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Sorafenib-Induced Eruptive Melanocytic Lesions

Sorafenib-Induced Eruptive Melanocytic Lesions Herein, we report 2 cases of eruptive melanocytic lesions associated with sorafenib, a multikinase inhibitor approved by the US Food and Drug Administration for the treatment of advanced renal cell carcinoma. Understanding the development of this previously unknown adverse effect may provide further insight into sorafenib's mechanistic effects on tumors and normal tissues and into the development of pigmented lesions. Report of Cases Case 1 A 60-year-old black woman with metastatic renal cell carcinoma received sorafenib, 400 mg, orally twice daily. After 2 months of sorafenib treatment, she noticed new dark macules on her palms and soles. Additional lesions developed over the ensuing 2 months. Dermatologic evaluation revealed multiple, small, dark brown macules on the palms (Figure 1A) and soles (Figure 1B). The plantar surfaces of her feet exhibited focal scaling consistent with her prior diagnosis of mild acral erythema (hand-foot skin reaction; hand-foot syndrome). Histologic examination of a palmar lesion demonstrated small nests of normal melanocytes at the dermoepidermal junction (Figure 1C). A diagnosis of sorafenib-related eruptive benign melanocytic nevi was made. Figure 1. View LargeDownload Eruptive nevi and mild acral erythema (hand-foot skin reaction) in a patient taking sorafenib. A, Multiple brown macules on the palms and fingers; B, brown macules on the plantar surface of the foot with associated scaling; and C, palmar biopsy specimen shows small nests of normal melanocytes at the dermoepidermal junction (hematoxylin-eosin, original magnification ×200). Case 2 A 59-year-old man with metastatic renal cell carcinoma began treatment with sorafenib, 400 mg, twice daily. One month after initiation of therapy, he reported the sudden appearance of multiple pigmented skin lesions without preceding cutaneous inflammation or eruption. Examination revealed multiple monomorphic pigmented macules on the neck, trunk, anterior aspects of the thighs (Figure 2A), palms, and soles. Histologic evaluation of a thigh macule demonstrated a proliferation of melanocytes at the basal layer of the epidermis with dermal melanophages (Figure 2B and C). The patient was diagnosed with sorafenib-associated lentigines. Figure 2. View LargeDownload Clinical and histologic images from the patient in case 2. A, Multiple brown macules on the anterior aspect of the thigh; B, thigh biopsy specimen shows increased pigmentation in the epidermis and superficial dermis (hematoxylin-eosin, original magnification ×100); C, higher magnification of the same biopsy specimen shows melanocytic proliferation at the basal epidermal layer and melanophages in the superficial dermis (hematoxylin-eosin, original magnification ×400). Comment Rapid development of pigmented lesions has been previously associated with chemotherapeutic agents, immunodeficiency, and blistering dermatoses.1 Commonly affected sites include the palms and soles, though eruptive pigmented lesions may be widespread. Sporadic nevi and lentigines are less frequent in acral locations.2 The significance of the acral predilection of eruptive nevi and lentigines is uncertain. Development of eruptive pigmented lesions has been related to local skin inflammation or to immunosuppression, with potentially diminished immune surveillance allowing melanocyte growth factors to promote development of pigmented lesions in genetically predisposed individuals.1 In blistering skin disorders, eruptive nevi may localize to sites of prior cutaneous lesions. Inflammation from sorafenib-related acral erythema may similarly predispose to the development of nevi on the palms and soles. Alternatively, preliminary data suggest that sorafenib inhibits the function of human dendritic cells and may be immunomodulatory.3 Interestingly, eruptive keratoacanthomas are also associated with states of immunosuppression and have been reported with sorafenib.4 Sorafenib inhibits a variety of serine/threonine and tyrosine kinases including wild-type and mutant BRAF (BRAFV600E), Raf-1, c-KIT, VEGFR-2, VEGFR-3, PDGFR-β, and Flt3.5 Activated RAF promotes melanocyte proliferation and induces oncogene-induced senescence in melanocytes.6 Differential inhibition of these distinct activities of BRAF or BRAFV600E by sorafenib may promote the development of nevi and lentigines in unusual locations prior to onset of RAF-dependent senescence. The possibility that factors unrelated to the drug sorafenib, but instead related to the underlying malignant condition, contributed to the development of these melanocytic lesions also cannot be excluded. To our knowledge, the literature includes only 1 report of melanoma in situ diagnosed in a patient with chemotherapy-related eruptive nevi.7 The premalignant potential of sorafenib-associated melanocytic lesions is unknown. Close follow-up may be warranted. Correspondence: Dr Kong, Dermatology Branch, National Cancer Institute, National Institutes of Health, 10 Center Dr, Bldg 10, Rm 12N238, MSC 1908, Bethesda, MD 20892-1908 (konghe@mail.nih.gov). Financial Disclosure: None reported. References 1. Bovenschen HJTjioe MVermaat H et al. Induction of eruptive benign melanocytic naevi by immune suppressive agents, including biologicals. Br J Dermatol 2006;154 (5) 880- 884PubMedGoogle ScholarCrossref 2. Autier PBoniol MSeveri G et al. The body site distribution of melanocytic naevi in 6-7 year old European children. Melanoma Res 2001;11 (2) 123- 131PubMedGoogle ScholarCrossref 3. Hipp MMHilf NWalter S et al. Sorafenib but not sunitinib affects the induction of immune responses. Paper presented at: the Annual Meeting of the American Society of Clinical Oncology June 1-5, 2007 Chicago, Illinois 4. Kong HHCowen EWAzad NSDahut WGutierrez MTurner ML Keratoacanthomas associated with sorafenib therapy. J Am Acad Dermatol 2007;56 (1) 171- 172PubMedGoogle ScholarCrossref 5. Flaherty KT Chemotherapy and targeted therapy combinations in advanced melanoma. Clin Cancer Res 2006;12 (7, pt 2) 2366s- 2370sPubMedGoogle ScholarCrossref 6. Michaloglou CVredeveld LCSoengas MS et al. BRAFE600-associated senescence-like cell cycle arrest of human naevi. Nature 2005;436 (7051) 720- 724PubMedGoogle ScholarCrossref 7. Reutter JCLong EMMorrell DSThomas NEGroben PA Eruptive post-chemotherapy in situ melanomas and dysplastic nevi. Pediatr Dermatol 2007;24 (2) 135- 137PubMedGoogle ScholarCrossref http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Archives of Dermatology American Medical Association

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Publisher
American Medical Association
Copyright
Copyright © 2008 American Medical Association. All Rights Reserved.
ISSN
0003-987X
eISSN
1538-3652
DOI
10.1001/archderm.144.6.820
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Abstract

Herein, we report 2 cases of eruptive melanocytic lesions associated with sorafenib, a multikinase inhibitor approved by the US Food and Drug Administration for the treatment of advanced renal cell carcinoma. Understanding the development of this previously unknown adverse effect may provide further insight into sorafenib's mechanistic effects on tumors and normal tissues and into the development of pigmented lesions. Report of Cases Case 1 A 60-year-old black woman with metastatic renal cell carcinoma received sorafenib, 400 mg, orally twice daily. After 2 months of sorafenib treatment, she noticed new dark macules on her palms and soles. Additional lesions developed over the ensuing 2 months. Dermatologic evaluation revealed multiple, small, dark brown macules on the palms (Figure 1A) and soles (Figure 1B). The plantar surfaces of her feet exhibited focal scaling consistent with her prior diagnosis of mild acral erythema (hand-foot skin reaction; hand-foot syndrome). Histologic examination of a palmar lesion demonstrated small nests of normal melanocytes at the dermoepidermal junction (Figure 1C). A diagnosis of sorafenib-related eruptive benign melanocytic nevi was made. Figure 1. View LargeDownload Eruptive nevi and mild acral erythema (hand-foot skin reaction) in a patient taking sorafenib. A, Multiple brown macules on the palms and fingers; B, brown macules on the plantar surface of the foot with associated scaling; and C, palmar biopsy specimen shows small nests of normal melanocytes at the dermoepidermal junction (hematoxylin-eosin, original magnification ×200). Case 2 A 59-year-old man with metastatic renal cell carcinoma began treatment with sorafenib, 400 mg, twice daily. One month after initiation of therapy, he reported the sudden appearance of multiple pigmented skin lesions without preceding cutaneous inflammation or eruption. Examination revealed multiple monomorphic pigmented macules on the neck, trunk, anterior aspects of the thighs (Figure 2A), palms, and soles. Histologic evaluation of a thigh macule demonstrated a proliferation of melanocytes at the basal layer of the epidermis with dermal melanophages (Figure 2B and C). The patient was diagnosed with sorafenib-associated lentigines. Figure 2. View LargeDownload Clinical and histologic images from the patient in case 2. A, Multiple brown macules on the anterior aspect of the thigh; B, thigh biopsy specimen shows increased pigmentation in the epidermis and superficial dermis (hematoxylin-eosin, original magnification ×100); C, higher magnification of the same biopsy specimen shows melanocytic proliferation at the basal epidermal layer and melanophages in the superficial dermis (hematoxylin-eosin, original magnification ×400). Comment Rapid development of pigmented lesions has been previously associated with chemotherapeutic agents, immunodeficiency, and blistering dermatoses.1 Commonly affected sites include the palms and soles, though eruptive pigmented lesions may be widespread. Sporadic nevi and lentigines are less frequent in acral locations.2 The significance of the acral predilection of eruptive nevi and lentigines is uncertain. Development of eruptive pigmented lesions has been related to local skin inflammation or to immunosuppression, with potentially diminished immune surveillance allowing melanocyte growth factors to promote development of pigmented lesions in genetically predisposed individuals.1 In blistering skin disorders, eruptive nevi may localize to sites of prior cutaneous lesions. Inflammation from sorafenib-related acral erythema may similarly predispose to the development of nevi on the palms and soles. Alternatively, preliminary data suggest that sorafenib inhibits the function of human dendritic cells and may be immunomodulatory.3 Interestingly, eruptive keratoacanthomas are also associated with states of immunosuppression and have been reported with sorafenib.4 Sorafenib inhibits a variety of serine/threonine and tyrosine kinases including wild-type and mutant BRAF (BRAFV600E), Raf-1, c-KIT, VEGFR-2, VEGFR-3, PDGFR-β, and Flt3.5 Activated RAF promotes melanocyte proliferation and induces oncogene-induced senescence in melanocytes.6 Differential inhibition of these distinct activities of BRAF or BRAFV600E by sorafenib may promote the development of nevi and lentigines in unusual locations prior to onset of RAF-dependent senescence. The possibility that factors unrelated to the drug sorafenib, but instead related to the underlying malignant condition, contributed to the development of these melanocytic lesions also cannot be excluded. To our knowledge, the literature includes only 1 report of melanoma in situ diagnosed in a patient with chemotherapy-related eruptive nevi.7 The premalignant potential of sorafenib-associated melanocytic lesions is unknown. Close follow-up may be warranted. Correspondence: Dr Kong, Dermatology Branch, National Cancer Institute, National Institutes of Health, 10 Center Dr, Bldg 10, Rm 12N238, MSC 1908, Bethesda, MD 20892-1908 (konghe@mail.nih.gov). Financial Disclosure: None reported. References 1. Bovenschen HJTjioe MVermaat H et al. Induction of eruptive benign melanocytic naevi by immune suppressive agents, including biologicals. Br J Dermatol 2006;154 (5) 880- 884PubMedGoogle ScholarCrossref 2. Autier PBoniol MSeveri G et al. The body site distribution of melanocytic naevi in 6-7 year old European children. Melanoma Res 2001;11 (2) 123- 131PubMedGoogle ScholarCrossref 3. Hipp MMHilf NWalter S et al. Sorafenib but not sunitinib affects the induction of immune responses. Paper presented at: the Annual Meeting of the American Society of Clinical Oncology June 1-5, 2007 Chicago, Illinois 4. Kong HHCowen EWAzad NSDahut WGutierrez MTurner ML Keratoacanthomas associated with sorafenib therapy. J Am Acad Dermatol 2007;56 (1) 171- 172PubMedGoogle ScholarCrossref 5. Flaherty KT Chemotherapy and targeted therapy combinations in advanced melanoma. Clin Cancer Res 2006;12 (7, pt 2) 2366s- 2370sPubMedGoogle ScholarCrossref 6. Michaloglou CVredeveld LCSoengas MS et al. BRAFE600-associated senescence-like cell cycle arrest of human naevi. Nature 2005;436 (7051) 720- 724PubMedGoogle ScholarCrossref 7. Reutter JCLong EMMorrell DSThomas NEGroben PA Eruptive post-chemotherapy in situ melanomas and dysplastic nevi. Pediatr Dermatol 2007;24 (2) 135- 137PubMedGoogle ScholarCrossref

Journal

Archives of DermatologyAmerican Medical Association

Published: Jun 1, 2008

Keywords: sorafenib

References