosis from ichthyosiform erythroderma. The course of the disease is variable. Histopathologic evaluation is necessary to exclude more common causes of erythroderma such as psoriasis, eczema, drug eruptions, and cutaneous T-cell lymphoma [71].
Perforating sarcoidosis — The typical cutaneous manifestations of perforating sarcoidosis are papules with keratotic plug [72]. However, transepithelial elimination, a characteristic histopathologic finding of perforating disorders, has been reported in other types of lesions, such as facial papules. In one report, the presence of transepithelial elimination in scaly pruritic pubic papules and atrophic vulvar patches resembling lichen sclerosus prompted the authors to examine previous biopsies of cutaneous sarcoidosis cases [73]. They found that transepithelial elimination, defined as "epithelial channel formation with a sarcoidal-type granuloma completely surrounded by squamous epithelium," was present in 9 of 50 (18 percent) of their skin sarcoidosis cases.
Other — Other rare forms of cutaneous sarcoidosis reported in the literature include pustular sarcoidosis and a photodistributed form of sarcoidosis [12,74-76]. It is unclear whether photodistributed sarcoidosis is a true entity, or whether lesions actually represent the granulomatous variant of rosacea.
In addition, it remains to be seen whether syringotropic sarcoidosis, cutaneous sarcoidosis histologically characterized by granulomas surrounding eccrine glands, is a distinct clinical variant. Syringotropic sarcoidosis was reported in three young women who presented with erythematous patches and plaques on the lower extremities (resembling asteatotic eczema) and localized hypohidrosis [77]. Anhidrosis may also occur as a feature of systemic sarcoidosis due to sarcoidosis-associated autonomic dysfunction [78].
SARCOIDOSIS OF SPECIAL SITES
Scar sarcoidosis — The presence of sarcoidal granulomas in scar tissue is a relatively common manifestation of cutaneous sarcoidosis [9]. In one series of 170 patients with cutaneous sarcoidosis, 15 patients (9 percent) presented with disease involving scars [9]. Scars from surgical incisions, venipuncture, acne, pseudofolliculitis barbae, herpes zoster virus, and other forms of skin trauma are potential sites for the development of lesions [79-81]. Affected scars thicken, and occasionally become erythematous or violaceous. Lesions are often asymptomatic, but some patients may note a sensation of irritation.
Scar sarcoidosis can occur as early as six months to as long as 59 years after an injury [82]. Scar sarcoidosis can also appear acutely in patients with Löfgren syndrome. (See "Sarcoid arthropathy" and "Extrapulmonary manifestations of sarcoidosis", section on 'Löfgren syndrome'.)
Scar sarcoidosis may be more common than recognized since some lesions may be misdiagnosed as hypertrophic scars or keloids. Like sarcoidosis, keloids preferentially affect African-Americans and respond to intralesional corticosteroid therapy.
Koebnerization (the appearance of skin disease at sites of skin injury) may be a factor in some cases of scar or tattoo sarcoidosis. In two reported cases, erythematous sarcoidosis papules developed along veins on sites previously injected with narcotics [83].
The relationship between scar sarcoidosis and systemic sarcoidosis remains unclear. While some authors have proposed a strong link between scar sarcoidosis and systemic disease [84,85], others have commented on a more benign nature and good prognosis in patients who present with isolated scar sarcoidosis [7,86].
Tattoo sarcoidosis — Sarcoidal granulomas can develop in tattoos and may be the initial presentation of sarcoidosis in some patients. Tattoo sarcoidosis can occur within one year of tattoo placement or may develop decades after the tattoo was obtained [87]. Although red ink (cinnabar) tattoos are most commonly affected, sarcoidal infiltration in tattoos created with other pigments can also occur. The development of sarcoidal granulomas in tattoos of the eyebrows and lips has also been reported [87].
Affected tattoos develop papules within them or become raised, firm, and edematous (picture 16). Patients may experience pain or pruritus at sites of involvement.
Histopathologic examination reveals the presence of sarcoidal granulomas showing aggregates of epithelioid cells surrounded by peripheral rings of lymphocytes [87]. The histopathologic differential diagnosis includes foreign body reactions to tattoo pigment, which also present with granulomatous infiltrates in the dermis.
Since sarcoidal tattoo reactions can be the presenting signs of sarcoidosis, patients who present with these lesions should be evaluated for systemic disease. In one retrospective case series of 19 patients with scar sarcoidosis, hilar adenopathy, uveitis, arthritis, or pulmonary disease were present in 74, 21, 16, and 16 percent, respectively [87].
Alopecia — Hair loss is an uncommon specific manifestation of sarcoidosis. Sarcoidal alopecia is primarily seen on the scalp but may be seen in other areas, such as the face [88]. Alopecia may be scarring or nonscarring. Most cases have been reported in black patients [89].
Scalp sarcoidosis — Lesions on the scalp typically present as localized atrophic, annular, or indurated plaques, or flesh-colored or erythematous nodules (picture 17). Associated hair loss depends on the degree of sarcoidal involvement of the hair follicles and is not always present. Scale is usually absent but may be seen in some cases [89]. If scalp disease progresses, local destruction and scarring of hair follicles leads to the development of permanent alopecia that is indistinguishable from pseudopelade of Brocq. In some cases, scalp involvement may become extensive, leading to significant hair loss [89].
Follicular plugging, as seen in discoid lupus erythematosus, may also be present in patients with alopecia secondary to sarcoidosis [90]. The presence of orange spots on trichoscopy has been reported as a possible diagnostic clue for sarcoidosis [91].
Nail sarcoidosis — Sarcoidosis involving the fingers or toes can produce a wide variety of nail plate changes [92], such as thinning, brittleness, pitting, thickening, transverse layering (nail splitting), increased convexity, onycholysis [93], subungual hyperkeratosis [94], clubbing, pseudoclubbing, paronychia with nail fold fissuring, pterygium [95], longitudinal ridging [96], splinter hemorrhages [97], and red or brown discoloration of the nail bed [98,99]. Disease progression can eventually result in pterygium formation (adherence of the proximal nail fold to the nail bed) and total loss of the nail (anonychia).
Granulomatous infiltration of the nail matrix and compression by sarcoidal granulomas on nail structures may contribute to the appearance of nail dystrophy. Sarcoidal nail plate dystrophy is often accompanied by phalangeal bone disease.
The combination of nail disease and bone involvement can occur in sarcoidal dactylitis, a variant of sarcoidosis that presents with bilateral fusiform or sausage-shaped swellings of the fingers (picture 18) [45]. Radiographic examination of affected digits reveals erosions in the distal phalanges. "Drumstick dactylitis," a rare severe form of sarcoidal dactylitis characterized by bulbous swelling of the fingertips, has been associated with lupus pernio [46].
Genital sarcoidosis — There have been only a few reports of vulvar sarcoidosis, which can present with papules, plaques, or nodules [100-102]. Sarcoidosis of the male genitalia may present as indurated papules, painful nodules with or without ulceration, or swelling of the scrotum or penis [103-107].
Sarcoidosis of the oral cavity — Sarcoidosis involving the oral cavity is rare, with less than 70 reported cases. Presentations include papules, papulonodules, edema, ulcers, or gingival abnormalities such as gingivitis, gingival hyperplasia, or gingival recession (picture 19) [108-111]. In review of 47 cases of sarcoidal involvement of the soft tissues of the oral cavity, nodules and localized swelling were the most frequent manifestations of mucosal disease, occurring in 34 patients (72 percent) [108]. In the soft tissues of the oral cavity, the most commonly affected site was the buccal mucosa (28 percent), followed by the gingiva (22 percent), lips (13 percent), floor of the mouth or sublingual glands (11 percent), tongue (11 percent), palate (6 percent), and submandibular gland (4 percent) [108].
NONSPECIFIC ERUPTIONS — Erythema nodosum is the most common nonspecific cutaneous eruption of sarcoidosis. Examples of other nonspecific eruptions include calcinosis cutis, erythema multiforme, prurigo, Sweet syndrome, and nail clubbing.
Erythema nodosum — Erythema nodosum (EN) develops in up to 25 percent of patients with sarcoidosis and is clinically and histologically identical to erythema nodosum secondary to other causes [11]. Sarcoidosis is a relatively common cause of EN; in a Spanish study of 106 biopsy proven cases of EN, 20 percent of patients had sarcoidosis [112].
Patients with EN develop erythematous, tender, subcutaneous plaques and nodules predominantly located on the anterior tibial areas (picture 20A-B) [35]. Arthritis, lower extremity edema, and low grade fever are the most common systemic symptoms associated with EN. (See "Erythema nodosum".)
EN is a transient disorder. In a case series that included 251 patients with sarcoidosis-associated EN, over 85 percent had complete resolution within two years [113]. In addition, EN has been associated with a favorable prognosis for sarcoidosis [113,114].
The clinical features of subcutaneous sarcoidosis can resemble erythema nodosum [115]. Biopsy is useful for distinguishing between these disorders. Histopathologic findings in EN are consistent with a septal panniculitis.
Löfgren syndrome — Löfgren syndrome is an acute presentation of sarcoidosis characterized by the triad of hilar adenopathy, erythema nodosum, and polyarthralgia or arthritis, with or without parenchymal infiltrates or fever. The definition has been expanded to include patients with hilar adenopathy and periarticular inflammation with or without erythema nodosum. [116-118]. (See "Sarcoid arthropathy" and "Extrapulmonary manifestations of sarcoidosis", section on 'Löfgren syndrome'.)
The presence of bilateral hilar adenopathy and erythema nodosum is usually, but not always, caused by acute sarcoidosis. This presentation has also been reported in tuberculosis, lymphoma, streptococcal infection, histoplasmosis, coccidiomycosis, and Chlamydia pneumonia [119,120]. (See "Erythema nodosum".)
PEDIATRIC SARCOIDOSIS — Cutaneous involvement may be more common in the pediatric population than in adults. The skin may be involved in approximately 80 percent of children younger than five years of age with sarcoidosis and between 24 and 40 percent of older children with sarcoidosis [121]. The most common specific eruptions are papular, consisting of red to yellow-brown or violaceous flat-topped papules, usually on the face. However, the entire spectrum of clinical cutaneous sarcoidosis has been described in children [122]. In a retrospective study of 46 children with sarcoidosis (mean age of presentation 14 years), 10 (22 percent) had erythema nodosum, 10 had unspecified skin sarcoidosis, and 3 (7 percent) exhibited sarcoidosis involving scar tissue [123].
DIAGNOSIS — According to a consensus statement on sarcoidosis from the American Thoracic Society, the European Respiratory Society, and the World Association of Sarcoidosis and Other Granulomatous Disorders, the diagnosis of sarcoidosis requires a compatible clinical picture, the demonstration of noncaseating granulomas on tissue biopsy, and the exclusion of other disorders that can present with similar clinical and histopathologic findings [124]. The skin is easily accessible, and a biopsy of a specific cutaneous lesion of sarcoidosis is a simple and safe method of obtaining a tissue specimen. Thus, recognition of lesions of cutaneous sarcoidosis can be highly valuable in patients with symptoms or radiologic findings that are suggestive of systemic disease.
The detection of noncaseating granulomas in the skin is not sufficient to confirm a diagnosis of sarcoidosis in the absence of evidence for other organ involvement [124]. However, the identification of lesions that are clinically and histopathologically consistent with cutaneous sarcoidosis is useful for identifying patients who may benefit from further evaluation.
Examination and biopsy — The diagnosis of cutaneous sarcoidosis is supported by the identification of lesions that are morphologically compatible with sarcoidosis, the detection of sarcoidal granulomas on histopathologic examination, and the exclusion of other disorders in the differential diagnosis.
Clinical examination of the skin is the first step towards confirming a diagnosis of cutaneous sarcoidosis. Diascopy, a procedure that involves compressing a skin lesion with a clear glass microscope slide, is a simple method for detecting cutaneous granulomatous disorders on clinical examination. In granulomatous conditions, diascopy often reveals a subtle, brown-yellow or "apple jelly" color during lesion compression. This sign is most appreciable in individuals with light skin pigmentation. Diascopy is not a specific test for sarcoidosis, and other granulomatous disorders can exhibit similar findings.
Dermatoscopic evaluation is also not a specific diagnostic technique for cutaneous sarcoidosis, as similar findings may occur in other granulomatous lesions. The typical findings consist of translucent, yellowish or reddish-orange, focally distributed globules or large background areas. Common vascular features include linear vessels, branching vessels, or arborizing vessels; less common vascular findings are glomerular or dotted structures [125].
In lesions that are clinically suspicious for sarcoidosis, a skin biopsy should be performed to look for histopathologic features that are consistent with the diagnosis. Although noncaseating granulomas with sparse, peripheral lymphocytic infiltrates are characteristic of sarcoidosis, similar histopathologic features may be seen in other disorders, and not all lesions of sarcoidosis demonstrate classic findings [126]. (See 'Histopathology' above.)
Biopsy specimens should be examined under polarized light to evaluate for the presence of refractile material that could indicate granuloma formation secondary to a foreign body reaction. In addition, tissue staining for acid fast bacilli and fungi, microbial cultures of fresh tissue, and tuberculin skin testing should be performed if clinical or histopathologic features suggest the possibility of mycobacterial or deep fungal infections [18,85,127].
Evaluation for systemic disease — In the patient presenting with cutaneous lesions that are clinically and histopathologically consistent with sarcoidosis, the following work-up for systemic disease should be performed [128-130]:
●Focused patient history and review of systems
●Complete physical examination
●Posterior and anterior chest radiography
●Pulmonary function tests including diffusing capacity studies (see "Overview of pulmonary function testing in adults" and "Overview of pulmonary function testing in children")
●Electrocardiogram
●Tuberculin skin test or interferon-gamma release assay for latent tuberculosis (see "Use of interferon-gamma release assays for diagnosis of latent tuberculosis infection (tuberculosis screening) in adults" and "Tuberculosis infection (latent tuberculosis) in adults: Approach to diagnosis (screening)")
●Ophthalmologic examination
●Laboratory studies (complete blood count [CBC], serum calcium, hepatic transaminases, alkaline phosphatase, blood urea nitrogen [BUN], serum creatinine, urinalysis, baseline serum angiotensin converting enzyme level)
Other tests — Measurement of serum angiotensin converting enzyme (ACE) level is often considered in patients who present with signs or symptoms suggestive of sarcoidosis. However, ACE levels are nonspecific for the diagnosis of sarcoidosis [7]. ACE levels are sometimes used for following the response to treatment in patients with systemic sarcoidosis; the value of the test for this indication remains unclear. (See "Clinical manifestations and diagnosis of pulmonary sarcoidosis", section on 'Serum markers'.)
Other markers, such as serum lysozyme, neopterin, soluble interleukin-2 receptor, and osteopontin that can be elevated in the presence of granulomatous disease are even less specific than ACE levels for the diagnosis of sarcoidosis and are unlikely to be elevated in patients in whom the disease burden is limited to the skin [131]. In a targeted evaluation of primers associated with sarcoidosis in RNA from paraffin-embedded sarcoidal tissue (most from lymph nodes), T-bet mRNA expression was the only marker significantly greater in sarcoid granulomas than both suture granulomas and fungal granulomas [132]. Laboratory abnormalities such as leukopenia, anemia, eosinophilia, and hypercalcemia are rare in the absence of systemic disease.
Historically, the Kveim-Siltzbach test was used in the diagnosis of sarcoidosis [47]. The test involves the injection of spleen extract from an individual with systemic sarcoidosis into the dermis of patients with signs or symptoms suggestive of sarcoidosis. The injection site is subsequently biopsied to assess for the formation of granulomas. In one series of 127 patients with cutaneous sarcoidosis, 38 percent had a positive Kveim test six weeks after injection [47].
Due to poor standardization of the test, concern about transfer of viral infections, and unavailability of the substrate in many countries, the Kveim-Siltzbach test is rarely performed in the clinical setting.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Sarcoidosis".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topic (see "Patient education: Erythema nodosum (The Basics)")
SUMMARY AND RECOMMENDATIONS
●Sarcoidosis is a granulomatous disease that can affect one or more organs. Cutaneous involvement occurs in up to 25 percent of patients. (See 'Epidemiology and classification' above.)
●The pathogenesis of cutaneous sarcoidosis is not well understood. A combination of genetic and environmental factors may contribute an aberrant immune response and granuloma formation. (See 'Pathogenesis' above.)
●Specific lesions of sarcoidosis classically demonstrate noncaseating granulomas with sparse peripheral lymphocytic infiltrates on biopsy. Asteroid bodies or Schaumann bodies may be visible in giant cells within the granulomas. Foreign body reactions, mycobacterial infections, and fungal infections are among the disorders that should be considered in the histopathologic differential diagnosis. (See 'Histopathology' above.)
●The morphology of cutaneous lesions of sarcoidosis is variable. Examples of specific skin manifestations of sarcoidosis include papules, nodules, plaques, and atrophic or ulcerative lesions. The risk of the development of systemic sarcoidosis in patients who present with disease limited to the skin is unknown. (See 'Clinical manifestations' above and 'Association with systemic disease' above.)
●Lupus pernio is a distinct variant of cutaneous sarcoidosis that presents with violaceous or erythematous papules, plaques, or nodules predominantly involving the central facial skin. The nasal alae are often affected. Patients with lupus pernio appear to have an increased risk for sarcoidosis involving the respiratory tract. (See 'Lupus pernio' above.)
●The development of sarcoidosis in a scar or tattoo site may be the initial sign of sarcoidosis in some patients. Lesions may occur up to decades after the initial injury or tattoo. Clinicians should be aware of the possibility of sarcoidosis in patients with a changing or persistently inflammatory scar. (See 'Scar sarcoidosis' above and 'Tattoo sarcoidosis' above.)
●Erythema nodosum is the most common nonspecific manifestation of sarcoidosis. Patients usually present with inflammatory plaques or nodules involving the lower legs. Biopsy is useful for distinguishing erythema nodosum from subcutaneous sarcoidosis. Development of erythema nodosum is associated with a favorable prognosis for sarcoidosis with increased disease resolution. (See 'Erythema nodosum' above.)
●Diascopy is a useful test to identify signs of granulomatous disease during clinical examination. A skin biopsy should be performed to confirm the diagnosis of cutaneous sarcoidosis. Specimens should be examined under polarized light to look for evidence for foreign bodies. Stains of biopsied tissue and exudate and tissue cultures should be performed when clinical or histologic findings suggest the possibility of mycobacterial or deep fungal infections. (See 'Diagnosis' above.)
●Patients with cutaneous sarcoidosis should be evaluated for the possibility of systemic disease. Testing should include a complete physical exam, chest radiograph, pulmonary function test, electrocardiogram, tuberculin skin testing, a urinalysis, and several blood studies. (See 'Evaluation for systemic disease' above.)
