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Originally published as JCO Early Release 10.1200/JCO.2009.23.4823 on July 13 2009 © 2009 American Society of Clinical Oncology.
Keratoacanthomas and Squamous Cell Carcinomas in Patients Receiving SorafenibDermatology Service, Gustave Roussy Institute, France
Pathology Department, Henri-Mondor University Hospital, Créteil, France
Department of Medicine, Gustave Roussy Institute, Villejuif, France
Pathology Department, Gustave Roussy Institute, Villejuif, France
Dermatology Department, Institut Claudius Regaud, Toulouse, France
Dermatology Service, Tenon Hospital, Paris, France
Gastrointestinal Service, Tenon Hospital, Paris, France
Dermatology Service, Gustave Roussy Institute, France
Department of Medicine, Gustave Roussy Institute, Villejuif, France
Dermatology Service, Gustave Roussy Institute, France To the Editor: Sorafenib (Nexavar; Bayer HealthCare, Montville, NJ; Onyx Pharmaceuticals, Emeryville, CA) therapy is associated with multiple adverse effects involving the skin that are usually manageable and do not require interruption of treatment.1–3 To our knowledge, two isolated cases of squamous cell carcinomas (SCCs) of the skin associated with sorafenib have been published,4,5 as have rare cases of borderline squamous cell proliferations of the skin (ie, keratoacanthomas [KAs]).1,6 More recently, nine cases of either KA or SCC were reported in a retrospective study of 131 patients treated with sorafenib for renal cell carcinoma.7 Our present observations of 13 patients who developed solitary or multiple cutaneous squamous cell proliferations 1 to 9 months after initiation of sorafenib therapy highlight the link between sorafenib and atypical squamous cell proliferations and the need for prospective and biologic studies to uncover the pathophysiologic bases of this association. Patient demographics and clinical characteristics are listed in Table 1. All patients had type III to IV Fitzpatrick skin phototype except patient 12, who had type II. No patient had a history of previous skin squamous cell proliferation. All but one patient (patient 12) presented with clinical appearance of KA (ie, a firm round nodule with a central crateriform keratotic zone). Four patients had multiple skin lesions (patients 3, 6, 7, and 11).
A total of 22 lesions were excised (at least one per patient), and histologic examination using hematoxylin and eosin staining revealed three types of lesions in this series of patients. Sixteen lesions from seven patients were consistent with classic KA. They were exoendophytic proliferations with an invaginating and crateriform mass of keratinizing, well-differentiated squamous epithelium surrounding a large central keratin plug. The epithelial component was composed of pale acidophilic squamous cells exhibiting no atypia. There was no stromal dysplasia or any deep dermal invasion (Fig 1). Five lesions from five patients were diagnosed as KA-like SCCs and characterized by an incomplete or asymmetric crateriform pattern with bulging borders and irregular nests of squamous cells invading the dermis and/or nuclear atypias. Finally, one lesion appeared as a classic invasive SCC that developed on pre-existing actinic keratosis.
None of these patients relapsed after complete surgical excision of skin neoplasm, nor did they develop any regional or systemic metastases after median follow-up of 13.6 months (range, 2 to 25 months). Concerning treatment, skin lesions were excised in most cases. For patients with multiple lesions, a watchful waiting policy was adopted for some small and nonprogressive skin lesions that were clinically typical of KA. In two patients, the keratoacanthomas were monitored over a 6-month period because surgery was either postponed (patient 2) or refused (patient 4) by the patient; seemingly spontaneous involution of these lesions occurred despite sorafenib continuation. Two patients with multiple KAs who stopped sorafenib therapy (patients 3 and 7) experienced spontaneous resolution of their skin lesions over a few weeks. We observed no new or persisting KAs or SCCs in patients who experienced interruption of sorafenib therapy. KAs are characterized by rapidly growing nodules and frequent spontaneous resolution. They are often clinically and histologically indistinguishable from well-differentiated SCCs,8 and some authors have considered them to be low-grade cutaneous SCCs.9–11 In our patients, most of the skin lesions were clinically and histologically typical KAs with no sign of aggressiveness. However, we observed a spectrum of keratinizing squamous cell neoplasms ranging from atypical KAs to invasive SCCs. Multiple lesions with varying degrees of atypia can occur in the same patient (eg, patient 3), which could be an argument for systematically biopsying several lesions from the same patient. Known risk factors for cutaneous squamous cell proliferations are ultraviolet exposure (especially in fair-skinned individuals), immunosuppression, and papillomavirus infection. KAs most often arise on sun-exposed sites of light-skinned people of middle or older age and are more frequent in immunocompromised patients. Multiple KAs are rare. They can be seen in the context of the Fergusson Smith syndrome (an autosomal dominant disorder), the Muir-Torre syndrome, and the rare Grybowski syndrome with generalized eruptive KAs.12,13 A few cases of multiple KAs have been described in the context of infliximab treatment, ultraviolet B therapy, and cyclosporine treatment.14–16 In our series, lesions were located on various skin sites (Table 1), with no clear association with sun-exposed areas. In patient 12, who was 80 years of age, SCC developed on the scalp in the context of numerous pre-existing actinic keratoses and did not clinically or histopathologically resemble a KA-like lesion. It was similar to SCCs frequently observed in elderly patients on sun-exposed skin and was observed soon after the beginning of sorafenib therapy (2 weeks). Consequently, we do not think it was imputable to sorafenib. No pathologic sign of cell infection by papillomavirus was found in the tumors. Regarding their immune status, none of our patients were overtly immunodepressed. However, sorafenib has been shown to decrease the function of dendritic cells and induction of primary immune response,17 suggesting that sorafenib may impair skin immunosurveillance. Keratinocytes express vascular endothelial growth factor (VEGF) and B-Raf,18,19 and blocking these receptors is expected to elicit an antiproliferative action. Sunitinib is another inhibitor of the VEGF receptor, but it does not target the Raf protein and does not seem to be associated with KAs, suggesting that this effect is not mediated by inhibition of the VEGF receptor. Thus, the mechanism behind the proliferations of differentiated keratinocytes is obscure. Surgical excision is the recommended treatment for KAs because their relationship with SCCs is still unclear. Systemic retinoid therapy has been shown to be effective in some cases of multiple KAs and should probably be evaluated in patients presenting with multiple nonresectable KAs.20 Our present study of squamous cell proliferations of the skin in 13 patients treated with sorafenib, in addition to the few similar cases previously reported, suggest the strong imputability of sorafenib in the occurrence of this adverse effect. Concerning the incidence of this skin manifestation, Dubauskas et al7 retrospectively reported nine patients (6.8%) with SCCs and/or KAs in a group of 131 patients. During the time of our study, we determined the number of patients treated with sorafenib to be approximately 180 to 200, which would also suggest a 6% to 7% incidence; however, the exact incidence will be determined on the basis of future prospective studies and is still unknown. We think that those prescribing sorafenib should be informed of this adverse effect for several practical reasons. First, the skin of patients treated with sorafenib should be examined regularly to monitor for this adverse effect. KAs should be surgically excised when possible. The question of whether to interrupt sorafenib might be discussed in situations in which patients develop multiple unresectable KAs. In addition to these practical considerations, exploring and unraveling the mechanism leading to benign or malignant skin squamous cell proliferations associated with sorafenib are important and will certainly provide us with critical clues in understanding the pathophysiology of keratinocyte transformation. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. REFERENCES
1. Autier J, Escudier B, Wechsler J, et al: Prospective study of the cutaneous adverse effects of sorafenib, a novel multikinase inhibitor. Arch Dermatol 144:886–892, 2008. 2. Robert C, Mateus C, Spatz A, et al: Dermatologic symptoms associated with the multikinase inhibitor sorafenib. J Am Acad Dermatol 60:299–305, 2009.[CrossRef][Medline] 3. Robert C, Soria JC, Spatz A, et al: Cutaneous side-effects of kinase inhibitors and blocking antibodies. Lancet Oncol 6:491–500, 2005.[CrossRef][Medline] 4. Hong DS, Reddy SB, Prieto VG, et al: Multiple squamous cell carcinomas of the skin after therapy with sorafenib combined with tipifarnib. Arch Dermatol 144:779–782, 2008. 5. Lacouture ME, Desai A, Soltani K, et al: Inflammation of actinic keratoses subsequent to therapy with sorafenib, a multitargeted tyrosine-kinase inhibitor. Clin Exp Dermatol 31:783–785, 2006.[CrossRef][Medline] 6. Kong HH, Cowen EW, Azad NS, et al: Keratoacanthomas associated with sorafenib therapy. J Am Acad Dermatol 56:171–172, 2007.[CrossRef][Medline] 7. Dubauskas Z, Kunishige J, Prieto VG, et al: Cutaneous squamous cell carcinoma and inflammation of actinic keratoses associated with sorafenib. Clin Genitourin Cancer 7:20–23, 2009.[CrossRef][Medline] 8. Magalhães RF, Cruvinel GT, Cintra GF, et al: Diagnosis and follow-up of keratoacanthoma-like lesions: Clinical-histologic study of 43 cases. J Cutan Med Surg 12:163–173, 2008.[Medline] 9. Clausen OP, Aass HC, Beigi M, et al: Are keratoacanthomas variants of squamous cell carcinomas? A comparison of chromosomal aberrations by comparative genomic hybridization. J Invest Dermatol 126:2308–2315, 2006.[CrossRef][Medline] 10. Cribier B, Asch P, Grosshans E: Differentiating squamous cell carcinoma from keratoacanthoma using histopathological criteria: Is it possible? A study of 296 cases. Dermatology 199:208–212, 1999.[CrossRef][Medline] 11. Hodak E, Jones RE, Ackerman AB: Solitary keratoacanthoma is a squamous-cell carcinoma: Three examples with metastases. Am J Dermatopathol, 15–342, 332,discussion 343-342, 1993; discussion 343-352. 12. Schwartz RA: Keratoacanthoma: A clinico-pathologic enigma. Dermatol Surg 30:326–333, 2004 discussion 333.[CrossRef][Medline] 13. Schwartz RA: Keratoacanthoma. J Am Acad Dermatol 30:1–19, 1994 quiz 20-22.[Medline] 14. Craddock KJ, Rao J, Lauzon GJ, et al: Multiple keratoacanthomas arising post-UVB therapy. J Cutan Med Surg 8:239–243, 2004.[CrossRef][Medline] 15. Esser AC, Abril A, Fayne S, et al: Acute development of multiple keratoacanthomas and squamous cell carcinomas after treatment with infliximab. J Am Acad Dermatol 50:S75–S77, 2004 (suppl 5.[Medline] 16. Lain EL, Markus RF: Early and explosive development of nodular basal cell carcinoma and multiple keratoacanthomas in psoriasis patients treated with cyclosporine. J Drugs Dermatol 3:680–682, 2004.[Medline] 17. Hipp MM, Hilf N, Walter S, et al: Sorafenib, but not sunitinib, affects function of dendritic cells and induction of primary immune responses. Blood 111:5610–5620, 2008. 18. Man XY, Yang XH, Cai SQ, et al: Immunolocalization and expression of vascular endothelial growth factor receptors (VEGFRs) and neuropilins (NRPs) on keratinocytes in human epidermis. Mol Med 12:127–136, 2006.[Medline] 19. Takahashi H, Honma M, Miyauchi Y, et al: Cyclic AMP differentially regulates cell proliferation of normal human keratinocytes through ERK activation depending on the expression pattern of B-Raf. Arch Dermatol Res 296:74–82, 2004.[CrossRef][Medline] 20. Street ML, White JW Jr, Gibson LE: Multiple keratoacanthomas treated with oral retinoids. J Am Acad Dermatol 23:862–866, 1990.[Medline]
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Copyright © 2009 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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