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Langerhans Cell Histiocytosis: Treatment Failure With Imatinib

Langerhans Cell Histiocytosis: Treatment Failure With Imatinib Histiocytoses are a heterogeneous group of idiopathic diseases with a localized or disseminated accumulation of histiocytic cells and are classified into Langerhans cell histiocytosis (LCH) and non-Langerhans cell histiocytosis (N-LCH). Lesional cells in LCH are characterized by dendritic cell markers such as S-100 as well as Langerhans cell–specific features such as Birbeck granules and expression of CD1a, langerin, and fascin. Langerhans cell histiocytosis generally occurs during childhood, but an increasing incidence in adults has been reported.1 Multiorgan LCH is associated with a considerable mortality, and so new treatment options beyond established chemotherapy protocols are needed. Herein, we report 2 cases of LCH that did not respond to imatinib, a kinase inhibitor recently used to treat LCH2 and N-LCH.3 Report of Cases Case 1 A 21-year-old man presented with a 1½-year history of painful erosions and papules in the intertriginous areas (Figure 1) and erythematous follicular papules in the temporoparietal areas. Histologic examination showed dermal infiltration with histiocytic cells, and immunohistochemical analysis revealed reactions with antibodies against CD1a and S-100, characteristics compatible with the diagnosis of cutaneous LCH. Staging showed additional involvement of bone and lung. Figure 1. View LargeDownload Case 1. Before treatment, fluid-filled, macerating erosions and papules were present in the intertriginous area. The patient was treated with imatinib, 600 mg/d,2,3 and within 3 months the disease had worsened, showing considerable progression of skin and bone lesions. In addition, hepatomegaly, depression, loss of appetite, hypoalbuminemia, peripheral edema, anemia, and increased international normalized ratio occurred. Owing to treatment failure and adverse effects, imatinib therapy was discontinued. Systemic treatment with corticosteroids and vinblastine, 6 mg/m2 of body surface, was administered for 9 months and led to a considerable improvement in the disease. Case 2 An 84-year-old man presented with a 6-month history of increasing erythematous papules on the trunk (Figure 2) and intertriginous areas and a strong perianal burning sensation. Histologic examination showed a diffuse infiltration with histiocytic cells, and immunohistochemical analysis revealed reactions with antibodies against CD1a and S-100, characteristics compatible with the diagnosis of cutaneous LCH. Staging did not show any other organ involvement. Figure 2. View LargeDownload Case 2. Before treatment, symmetrical, scaly, erythematous papules were present on the abdominal area. Therapy with imatinib, 400 mg/d,2 was well tolerated but ineffective. An initial therapy with thalidomide, 200 mg/d, and further therapy trials with topical corticosteroids, psoralen–UV-A, imiquimod, and subcutaneous methotrexate, 25 mg/wk, remained unsuccessful or were discontinued owing to increasing adverse effects.1,4 Without adequate therapy, the symptoms of LCH increased. Finally, the patient died from multiple morbidities. Comment For adults, the current treatment options for LCH include systemic corticosteroids, methotrexate or thalidomide, topical corticosteroids or tacrolimus, surgical removal, bisphosphonates, radiotherapy, 2-chlorodeoxyadenosin, cytosine-arabinoside, and stem cell transplantation.1,4 In cases of multiorgan involvement, a combination therapy consisting of systemic corticosteroids, vinblastine, and 6-mercaptopurin is recommended by the Histiocyte Society (www.histio.org).5 Imatinib is a multikinase inhibitor targeting the macrophage colony-stimulating factor receptor, platelet-derived growth factor receptor β, and c-Kit. Since these receptors are expressed by histiocytes, it seemed promising to use this compound to treat histiocytic disorders. However, while effective in the treatment of systemic N-LCH,3 imatinib treatment does not seem to be an option in case of multiorgan or cutaneous LCH, as evidenced by the 2 patients described herein. Back to top Article Information Correspondence: Dr Wagner, Department of Dermatology, Venereology, and Allergy, University Medical Center and Medical Faculty Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, D-68167 Mannheim, Germany (christina.wagner@haut.ma.uni-heidelberg.de). Financial Disclosure: None reported. References 1. Götz GFichter J Langerhans' cell histiocytosis in 58 adults. Eur J Med Res 2004;9 (11) 510- 514PubMedGoogle Scholar 2. Montella LInsabato LPalmieri G Imatinib mesylate for cerebral Langerhans’-cell histiocytosis. N Engl J Med 2004;351 (10) 1034- 1035PubMedGoogle ScholarCrossref 3. Utikal JUgurel SKurzen H et al. Imatinib as a treatment option for systemic non-Langerhans cell histiocytoses. Arch Dermatol 2007;143 (6) 736- 740PubMedGoogle Scholar 4. McClain KL Drug therapy for treatment of Langerhans cell histiocytosis. Expert Opin Pharmacother 2005;6 (14) 2435- 2441PubMedGoogle ScholarCrossref 5. Minkov MGrois NHeitger APotschger UWestermeier TGadner HDAL-HX Study Group, Response to initial treatment of multisystem Langerhans cell histiocytosis: an important prognostic indicator. Med Pediatr Oncol 2002;39 (6) 581- 585PubMedGoogle ScholarCrossref http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Archives of Dermatology American Medical Association

Langerhans Cell Histiocytosis: Treatment Failure With Imatinib

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References (9)

Publisher
American Medical Association
Copyright
Copyright © 2009 American Medical Association. All Rights Reserved.
ISSN
0003-987X
eISSN
1538-3652
DOI
10.1001/archdermatol.2009.164
Publisher site
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Abstract

Histiocytoses are a heterogeneous group of idiopathic diseases with a localized or disseminated accumulation of histiocytic cells and are classified into Langerhans cell histiocytosis (LCH) and non-Langerhans cell histiocytosis (N-LCH). Lesional cells in LCH are characterized by dendritic cell markers such as S-100 as well as Langerhans cell–specific features such as Birbeck granules and expression of CD1a, langerin, and fascin. Langerhans cell histiocytosis generally occurs during childhood, but an increasing incidence in adults has been reported.1 Multiorgan LCH is associated with a considerable mortality, and so new treatment options beyond established chemotherapy protocols are needed. Herein, we report 2 cases of LCH that did not respond to imatinib, a kinase inhibitor recently used to treat LCH2 and N-LCH.3 Report of Cases Case 1 A 21-year-old man presented with a 1½-year history of painful erosions and papules in the intertriginous areas (Figure 1) and erythematous follicular papules in the temporoparietal areas. Histologic examination showed dermal infiltration with histiocytic cells, and immunohistochemical analysis revealed reactions with antibodies against CD1a and S-100, characteristics compatible with the diagnosis of cutaneous LCH. Staging showed additional involvement of bone and lung. Figure 1. View LargeDownload Case 1. Before treatment, fluid-filled, macerating erosions and papules were present in the intertriginous area. The patient was treated with imatinib, 600 mg/d,2,3 and within 3 months the disease had worsened, showing considerable progression of skin and bone lesions. In addition, hepatomegaly, depression, loss of appetite, hypoalbuminemia, peripheral edema, anemia, and increased international normalized ratio occurred. Owing to treatment failure and adverse effects, imatinib therapy was discontinued. Systemic treatment with corticosteroids and vinblastine, 6 mg/m2 of body surface, was administered for 9 months and led to a considerable improvement in the disease. Case 2 An 84-year-old man presented with a 6-month history of increasing erythematous papules on the trunk (Figure 2) and intertriginous areas and a strong perianal burning sensation. Histologic examination showed a diffuse infiltration with histiocytic cells, and immunohistochemical analysis revealed reactions with antibodies against CD1a and S-100, characteristics compatible with the diagnosis of cutaneous LCH. Staging did not show any other organ involvement. Figure 2. View LargeDownload Case 2. Before treatment, symmetrical, scaly, erythematous papules were present on the abdominal area. Therapy with imatinib, 400 mg/d,2 was well tolerated but ineffective. An initial therapy with thalidomide, 200 mg/d, and further therapy trials with topical corticosteroids, psoralen–UV-A, imiquimod, and subcutaneous methotrexate, 25 mg/wk, remained unsuccessful or were discontinued owing to increasing adverse effects.1,4 Without adequate therapy, the symptoms of LCH increased. Finally, the patient died from multiple morbidities. Comment For adults, the current treatment options for LCH include systemic corticosteroids, methotrexate or thalidomide, topical corticosteroids or tacrolimus, surgical removal, bisphosphonates, radiotherapy, 2-chlorodeoxyadenosin, cytosine-arabinoside, and stem cell transplantation.1,4 In cases of multiorgan involvement, a combination therapy consisting of systemic corticosteroids, vinblastine, and 6-mercaptopurin is recommended by the Histiocyte Society (www.histio.org).5 Imatinib is a multikinase inhibitor targeting the macrophage colony-stimulating factor receptor, platelet-derived growth factor receptor β, and c-Kit. Since these receptors are expressed by histiocytes, it seemed promising to use this compound to treat histiocytic disorders. However, while effective in the treatment of systemic N-LCH,3 imatinib treatment does not seem to be an option in case of multiorgan or cutaneous LCH, as evidenced by the 2 patients described herein. Back to top Article Information Correspondence: Dr Wagner, Department of Dermatology, Venereology, and Allergy, University Medical Center and Medical Faculty Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, D-68167 Mannheim, Germany (christina.wagner@haut.ma.uni-heidelberg.de). Financial Disclosure: None reported. References 1. Götz GFichter J Langerhans' cell histiocytosis in 58 adults. Eur J Med Res 2004;9 (11) 510- 514PubMedGoogle Scholar 2. Montella LInsabato LPalmieri G Imatinib mesylate for cerebral Langerhans’-cell histiocytosis. N Engl J Med 2004;351 (10) 1034- 1035PubMedGoogle ScholarCrossref 3. Utikal JUgurel SKurzen H et al. Imatinib as a treatment option for systemic non-Langerhans cell histiocytoses. Arch Dermatol 2007;143 (6) 736- 740PubMedGoogle Scholar 4. McClain KL Drug therapy for treatment of Langerhans cell histiocytosis. Expert Opin Pharmacother 2005;6 (14) 2435- 2441PubMedGoogle ScholarCrossref 5. Minkov MGrois NHeitger APotschger UWestermeier TGadner HDAL-HX Study Group, Response to initial treatment of multisystem Langerhans cell histiocytosis: an important prognostic indicator. Med Pediatr Oncol 2002;39 (6) 581- 585PubMedGoogle ScholarCrossref

Journal

Archives of Dermatology – American Medical Association

Published: Aug 1, 2009

Keywords: histiocytosis, langerhans-cell,treatment failure,imatinib mesylate

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