5. Ueda N, Satoh T, Yamamoto T, Yokozeki H. Nodular cystic fat necrosis in Heerfordt’s syndrome. J Eur Acad Dermatol Venereol 2007; 21: 708-9. 6. Tsunoda K, Onodera H, Akasaka T. Case of malignant melanoma associated with a sarcoid reaction. J Dermatol 2011; 39: 939-42.
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doi:10.1684/ejd.2014.2463
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Eruptive nevi and hair depigmentation related to regorafenib Regorafenib (Stivarga® ) is a new orally available multikinase inhibitor that targets several protein kinases involved in angiogenesis (VEGFR1-3, TIE2), oncogenesis (c-KIT, RET, RAF1, wild-type BRAF and mutated BRAFV600 ) and maintenance of the tumor microenvironment (PDGF, FGFR-1). It has been shown to improve overall or progression-free survival in patients with colorectal cancer and gastrointestinal stromal tumors, respectively [1, 2]. Drug-related toxicity occurs in the majority of patients, with asthenia, diarrhea, hypertension and hand foot skin reaction (HFSR) accounting for the most prevalent and severe adverse events [1-4]. Besides HFSR, other cutaneous manifestations induced by regorafenib, such as skin rash or mucositis, are also common but have not yet been characterized in prospective studies. We report here the rapid development of eruptive nevi and hair depigmentation, adverse events which have never been reported previously with regorafenib and which are potentially related to BRAF and c-Kit signaling inhibition, respectively. A 61-year old patient had been treated by regorafenib (160 mg/day during 21 days every 28 days) for 3 months for metastatic colorectal cancer. He was followed-up in the Dermatology department for bilateral HFSR, mainly located on areas subjected to pressure, and microtraumas of the feet with painful hyperkeratotic inflammatory lesions. Physical examination also showed the appearance of more than 50 new asymptomatic melanocytic lesions on the abdomen, back and thighs (figure 1A). The lesions were monomorphous, measuring a few millimeters in diameter, with dark homogeneous coloration. Microscopic examination of a newly-developed lesion showed a melanocytic nevus, made of small nests of normal melanocytes at the dermal-epidermal junction and the upper dermis, lacking mitoses or dysplasia (figure 1B). Mutational testing of BRAFV600 by HRM analysis using standard protocols showed a BRAFwild-type genotype. These eruptive nevi remained stable during treatment. Finally, hair changes were also observed since the beginning of treatment, with the progressive development of curlier, more brittle and depigmented scalp hair (figures 1C-D). The development of eruptive nevi or melanocytic lesions has never been reported so far with regorafenib. However, this adverse event is well known with other RAF inhibitors and its incidence is thus likely to be underestimated with regorafenib. We first described the abrupt development of such lesions with the pan RAF inhibitor sorafenib (Nexavar® ) [5]. More recently, eruptive nevi were reported in more than 10% of patients treated with EJD, vol. 25, n◦ 1, January-February 2015
Figure 1. A) Monomorphous eruptive nevi on the ventral aspect of the trunk. B) Proliferation of normal melanocytes consistent with a melanocytic nevus (hematoxylin-eosin, ×40) C, D) Curly depigmented hair.
vemurafenib (Zelboraf® ) and dabrafenib (Tafinlar® ) [6, 7], which are, like regorafenib, specific serine-threonine kinase inhibitors of mutated BRAFV600 . It has been suggested that the emergence of these lesions could be related to a downstream paradoxical activation of the MAP (mitogen activated protein) kinase in wild-type BRAF melanocytes [6, 8], especially after heterodimerization to BRAF-CRAF or CRAF-CRAF complexes [8]. This would also explain why some preexisting nevi (harboring the V600 mutation) can fade during these treatments or, conversely, become darker (in nevi with wild-type BRAF status). More importantly, several cases of new primary melanomas linked to the same mechanism of paradoxical melanocytic proliferation have also been reported with these BRAF inhibitors [6, 8]. More recently, Perier-Muzet et al. prospectively estimated that more than 20% of patients treated with vemurafenib could be concerned by primary melanoma [9]. Reporting such melanocytic lesions with regorafenib is therefore not just anecdotal. Patients treated with regorafenib should be closely monitored with regular dermatologic examination in order to follow prospectively the development of induced melanocytic lesions, including de novo melanoma. Patients treated with regorafenib are very likely to develop other cutaneous adverse events related to the inhibition of the RAF pathway and similar to those reported with sorafenib and vemurafenib [6, 10]. For example, several cases of keratoacanthomas have been reported with regorafenib; these skin tumors were also observed in almost 10% of patients treated with sorafenib [10] and 9-14% of those treated with vemurafenib [6]. Likewise, the development of curly hair observed in our patient seems very similar to the hair changes induced by these other RAF inhibitors [6, 7, 10]. Furthermore, in our patient we observed hair depigmentation which has not been reported so far with regorafenib. This latter adverse event is potentially related to c-KIT inhibition as it has previously been observed with other multikinase inhibitors such as pazopanib and sunitinib [10]. Disclosure. Financial support: none. Conflict of interest: none.
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Department of Dermatology, Department of Pathology, Institut Claudius Regaud - Institut Universitaire du Cancer, Toulouse Oncopole, 1 rue Irène-Joliot-Curie, 31100 Toulouse, France 2
Vincent SIBAUD1 Coline MUNSCH1 Laurence LAMANT2
1. Grothey A, Van Cutsem E, Sobrero A, et al. Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet 2013; 381: 303-12. 2. Demetri GD, Reichardt P, Kang YK, et al. Efficacy and safety of regorafenib for advanced gastrointestinal stromal tumours after failure of imatinib and sunitinib (GRID): an international , multicentre, randomised, placebo-controlled, phase 3 trial. Lancet 2013; 381: 295302. 3. De Wit M, Boers-Doets CB, Saettini A, et al. Prevention and management of adverse events related to regorafenib. Support Care Cancer 2014; 22: 837-46. 4. Belum VR, Wu S, Lacouture ME. Risk of hand-foot skin reaction with the novel multikinase inhibitor regorafenib: a meta-analysis. Invest New Drugs 2013; 31: 1078-86. 5. Kong HH, Sibaud V, Chanco Turner ML, et al. Sorafenib-induced eruptive melanocytic lesions. Arch Dermatol 2008; 144: 820-2. 6. Boussemart L, Routier E, Mateus C, et al. Prospective study of cutaneous side-effects associated with the BRAF inhibitor vemurafenib: a study of 42 patients. Ann Oncol 2013; 24: 1691-7. 7. Anforth R, Blumetti TC, Kefford RF, et al. Manifestations of dabrafenib (GSK2118436): A selective inhibitor of mutant BRAF in patients with metastatic melanoma. Br J Dermatol 2012; 167: 115360. 8. Zimmer L, Hillen U, Livingstone E, et al. Atypical melanocytic proliferations and new primary melanomas in patients with advanced melanoma undergoing selective BRAF inhibition. J Clin Oncol 2012; 30: 2375-83. 9. Perier-Muzet M, Thomas L, Poulalhon N, et al. Melanoma Patients under Vemurafenib: Prospective Follow-Up of Melanocytic Lesions by Digital Dermoscopy. J Invest Dermatol 2014; 134: 1351-8. 10. Robert C, Sibaud V, Mateus C, et al. Advances in the management of cutaneous toxicities of targeted therapies. Semin Oncol 2012; 39: 227-40. doi:10.1684/ejd.2014.2462
Acute generalized exanthematous pustulosis possibly induced by isoniazid in a patient with psoriatic erythroderma A 49-year-old man was admitted complaining of pustular eruptions on the trunk associated with high-grade fever. He had a 27-year history of psoriasis vulgaris. Various treatments were tried, however, he eventually developed psoriatic erythroderma. To initiate treatment with infliximab, he was prophylactically administered with isoniazid 300 mg/day for 18 days until the eruption was aggravated with pustule development on the abdomen. On examination he presented with diffuse dark erythema and multiple small sterile pustules coalesced on the trunk, as well as a fever of 38.4 ◦ C (figure 1A). Laboratory investigations revealed an increased number of white blood cells (13,200/L with
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Figure 1. Clinical appearance of the eruption. Dark diffuse erythematous lesions with multiple coalesced pustules on the trunk (A). Histological analysis of an abdominal skin biopsy. Hematoxylin-eosin staining shows acanthosis of the epidermis with elongation of rete ridges, a subcorneal pustule with peripheral spongiform abscess around the follicle, dilated blood vessels and perivascular infiltration of mononuclear cells in the upper dermis. Focal necrosis of keratinocytes, extravasated erythrocytes and leukocytoclastic vasculitis were not observed (B).
89% neutrophils) and an elevated level of C-reactive protein (4.22 mg/dL, normal value;
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C
doi:10.1684/ejd.2014.2463
B
D
Eruptive nevi and hair depigmentation related to regorafenib Regorafenib (Stivarga® ) is a new orally available multikinase inhibitor that targets several protein kinases involved in angiogenesis (VEGFR1-3, TIE2), oncogenesis (c-KIT, RET, RAF1, wild-type BRAF and mutated BRAFV600 ) and maintenance of the tumor microenvironment (PDGF, FGFR-1). It has been shown to improve overall or progression-free survival in patients with colorectal cancer and gastrointestinal stromal tumors, respectively [1, 2]. Drug-related toxicity occurs in the majority of patients, with asthenia, diarrhea, hypertension and hand foot skin reaction (HFSR) accounting for the most prevalent and severe adverse events [1-4]. Besides HFSR, other cutaneous manifestations induced by regorafenib, such as skin rash or mucositis, are also common but have not yet been characterized in prospective studies. We report here the rapid development of eruptive nevi and hair depigmentation, adverse events which have never been reported previously with regorafenib and which are potentially related to BRAF and c-Kit signaling inhibition, respectively. A 61-year old patient had been treated by regorafenib (160 mg/day during 21 days every 28 days) for 3 months for metastatic colorectal cancer. He was followed-up in the Dermatology department for bilateral HFSR, mainly located on areas subjected to pressure, and microtraumas of the feet with painful hyperkeratotic inflammatory lesions. Physical examination also showed the appearance of more than 50 new asymptomatic melanocytic lesions on the abdomen, back and thighs (figure 1A). The lesions were monomorphous, measuring a few millimeters in diameter, with dark homogeneous coloration. Microscopic examination of a newly-developed lesion showed a melanocytic nevus, made of small nests of normal melanocytes at the dermal-epidermal junction and the upper dermis, lacking mitoses or dysplasia (figure 1B). Mutational testing of BRAFV600 by HRM analysis using standard protocols showed a BRAFwild-type genotype. These eruptive nevi remained stable during treatment. Finally, hair changes were also observed since the beginning of treatment, with the progressive development of curlier, more brittle and depigmented scalp hair (figures 1C-D). The development of eruptive nevi or melanocytic lesions has never been reported so far with regorafenib. However, this adverse event is well known with other RAF inhibitors and its incidence is thus likely to be underestimated with regorafenib. We first described the abrupt development of such lesions with the pan RAF inhibitor sorafenib (Nexavar® ) [5]. More recently, eruptive nevi were reported in more than 10% of patients treated with EJD, vol. 25, n◦ 1, January-February 2015
Figure 1. A) Monomorphous eruptive nevi on the ventral aspect of the trunk. B) Proliferation of normal melanocytes consistent with a melanocytic nevus (hematoxylin-eosin, ×40) C, D) Curly depigmented hair.
vemurafenib (Zelboraf® ) and dabrafenib (Tafinlar® ) [6, 7], which are, like regorafenib, specific serine-threonine kinase inhibitors of mutated BRAFV600 . It has been suggested that the emergence of these lesions could be related to a downstream paradoxical activation of the MAP (mitogen activated protein) kinase in wild-type BRAF melanocytes [6, 8], especially after heterodimerization to BRAF-CRAF or CRAF-CRAF complexes [8]. This would also explain why some preexisting nevi (harboring the V600 mutation) can fade during these treatments or, conversely, become darker (in nevi with wild-type BRAF status). More importantly, several cases of new primary melanomas linked to the same mechanism of paradoxical melanocytic proliferation have also been reported with these BRAF inhibitors [6, 8]. More recently, Perier-Muzet et al. prospectively estimated that more than 20% of patients treated with vemurafenib could be concerned by primary melanoma [9]. Reporting such melanocytic lesions with regorafenib is therefore not just anecdotal. Patients treated with regorafenib should be closely monitored with regular dermatologic examination in order to follow prospectively the development of induced melanocytic lesions, including de novo melanoma. Patients treated with regorafenib are very likely to develop other cutaneous adverse events related to the inhibition of the RAF pathway and similar to those reported with sorafenib and vemurafenib [6, 10]. For example, several cases of keratoacanthomas have been reported with regorafenib; these skin tumors were also observed in almost 10% of patients treated with sorafenib [10] and 9-14% of those treated with vemurafenib [6]. Likewise, the development of curly hair observed in our patient seems very similar to the hair changes induced by these other RAF inhibitors [6, 7, 10]. Furthermore, in our patient we observed hair depigmentation which has not been reported so far with regorafenib. This latter adverse event is potentially related to c-KIT inhibition as it has previously been observed with other multikinase inhibitors such as pazopanib and sunitinib [10]. Disclosure. Financial support: none. Conflict of interest: none.
85
1
Department of Dermatology, Department of Pathology, Institut Claudius Regaud - Institut Universitaire du Cancer, Toulouse Oncopole, 1 rue Irène-Joliot-Curie, 31100 Toulouse, France 2
Vincent SIBAUD1 Coline MUNSCH1 Laurence LAMANT2
1. Grothey A, Van Cutsem E, Sobrero A, et al. Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet 2013; 381: 303-12. 2. Demetri GD, Reichardt P, Kang YK, et al. Efficacy and safety of regorafenib for advanced gastrointestinal stromal tumours after failure of imatinib and sunitinib (GRID): an international , multicentre, randomised, placebo-controlled, phase 3 trial. Lancet 2013; 381: 295302. 3. De Wit M, Boers-Doets CB, Saettini A, et al. Prevention and management of adverse events related to regorafenib. Support Care Cancer 2014; 22: 837-46. 4. Belum VR, Wu S, Lacouture ME. Risk of hand-foot skin reaction with the novel multikinase inhibitor regorafenib: a meta-analysis. Invest New Drugs 2013; 31: 1078-86. 5. Kong HH, Sibaud V, Chanco Turner ML, et al. Sorafenib-induced eruptive melanocytic lesions. Arch Dermatol 2008; 144: 820-2. 6. Boussemart L, Routier E, Mateus C, et al. Prospective study of cutaneous side-effects associated with the BRAF inhibitor vemurafenib: a study of 42 patients. Ann Oncol 2013; 24: 1691-7. 7. Anforth R, Blumetti TC, Kefford RF, et al. Manifestations of dabrafenib (GSK2118436): A selective inhibitor of mutant BRAF in patients with metastatic melanoma. Br J Dermatol 2012; 167: 115360. 8. Zimmer L, Hillen U, Livingstone E, et al. Atypical melanocytic proliferations and new primary melanomas in patients with advanced melanoma undergoing selective BRAF inhibition. J Clin Oncol 2012; 30: 2375-83. 9. Perier-Muzet M, Thomas L, Poulalhon N, et al. Melanoma Patients under Vemurafenib: Prospective Follow-Up of Melanocytic Lesions by Digital Dermoscopy. J Invest Dermatol 2014; 134: 1351-8. 10. Robert C, Sibaud V, Mateus C, et al. Advances in the management of cutaneous toxicities of targeted therapies. Semin Oncol 2012; 39: 227-40. doi:10.1684/ejd.2014.2462
Acute generalized exanthematous pustulosis possibly induced by isoniazid in a patient with psoriatic erythroderma A 49-year-old man was admitted complaining of pustular eruptions on the trunk associated with high-grade fever. He had a 27-year history of psoriasis vulgaris. Various treatments were tried, however, he eventually developed psoriatic erythroderma. To initiate treatment with infliximab, he was prophylactically administered with isoniazid 300 mg/day for 18 days until the eruption was aggravated with pustule development on the abdomen. On examination he presented with diffuse dark erythema and multiple small sterile pustules coalesced on the trunk, as well as a fever of 38.4 ◦ C (figure 1A). Laboratory investigations revealed an increased number of white blood cells (13,200/L with
86
A
B
Figure 1. Clinical appearance of the eruption. Dark diffuse erythematous lesions with multiple coalesced pustules on the trunk (A). Histological analysis of an abdominal skin biopsy. Hematoxylin-eosin staining shows acanthosis of the epidermis with elongation of rete ridges, a subcorneal pustule with peripheral spongiform abscess around the follicle, dilated blood vessels and perivascular infiltration of mononuclear cells in the upper dermis. Focal necrosis of keratinocytes, extravasated erythrocytes and leukocytoclastic vasculitis were not observed (B).
89% neutrophils) and an elevated level of C-reactive protein (4.22 mg/dL, normal value;
