Foreign Bodies in Granulomatous Cutaneous Lesions of Patients with Systemic Sarcoidosis

STUDY Foreign Bodies in Granulomatous Cutaneous Lesions of Patients With Systemic Sarcoidosis

Joaquim Marcoval, MD; Juan Man˜a´, MD; Abelardo Moreno, MD; Isabel Gallego, MD; Yolanda Fortun˜o, MD; Jordi Peyrı´, MD

Objective: To assess the presence of foreign material demonstrated in 65 (15.3%) of 425 patients with sys- in the granulomatous cutaneous lesions of patients with temic sarcoidosis. In 14 (22%) of the 65 patients, the cu- systemic sarcoidosis. taneous biopsy specimen showed foreign particles in polarized light. The skin lesions corresponded to 3 different Design and Setting: Observational study reevaluat- clinical patterns: an admixture of papules and infiltra- ing histological specimens at a university referral hos- tion of previously undetected minute scars (n=6); scar pital. sarcoidosis (n=4); and subcutaneous nodules (n=4). The lesions were located most frequently in the extremities, Patients: Sixty-five patients diagnosed as having sar- involving the knees in 10 patients. coidosis who developed granulomatous cutaneous involvement. Conclusions: The presence of polarizable foreign body material in granulomatous cutaneous lesions is not in- Main Outcome Measures: To detect the presence of frequent in patients with systemic sarcoidosis. Inocula- polarizable foreign particles in cutaneous biopsy speci- tion of foreign matter from a previous inapparent minor mens and to evaluate the association with clinical fea- trauma may induce granuloma formation in individuals tures of the patients. with sarcoidosis.

Results: Granulomatous cutaneous involvement was Arch Dermatol. 2001;137:427-430

ARCOIDOSIS is a multisys- nificance of the presence of foreign bod- temic granulomatous dis- ies in granulomatous skin lesions of ease of unknown etiology that patients with sarcoidosis. With these con- involves mainly the lungs, siderations in mind, we reviewed the data mediastinal and peripheral Slymph nodes, eyes, and skin. The liver, For editorial comment spleen, salivary glands, heart, nervous sys- see page 485 tem, muscles, bones, and other organs may also be involved.1 The diagnosis is well es- in a series of patients with systemic sar- tablished when clinical and radiological coidosis and granulomatous cutaneous in- findings are supported by histological evi- volvement to ascertain the presence of for- dence of widespread noncaseous granu- eign body material in the skin biopsy lomas in 1 or more tissues or positive re- specimens and to reevaluate the clinical sults of a Kveim test.2 Because of its easy aspects. accessibility, the skin biopsy is of great value as a less-invasive diagnostic proce- RESULTS dure.1 The finding of polarizable foreign Of 425 patients diagnosed as having sys- matter in cutaneous epithelioid granulo- temic sarcoidosis, the biopsy specimens in From the Departments of mas traditionally permits the exclusion of 65 (15.3%) patients showed granuloma- Dermatology (Drs Marcoval, the diagnosis of sarcoidosis.3-5 However, tous cutaneous involvement. In 15 bi- Gallego, Fortun˜o, and Peyrı´), Internal Medicine (Dr Man˜a´), some cases have been reported in which opsy specimens obtained from 14 (22%) and Pathology (Dr Moreno), foreign particles were present in granulo- of the 65 patients, foreign particles were Hospital de Bellvitge, matous cutaneous lesions in patients with observed under polarized light. Of these University of Barcelona, well-demonstrated systemic sarcoid- 14 patients, there were 13 women and 1 Barcelona, Spain. osis.3,4,6 These findings questioned the sig- man (mean age, 50.3 years; range, 33-70

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©2001 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/01/2021 years). The chest radiograph stages and extrathoracic involvement in these patients are shown in the Table. Only PATIENTS AND METHODS patient 3, who formerly took care of a garden, admitted to previous contact with cactus, and vegetal particles were During a 26-year period (1974-1999), 425 patients found in her skin lesions. None of the remaining pa- were diagnosed as having sarcoidosis at the Sarcoid tients had noticed the inoculation of exogenous mate- Clinic of the Hospital de Bellvitge, a 1000-bed teach- rial into the skin. ing institution in Barcelona, Spain. The diagnosis of We identified 3 types of cutaneous lesions showing sarcoidosis was made according to the classic crite- foreign particles: (1) an admixture of papules and previ- ria: a compatible clinical and radiological picture; his- ously undetected, infiltrated, minute scars located on the tological demonstration of noncaseous granulomas knees (n=5) (Figure 1) or discrete papules on the el- involving 1 or more tissues, with stains and cultures bow (n=1); (2) infiltration of previously known scars (scar negative for mycobacteria and fungi or positive re- sarcoidosis) involving the knees (n=4) (Figure 2); and sults of the Kveim test; and exclusion of other granu- (3) subcutaneous nodules involving the forearms (n=3) lomatous diseases. In patients whose tissue biopsy Figure 3 specimens did not provide histological confirma- ( ) and the face (n=1). In general, the lesions were tion, the diagnosis of sarcoidosis was accepted if the located more frequently in the extremities, involving the purified protein derivative of tuberculin test results knees (n=10), the arms (n=4), and the face (n=1). were negative, other diseases were excluded, and the Histologically, the lesions were noncaseous (sar- clinical course was consistent with sarcoidosis.7-9 We coid) granulomas involving the dermis, subcutis, or both, also accepted a diagnosis without a biopsy speci- with minor or no lymphocytic component at the periph- men when the intrathoracic gallium citrate Ga 67 up- ery. In the majority of cases, foreign material was de- take showed a lambda pattern (image resembling the tected by standard observation as amorphous or crystal- Greek letter produced by gallium uptake in the right loid material or was suspected when a hole in the vicinity paratracheal and bilateral hilar lymph nodes), with of giant cells was detected during tissue processing. The or without the panda image (image of the face of a panda produced by gallium uptake in the symmetri- presence of all foreign bodies was confirmed by exam- cal lacrimal and parotid glands).9-11 All patients with ining the specimen under polarized light. Figure 4 shows systemic sarcoidosis who had cutaneous lesions were a sarcoid granuloma with foreign particles, and Figure 5 evaluated at the Department of Dermatology. Skin bi- shows the same microscopic field under polarized light. opsies were performed when granulomatous cutaneous involvement was clinically suspected. Those patients with histologically demonstrated granulo- COMMENT matous skin lesions were included in this study. We collected data about the stage of baseline radio- The presence of foreign particles in granulomatous cuta- graph and extrathoracic sarcoidosis and the history neous lesions was demonstrated in 14 (22%) of 65 pa- concerning inoculation of exogenous material into tients with systemic sarcoidosis and skin involvement. The the skin from all patients. Cutaneous biopsy speci- systemic character of the disease was well documented in mens with granulomatous involvement were reex- amined under polarized light to detect foreign par- all patients by the demonstration of intrathoracic and/or ticles. We excluded asteroid bodies, Schaumann extrathoracic disease, in addition to specific (granuloma- bodies, and the small refractive crystals of calcium tous) skin involvement. These results agreed with previ- carbonate usually encountered in sarcoidosis. ous reports by Walsh et al3 and Val-Bernal et al4 and cor- roborated the observation that foreign body granuloma and sarcoidosis are not mutually exclusive.

Clinical Data of the Patients*

Patient No./ Chest Age, y/Sex Extrathoracic Involvement Radiograph Stage Cutaneous Lesions Site 1/45/F Erythema nodosum II Papules, scars Knees 2/54/F . . . I Nodules Face 3/70/F . . . I Nodules Arms 4/37/M Axillary adenopathy II Nodules Arms 5/43/F Erythema nodosum, cutaneous plaques I Papules Right elbow 6/60/F Erythema nodosum II Scar Left knee 7/42/F Uveitis II Scar Right knee 8/58/F . . . 0† Nodules Arms, legs 9/53/F Erythema nodosum I Papules, scars Knees, elbows 10/70/F Erythema nodosum I Scar Right knee 11/33/F Erythema nodosum I Papules, scars Knees 12/33/F Erythema nodosum I Scar Right knee 13/53/F Erythema nodosum I Papules, scars Knees 14/53/F Erythema nodosum, uveitis 0 Papules, scars Knees

*Ellipses indicate that there was no extrathoracic involvement. †Micronodular pattern shown in the results of high-resolution computed tomography.

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©2001 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/01/2021 Figure 1. Papules and scars on the knees in patient 1. Figure 4. Cutaneous biopsy specimen showing sarcoid granulomas and foreign particles (hematoxylin-eosin, original magnification ϫ400).

Figure 2. Scar sarcoidosis in patient 7.

Figure 5. The microscopic field shown in Figure 4 under polarized light.

Based on a large series of patients with cutaneous sarcoidosis, Veien et al6 reported that foreign material was sometimes found in old cutaneous scars probably intro- duced as a consequence of the initial injury. The pro- pensity of cutaneous sarcoidosis to localize in tattoos has also been reported.12-16 More infrequently, specific (granulomatous) cutaneous sarcoidosis involved areas of long- Figure 3. Subcutaneous nodular lesions in patient 3. term trauma, surgery, venipuncture, vaccination or inoculation, purified protein derivative of tuberculin skin test, and long-standing scarification marks.4 In all these In our series, we identified 3 different clinical forms cases, contamination by foreign matter, such as talc and of cutaneous sarcoidosis associated with the presence of ash, was suspected. In the present series, the granulo- foreign bodies: papular sarcoidosis of the knees, scar sar- matous cutaneous lesions with foreign bodies were lo- coidosis, and subcutaneous sarcoidosis. Papular sarcoid- cated, in most of the cases, on the knees or forearms of osis of the knees was the most frequently occurring form middle-aged women. The knees and forearms are easily in this series, and it was usually associated with acute sar- exposed to trauma, and prior minor injury in these arcoidosis, particularly Lo¨fgren syndrome. Clinically, it con- eas may be imperceptible. Consequently, a history of ac- sisted of minute granulomatous papules grouped over the cidental inoculation of foreign particles cannot be elic- knees; some of the papules were linearly arranged, and, ited in the majority of cases; we were able to obtain this in some cases, the papules coexisted with infiltrated information in only 1 of our patients. minute scars not previously noted by the patient. Of the As in previous reports,3,4 our results suggested that 4 patients with scar sarcoidosis (granulomatous infiltra- the presence of polarizable matter in a cutaneous granu- tion of previously known scars), we observed an asso- loma does not exclude the diagnosis of sarcoidosis, par- ciation with Lo¨fgren syndrome in 3 patients. In con- ticularly when systemic features of the disease are pres- trast, subcutaneous nodules were not associated with ent. Moreover, the presence of foreign bodies in 22% of erythema nodosum but were observed in chronic forms our patients with systemic sarcoidosis and granuloma- of the disease. tous skin involvement suggested that it is not a rare event

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©2001 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/01/2021 in specific cutaneous lesions of sarcoidosis. This find- REFERENCES ing may contribute to the understanding of the patho- genesis of the disease. The cause of sarcoidosis remains 1. Man˜a´ J, Marcoval J, Graells J, Salazar A, Peyrı´J, Pujol R. Cutaneous involvement in obscure. It has been hypothesized that the disease oc- sarcoidosis: relationship to systemic disease. Arch Dermatol. 1997;133:882-888. curs when a genetically susceptible host is exposed to a 2. Hunninghake GW, Costabel U, Ando M, et al, for the American Thoracic Society/ specific environmental antigen(s). In this event, an ex- European Respiratory Society/World Association of Sarcoidosis and Other Granu- lomatous Disorders. ATS/ERS/WASOG statement on sarcoidosis. Sarcoidosis aggerated inflammatory response takes place, character- Vasc Diffuse Lung Dis. 1999;16:149-173. ized by large numbers of activated macrophages and T 3. Walsh NMG, Hanly JG, Tremaine R, Murray S. Cutaneous sarcoidosis and for- lymphocytes bearing the CD4 helper phenotype, with a eign bodies. Am J Dermatopathol. 1993;15:203-207. 4. Val-Bernal JF, Sanchez-Quevedo MC, Corral J, Campos A. Cutaneous sarcoid- pattern of cytokine production consistent with a TH1- type immune response. As a consequence, granulomas osis and foreign bodies: an electron probe roentgenographic microanalytic study. 2,17 Arch Pathol Lab Med. 1995;119:471-474. develop in the involved organs. In addition, it has also 5. Callen JP. Sarcoidosis. In: Callen JP, Jorizzo JL, Greer KE, Penneys NS, Piette been hypothesized that sarcoidosis is a disease in which WW, Zone JJ, eds. Dermatological Signs of Internal Diseases. Philadelphia, Pa: the immune system’s capacity to handle particulate for- WB Saunders Co; 1995:293-300. eign matter is altered and that the presence of foreign bod- 6. Veien NK, Stahl D, Brodthagen H. Cutaneous sarcoidosis in Caucasians. JAm ies, which are often not apparent and remain undetec- Acad Dermatol. 1987;16(3, pt 1):534-540. 7. Winterbauer RH, Belic N, Moores KD. A clinical interpretation of bilateral hilar ted, in the skin and other organs might provide the adenopathy. Ann Intern Med. 1973;78:65-71. 3 stimulus necessary for granuloma formation. There- 8. Carr PL, Singer DE, Goldenheim P, et al. Noninvasive testing of asymptomatic fore, the presence of foreign bodies in some tissues may bilateral hilar adenopathy. J Gen Intern Med. 1990;5:138-146. contribute to defining the patterns of organ involve- 9. Man˜a´ J, Gomez-Vaquero C, Montero A, et al. Lo¨fgren’s syndrome revisited: a study of 186 patients. Am J Med. 1999;107:240-245. ment and the distribution of the lesions in the skin. 10. Israel HL, Albertine KH, Park CH, Patrick H. Whole-body gallium 67 scans: role In summary, in our results, the presence of polar- in the diagnosis of sarcoidosis. Am Rev Respir Dis. 1991;144:1182-1186. izable matter in granulomatous cutaneous lesions was not 11. Sulavik SB, Spencer RP, Palestro CJ, et al. Specificity and sensitivity of distinc- infrequent in patients with systemic sarcoidosis. Accord- tive chest radiographic and/or 67Ga images in the noninvasive diagnosis of sar- ingly, foreign bodies and sarcoidosis were not mutually coidosis. Chest. 1993;103:403-409. 12. Rorsman H, Dahlquist I, Jacobson S, et al. Tattoo granuloma and uveitis. Lan- exclusive. The clinical pattern of the lesions observed in cet. 1969;2:27-28. our patients suggested that previously undetected mi- 13. Kennedy C. Sarcoidosis presenting in tattoos. Clin Exp Dermatol. 1976;1:395-399. nor traumas may provide a nidus for granuloma forma- 14. Sowden JM, Cartwright PH, Smith AG, Hiley C, Slater DN. Sarcoidosis present- tion in individuals with sarcoidosis. ing with a granulomatous reaction confined to red tattoos. Clin Exp Dermatol. 1992;17:446-448. 15. Collins P, Evans AT, Gray W, Levison DA. Pulmonary sarcoidosis presenting as Accepted for publication October 18, 2000. a granulomatous tattoo reaction. Br J Dermatol. 1994;130:658-662. Corresponding author and reprints: Joaquim Mar- 16. Papageorgiou PP, Hongcharu W, Chu AC. Systemic sarcoidosis presenting with multiple tattoo granulomas and extra-tattoo cutaneous granuloma. J Eur Acad coval, MD, Department of Dermatology, Hospital de Bel- Dermatol Venereol. 1999;12:51-53. lvitge, Carrer Feixa Llarga s/n, Hospitalet de Llobregat, 17. Newman LS, Rose CS, Maier LA. Sarcoidosis. N Engl J Med. 1997;336:1224- 08907 Barcelona, Spain (e-mail: [email protected]). 1234.

News and Notes

he 20th World Congress of Dermatology will be held from July 1 to July 5, 2002, at the Palais des Congre`s de Paris, France. For fur- T ther information, please contact the congress secretariat, P. Fournier, Colloquium, 12, rue de la Croix St Faubin, 75011 Paris, France; phone: 33 (0) 144641515; fax: 33 (0) 144641516; e-mail; [email protected]; Website: www.derm-wcd-2002.com.

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©2001 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/01/2021 Farber spearheaded and assumed leadership posi- While in high school and college, in addition to be- tions in many dermatological societies and organiza- ing an exceptional student, he was an excellent athlete, tions. He was on the board of directors of the American having performed as a champion hurdler and basketball Academy of Dermatology, the American Dermatological player. He remained a loyal supporter of Stanford sports Association, the Association of Professors of Dermatol- throughout his life. ogy, the Pacific Dermatologic Association, and the Soci- He was also a devoted family man, marrying his life’s ety for Investigative Dermatology. In addition, he held edi- companion and best friend, Ruth, in 1944. They re- torial positions on many publications, including the Journal mained together for 56 years, raising 4 children and many of Investigative Dermatology, Scientific American, Skin and large animals at their Portola Valley, Calif, home. He is Allergy News, and Cutis. He also served as president of the survived by his wife; a son, Donald; daughters Charlotte Association of Professors of Dermatology, the Pacific Der- and Nancy; grandchildren Elinor and Ben; and his great matology Association, and the Society for Investigative grandchild Henry. Dermatology. He will be dearly missed by many who were influ- On retiring from his post at Stanford University in enced or cared for by him, including 2 generations of fel- 1986, he assumed the presidency of the Psoriasis Re- low physicians and students and thousands of grateful search Institute, a unique nonprofit foundation, estab- patients. lished by Russell Smith, Alejandro Zaffaroni (founder of ALZA Pharmaceuticals, Mountain View, Calif), and him- David R. Harris, MD self. They created a skin biology unit with a focus on the Age Defying Dermatology etiology, epidemiology, and treatment of psoriasis. Schol- 3803 S Bascom Ave, Suite 200 ars from nearly a dozen countries outside the United States Campbell, CA 95008 have studied at the Psoriasis Research Institute on fel- Robert Walton, MD lowships or during sabbatical leaves. Campbell

Correction Correction

Error in Placement of Figures. In the study titled “Foreign Bodies in Granu- lomatous Cutaneous Lesions of Patients With Systemic Sarcoidosis,” pub- lished in the April issue of the ARCHIVES (2001;137:427-430), Figure 4 and Figure 5 were accidentally transposed in the article and on the cover, where they are referred to as parts B and C.

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