DO NOT REPRODUCE. Sarcoidosis is a multisystem granulomatous disorder. Its etiology. Sarcoid Ulcer of the Leg: A Challenging Chronic Wound CASE REPORT

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1 CASE REPORT WOUNDS 2010;22(1):E1 E5 From the 1 AtlantiCare Regional Medical Center, Galloway, NJ; 2 Touro College of Osteopathic Medicine, New York, NY Address correspondence to: Philip Paparone, DO Stockton Medical Complex 72 West Jimmie Leeds Rd. Absecon, NJ Phone: ppaparone@comcast.net Sarcoid Ulcer of the Leg: A Challenging Chronic Wound Pamela Paparone, MSN, APN; 1 Paige Paparone, MSBS; 2 Philip Paparone, DO 1 Abstract: Sarcoidosis, a systemic inflammatory disease of unknown cause(s), is a diagnosis of exclusion. While skin lesions are common, chronically nonhealing wounds caused by this idiopathic disease are rare and often misdiagnosed. Definitive diagnostic tests do not exist. The finding of noncaseating granulomas on biopsy of wounds is useful. Mistreatment or any delay in proper treatment of ulcerative sarcoidosis can be painful to patients. Corticosteroid therapy generally is effective. The authors present the case of a chronic sarcoid ulcer of the leg that posed a significant diagnostic challenge. The need to include sarcoidosis in the differential diagnosis of nonhealing wounds is emphasized. Sarcoidosis is a multisystem granulomatous disorder. Its etiology remains unknown, its treatment is not standardized, and its prognosis cannot be easily predicted. 1 Its prevalence is estimated at 10 to 20 per 100,000 in the population. 2 Although the lung is the most commonly affected organ, the skin often is involved. In fact, the term sarcoidosis is derived from Boeck s 1899 case report of multiple benign sarkoid of the skin, because he thought the extensive lesions resembled sarcoma but were benign. 3 The patient s skin nodules that he examined were characterized by compact, sharply defined foci of epithelioid cells with large pale nuclei in addition to a few giant cells. Skin involvement occurs in 25% to 35% of patients with sarcoidosis, and is often overlooked or misinterpreted given the variability of the lesions. 4 These lesions include erythema nodosum, macular or papular rash, nodules, hypo- or hyper-pigmented patches, scar sarcoid, lupus pernio, and plaques. 5 Ulceration of sarcoid lesions is rare. 5 7 We describe the case of an unusual sarcoid ulcer of the leg that presented as a chronically nonhealing wound, which ultimately was treated successfully with corticosteroid therapy. Case Report In April 2005 an 82-year-old white woman presented with a large wound (7 cm x 9 cm) on the left leg 10 cm above the lateral malleolus, and mild cel- E1

2 E2 WOUNDS lulitis of the same leg. The patient had chronic venous insufficiency and both legs were edematous. The wound resembled a large, shallow venous ulcer with a serpiginous border. Although it was closer to the knee than most venous ulcers, it had no distinguishing features. The patient gave a history of suffering from a similar wound several years previously that had healed with compression therapy, but which recently reappeared. Prior to her visit to our clinic, the wound had been treated by another physician who unsuccessfully used antibiotic therapy (ciprofloxacin 500 twice daily; switched to clindamycin 300 mg, 3 times daily) and compression therapy. The wound started to heal, but spontaneously recurred, resulting in the patient presenting to our center. Our initial approach was to treat the wound as an infected venous ulcer with mild cellulitis. The patient was given a lower dosage of clindamycin (150 mg, 3 times daily), and she was instructed to take ibuprofen (400 mg, 3 4 times daily) to reduce pain caused by the wound. The wound was dressed with a 3-layer compression bandage (Dyna-Flex, Johnson & Johnson, Somerville, NJ) applied at light tension to facilitate venous return. Four days later, the wound was found to be unchanged. The patient returned 1 week after that, and when the dressing was removed to inspect the wound, less slough tissue was observed, and buds of red granulation tissue had appeared. At this time, the wound was deemed a venous ulcer and the patient was instructed to wear a Dyna-Flex boot for 1 week. Nine days later, after the patient had worn the new dressing for a week without pain, the wound showed significant improvement with areas of epithelial tissue and about 90% red granulation tissue. Subsequently, the wound was inspected weekly and showed continued improvement. In mid-june, after 6 weeks of positive response to treatment, the wound was found to be composed of nearly 100% granulation tissue. Nine days later, however, the wound appeared slightly larger than it was at the patient s previous visit, though it was still 100% granulation tissue. Culture specimens were soon taken and the patient stated that the wound had been noticeably more painful in recent days. She was placed on clindamycin (150 mg 3 times daily), and continued with compression therapy at low tension. The wound culture revealed a moderate amount of methicillin-resistant Staphylococcus aureus (MRSA). However, at the patient s evaluation on July 6, the wound showed improvement with complete coverage by granulation tissue, and the patient was continued on clindamycin for 7 more days. At her next visit the following week, the wound still showed signs of healing with complete coverage by granulation tissue. Peripheral vascular disease was suspected, and magnetic resonance angiography (MRA) of both legs was ordered. By the end of the month, the wound had the same dimensions, with no periwound redness. However, because of increased drainage and moderate MRSA growth, the patient was put on trimethoprim/sulfamethoxazole (twice daily) for 14 days. Although the MRA showed some stenosis of the artery of the left leg, no significant arterial circulation problem was present in either leg, and vascular disease was ruled out. During the first 3 weeks of August, the wound showed signs of steady improvement, despite the presence of some drainage. New epithelial tissue was noted. However, the wound then abruptly began to regress. At the patient s request, conservative means were used to increase circulation to the wound, since she preferred not to undergo an angiogram and potential vascular surgery. Bioelectric stimulation therapy (POSiFECT, Biofisica, Atlanta, GA) was administered to promote healing, in keeping with the patient s preference. Ten days later she was seen, and the wound showed signs of minor deterioration. Linezolid (400 mg twice daily) was prescribed to treat apparent infection, which proved to be MRSA. The wound then began to recuperate, with signs of slow but steady healing such as new epithelial tissue was noted at each subsequent office visit through September and October. Recurrent infections were treated with antibiotic therapy. Because of the wound s atypical nature and behavior, a biopsy was perfomed in late October. The findings of this biopsy indicated an inflammatory process but were negative for sarcoidosis (Figure 1). The following month, while the wound contined to improve slowly, erythematous nodules were noted on the patient s forehead and face. Biopsy of lesions on the chin revealed a granulomatous dermatitis consistent with sarcoidosis. Computed tomography (CT) of the chest was then ordered to confirm the diagnosis of sarcoidosis. The most recent wound cultures found Pseudomonas, for which ciprofloxin (500 mg twice daily) was prescribed. At this point, a bridge of epithelial tissue had divided the wound into 2 smaller wounds. No heat and no odorous drainage were present. Use of bioelectric stimulation therapy was associated with improved healing of the wound. By mid-december the diagnosis of sarcoidosis was established with the CT findings of tiny bilateral scat-

3 Figure 1. Early biopsy of wound indicating dermal edema, proliferation of blood vessels, and acute and chronic inflammatory infiltrate. Figure 2. Late biopsy of wound indicating granulomatous inflammation. The histologic changes shown here are consistent with sarcoidosis, but alone they are not diagnostic. The observed mixed cell infiltrate includes rare neutrophils; thus, infectious etiology cannot be excluded with certainty. PAS and AFB stains failed to reveal organisms. tered opacities with extensive mediastinal adenopathy and pleural-based nodular densities. For an episode of hives at this time, the patient was placed on loratadine (10 mg once daily) and given a methylprednisolone dose pack of 4-mg tablets. She started the corticosteroid therapy at 24 mg/day, which was tapered by 4 mg/day over 6 days. This therapy resulted in significant improvement of the wound. The underlying cause of the wound was then presumed to be sarcoidosis, and the patient was started on prednisone (20 mg once daily), which was tolerated without event. Over the next 2 months, the wound showed steady improvement, despite a recurrence of MRSA. In March the dosage of prednisone was increased to 30 mg daily, and by the end of the month the wound had healed. The prednisone was slowly tapered over the next 2 months. When the wound reopened at the end of April 1 full year after the initial presentation of the wound at our clinic a second biopsy of it revealed granulomatous dermatitis consistent with sarcoidosis (Figure 2). The high dosage of prednisone used previously (30 mg once daily) was reinstituted, and over the next month the wound finally healed. The prednisone was tapered in June, and by mid-summer the skin covering the wound was intact and maturing well. Discussion Chronic wounds are characterized by chronicity and frequent relapse. 8 They are associated with many complications that can further impair the healing process. Approximately 70% of nonhealing ulcers are caused by ischemia secondary to diabetes mellitus, venous stasis, and pressure. 9 Nonetheless, the differential diagnosis of the underlying cause(s) of a chronic wound includes an array of possibilities, some of which are uncommon such as sarcoidosis. The chronic wound with an uncommon etiology is most likely to present a diagnostic dilemma that may frustrate both clinicians and patients. Sarcoidosis affects people of all racial and ethnic groups. 4 It occurs at all ages, though its incidence peaks in young adulthood. 2 In the United States, the disease is 3 times more common in blacks than whites. 2 Women are affected much more than men, in all racial and ethic groups. 4 While skin lesions are common in sarcoidosis, they rarely ulcerate. Veien et al 10 studied prospectively a total of 188 white patients with cutaneous sarcoid lesions, and found that only 1.1% of patients developed ulcerative lesions. 10 Ulcerative sarcoidosis affects women and blacks most commonly. 6 Given the preponderance of sarcoidosis in women in general, it is not surprising that sarcoid ulcers have been reported to be 3 times more common in women than in men. 5 The rarity of sarcoid ulcers is underscored by the finding of Schwartz et al 11 who in 1982 reviewed the literature and identified only 26 patients with cutaneous ulceration. In 1997, Albertini et al 6 reviewed the literature and found only 8 additional cases, to which they added their own case, for a total of 35 cases. E3

4 Sarcoid skin lesions may appear on different parts of the body including the face, trunk, and limbs. Ulcers may develop de novo but more commonly develop within preexisting lesions. 7 The most common site of ulcerative sarcoidosis is the lower extremities, and patients with ulcerative disease generally have evidence of systemic involvement. 6,7 Noncaseating granulomas, a distinctive feature of sarcoidosis, are generally present within the ulcers and the surrounding tissue. Sarcoid ulcers are found more commonly among blacks than in whites and in women more than men. Local trauma has been suggested as a possible cause of ulcerative sarcoidosis in the lower limbs. 5,12,13 Such trauma might have been a contributing factor in the case described in the present report, since the wound recurred in the lower leg above the lateral malleous. Because the legs are the most common site for sarcoid skin lesions to ulcerate and because the legs commonly sustain minor trauma that goes unnoticed, the development of ulcerated lesions in sarcoidosis may well be related to minor trauma. This possibility points to the process called pathergy, that is, the induction of a lesion at a site of minor trauma. Of course, trauma would not explain the appearance of sarcoid ulcers on nontraumatized areas of skin, such as the face or trunk. Nonetheless, trauma may be a possible trigger of sarcoid ulcers of the lower limbs, and trauma preceding the development of an ulcer may be an important piece of historical data to obtain in the differential diagnosis of a nonhealing wound when sarcoidosis is suspected. Pathergy is likewise associated with pyoderma gangrenosum, 14 another uncommon cause of chronic wounds, which has been found to coexist with sarcoidosis. 13 It should be noted that a biopsy procedure anywhere on the skin could provoke pathergy, which may exacerbate a preexisting lesion. Sarcoid skin lesions are classified as specific when the histologic examination shows typical noncaseating granulomas. Nonspecific skin lesions, which demonstrate a nondiagnostic inflammatory reaction pattern on histologic examination, are often associated with an acute presentation of sarcoidosis. The most important nonspecific skin lesion seen in sarcoidosis is erythema nodosum. Specific lesions tend to be chronic and more problematic than nonspecific lesions, and are associated with worse outcomes. 15 Specific lesions include lupus pernio, infiltrated plaques, maculopapular eruptions, subcutaneous nodules, and scars. The clinical appearance of chronic sarcoid skin lesions is highly variable. 16 E4 WOUNDS Sarcoidosis is a diagnosis of exclusion, since the causative factors remain unknown. Most cases of sarcoidosis involving the skin occur before the diagnosis of sarcoidosis is made in other organs. 6 Biopsy of the wound is indicated for all patients presumed to have a sarcoid ulcer. 4 The firm diagnosis usually requires tissue confirmation of granulomatous inflammation, exclusion of known causes of such inflammation, and clinical evidence of involvement in more than one organ. 7,17 However, if the presence of noncaseating granulomatous inflammation of unknown cause is identified in 1 organ, certain clinical findings in another organ are sufficient to establish the diagnosis of sarcoidosis without the use of other organs for biopsy. 18 Chest radiographic evidence can provide the necessary corroboration to support the diagnosis of sarcoidosis. The findings are abnormal in more than 90% of patients with the disease, with bilateral hilar lymphadenopathy noted in 50% to 85% of cases, and pulmonary parenchymal infiltrates in 25% to 60%. 1 In the presented case, sarcoidosis was presumed to be the underlying cause of the patient s chronically nonhealing wound after the findings of cutaneous sarcoidosis on her face and also pulmonary sarcoidosis. This evidence of systemic disease, together with the wound s subsequent response to corticosteroid therapy used for treating her outbreak of hives, strongly suggested sarcoidosis as the main cause of the wound, even though a recent biopsy of it did not reveal a granulomatous process. While a therapeutic response to corticosteroid treatment does not establish the diagnosis of sarcoidosis, 4 the second biopsy of the wound performed later in its management showed granulomatous inflammation, which ultimately confirmed it as a case of ulcerative sarcoidosis. Corticosteroids are in general the treatment of choice for sarcoidosis, though therapy is not mandated for all cases because the disease may remit spontaneously. 1 Indications for the treatment of cutaneous disease include widespread, progressive lesions, or those that impair function. 6 Treatment is often frustrating because sarcoid lesions may be refractory to treatment or may recur following successful treatment. 19 In their review of 34 cases of ulcerative sarcoidosis, Albertini et al 6 found that systemic corticosteroid treatment alone was used in 16 patients. Initial doses of prednisone ranged from 10 mg/day to 80 mg/day that were tapered over weeks to months. In 12 patients the skin ulcers resolved, and in the remaining 4 patients, relapses occurred with taper-

5 ing of the steroid dosages, 6 as happened in the case described in the present report. Use of prednisone at the initial dose of 20 mg 40 mg/day is currently the most common approach to the treatment of cutaneous sarcoidosis. 4 Several alternative drugs, alone or in combination with corticosteroids, have also been used successfully. These agents include methotrexate (10 mg 25 mg/wk), chloroquine (250 mg 750 mg/day), hydroxychloroquine (200 mg 400 mg/day), and infliximab (5 mg/kg IV q 4 8 wk). 1 They are usually less effective than corticosteroids when used alone, and they may require several months to reach their maximum potency. However, they may function effectively as corticosteroid-sparing medications used in combination with a small dose of concomitant corticosteroids. Other medications, such as monocycline and doxycycline, may also have a role in cutaneous sarcoidosis. 1 Conclusion Sarcoidosis is a multisystem idiopathic inflammatory disease that can manifest itself in the form of a cutaneous ulcer, most commonly on the lower extremities. The authors experience illustrates that ulcerative sarcoidosis may present a diagnostic challenge. Sarcoid skin ulcers of the leg can mimic infectious ulcers and venous ulcers. Sarcoidosis should be included in the differential diagnosis of chronically nonhealing wounds. Attention must be paid to the exclusion of alternate causes of noncaseating granulomatous inflammation before making the diagnosis of sarcoidosis and initiating corticosteroid therapy. References 1. Judson MA. Sarcoidosis: clinical presentation, diagnosis, and approach to treatment. Am J Med Sci. 2008;335(1): Rybicki BA, Major M, Popovich J Jr, Maliarik MJ, Iannuzzi MC. Racial differences in sarcoidosis incidence: a 5-year study in a health maintenance organization. Am J Epidemiol. 1997;145(3): Boeck C. Multiple benign sarkoid of the skin. J Cutan Genito Urin Dis. 1899:17: Iannuzzi MC, Rybicki BA, Teirstein AS. Sarcoidosis. N Engl J Med. 2007;357(21): Verdegem TD, Sharma OP. Cutaneous ulcers in sarcoidosis. Arch Dermatol. 1987;123(11): Albertini JG, Tyler W, Miller OF 3rd. Ulcerative sarcoidosis. Case report and review of the literature. Arch Dermatol. 1997;133(2): Marchell RM, Judson MA. Chronic cutaneous lesions of sarcoidosis. Clin Dermatol. 2007;25(3): Menke NB, Ward KR, Witten TM, Bonchev DG, Diegelmann RF. Impaired wound healing. Clin Dermatol. 2007;25(1): Nwomeh BC, Yager DR, Cohen IK. Physiology of the chronic wound. Clin Plast Surg. 1998;25(3): Veien NK, Stahl D, Brodthagen H. Cutaneous sarcoidosis in Caucasians. J Am Acad Dermatol. 1987;16(3 Pt 1): Schwartz RA, Robertson DB, Tierney LM Jr, McNutt NS. Generalized ulcerative sarcoidosis. Arch Dermatol. 1982;118(11): Boyd RE, Andrews BS. Sarcoidosis presenting as cutaneous ulceration, subcutaneous nodules and chronic arthritis. J Rheumatol. 1981;8(2): Herrero JE, Mascaró JM Jr, Llambrich A, Herrero C. Sarcoidosis and pyoderma gangrenosum: an exceptional association. The role of trauma and immunosuppressive agents. J Eur Acad Dermatol Venereol. 2005;19(1): Paparone PP, Paparone W, Paparone PA. Post-traumatic pyoderma gangrenosum. WOUNDS. 2009:21(4): Yanardag H, Pamuk ON, Karayel T. Cutaneous involvement in sarcoidosis: analysis of the features in 170 patients. Respir Med. 2003;97(8): Mañá J, Marcoval J, Graells J, Salazar A, Peyrí J, Pujol R. Cutaneous involvement in sarcoidosis. Relationship to systemic disease. Arch Dermatol. 1997;133(7): Statement on sarcoidosis. Joint Statement of the American Thoracic Society (ATS), the European Respiratory Society (ERS), and the World Association of Sarcoidosis and Other Granulomatous Disorders (WASOG) adopted by the ATS Board of Directors and by the ERS Executive Committee. Am J Respir Crit Care Med. 1999;160(2): Judson MA, Thompson BW, Rabin DL, et al. The diagnostic pathway to sarcoidosis. Chest. 2003;123(2): Katta R. Cutaneous sarcoidosis: a dermatologic masquerader. Am Fam Physician. 2002;15;65(8): E5