Granulomatous and suppurative dermatitis at interferon alfa injection sites: Report of 2 cases

Granulomatous and suppurative dermatitis at interferon alfa injection sites: Report of 2 cases Scott Sanders, MD,a Klaus Busam, MD,b Steven R. Tahan, MD,c Richard A. Johnson, MD,d and Dana Sachs, MDe New York, New York, and Boston, Massachusetts It has previously been reported that interferon alfa injection sites may develop pyoderma gangrenosum, interface dermatitis, vasculitis, or, more commonly, ulcers characterized by intravascular thrombi and a mixed inflammatory cell infiltrate. We describe 2 patients in whom granulomatous and suppurative dermatitis developed at interferon alfa injection sites. These cases extend the spectrum of interferon alfa injection site reactions. The histologic and clinical similarities of these cases with pyoderma gangrenosum and cutaneous Crohn’s disease are explored. (J Am Acad Dermatol 2002;46:611-6.)

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njection site reactions are noninfectious inflammatory reactions at the site of an injected substance. There is insufficient knowledge about the spectrum of clinical appearances and histologic reaction patterns for this phenomenon. Interferon alfa (IFN-α) administration has been reported to produce a variety of cutaneous1,2 and autoimmune sequelae3 including pyoderma gangrenosum,4 vasculitis5, interface dermatitis,6 dermal hypersensitivity,7 and necrotizing ulcerations at the injection site.8-29 We report 2 cases of granulomatous and suppurative dermatitis at IFN-α injection sites and discuss their possible relationship to previously described IFN-α injection site lesions.

Fig 1. Case 1. Violaceous, multilobulated granulomatous plaque on right thigh.

CASE REPORTS Case 1 A 55-year-old white man with a history of renal cell carcinoma was first seen for evaluation of skin lesions on the lower abdomen and both thighs. He had undergone nephrectomy and a 15-month course of interleukin 12. Because of disease progression, subcutaneous IFN-α (9 million units daily) and oral tretinoin (90 mg daily) were started. Apart from renal cell carcinoma, his medical history was unremarkable. From the Department of Dermatology, New York Hospital,a Department of Pathology, Memorial Sloan-Kettering Cancer Center,b Division of Dermatopathology, Department of Pathology, Beth Israel Deaconess Medical Center,c and Department of Dermatology, Massachusetts General Hospital,d and the Division of Dermatology, Memorial Sloan-Kettering Cancer Center, New York.e Reprint requests: Steven Tahan, Director of Dermatopathology, Beth Israel Deaconess Medical Center, 330 Brookline Ave, Boston, MA 02115. Copyright © 2002 by the American Academy of Dermatology, Inc. 0190-9622/2002/$35.00 + 0 16/91/119087 doi:10.1067/mjd.2002.119087

Several months into treatment, painless skin lesions developed at IFN-α injection sites. Bacterial culture was negative. An abdominal lesion did not improve with intralesional triamcinolone acetonide. In the month before his presentation to the dermatology service, the IFN-α injections were discontinued because of their apparent relationship to the skin lesions. The tretinoin was discontinued 3 days before presentation. He was receiving no other medications. He complained of fatigue but otherwise remained systemically well, without fevers, chills, or diaphoresis. Examination of the left side of the lower abdomen revealed an oval 1.5 cm ulcerated papule with raised, rolled borders. Biopsy specimens for histologic examination and tissue cultures were taken from a 4-cm dusky purple granulomatous plaque on the right anterior thigh (Fig 1). The initial clinical impression was of an infectious granulomatous dermatitis, a local reaction to the IFN-α or pyoderma gangrenosum. 611

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Fig 2. Case 1. An acanthotic epidermis overlying a perivascular and interstitial mixed inflammatory infiltrate with granulomatous foci. (Hematoxylin-eosin stain; original magnification ×40.)

Histologic examination revealed a suppurative and granulomatous dermatitis involving the papillary and reticular dermis. No vasculitis was seen. No birefringent foreign particles were found on polarization microscopy. Special stains and cultures for acid-fast bacilli, fungi, and bacteria were negative (Figs 2 and 3). Over the subsequent months, the lesions slowly regressed with local wound care. At 2 months’ follow-up, the abdominal and right thigh lesions were well-healed scars. Case 2 A 45-year-old white man had a 6-mm thick melanoma on his neck. One year earlier, the patient had been given a diagnosis of Crohn’s disease. The patient had recently been found to be HIV positive, although he was asymptomatic with a CD4 cell count of 890. His other medical history was significant only for prior alcohol abuse and a distant history of hepatitis B.

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Two years after initial presentation with melanoma, the appearance of cervical node and pulmonary metastases prompted initiation of IFN-α (18 million units 3 times a week) injected subcutaneously in the suprapubic area. His only other medication was a mesalamine enema. Ulcerating, erythematous suprapubic plaques developed after 7 months of IFN-α therapy. The appearance of injection site ulcers prompted a dosage reduction to 1 million units daily. Wound culture failed to grow any pathogens, and the patient began receiving intralesional steroid injections with partial response. IFN-α injection sites were rotated and no lesions developed at the new sites. The patient came to our attention (R. A. J.) 7 months after the ulcers had first appeared. Examination revealed 4 pyoderma gangrenosum– like ulcers across the lower abdomen, each about 4 cm with erythematous and indurated borders. Wound cultures grew Staphylococcus aureus and Candida albicans but no other fungi or mycobacteria. Over the next 4 months, minimal improvement was observed after treatment with debridement, intralesional steroids, oral antibiotics, and various dressings. Therefore 3 remaining ulcers were debrided while the patient was under general anesthesia. The material removed grew Proteus, Pseudomonas, and Bacteroides species. The surgical wounds healed completely within 2 months. The IFN-α dosage was increased back to 9 million units daily, given subcutaneously in the buttocks. Two years later, the patient returned with a new, 60-cm subcutaneous nodule with a fluctuant violaceous center on the right buttock (Fig 4). A wedge biopsy specimen showed ulceration and florid mononuclear and neutrophilic infiltrate with granulation tissue formation and fibrosis. Multinucleated giant cells and several granulomatous foci were noted within this infiltrate (Fig 5). Sitz baths were begun, and the injection sites were rotated elsewhere. Four months after this recurrence, the buttock lesions were clean wounds, and in another 2 months, they had healed completely.

DISCUSSION We report 2 cases of indurated plaques, nodules, and ulcers at IFN-α injection sites. In both cases histologic examination revealed suppuration with granulomas or giant cells. The clinical presentation suggested an infection, a granulomatous dermatitis, or pyoderma gangrenosum. In case 1 the patient was receiving IFNα for metastatic renal cell carcinoma. The patient in case 2 received IFN-α for metastatic melanoma. The interferons are a family of glycosylated proteins demonstrated to have antiproliferative, antitu-

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Fig 3. Case 1. Neutrophilic and granulomatous inflammation within an edematous reticular dermis. (Hematoxylin-eosin stain; original magnification ×200.)

Fig 4. Case 2. Buttock lesion composed of discrete violaceous nodules with crusted central ulcers. Nodules rest on the outlined, indurated plaque.

moral, and immunomodulatory effects, earning them a role in the treatment of tumors, viral infections, and inflammatory conditions.30 Although most IFN treatment protocols call for subcutaneous administration, animal models suggest that 60% of IFN-α2a is taken up by lymphatics within 24 hours.31 The incomplete absorption of subcutaneously

administered IFNs allows for the possibility of local effects. Indeed, since the first report in 1991,8 at least 22 other articles have documented cutaneous ulcerations near IFN-α injection sites.8-29 Less than 5% of 938 patients treated with IFN-α had injection site reactions, including ulceration.32 Similar ulcers near IFN-β injection sites have also been described and

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Table I. IFN-α injection site reactions Pyoderma gangrenosum4 Leukocytoclastic vasculitis5 Interface dermatitis6 Dermal hypersensitivity7 Necrotizing ulcerations8-29 Suppurative and granulomatous dermatitis* *Present report.

Fig 5. Case 2. Dermal inflammation with prominent multinucleated giant cells amid nearly confluent interstitial lymphocytes, histiocytes, and neutrophils. (Hematoxylineosin stain; original magnification ×200.)

may share a similar pathogenesis because IFN-α and IFN-β share a common receptor.33 A variety of reactions have been reported at IFNα injection sites. Indurated erythema at the injection site of IFN-α2c has been reported in a patient later shown to have a positive patch test response to this compound.7 Of note, antibodies to IFN-α, as well as patch and scratch test results, were negative in other reported cases of IFN-α–induced ulcers.7,11 Injection site leukocytoclastic vasculitis developed in a patient with mixed cryoglobulinemia.5 Vesiculating, painful nodules with the histologic features of an interface dermatitis have been reported in 5 patients who had undergone bone marrow transplantation and were receiving a combination of interleukin-2 and IFN-α.6 In addition, there is a single case report of pyoderma gangrenosum developing in a patient with chronic myelogenous leukemia at IFN-α injection sites.4 To our knowledge, none of these injection site reactions have had a granulomatous reaction. Typical IFN-α–induced ulcers have violaceous, overhanging borders with minimally purulent bases.13 Histologic examination of these lesions has shown venous but not arteriolar thrombosis. Vasculitis is rarely reported.23 When present, an inflammatory infiltrate ranges from sparse to moderate and is composed of perivascular lymphocytes, histiocytes, neutrophils, and eosinophils. An underlying panniculitis may accompany a primarily dermal infiltrate. Fibroplasia is occasionally present. Our patients’ lesions clinically and histologically differed from previously described IFN-α–induced cutaneous ulcers. Specifically, our patients’ lesions contained a prominent neutrophilic component, nonpolarizing sarcoidal giant cells, and in case 1, granulomas. Similar histologic findings, identified as

cutaneous and visceral sarcoidosis, have been described after systemic IFN-α administration but not at an IFN-α injection site.34 In our cases, a foreign body reaction is difficult to completely rule out because minuscule foreign bodies could have been introduced with the IFN-α injections; however, several biopsied lesions had not ulcerated, nor had they been iatrogenically manipulated. It is unlikely the granulomatous reaction represents infection. Cultures in case 1 remained sterile. Cultures in case 2 grew various bacteria, which we believe represented surface colonization and could not produce granulomas. The pathogenesis of previously described IFNα–induced cutaneous ulcers remains uncertain. These injection site ulcers may arise through local IFN cytotoxicity to fibroblasts and capillary buds as observed in murine wound healing after IFN-α/β injections.35 Other hypothetical mechanisms include IFN-α’s toxicity to keratinocytes9,10,36,37 and induction of a local cellular inflammatory response,12,38-41 but most speculation has centered on an ischemic insult. IFN-α could contribute to local ischemia by several mechanisms. IFN-α inhibits angiogenesis,42 limits endothelial cell migration,43 and promotes endothelial cell apoptosis44 as well as vasospasm.26,45 Additionally, IFN-α promotes intravascular thrombosis by diminishing endothelial urokinase type plasminogen inhibitor.43 The presence of intravascular thrombi has been well reported and was observed in our cases (Fig 6). The original report of IFN-α cutaneous ulcers suggested an origin in unintentional intra-arterial injection, though intra-arterial thrombosis has not been subsequently observed.12 A local pro-coagulant effect of IFN-α was first proposed after injection site ulcers developed in a patient with antithrombin III deficiency.8,46 Experimentally, histologic examination of murine tumors injected with IFN-α/β showed noninflammatory necrosis caused by intramicrovascular coagulation preceded by endothelial damage.47 Clinically, IFN-α has been reported to exacerbate ischemic cutaneous ulcers from cryoglobulins, despite falling serum levels of these proteins.48 Induction of ischemia and inflammation by IFN-α may account for the histopathologic changes

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Fig 6. Case 2. Dermal venule with noninflammatory, intravascular thrombosis. (Hematoxylineosin stain; original magnification ×400.)

observed in our cases. In case 2, the observed intravascular thrombi are similar to previously reported IFN-α cutaneous ulcers. However, many of the features observed in our cases—prominent suppuration, giant cells, granulomatous changes—are unusual for IFN-α cutaneous ulcers. Instead, these features are similar to the histopathologic findings reported in pyoderma gangrenosum49 and cutaneous Crohn’s disease.50 There may, in fact, be an overlap in the morphology and pathogenesis of pyoderma gangrenosum and cutaneous Crohn’s disease.51 Our cases extend the spectrum of IFN-α injection site reactions (Table I). Their suppurative and granulomatous morphology suggests a possible pathogenetic similarity with pyoderma gangrenosum and cutaneous Crohn’s disease. The production of ulcers by IFN-α injection is reminiscent of a “dermonecrotic factor” reported in the serum of a patient with pyoderma gangrenosum.52 The intravascular thrombi seen in IFN-α ulcers have been described in half of 66 cases of pyoderma gangrenosum.53 Vaso-occlusion has also been proposed in the origins of mucosal Crohn’s disease.54,55 IFN-α has been found in the lymphocytes of mucosal Crohn’s disease and not in normal mucosa.56 IFN injection site reactions offer insight into the physiology of IFN-α and, perhaps, the pathogenesis of idiopathic inflammatory dermatoses. There is a broad spectrum of IFN-α injection site reactions, some of which may simulate infection.

REFERENCES 1. Asnis LA, Gaspari AA. Cutaneous reactions to recombinant cytokine therapy. J Am Acad Dermatol 1995;33:393-410. 2. Chang LW, Liranzo M, Bergfeld WF. Cutaneous side effects associated with interferon alpha therapy: a review. Cutis 1995;56:144. 3. Vial T, Descotes J. Clinical toxicity of interferons. Drug Safety 1994;10:115-50. 4. Montoto S, Bosch F, Estrach T, Blade J, Nomdedeu B, Nontserrat E. Pyoderma gangrenosum triggered by alpha 2b interferon in a patient with chronic granulocytic leukemia. Leuk Lymphoma 1998;30:199-202. 5. Christian MM, Diven DG, Sanchez RL, Soloway RD. Injection site vasculitis in a patient receiving interferon alfa for chronic hepatitis C. J Am Acad Dermatol 1997;37:118-20. 6. Klapholz L, Ackerstein A, Goldenhersh MA, Vardy D, Nagler A. Local cutaneous reaction induced by subcutaneous interleukin-2 and interferon alpha-2a immunotherapy following ABMT. Bone Marrow Transplant 1993;11:443-6. 7. Detmar U, Agathos M, Nerl C. Allergy of delayed type of recombinant interferon alpha-2C. Contact Dermatitis 1989;20:149-50. 8. Cnudde F, Gharakhanian S, Luboinski J, Dry J, Rozenbaum W. Cutaneous local necrosis following interferon injections [letter]. Int J Dermatol 1991;30:147. 9. Azagury M, Pauwels C, Kornfeld S, Bataille N, Perie G. Severe cutaneous reactions following interferon injections [letter]. Eur J Cancer 1996;32A:1821. 10. Christian B, Derriennic X, Aymard JP. Necrose cutanee locale apres injection d’interferon alpha [letter]. Presse Med 1993;22: 783. 11. Levesque H, Cailleux N, Moore N, Tilly H, Monconduit M, Courtois H. Autoimmune phenomenon associated with cutaneous aseptic necrosis during interferon alpha treatment for chronic myelogenous leukemia [letter]. Br J Dermatol 1995;34: 582-3. 12. Oeda E, Shinohara K. Cutaneous necrosis caused by injection of alpha interferon in a patient with chronic myelogenous leukemia [letter]. Am J Hematol 1993;44:213-4.

616 Sanders et al

13. Orlow SJ, Friedman-Kien AE. Cutaneous ulcerations secondary to interferon alpha therapy in Kaposi’s sarcoma [letter]. Arch Dermatol 1992;128:566. 14. Rasokat H, Bendick C, Wemmer U, Steigleder GK. Aseptic skin necrosis after subcutaneous injection of alpha interferon. Dtsch Med Wochenschr 1989;114:458-60. 15. Sparsa A, Loustaud-Ratti V, Liozon E, et al. Cutaneous reactions or necrosis from interferon alpha: can interferon be reintroduced after healing? Six case reports. Rev Med Interne 2000; 21:756-63. 16. Konohana A, Hasegawa Y, Kobayashi T. Cutaneous ulcerations resulting from intramuscular injections of interferon alpha [letter]. J Am Acad Dermatol 1996;35:788-9. 17. Mihara K, Goto T, Shigenaga T. Interferon therapy of C-type chronic hepatitis. Miyazakiikaishi 1993;17:40-4. 18. Nagai A, Nishikiori M, Masuda R. A case of chronic myelogenous leukemia developing cutaneous ulcers during interferon alpha therapy. Int J Hematol 1993;58:129-30. 19. Akiyama Y, Yamada Y, Jidoi J. A case of cutaneous ulcers after intramuscular injections of interferon alpha [abstract]. Jpn J Dermatol 1994;104:436. 20. Tone T, Kawana M, Kinoshita M. Drug eruptions of interferon alpha in patients with C-type hepatitis [abstract]. Jpn J Dermatol 1994;104:1047. 21. Kontochristopoulos G, Stavrinos C, Aroni K, Tassapoulos NC. Cutaneous necrosis by subcutaneous injection of a-interferon in a patient with chronic type B hepatitis [letter].J Hepatol 1996;25:271. 22. Prussick R, Knowles S, Shear NH. Cutaneous drug reactions. Curr Probl Dermatol 1994;6:81-124. 23. Krainick U, Kantarijan H, Broussard S, Talpaz M. Local cutaneous necrotizing lesions associated with interferon injections. J Interferon Cytokine Res 1998;18:823-7. 24. Sickler JB, Simmons RA, Cobb DK, Sherman KE. Cutaneous necrosis associated with interferon alpha-2b. Am J Gastroenterol 1998;93:463-4. 25. de Ledinghen V, Brudieux E, Beylot-Barry M, Belleannee G, Doutre MS, Couzigou P. Severe local cutaneous necrosis during treatment with interferon-alpha and ribavarin for chronic viral hepatitis C [letter]. Gastroenterol Clin Biol 1997;21:523-4. 26. Virgili A, Corazza M, Lombardi AR, Sighinolfi L. Cutaneous ulcers due to interferon seem not to be related to dosage [letter]. J Eur Acad Dermatol Venereol 1999;13:141-3. 27. Sasseville D, Ghamdi WA, Khenaizan SA. Interferon-induced cutaneous necrosis. J Cutan Med Surg 1999;3:320-3. 28. Okamoto E, Morisaki S, Kitano Y. A case of skin ulceration after subcutaneous injection of IFN-alpha. Skin Res 1995;37:570-2. 29. Matsukura M, Yamada H, Yamashita Y, Tezuka T. Local cutaneous necrosis following interferon-alpha injection. Skin Res 1995;37: 563-9. 30. Stadler R. Interferons in dermatology: present-day standard. Dermatol Clin 1998;16:377-98. 31. Supersaxo A, Hein W, Gallati H, Steffen H. Recombinant human interferon alpha-2a: delivery to lymphoid tissue by selected modes of application. Pharm Res 1988;5:472-6. 32. Gaspari AA. Reply to Konohana [letter]. J Am Acad Dermatol 1996;35:789. 33. Elgart GW, Sheremata W, Ahn YS. Cutaneous reactions to recombinant human interferon beta-1b: the clinical and histologic spectrum. J Am Acad Dermatol 1997;37:553-8. 34. Eberlein-Konig B, Hein R, Abeck D, Engst R, Ring J. Cutaneous sarcoid foreign body granulomas developing in sites of previous skin injury after systemic interferon-alpha treatment for chronic hepatitis C [letter]. Br J Dermatol 1999;140:370-2. 35. Stout AJ, Gresser I, Thompson D. Inhibition of wound healing in mice by local interferon a/b injection. Int J Exp Pathol 1993;74: 79-86.

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36. Stadler R, Muller R, Orfanos CE. Effect of recombinant alpha Ainterferon on DNA synthesis and differentiation of human keratinocytes. Br J Dermatol 1986;1:273-7. 37. Yaar M, Karassik RL, Schnipper LE, Gilchrest BA. Effects of alpha and beta interferons on cultured human keratinocytes. J Invest Dermatol 1985;85:70-4. 38. Tong Y,Tucker SB. Normal mouse skin lymphocyte, Langerhans’cell and keratinocyte responses to intradermal injections of interferonA and interferon-G. J Interferon Cytokine Res 1995;15:235-41. 39. Tong Y, Tucker SB. Normal human skin lymphocytic and Langerhan’s cell responses to intradermal interferon alpha-2B injections. Am J Med Sci 1993;306:23-7. 40. Mozzanica N, Cattaneo A, Boneschi V, Brambilla L, Melotti E, Finzi AF. Immunohistochemical evaluation of basal cell carcinoma during intralesional treatment with alpha-2 interferon. Arch Dermatol Res 1990;282:311-7. 41. Buechner SA. Intralesional interferon alpha-2B in the treatment of basal cell carcinoma. J Am Acad Dermatol 1991;24:731-4. 42. Sidky YA, Borden EC. Inhibition of angiogenesis by interferons: effects on tumor and lymphocyte-induced vascular responses. Cancer Res 1987;47:5155-61. 43. Pepper MS, Vassalli JD, Wilks JW, Schweigerer L, Orci L, Montesano R. Modulation of bovine microvascular endothelial cell proteoloytic properties by inhibitors of angiogenesis. J Cell Biochem 1994;55:419-34. 44. Sgonc R, Fuerhapter C, Boeck G, Swerlick R, Fritsch P, Sepp N. Induction of apoptosis in human dermal microvascular endothelial cells and infantile hemangiomas by interferonalpha. Int Arch Allergy Immunol 1998;117:209-14. 45. Zeidman A, Dicker D, Mittelman M. Interferon-induced vasospasm in chronic myelogenous leukemia. Acta Hematol 1998;100:94-6. 46. Durand JM, Quiles N, Kaplanski G, Soubeyard J.Thrombosis and recombinant interferon alpha. Am J Med 1993;95:115-6. 47. Dvorak HF, Gresser I. Microvascular injury in pathogenesis of interferon-induced necrosis of subcutaneous tumors in mice. J the Natl Cancer Inst 1989;81:497-501. 48. Cid MC, Hernandez-Rodriguez J, Robert J, del Rio A, Casademont J, Coll-Vincent B, et al. Interferon-a may exacerbate cryoglobulinemia-related ischemic manifestations. Arthritis Rheum 1999;42:1051-5. 49. Magro C, Crowson AN, Mihm M Jr. Cutaneous manifestations of nutritional deficiency states and gastrointestinal disease. In: Elder D, editor. Lever’s histopathology of the skin. 8th ed. New York: Lippincott-Raven; 1997. p. 353-68. 50. Hackzell-Bradley M, Hedblad MA, Stephansson EA. Metastatic Crohn’s disease: report of 3 cases with special reference to histopathologic findings. Arch Dermatol 1996;132:928-32. 51. Sanders S,Tahan SR, Kwan T, Magro CM. Giant cells in pyoderma gangrenosum. J Cutan Pathol 2001;28:97-100. 52. Su WPD, Schroeter AL, Perry HO, Powell FC. Histopathologic and immunopathologic study of pyoderma gangrenosum. J Cutan Pathol 1996;13:323-30. 53. Delecluse J, de Bast C, Achten G. Pyoderma gangrenosum with altered cellular immunity and dermonecrotic factor. Br J Dermatol 1972;87:529-32. 54. Wakefield AJ, Dhillon AP, Pittilo RM, Rowles PM, Lewis AA. Pathogenesis of Crohn’s disease: multifocal gastrointestinal infarction. Lancet 1989;2:1057-62. 55. Wakefield AJ, Sankey EA, Dhillon AP, Sawyerr AFM, More L, Sim R, et al. Granulomatous vasculitis in Crohn’s disease. Gastroenterology 1991;100:1279-87. 56. Fais S, Capobianchi MR, Silvestri M, Mercuri F, Pallone E, Dianzani F. Interferon expression in Crohn’s disease patients: increased interferon-gamma and alpha mRNA in the intestinal lamina propria mononuclear cells. J Interferon Res 1994;14:235-8.