Cutaneous Sarcoidosis – Diagnostic Challenges

1 Department of Dermatology, „Elias” Emergency University Hospital, Bucharest, Romania 2 „Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania 3 Department of Obstetrics and Gynecology, Emergency University Hospital, Bucharest, Romania 4 Department of Gastroenterology, „Dr. Carol Davila” Central Military Emergency University Hospital, Bucharest, Romania 5 Department of Urology, „Prof. Dr. Th. Burghele” Clinical Hospital, Bucharest, Romania Corresponding author: Mihai Cristian DUMITRASCU, 169 Splaiul Independentei, Bucharest, Romania. E-mail: drdumitrascu@yahoo.com Abstract


CASE REPORT
Diff erential diagnosis of cutaneous sarcoidosis includes a variety of other granulomatous disorders: classic ring granuloma, necrobiosis lipoidica, cutaneous Crohn, foreign body reactions, tuberculosis, tuberculoid leprosy 7 .
Management of cutaneous sarcoidosis begins with evaluation of the extent and severity of disease to determine the most appropriate treatment pathway. For localized disease, fi rst-line therapy consists in: intralesional or topical corticosteroids. In case of systemic disease, the options are: oral glucocorticoids, antimalaric drugs (hydroxychloroquine or chloroquine), methotrexate, tetracyclines 9,10 .

CASE REPORT
We present the case of a 60 years old woman, reff ered to our Dermatology for the evaluation of a bilateral, pruritic papular eruption, disseminated at the level of the trunk and the lower limbs, in evolution for 2 years. Her medical history included: pulmonary sarcoidosis diagnosed six years previously, autoimmune thyroiditis, psoriasis vulgaris, papulo-pustular rosacea, lumbar di-

INTRODUCTION
Sarcoidosis is a systemic granulomatous disorder of unknown origin, that most commonly involves the lungs. Cutaneous manifestations may be the clue to diagnose the disease, as they are present in up to onethird of patients 1 . Th e disease can aff ect any organ in the body, and is characterized by the formation of epitheloid cell tubercles, without caseation, although fibrinoid necrosis may be present at the centre of a few, proceeding either to resolution, or to conversion into hyaline fi brous tissue 2 . Sarcoidosis aff ects both women and men, usually under 40 years old. It can aff ect any race, but it is more frequent in Nothern European countries 3 .
Clinically, the cutaneous lesions consist of translucent-looking papules, with "apple jelly" appereance on diascopy, nodules, and red-blue plaques. Most commonly, they are found on scars. When involving the scalp, scarring alopecia may occur 4 .
Erythema nodosum represents the non-specifi c cutaneous lesion, frequently encountered in sarcoidosis. It presents as painful, erythematous nodules, predominantly found on the anterior surface of the lower extremities. It is undistinguishable from erythema nodosum of other causes. It is important to know that, if it is present, it may indicate the acute form of sarcoidosis. Th e triad (erythema nodosum, arthritis, bilateral hilar adenophaty on chest radiography) is known as Lofgren syndrome. Patients may also associate fever, malaise. Th e resolution usually occurs in 3 to 6 months, spontaneous 5 .
It is important to know that, general (non-organ specifi c) manifestations may be present in sarcoidosis: fatigue, small fi ber neuropathy and neuropsychological symptoms. Th eir recognition and impact on patient's life quality is essential for the optimal management of the patient with sarcoidosis 6 .
Th e diagnosis of sarcoidosis requires a compatible clinical picture, the demonstration of non-caseating granulomas on tissue biopsy, and the exclusion of other disorders that can present with similar clinical and histopathological fi ndings. Evaluation for systemic disease should consist in: complete physical examination, chest radiography, pulmonary function tests including diff usion capacity studies, electrocardiogram, assesment for latent tuberculosis (by tuberculin skin test or interferon gamma release assay, ophthalmologic examination, laboratory studies (complete blood count, serum calcium, liver and kidney function tests, baseline serum angiotensin converting enzyme level) 7,8 . scopathy, and total hysterectomy (for uterine fi broma). Family history was unremarkable. She was on chronic treatment with levothyroxine 100μg/day and dermatocorticoids.
Physical examination was normal, except skin lesions. On clinical exam of the skin we revealed numerous pruritic, erythematous papules, well defi ned, with regular edges, 0.5-4cm in diameter, some covered with fi ne scales, located on the posterior trunk and both upper and lower limbs (Figure 1, Figure 2).
Routine blood work revealed: infl ammatory syndrome with elevated CRP and ESR, mixed dyslipidemia. Abdominal ultrasound examination found 2 cm ovalshaped adenopathy in the celiac trunk area. Chest radiography showed the presence of several nodules, with stationary appearance from previous examinations, which were confi rmed by CT scan.
We suspected cutaneous sarcoidosis, and we performed a skin biopsy with histopathological examinationto confi rm our clinical presumption: at the dermal level, lympho-histiocitary infl ammatory infi ltrates with nodular distribution, forming several granulomas, without areas of necrosis of caseifi cation, including frequent cells with epithelioid appearance. (Fig 3, Fig 4).
Corroborating the clinical, paraclinical data, and histopathological examination, we set the fi nal diagnosis of cutaneous sarcoidosis.
A tapering course of oral prednisone 0,5mg/kg body weight was started. Because of adverse eff ects, steroids should be avoided for long term therapy and while slowly tapering the prednisone dosage, we associated hydroxychloroquine 200mg daily, gradually increasing it to 600mg daily 11,12 . Th e systemic treatment was accompanied with local therapy: dermatocorticoids   lymphocytes, and TNF production by macrophages. Th e mechanism is based on release of cytokines (accumulated within the dermis), and release of lysosomal enzymes (which lead to degradation of connective tissue). Th e pathognomonic element in the histopathological examination is mucin deposition, and focal degeneration of collagen and elastic fi bres, perivascular and interstitial lympho-histiocytic infl itrate in the upper and mid dermis. Treatment must be adjusted to the clinical form: in case of localized disease, therapeutic alternatives are dermatocorticoids or intralesional corticosteroids, cryosurgery or topical tacrolimus. Antimalarials or phototherapy are reserved to more extensive forms. Necrobiosis lipoidica aff ects women, 30 years old. At clinical examination, we can fi nd violaceous or redbrown plaques, with elevated edges, central telangiectases. Usually, the patient presents 1 to 3 lesions, which initially appears as a reddish-brown papule that slowly evolves into a well-defi ned waxy plaque. Histopatholo-and emollients.
Two months after starting the treatment, the patient presented for revaluation. On history taking and clinical examination, signifi cant improvement in symptoms and lesions was seen ( Figure 5).

DISCUSSIONS
Sarcoidosis is a granulomatous disease that can aff ect any organ, and the diff erential diagnosis represents the major challenge of cutanous sarcoidosis. First, the diff erentiation from lichen planus. It usually occurs in women, at 30-60 years old. Clinically it presents as multiple fl attened pruritic papules, with pinkish-purple color, polygonal, glossy in appearance, disseminated on fl ex areas, with a tendency to generalize. Pathogenesis is based on cell-mediated immunity. As for the histopathological examination, it is characterized by: hyperkeratosis, granular layer growth, acanthosis degeneration with basal cell layer liquefaction; mononuclear cells in the band around the epidermis; keratinocyte apoptosis at the dermo-epidermal junction 13 .
We may also diff erentiate sarcoidosis from noninfectious granulomatous dermatitis. Granuloma annulare appears more frequently at women, 30 years old, as symmetrical papules and plaques with central hyperpigmentation, located on hands and feet. Th e forms are: localized, generalized, subcutaneous. Usually, there are around 10 lesions. Th e pathogenesis is not well understood. It has been theorized that some triggering factors may contribute: vaccination, viral infections, trauma, insecte bite reactions. Granuloma anulare is mediated by Th 1, and studies showed elevations in IL-2R-positive lymphocytes, IFN--producing  gical examination reveals: sclerosis, obliteration of the fascicular pattern of collagen, necrobiosis, microangiopathy.
Most commonly, local corticosteroid treatment is suffi cient, but, in the case of a non-responsive ulceration to this treatment, excision of the lesion and covering with graft is recommended. Up to one third of patients associate diabetes mellitus, but the severity of the disease is not related to the severity of diabetes 15,16 .
Cutaneous lesions in Crohn's disease can occur anytime in the evolution of the disease, sometimes even preceding the formal diagnosis of infl ammatory bowel disease. From the wide range of extraintestinal manifestations, skin involvement in Crohn's disease is the most common one and includes specifi c lesions (with histopathological features consistent with Crohn's on biopsy), reactive lesions (infl ammatory in nature but without specifi c histopathological fi ndings of Crohn's), associated lesions (such as erythema nodosum) or therapy (particularly anti-TNF) induced lesion. Th e specifi c lesions can occur as a direct extension of bowel lesions to the skin or as metastatic lesions, meaning non-contiguous with the gastrointestinal tract. Th ese latter lesions include erythema, vegetative papules, ulceration, lymphedema 17,18 .
In conclusion, sarcoidosis can be defi ned as "the great imitator" as several other conditions may mimic the clinical and histopathological picture of the disease. A diagnosis of certainty can not be achieved by a single examination; history taking, physical examination, imaging tests, tissue sampling with histopathological examination revealing non-caseating granulomas and exclusion of other causes are required. In patients with longstanding evolution of the disease, checkups are required as involvement of other organs or systems can occur.
Compliance with ethics requirements: Th e authors declare no confl ict of interest regarding this article. Th e authors declare that all the procedures and experiments of this study respect the ethical standards in the Helsinki Declaration of 1975, as revised in 2008 (5), as well as the national law. Informed consent was obtained from all the patients included in the study.