Advertisement

Sarcoidosis

  • Katerina DamevskaEmail author
  • Snejina Vassileva
  • Kossara Drenovska
  • Slavica Kostadinova-Kunovska
Living reference work entry

Abstract

Sarcoidosis (Boeck’s disease) is a multisystemic inflammatory disorder, characterized by the presence of noncaseating granulomas in multiple organs.

Cutaneous sarcoidosis is the first manifestation of the disease in almost one-third of the patients, providing valuable opportunity for early and correct diagnosis. It occurs in about 25% of the patients with systemic disease or can also be isolated. Some patients with systemic sarcoidosis may develop skin manifestations later in the disease course.

There are many different forms of cutaneous sarcoidosis, some of which are extremely rare. Nevertheless, patients may display more than one form simultaneously. Erythema nodosum and lupus pernio are the most common skin lesions.

Keywords

Sarcoidosis Boeck’s disease Noncaseating granuloma Naked granuloma Papular sarcoidosis Annular sarcoidosis Photodistributed sarcoidosis Lichenoid sarcoidosis Micropapular sarcoidosis Lichen nitidus-like sarcoidosis Maculopapular sarcoidosis Lupus pernio Besnier Angiolupoid sarcoidosis Brocq-Pautrier Plaque sarcoidosis Hypopigmented sarcoidosis Ichthyosiform sarcoidosis Verrucose sarcoidosis Erythrodermic sarcoidosis Scar sarcoidosis Morphea-form sarcoidosis Nodular sarcoidosis Subcutaneous sarcoidosis Darier-Roussy sarcoid Ulcerative sarcoidosis Mucosal sarcoidosis Erythema nodosum Löfgren syndrome Bilateral hilar lymphadenopathy 

1 Introduction

Sarcoidosis (Boeck’s disease) is a multisystemic inflammatory disorder, characterized by the presence of noncaseating granulomas in multiple organs. The incidence of sarcoidosis varies widely throughout the world, possibly related to differences in the genetic background or various environmental exposures, including infectious and noninfectious agents. The disease is more prevalent in women and among some ethnic groups.

The skin is the second most common organ affected by sarcoidosis (Wanat and Rosenbach 2015). Cutaneous sarcoidosis is the first manifestation of the disease in almost one-third of the patients, providing valuable opportunity for early and correct diagnosis. It occurs in about 25% of the patients with systemic disease or can also be isolated. Some patients with systemic sarcoidosis may develop skin manifestations later in the disease course.

Lesions of cutaneous sarcoidosis are presented across a broad clinical spectrum and distribution. Furthermore, they are divided into specific and nonspecific subgroups based on histological findings (Table 1). Specific lesions exhibit noncaseating granulomas. Nonspecific lesions do not have granulomas and are considered as reactive events associated with sarcoidosis. The frequency of specific cutaneous involvement in sarcoidosis ranges from 9% to 37%. The prevalence of a particular type of cutaneous lesion varies among races (Rose et al. 2008). The extent of cutaneous lesions does not correlate with that of systemic involvement (Veien et al. 1987). Patients may have more than one type of specific and nonspecific skin lesion, either at the same time or during the course of their disease (Sanchez et al. 2015).
Table 1

Classification of cutaneous sarcoidosis

 

Common

Rare

Specific lesions

Angiolupoid

Lupus pernio

Maculopapular

Micropapular

Papular

Plaque

Subcutaneous

Alopecia

Annular

Erythrodermic

Hypopigmented

Ichthyosiform

Lichenoid

Morphea-form

Mucosal

Sarcoidosis in scars

Ulcerative

Nonspecific skin lesion

Erythema nodosum

Calcifications

Erythema multiforme

Leucocytoclastic vasculitis

Nail clubbing

Prurigo

Sweet’s syndrome

Cutaneous lesions have prognostic significance. Löfgren’s syndrome is usually associated with spontaneous resolution, while plaques and, mainly, lupus pernio are hallmarks of chronic disease (Mañá and Marcoval 2012).

Sarcoidal granulomas represent compact, centrally organized collections of macrophages and epithelioid histiocytes (Fig. 1), and multinucleate giant cells of either Langhans or foreign body type (Fig. 2). Typical granulomas are surrounded by a sparse rim of lymphocytes and plasma cells (“naked” granulomas). The giant cells may contain intracytoplasmatic inclusions (Fig. 3), though these structures are not pathognomonic of sarcoidosis. Systemic work-up is necessary in any patient with cutaneous sarcoidosis. Treatment depends on other organ involvement and severity of the disease.
Fig. 1

Sarcoidal granulomas representing compact, centrally organized collections of macrophages and epithelioid histiocytes. (Taken by Dr. Slavica Kostadinova – Kunovska, Institute of Pathology, Medical Faculty, University “Ss Cyril and Methodius,” Skopje, Republic of Macedonia)

Fig. 2

Multinucleate giant cell in the sarcoidal granuloma. (Taken by Dr. Slavica Kostadinova – Kunovska, Institute of Pathology, Medical Faculty, University “Ss Cyril and Methodius,” Skopje, Republic of Macedonia)

Fig. 3

The giant cells containing intracytoplasmatic inclusions. (Taken by Dr. Slavica Kostadinova – Kunovska, Institute of Pathology, Medical Faculty, University “Ss Cyril and Methodius,” Skopje, Republic of Macedonia)

2 Specific Skin Manifestations of Sarcoidosis

2.1 Papular Sarcoidosis

  • Definition: Papular sarcoidosis is one of the most common form of cutaneous sarcoidosis that presents with nonscaly, asymptomatic papules.

  • Clinical feature: The papules are slightly infiltrated and measured 1–10 mm. Lesions are most commonly located on the face, with a predilection for the eyelids, nasolabial folds, and extensor aspects of the extremities (Fig. 4). Papules may be skin-colored, red-brown to purple, yellow-brown, or hypopigmented. Annular sarcoidosis may be regarded as a variant of papular sarcoidosis with annular pattern (Fig. 5). It may appear on the face and present with persistent circinate lesions with central atrophy and telangiectasia. Photodistributed sarcoidosis represents a form of sunlight-induced papular sarcoidosis. Lichenoid sarcoidosis is more frequent in children and can present as small, flat-topped, skin-colored to erythematous papules (Garrido-Ruiz et al. 2008).

  • Pathological manifestation: Noncaseating granulomas superficially located in the upper dermis are seen in this type of sarcoidosis.

  • Prognosis and treatment: Spontaneous resolution is common. The first-line therapies are topical corticosteroids and topical tacrolimus. Antimalarials and oral corticosteroids are recommended for resistant to topical therapy. Tumor necrosis factor-alfa (TNF-α) inhibitors may also be effective.

  • Differential diagnosis: Granulomatous rosacea, appendageal tumors, xanthelasma, xanthomas, syringoma, trichoepithelioma, acne agminata (lupus miliaris disseminatus faciei) for clinical view, and acne agminata (lupus miliaris disseminatus faciei) for histological view
    Fig. 4

    Papular sarcoidosis showing linearly distributed papules. (Courtesy of Dr. Mina Saleva, Department of Dermatology and Venereology, Medical Faculty, University of Medicine, Sofia, Bulgaria)

    Fig. 5

    Annular sarcoidosis on the upper back. (Taken by Dr. Katerina Damevska, Clinic of Dermatology, Medical Faculty, University “Ss Cyril and Methodius,” Skopje, Republic of Macedonia)

2.2 Micropapular Sarcoidosis (Lichen Nitidus-Like Sarcoidosis)

  • Definition: Micropapular sarcoidosis, also known as lichen nitidus-like sarcoidosis, is very rare morphologic variety of papular sarcoidosis, characterized by acute or gradual onset of pinpoint flesh-colored papules and favorable prognosis.

  • Clinical feature: Innumerable agminated micropapules on the face, trunk (Fig. 6), and extremities around 1 mm in diameter are seen in this type. Systemic involvement is rare with the micropapular variant; however, ocular involvement tends to occur more frequently (Modi and Rosen 2008).

  • Pathological manifestation: Noncaseating granulomas superficially located in the papillary dermis are seen in this type of sarcoidosis.

  • Prognosis and treatment: It has good prognosis without a tendency to scar. Hydroxychloroquine sulfate is the first-line systemic treatment in this clinical setting (Modi and Rosen 2008).

  • Differential diagnosis: Lichen nitidus, lichen scrophulosorum, generalized papular granuloma annulare, and generalized eruptive histiocytoma.
    Fig. 6

    Micropapular sarcoidosis; (a) small, flat-topped, skin-colored to erythematous papules, and (b) atrophic and hypopigmented residual lesions following systemic treatment. (Taken by Dr. Katerina Damevska, Clinic of Dermatology, Medical Faculty, University “Ss Cyril and Methodius,” Skopje, Republic of Macedonia)

2.3 Maculopapular Sarcoidosis

  • Definition: Maculopapular sarcoidosis is one of the most common specific lesions of cutaneous sarcoidosis, manifesting as an acute maculopapular eruption, and associated with a favorable outcome (Ruocco et al. 2015; English et al. 2001).

  • Clinical feature: It is characterized by acute eruption of indolent, red-brown, or purple macules and papules up to 5 mm in diameter (Fig. 7). Lesions may be localized or generalized, sparsely distributed or in clusters. Maculopapular lesions are commonly associated with the acute forms of sarcoidosis such as bilateral hilar lymphadenopathy, erythema nodosum, acute uveitis, or parotid enlargement.

  • Pathological manifestation: Noncaseating granulomas superficially located in the upper dermis are seen in this type of sarcoidosis.

  • Prognosis and treatment: Maculopapular lesions are more often associated with remission of the systemic disease at 2 years (Mañá and Marcoval 2012). Spontaneous resolution is possible with or without atrophic scarring. First-line therapies are topical corticosteroids and topical tacrolimus. Oral corticosteroids are recommended for rapidly progressive or resistant to topical therapy cases. Immunosuppressants, antimalarials, and TNF-α inhibitors may also be effective (Haimovic et al. 2012; Badgwell and Rosen 2007; Baughman and Lower 2007).

  • Differential diagnosis: Lichen nitidus, generalized papular granuloma annulare, lichen scrofulosorum, xanthoma disseminatum, and urticarial pigmentosa (Tchernev et al. 2010)

Fig. 7

Maculopapular sarcoidosis: asymptomatic, red-brown and purple macules and papules up to 5 mm in diameter. (Taken by Dr. Katerina Damevska, Clinic of Dermatology, Medical Faculty, University “Ss Cyril and Methodius,” Skopje, Republic of Macedonia)

2.4 Lupus Pernio (Besnier)

  • Definition: Lupus pernio, also known as Besnier, is the most characteristic cutaneous lesion of sarcoidosis that frequently results in considerable cosmetic disfigurement.

  • Clinical feature: Indolent, red-to-purple, or violaceous nodular or plaque-like lesions that may affect the cheeks (Fig. 8), nose (Fig. 9), forehead, ears, perioral, or periocular regions. The lesions are thick and indurated, with a network of telangiectases. They heal with atrophy, sometimes causing characteristic mutilation of the nose and ears. Lupus pernio commonly coexists with other cutaneous involvement. The diascopy of the lesions reveals an apple jelly appearance (Fig. 10).

  • Pathological manifestation: Noncaseating granulomas located in the upper dermis associated with dilated capillaries are seen in this type of sarcoidosis.

  • Prognosis and treatment: It is the hallmark of chronic disease, and systemic sarcoidosis is frequently concurrent (Mañá and Marcoval 2012). High potency topical corticosteroids and tacrolimus may be effective. The CO2 laser has been used successfully in the remodeling of lupus pernio (O’Donoghue and Barlow 2006). Systemic corticosteroids are effective although rarely result in resolution (Stagaki et al. 2009). Other systemic treatments include methotrexate, azathioprine, chloroquine, hydroxychloroquine, thalidomide, fumaric acid esters, minocycline, doxycycline, mycophenolate mofetil, allopuranol, and anti-TNF agents (Heidelberger et al. 2017).

  • Differential diagnosis: Chilblain, lupus vulgaris, chilblain lupus, rhinophyma, tuberculoid leprosy, facial eosinophilic granuloma, cutaneous leishmaniasis, deep fungal, tertial syphilis, cheilitis granulomatosa, Wegener’s granulomatosis, polymorphic light eruption, and benign or malignant lymphocytic infiltrate (Tchernev et al. 2010).

Fig. 8

Lupus pernio in a patient with pulmonary sarcoidosis showing erythematous lesions on labial semi-mucosa. (Taken by Dr. Katerina Damevska, Clinic of Dermatology, Medical Faculty, University “Ss Cyril and Methodius,” Skopje, Republic of Macedonia)

Fig. 9

Lupus pernio; indolent reddish-purple plaques and nodules on the nose in a patient with pulmonary sarcoidosis. (Taken by Dr. Katerina Damevska, Clinic of Dermatology, Medical Faculty, University “Ss Cyril and Methodius,” Skopje, Republic of Macedonia)

Fig. 10

The diascopy of the lupus pernio lesions on the nose (an apple jelly appearance). (Taken by Dr. Katerina Damevska, Clinic of Dermatology, Medical Faculty, University “Ss Cyril and Methodius,” Skopje, Republic of Macedonia)

2.5 Angiolupoid Sarcoidosis (Brocq-Pautrier)

  • Definition: Angiolupoid sarcoidosis, also known as Brocq-Pautrier, is a rare variant of the disease, affecting 8% of the patients with cutaneous sarcoidosis, and characterized by the distinctive clinical appearance with purplish pink to light orange-brown plaques or nodules, and prominent telangiectasias.

  • Clinical feature: It affects mainly middle-aged women, and is preferentially located on the face (Fig. 11), ears, or scalp. Clinically, it manifests as single plaques, which eventually acquire annular shape with prominent telangiectasias (Sanchez et al. 2015; Arias-Santiago et al. 2010).

  • Pathological manifestation: Noncaseating granulomas situated in the dermis associated with large telangiectatic vessels are seen in this type of sarcoidosis.

  • Prognosis and treatment: Evolution is very slow, with little tendency for spontaneous regression. Pulse dye laser can be useful for vascular components. Anti-TNF drugs can be used in cases that are resistant to multiple treatments (Arias-Santiago et al. 2010).

  • Differential diagnosis: Lupus vulgaris, chilblain lupus, tuberculoid leprosy, facial eosinophilic granuloma, cutaneous leishmaniasis, deep fungal infections, polymorphic light eruption, benign or malignant lymphocytic infiltrate, and basal cell carcinoma (BCC).

Fig. 11

Angiolupoid sarcoidosis with prominent telangiectasias. (Taken by Dr. Kossara Drenovska, Department of Dermatology and Venereology, Medical Faculty, University of Medicine, Sofia, Bulgaria)

2.6 Plaque Sarcoidosis

  • Definition: Plaque sarcoidosis is a frequent form of cutaneous sarcoidosis with chronic course, characterized by well-demarcated infiltrated plaques.

  • Clinical feature: Plaques are round to oval, red-brown to purple, and have a predilection for the limbs, back, face, and scalp. When plaques are multiple, distribution of the lesions tends to be symmetric. Scaling plaques may mimic psoriasis (Fig. 12); plaques on the face can imitate discoid lupus (Fig. 13), particularly when central atrophy is present. When plaques involve the scalp, they may lead to alopecia (Fig. 14). Hypopigmented sarcoidosis mainly affects dark-skinned patients (Fig. 15). Some lesions may be centered by erythematous papules, leading to a “fried egg” appearance (Sanchez et al. 2015). Plaques on the legs can imitate necrobiosis lipoidica (Fig. 16). Verrucose sarcoidosis presents with well-demarcated hyperkeratotic lesions, usually located on the lower extremities. Ichthyosiform sarcoidosis (Fig. 17) presents as large, skin-colored to tan patches with adherent, polygonal, gray, or brown scale on the distal extremities. Erythrodermic sarcoidosis presents with slightly infiltrated, erythematous plaques coalescing over large areas (Fig. 18) (Sanchez et al. 2015).

  • Pathological manifestation: Noncaseating granulomas are present throughout the entire dermis (Fig. 19). In erythrodermic form, the foci of epithelioid cells are small (Fig. 20).

  • Prognosis and treatment: The evolution may extend over several years with remissions and relapses. Spontaneous resolution is possible with or without atrophic scarring. This form is often refractory to topical treatment. Oral corticosteroids are recommended for rapidly progressive cases. Immunosuppressants, antimalarials, and TNF-α inhibitors may also be effective (Haimovic et al. 2012; Badgwell and Rosen 2007; Baughman and Lower 2007).

  • Differential diagnosis: Psoriasis, lichen planus, cutaneous lupus erythematosus, erythema elevatum diutinum, necrobiotic xanthogranuloma, cutaneous T-cell lymphoma, Kaposi’s sarcoma, morphea, leprosy, and leishmaniasis (Tchernev et al. 2010).
    Fig. 12

    Plaque sarcoidosis; scaling plaques mimicking psoriasis. (Taken by Dr. Katerina Damevska, Clinic of Dermatology, Medical Faculty, University “Ss Cyril and Methodius,” Skopje, Republic of Macedonia)

    Fig. 13

    Plaque sarcoidosis on the face. (Taken by Dr. Katerina Damevska, Clinic of Dermatology, Medical Faculty, University “Ss Cyril and Methodius,” Skopje, Republic of Macedonia)

    Fig. 14

    Cicatricial alopecia due to sarcoidosis. (Taken by Dr. Katerina Damevska, Clinic of Dermatology, Medical Faculty, University “Ss Cyril and Methodius,” Skopje, Republic of Macedonia)

    Fig. 15

    Hypopigmented sarcoidosis mainly affecting dark-skinned patients who develop well-demarcated, round hypopigmented patches. (Taken by Dr. Katerina Damevska, Clinic of Dermatology, Medical Faculty, University “Ss Cyril and Methodius,” Skopje, Republic of Macedonia)

    Fig. 16

    Plaque sarcoidosis; plaques on the legs imitating necrobiosis lipoidica. (Taken by Dr. Snejina Vassileva, Department of Dermatology and Venereology, Medical Faculty, University of Medicine, Sofia, Bulgaria)

    Fig. 17

    Ichthyosiform sarcoidosis; asymptomatic, adherent, polygonal scales on the lower extremities. (Taken by Dr. Katerina Damevska, Clinic of Dermatology, Medical Faculty, University “Ss Cyril and Methodius,” Skopje, Republic of Macedonia)

    Fig. 18

    Erythrodermic sarcoidosis. (Taken by Dr. Katerina Damevska, Clinic of Dermatology, Medical Faculty, University “Ss Cyril and Methodius,” Skopje, Republic of Macedonia)

    Fig. 19

    Pathology of plaque sarcoidosis; well-formed noncaseating epithelioid granulomas throughout the entire dermis. (Taken by Dr. Katerina Damevska, Clinic of Dermatology, Medical Faculty, University “Ss Cyril and Methodius,” Skopje, Republic of Macedonia)

    Fig. 20

    Pathology of erythrodermic sarcoidosis showing small foci of epithelioid cells. (Taken by Dr. Katerina Damevska, Clinic of Dermatology, Medical Faculty, University “Ss Cyril and Methodius,” Skopje, Republic of Macedonia)

2.7 Scar Sarcoidosis

  • Definition: Scar sarcoidosis is one of the most specific and least prevalent forms of sarcoidosis characterized by onset of sarcoidal lesions in places of previous skin trauma.

  • Clinical feature: It develops through granulomatous infiltration of postsurgical scars (Fig. 21), vaccination sites, tattoos, traumas caused by tribal scarification, herpes zoster scars, venous puncture, and injections. Scars are infiltrated, and inflamed with a violaceous coloration (Kluger 2013).

  • Pathological manifestation: Noncaseating granulomas situated in the dermis are seen in this type of sarcoidosis.

  • Prognosis and treatment: The evolution may extend over several years with remissions and relapses. Treatment is guided by the individual patient’s manifestations.

  • Differential diagnosis: Hypertrophic scar, keloid, and incisional skin metastasis in a scar from a previous surgery for internal malignancy.
    Fig. 21

    Scar sarcoidosis. (Taken by Dr. Katerina Damevska, Clinic of Dermatology, Medical Faculty, University “Ss Cyril and Methodius,” Skopje, Republic of Macedonia)

2.8 Morphea-Form Sarcoidosis

  • Definition: Morphea-form sarcoidosis is a very rare manifestation of cutaneous sarcoidosis. The mechanisms involved in the fibrosis are unknown (Ginarte et al. 2006).

  • Clinical feature: The clinical picture is indistinguishable from the true morphea, frequently resembling a linear morphea. Most patients with this type of sarcoidosis have sarcoid arthritis, which is a rare manifestation of sarcoidosis (Ginarte et al. 2006).

  • Pathological manifestation: Prominent dermal sclerosis and presence of sarcoidal granulomas are seen in this type. The dermal sclerosis correlates with the clinical induration (Burov et al. 1998).

  • Prognosis and treatment: Good response to antimalarial drugs has been reported, so these drugs may be considered as first choice therapy (Ginarte et al. 2006).

  • Differential diagnosis: Morphea and lipodermatosclerosis (Huang and Mutasim 2005).

2.9 Nodular Sarcoidosis

  • Definition: Nodular sarcoidosis is a common form of cutaneous sarcoidosis that results from large collections of sarcoidal granulomas in the dermis or subcutaneous tissue.

  • Clinical feature: It predominantly affects the face (Fig. 22) and proximal parts of the limbs (Fig. 23). It is characterized by the presence of well-defined, red-brown nodules, above 5 mm in size, and often with surface telangiectasia. The lesions may remain static for years.

  • Pathological manifestation: Noncaseating granulomas situated deep in the dermis (Fig. 24) and subcutaneous tissue are seen in this type.

  • Prognosis and treatment: The evolution may extend over several years with remissions and relapses. Treatment is guided by the individual patient’s manifestations. Oral corticosteroids are recommended for rapidly progressive cases. Immunosuppressants, antimalarials, and TNF-α inhibitors may also be effective (Haimovic et al. 2012, Badgwell and Rosen 2007, Baughman and Lower 2007).

  • Differential diagnosis: Rheumatoid nodules, fibromas, BCC, metastatic lesions, xanthomas, epidermoid cysts, and subcutaneous granuloma annulare.
    Fig. 22

    Nodular sarcoidosis on the face. (Taken by Dr. Katerina Damevska, Clinic of Dermatology, Medical Faculty, University “Ss Cyril and Methodius,” Skopje, Republic of Macedonia)

    Fig. 23

    Nodular sarcoidosis showing tender, erythematous subcutaneous nodules on the upper arm. (Taken by Dr. Kossara Drenovska, Department of Dermatology and Venereology, Medical Faculty, University of Medicine, Sofia, Bulgaria)

    Fig. 24

    Pathology of nodular sarcoidosis showing noncaseating granulomas situated deep in the dermis and subcutaneous tissue. (Taken by Dr. Slavica Kostadinova – Kunovska, Institute of Pathology, Medical Faculty, University “Ss Cyril and Methodius,” Skopje, Republic of Macedonia)

2.10 Subcutaneous Sarcoidosis (Darier-Roussy Sarcoid)

  • Definition: Subcutaneous sarcoidosis, also known as Darier-Roussy sarcoid, is a specific subtype of nodular cutaneous sarcoidosis characterized by a peak in the incidence during the fourth decade, female predisposition, and a strong association with a systemic disease (Ahmed and Harshad 2006).

  • Clinical feature: It is characterized by asymptomatic to slightly tender subcutaneous lesions typically involving the upper extremities, trunk, face, head, and neck. Forearms are most commonly involved, with nodules or indurated linear bands from the elbow to the hand. Subcutaneous nodules are multiple, usually from 1 cm to 4 cm in diameter, deeply seated, skin-colored, more palpable than visible (Figs. 25 and 26). Rarely, the nodules may be blue or purplish. The coexistence of other types of lesions (specific and nonspecific) has been reported in two-thirds of patients with subcutaneous involvement.

  • Pathological manifestation: Noncaseating granulomas involving predominantly the panniculus are seen (Fig. 27).

  • Prognosis and treatment: It may resolve spontaneously within 1–2 years. The systemic involvement is nonsevere and is not associated with chronic fibrotic disease. Favorable response to oral corticosteroid therapy is typically observed (Marcoval et al. 2005).

  • Differential diagnosis: Panniculitis, lupus erythematosus profundus, erythema nodosum, erythema elevatum diutinum, and thrombophlebitis.

Fig. 25

Darier-Roussy subcutaneous sarcoidosis on the thighs showing multiple, deeply seated, skin-colored, more palpable than visible nodules. (Taken by Dr. Katerina Damevska, Clinic of Dermatology, Medical Faculty, University “Ss Cyril and Methodius,” Skopje, Republic of Macedonia)

Fig. 26

Darier-Roussy subcutaneous sarcoidosis; fingers affected by the osteitis cystica showing swellings due to bone changes and cutaneous infiltration. (Taken by Dr. Snejina Vassileva, Department of Dermatology and Venereology, Medical Faculty, University of Medicine, Sofia, Bulgaria)

Fig. 27

Pathology of subcutaneous sarcoidosis. (Taken by Dr. Katerina Damevska, Clinic of Dermatology, Medical Faculty, University “Ss Cyril and Methodius,” Skopje, Republic of Macedonia)

2.11 Ulcerative Sarcoidosis

  • Definition: Ulcerative sarcoidosis is a distinct form of cutaneous sarcoidosis, affecting roughly 5% of people with sarcoidosis, which clinically presents as plaque or nodular lesions with ulceration (Huang and Mutasim 2005).

  • Clinical feature: The legs are the most common location of ulcer formation. Ulceration may arise de novo, but more commonly arises in preexisting nodular or plaque lesions (Fig. 28a). It heals with scarring (Fig. 28b). This form is frequently associated with other types of cutaneous sarcoidosis (Fig. 29).

  • Pathological manifestation: Noncaseating granulomas situated in the dermis are seen. Necrotizing granulomas and granulomatous vasculitis are also described (Noiles et al. 2013).

  • Prognosis and treatment: Topical, intralesional, and systemic corticosteroids, and antimalarials and other immunosuppressive agents are used for it. Split thickness skin graft can be used for treatment of nonhealing ulcers.

  • Differential diagnosis: Foreign body granulomas, metastatic Crohn’s disease, and infectious granulomatous processes including gummatous ulceration, ulcerative form of leishmaniasis, tuberculosis cutis colliquativa, sporotrichosis, and actinomycosis.

Fig. 28

Ulcerative sarcoidosis in a patient with systemic disease; (a) before treatment and (b) after treatment. (Taken by Dr. Katerina Damevska, Clinic of Dermatology, Medical Faculty, University “Ss Cyril and Methodius,” Skopje, Republic of Macedonia)

Fig. 29

Other types of cutaneous sarcoidosis in the patient with ulcerative sarcoidosis presented on Fig. 25; (a) nodular type and (b) plaque type. (Taken by Dr. Katerina Damevska, Clinic of Dermatology, Medical Faculty, University “Ss Cyril and Methodius,” Skopje, Republic of Macedonia)

2.12 Mucosal Sarcoidosis

  • Definition: Mucosal sarcoidosis can affect the oral cavity, but also the nasal and anogenital mucosae. Mucosal involvement constitutes more serious disease and often requires high-dose corticosteroids and other immunosuppressive agents.

  • Clinical feature: The most common morphology is that of nontender, brownish-red or violaceous nodules of mucosal and semimucosal areas (Fig. 8) that typically appear in patients with chronic multisystem disease (Fernandez-Faith and McDonell 2007).

  • Pathological manifestation: Noncaseating granulomas situated in the corium are seen in this type of sarcoidosis.

  • Prognosis and treatment: Prognosis depends upon the location of inflammation, severity of the systemic disease, and the response of the patient to medical treatment (Yanardag et al. 2013). Treatment of these rare forms is guided by the individual patient’s manifestations. Oral corticosteroids are recommended for rapidly progressive cases. Immunosuppressants, antimalarials, and TNF-α inhibitors may also be effective.

3 Nonspecific Skin Manifestations of Sarcoidosis

3.1 Erythema Nodosum Associated with Sarcoidosis

  • Definition: Erythema nodosum, the most common nonspecific skin lesion in sarcoidosis, is a septal panniculitis characterized by tender nodules with warm, pink, overlying epidermis. It occurs in 11% of the adult patients with systemic sarcoidosis and may be the initial manifestation of the disease (Mert et al. 2004).

  • Clinical feature: It is characterized by slightly raised, nonulcerative painful nodules, 1–6 cm in diameter, sometimes coalescing. Pretibial involvement is most common, although the extensor surfaces of the forearms, thighs, and trunk may also be affected. They tend to be symmetrical in distribution. Red nodules resolve within 2–3 weeks with typical bruising (contusiform evolution) When located on the lower extremities, nodular or subcutaneous sarcoidosis can be differentiated from erythema nodosum by the absence of symmetry and tenderness (Fig. 30).

  • Pathological manifestation: When clinical diagnosis is in doubt, a deep excisional biopsy specimen should be obtained, because a punch biopsy produces an inadequate sample (Schwartz and Nervi 2007). Septal panniculitis without vasculitis is a typical finding. Lobular neutrophilic panniculitis with suppuration, small vessel vasculitis, and even medium vessel arteritis may rarely occur in erythema nodosum (Thurber and Kohler 2006).

  • Prognosis and treatment: Erythema nodosum is a good prognostic indicator in patients with sarcoidosis and spontaneously resolves within weeks or months. Rarely, it may have a chronic or recurrent course. The most common approach is treatment of underlying systemic sarcoidosis and supportive therapy, including bed rest and pain management.

  • Differential diagnosis: Other forms of panniculitis, erythema induratum, thrombophlebitis, and nodular or subcutaneous sarcoidosis (Ahmed and Harshad 2006).

Fig. 30

When located on the lower extremities, nodular or subcutaneous sarcoidosis can be differentiated from erythema nodosum by the absence of symmetry and tenderness. (Taken by Dr. Katerina Damevska, Clinic of Dermatology, Medical Faculty, University “Ss Cyril and Methodius,” Skopje, Republic of Macedonia)

3.2 Löfgren Syndrome

  • Definition: Löfgren syndrome is an acute benign form of sarcoidosis characterized by erythema nodosum, bilateral hilar lymphadenopathy, and polyarthritis. Among Caucasians, sarcoidosis initially presents with Löfgren syndrome in 10% of patients (Glennas et al. 1995).

  • Clinical feature: It is characterized by acute onset of erythema nodosum and/or ankle arthritis (Fig. 31), with bilateral hilar lymphadenopathy (and in some cases parenchymal infiltrates) and usually fever. The predominant pulmonary features include coughing, chest pain, and dyspnea. Ocular involvement occurs in 5% of Löfgren’s syndrome cases, mostly in the posterior segment (Takase et al. 2010). Manifestations differ between men and women, with erythema nodosum found predominantly in women, whereas an ankle arthritis without erythema nodosum is seen preferentially in men (Grunewald and Eklund 2007).

  • Pathological manifestation: Septal panniculitis without vasculitis is seen. Biopsy of a hilar lymph node reveals noncaseating granulomas.

  • Prognosis and treatment: It is a self-limiting disease, with a mean duration ranging from 3 weeks to 3 months (Mañá et al. 1999). However, 6% of the patients had episodes of recurrent sarcoidosis 2–20 years after diagnosis (Löfgren and Lundback 1952). HLA-DRB1∗03 is strongly associated with favorable disease course (Grunewald and Eklund 2009). Pain can be managed with nonsteroidal anti-inflammatory drugs; whereas, corticosteroids are the drug of choice for more sever forms.

  • Differential diagnosis: Other forms of panniculitis, hyper-IgG4 syndrome, familial Mediterranean fever, α1-antitrypsin deficiency, nodular fat necrosis, lymphoma, tuberculosis, and other malignancies.

Fig. 31

Löfgren syndrome; erythema nodosum of the lower legs in a patient with arthritis, hilar lymphadenopathy, and fever. (Taken by Dr. Snejina Vassileva, Department of Dermatology and Venereology, Medical Faculty, University of Medicine, Sofia, Bulgaria)

References

  1. Ahmed I, Harshad SR (2006) Subcutaneous sarcoidosis: is it a specific subset of cutaneous sarcoidosis frequently associated with systemic disease? J Am Acad Dermatol 54(1):55–60PubMedCrossRefGoogle Scholar
  2. Arias-Santiago S, Fernández-Pugnaire MA, Aneiros-Fernández J, Falcón CS, Callejas-Rubio JL, Ortego-Centeno N, Serrano-Ortega S (2010) Recurrent telangiectasias on the cheek: angiolupoid sarcoidosis. Am J Med 123(1):e7–e8PubMedCrossRefGoogle Scholar
  3. Badgwell C, Rosen T (2007) Cutaneous sarcoidosis therapy updated. J Am Acad Dermatol 56(1):69–83PubMedCrossRefGoogle Scholar
  4. Baughman RP, Lower EE (2007) Evidence-based therapy for cutaneous sarcoidosis. Clin Dermatol 25(3):334–340PubMedCrossRefGoogle Scholar
  5. Burov EA, Kantor GR, Isaac M (1998) Morpheaform sarcoidosis: report of three cases. J Am Acad Dermatol 39(2 Pt 2):345–348PubMedCrossRefGoogle Scholar
  6. English JC 3rd, Patel JC, Greer KE (2001) Sarcoidosis. J Am Acad Dermatol 44(5):725–743. quiz 744–746PubMedCrossRefGoogle Scholar
  7. Fernandez-Faith E, McDonnell J (2007) Cutaneous sarcoidosis: differential diagnosis. J Clin Dermatol 25(3):276–287CrossRefGoogle Scholar
  8. Garrido-Ruiz MC, Enguita-Valls AB, de Arriba MG, Vanaclocha F, Peralto JL (2008) Lichenoid sarcoidosis: a case with clinical and histopathologicallichenoid features. Am J Dermatopathol 30(3):271–273PubMedCrossRefGoogle Scholar
  9. Ginarte M, Zulaica A, Toribio J (2006) Morpheaform sarcoidosis. Acta Derm Venereol 86(3):264–265PubMedCrossRefGoogle Scholar
  10. Glennas A, Kvien TK, Melby K, Refvem OK, Andrup O, Karstensen B, Thoen JE (1995) Acute sarcoid arthritis: occurrence, seasonal onset, clinical features and outcome. Br J Rheumatol 34(1):45–50PubMedCrossRefGoogle Scholar
  11. Grunewald J, Eklund A (2007) Sex-specific manifestations of Löfgren’s syndrome. Am J Respir Crit Care Med 175(1):40–44PubMedCrossRefGoogle Scholar
  12. Grunewald J, Eklund A (2009) Löfgren’s syndrome: human leukocyte antigen strongly influences the disease course. Am J Respir Crit Care Med 179(4):307–312PubMedCrossRefGoogle Scholar
  13. Haimovic A, Sanchez M, Judson MA, Prystowsky S (2012) Sarcoidosis: a comprehensive review and update for the dermatologist: part I. Cutaneous disease. J Am Acad Dermatol 66(5):699.e1–699.18; quiz 717–718CrossRefGoogle Scholar
  14. Heidelberger V, Ingen-Housz-Oro S, Marquet A, Mahevas M, Bessis D, Bouillet L, Caux F, Chapelon-Abric C, Debarbieux S, Delaporte E, Duval-Modeste AB, Fain O, Joly P, Marchand-Adam S, Monfort JB, Noël N, Passeron T, Ruivard M, Sarrot-Reynauld F, Verrot D, Bouvry D, Fardet L, Chosidow O, Sève P, Valeyre D (2017) Efficacy and tolerance of anti-tumor necrosis factor α agents in cutaneous sarcoidosis: a French study of 46 cases. JAMA Dermatol 153(7):681–685PubMedPubMedCentralCrossRefGoogle Scholar
  15. Huang CL, Mutasim DF (2005) Sarcoidosis mimicking lipodermatosclerosis. Cutis 75(6):322–324PubMedGoogle Scholar
  16. Kluger N (2013) Sarcoidosis on tattoos: a review of the literature from 1939 to 2011. Sarcoidosis Vasc Diffuse Lung Dis 30(2):86–102PubMedGoogle Scholar
  17. Löfgren S, Lundback H (1952) The bilateral hilar lymphoma syndrome; a study of the relation to tuberculosis and sarcoidosis in 212 cases. Acta Med Scand 142(4):265–273PubMedCrossRefGoogle Scholar
  18. Mañá J, Marcoval J (2012) Skin manifestations of sarcoidosis. Presse Med 41(6 Pt 2):e355–e374PubMedCrossRefGoogle Scholar
  19. Mañá J, Gómez-Vaquero C, Montero A, Salazar A, Marcoval J, Valverde J, Manresa F, Pujol R (1999) Löfgren’s syndrome revisited: a study of 186 patients. Am J Med 107(3):240–245PubMedCrossRefGoogle Scholar
  20. Marcoval J, Maña J, Moreno A, Peyri J (2005) Subcutaneous sarcoidosis – clinicopathological study of 10 cases. Br J Dermatol 153(4):790–794PubMedCrossRefGoogle Scholar
  21. Mert A, Ozaras R, Tabak F, Pekmezci S, Demirkesen C, Ozturk R (2004) Erythema nodosum: an experience of 10 years. Scand J Infect Dis 36(6–7):424–427PubMedCrossRefGoogle Scholar
  22. Modi S, Rosen T (2008) Micropapular cutaneous sarcoidosis: case series successfully managed with hydroxychloroquine sulfate. Cutis 81(4):351–354PubMedGoogle Scholar
  23. Noiles K, Beleznay K, Crawford RI, Au S (2013) Sarcoidosis can present with necrotizing granulomas histologically: two cases of ulcerated sarcoidosis and review of the literature. J Cutan Med Surg 17(6):377–378PubMedCrossRefGoogle Scholar
  24. O’Donoghue NB, Barlow RJ (2006) Laser remodelling of nodular nasal lupus pernio. Clin Exp Dermatol 31(1):27–29PubMedCrossRefGoogle Scholar
  25. Rose AS, Tielker MA, Knox KS (2008) Hepatic, ocular and cutaneous sarcoidosis. Clin Chest Med 29(3):509–523PubMedCrossRefGoogle Scholar
  26. Ruocco E, Gambardella A, Langella GG, Lo Schiavo A, Ruocco V (2015) Cutaneous sarcoidosis: an intriguing model of immune dysregulation. Int J Dermatol 54(1):1–12PubMedCrossRefGoogle Scholar
  27. Sanchez M, Haimovic A, Prystowsky S (2015) Sarcoidosis. Dermatol Clin 33(3):389–416PubMedCrossRefGoogle Scholar
  28. Schwartz RA, Nervi SJ (2007) Erythema nodosum: a sign of systemic disease. Am Fam Physician 75(5):695–700PubMedGoogle Scholar
  29. Stagaki E, Mountford WK, Lackland DT, Judson MA (2009) The treatment of lupus pernio: results of 116 treatment courses in 54 patients. Chest 135(2):468–476PubMedCrossRefGoogle Scholar
  30. Takase H, Shimizu K, Yamada Y, Hanada A, Takahashi H, Mochizuki M (2010) Validation of international criteria for the diagnosis of ocular sarcoidosis proposed by the first international workshop on ocular sarcoidosis. Jpn J Ophthalmol 54(6):529–536PubMedCrossRefGoogle Scholar
  31. Tchernev G, Patterson JW, Nenoff P, Horn LC (2010) Sarcoidosis of the skin – a dermatological puzzle: important differential diagnostic aspects and guidelines for clinical and histopathological recognition. J Eur Acad Dermatol Venereol 24(2):125–137PubMedCrossRefGoogle Scholar
  32. Thurber S, Kohler S (2006) Histopathologic spectrum of erythema nodosum. J Cutan Pathol 33(1):18–26PubMedCrossRefGoogle Scholar
  33. Veien NK, Stahl D, Brodthagen H (1987) Cutaneous sarcoidosis in Caucasians. J Am Acad Dermatol 16(3 Pt 1):534–540PubMedCrossRefGoogle Scholar
  34. Wanat KA, Rosenbach M (2015) Cutaneous sarcoidosis. Clin Chest Med 36(4):685–702PubMedCrossRefGoogle Scholar
  35. Yanardag H, Tetikkurt C, Bilir M, Demirci S, Iscimen A (2013) Diagnosis of cutaneous sarcoidosis: clinical and the prognostic significance of skin lesions. Multidiscip Respir Med 8(1):26PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Katerina Damevska
    • 1
    Email author
  • Snejina Vassileva
    • 2
  • Kossara Drenovska
    • 2
  • Slavica Kostadinova-Kunovska
    • 3
  1. 1.Clinic of Dermatology, Medical Faculty, University“Ss Cyril and Methodius University”SkopjeRepublic of Macedonia
  2. 2.Department of Dermatology and Venereology, Medical FacultyUniversity of MedicineSofiaBulgaria
  3. 3.Institute of Pathology, Medical FacultyUniversity “Ss Cyril and Methodius”SkopjeRepublic of Macedonia

Personalised recommendations