Sneddon-Wilkinson Disease Induced by Sorafenib in a Patient with Advanced Hepatocellular Carcinoma

□ CASE REPORT □

Kazuto Tajiri 1, Takahiko Nakajima 2, Kengo Kawai 1, Masami Minemura 1 and Toshiro Sugiyama 1

Abstract

Sorafenib is the standard treatment for patients with advanced hepatocellular carcinoma (HCC), although it is known to cause a variety of dermatologic adverse events. Subcorneal pustular dermatosis (SCPD), also known as Sneddon-Wilkinson disease, is a rare skin eruption that accompanies various systemic disorders and may become chronically progressive. We herein describe the case of a patient who developed SCPD after sorafenib administration. The dermatologic reaction was improved by the cessation of sorafenib and wors- ened by its readministration. Clinicians treating HCC patients with sorafenib should be aware of the possibility of SCPD.

Key words: Sneddon-Wilkinson disease, subcorneal pustular dermatosis, advanced HCC, sorafenib

(Intern Med 54: 597-600, 2015) (DOI: 10.2169/internalmedicine.54.3675)

syndrome (12) and solid tumors, including lung carcinoma, Introduction apudoma and thymoma (13, 14). In particular, the occur- rence of SCPD in association with both benign and malig- Sorafenib is an oral multitargeted tyrosine kinase inhibitor nant IgA gammopathy has been documented (7, 8, 15, 16). with a potent anti-angiogenic activity (1). The administration In contrast, SCPD is hardly recognized as a side effect of of sorafenib has been shown to be effective for treating ad- this medicine (6). vanced hepatocellular carcinoma (HCC) (2, 3) and has be- We herein describe the case of a patient with advanced come a standard therapy for this disease (1). However, HCC who developed SCPD during treatment with sorafenib sorafenib has also been shown to cause many adverse der- and showed an improvement after sorafenib cessation. To matological effects, including hand-foot skin reaction our knowledge, this is the first description of a patient with (HFSR), alopecia, erythema and Steven-Johnson syn- sorafenib-induced SCPD. drome (4, 5). Subcorneal pustular dermatosis (SCPD), also called Case Report Sneddon-Wilkinson disease, is a rare skin eruption characterized by the presence of flaccid pustules grouped in a cir- A 76-year-old Japanese man was admitted to our depart- cinate or striate pattern (6). The exact epidemiology and ment for the treatment of advanced HCC. He had a history pathogenesis of this condition are unknown, although it is of cirrhosis due to chronic hepatitis C virus infection, as more common in women in the age group of 40-50 years well as pneumoconiosis and mild pleural effusion, lasting and an association with chemoattractants, such as tumor ne- for more than 10 years. However, he had no skin disorders crosis factor (TNF)-α, has been suggested (6). Although the before the administration of treatment for HCC. He had precise frequency is unknown, a series of case reports been diagnosed with HCC seven years earlier and treated showed that this skin disorder is observed in patients with periodically with radiofrequency ablation and transarterial systemic diseases, such as IgA myeloma (7, 8), rheumatoid chemoembolization (TACE). Nevertheless, the HCC had arthritis (9, 10), inflammatory bowel disease (11), Sjögren’s progressed, with the development of multiple nodules in

１The Third Department of Internal Medicine, Toyama University Hospital, Japan and ２Diagnostic Pathology, Toyama University Hospital, Japan Received for publication July 14, 2014; Accepted for publication August 25, 2014 Correspondence to Dr. Kazuto Tajiri, [email protected]

597 Intern Med 54: 597-600, 2015 DOI: 10.2169/internalmedicine.54.3675

A) B)

C) D) E)

Figure 1. A) Photograph of the leg showing circular and linear areas of erythema with pustules. B) Skin biopsy of the right leg showing subcorneal and intracorneal pustular formation with neutrophil infiltration as well as spongiosis and vacuolar changes in the epidermis. The arrows indicate the lesion (Hematoxylin and Eosin staining; original magnification ×200). C) Photograph of the right leg showing distinct areas of light circular and linear erythema. Seven months after sorafenib administration. D) Photograph of the leg. The areas of circular and linear erythema became considerably lighter. Twelve months after sorafenib administration. E) Photograph of the leg. Most of the erythema had disappeared. Thirteen months after sorafenib administration.

both lobes that were refractory to TACE. The patient’s he- (Fig. 1A). A skin biopsy showed spongiosis, vacuolar patic reserve and systemic organ function were good (serum changes and subcorneal pustular formation with neutrophil total protein: 8.6 g/dL, albumin: 4.0 g/dL, aspartate dominant infiltration in the superficial epidermis (Fig. 1B); aminotransferase: 49 U/L, alanine aminotransferase: 56 U/L, bacterial bodies and fungi were not detected on Gram or γ-glutamyl transpeptidase: 47 U/L, alkaline phosphatase: 326 PAS staining. Subepidermal blistering was absent. The pa- U/L, total bilirubin: 0.6 mg/dL, blood urea nitrogen: 9 mg/ tient was thus diagnosed with SCPD. Strong topical steroid dL, creatinine 0.6 mg/dL, white blood cell count: 4,620/μL, therapy was subsequently initiated, and the dose of sorafenib hemoglobin: 14.0 g/dL, platelet count: 12.7×104/μL). He was was reduced to 400 mg/day. Although the SCPD showed therefore started on sorafenib (800 mg/day). Twenty days some improvement, it persisted for approximately seven later, however, he developed grade 2/3 HFSR, and the dose months (Fig. 1C, 2). In addition, the SCPD resolved when of sorafenib was reduced to 400 mg/day. Computed to- the sorafenib therapy was transiently discontinued due to the mography performed after a total of 60 days of treatment use of additional TACE for progressive HCC nodules; how- with sorafenib showed stable disease according to the Re- ever, it again recurred when the sorafenib treatment was response Evaluation Criteria in Solid Tumors (RECIST) crite- started (Fig. 2). Sorafenib was therefore permanently discon- ria (17). The HFSR had also improved to grade 1, and the tinued 12 months after the start of treatment, which resulted dose of sorafenib was increased to 600 mg/day. Ten days in the disappearance of SCPD within two or three months later, or 70 days after the initiation of sorafenib, multiple (Fig. 1D, E). Since that time, the patient has received he- erythematous skin eruptions in a circular or linear pattern patic arterial infusion chemotherapy with 5-fluorouracil and with mild itching and pain were observed on the extremities cisplatin.

598 Intern Med 54: 597-600, 2015 DOI: 10.2169/internalmedicine.54.3675

d0 d20 d60 d100 6m 8m 10m 11m 16m Sorafenib 800400 600

SCPD

WBC (ʅL) 4,620 4,740 4,880 4,960 4,180 4,920 Eosino (ʅL) 210 220 146 n.e. 190 290 LDH (U/L) 154 174 179 168 170 170

Figure 2. Clinical course of the subcorneal pustular dermatosis (SCPD) and sorafenib treatment in the current patient. The numbers in the upper column represent the time after sorafenib administration. WBC: white blood cells, Eosino: eosinophil, LDH: lactate dehydrogenase, d: day, m: month, n.e.: not examined. The numbers in gray bars represent the doses of sorafenib.

trophils to the epidermis. A recent case report described the Discussion onset of pustular eruptions induced by sorafenib in a patient with HCC, liver cirrhosis and psoriasis vulgaris (22). In that Sorafenib is a multikinase inhibitor approved for the treat- patient, the pustules were thought to be associated with the ment of unresectable HCC and advanced renal cell carci- exacerbation of psoriasis, as they appeared only on pre- noma (RCC) in Japan. HFSR is frequently observed during existing psoriatic plaques (22). In addition, SCPD was noted the use of sorafenib in patients with HCC, including 21.0% at the injection site of recombinant human granulocyte- of the patients in the global phase III SHARP trial (2) and macrophage colony-stimulating factor in a patient with IgA 45.0% of the patients in the phase III Asia-Pacific trial (3). myeloma (8). Sorafenib inhibits a number of tyrosine Furthermore, adverse dermatological events have been re- kinases, including the vascular endothelial growth factor re- ported in 80.2% of sorafenib-treated patients with advanced ceptor family, platelet-derived growth factor receptor and raf RCC, with HFSR occurring in 55.0% of patients assessed in kinase (1). Sorafenib-induced HFSR has also been suggested a phase 2 trial in Japan (18). Furthermore, a retrospective to be caused by drug leakage from capillaries damaged by study in Korea showed that adverse cutaneous events are subclinical trauma (23). The administration of sorafenib may frequently noted in patients treated with sorafenib (81/109, be associated with the formation of pustules via the actions 74.3%) and sunitinib (96/119, 80.7%) (4), highlighting the of chemotactic factors induced by drug leakage from capil- importance of managing adverse skin events during treat- laries due to underlying hyperglobulinemia as a result of cir- ment with multitargeted kinase inhibitors with a potent anti- rhosis and chronic inflammation. angiogenic activity, such as sorafenib, especially in Asian In conclusion, the administration of sorafenib may be as- patients. sociated with the development and progression of SCPD, as SCPD is a rare chronic pustular eruption that accompa- well as various other skin disorders. Skin biopsies are re- nies various systemic disorders, such as autoimmune dis- quired to make an accurate diagnosis, and dose reduction of eases and malignancies. SCPD is characterized by the pres- sorafenib and the administration of topical steroids may en- ence of sterile pustular eruptions caused by neutrophil mi- able the continuation of sorafenib treatment. Clinicians treat- gration through the epidermis and aggregation beneath the ing patients with anti-angiogenic agents, including sorafenib, stratum corneum (19). This hyperactivation of neutrophils is should thus be aware of the possibility of SCPD as well as thought to be induced by chemotactic factors, such as TNF- other adverse cutaneous effects. α, in the uppermost epidermis, with increased TNF-α con- centrations in the serum and blister fluid in patients with The authors state that they have no Conflict of Interest (COI). SCPD (20). In addition, interleukin-8 and C5a concentra- tions above the normal levels have been observed in the References scale extracts of patients with SCPD (21). Although the precise mechanisms remain unknown, the presence of chemo- 1. Finn RS. Drug therapy: sorafenib. Hepatology 51: 1843-1849, tactic factors associated with systemic disorders in the epi- 2010. dermis may induce SCPD. Our patient developed SCPD af- 2. Llovet JM, Ricci S, Mazzaferro V, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 359: 378-390, 2008. ter sorafenib administration in the absence of any systemic 3. Cheng AL, Kang YK, Chen Z, et al. Efficacy and safety of sora- disorders, including IgA myeloma, rheumatoid arthritis, fenib in patients in the Asia-Pacific region with advanced hepato- Sjögren’s syndrome and inflammatory bowel disease. The cellular carcinoma: a phase III randomised, double-blind, placebo- presence of pneumoconiosis, a type of chronic pleural in- controlled trial. Lancet Oncol 10: 25-34, 2009. flammation, and/or liver cirrhosis, a type of chronic hepatic 4. Lee WJ, Lee JL, Chang SE, et al. Cutaneous adverse effects in patients treated with the multitargeted kinase inhibitors sorafenib inflammation, in our advanced HCC patient may have been and sunitinib. Br J Dermatol 161: 1045-1051, 2009. associated with the onset of SCPD via the migration of neu-

599 Intern Med 54: 597-600, 2015 DOI: 10.2169/internalmedicine.54.3675

5. McLellan B, Kerr H. Cutaneous toxicities of the multikinase in- IgA gammopathy: a report and review of the literature. J Am hibitors sorafenib and sunitinib. Dermatol Ther 24: 396-400, 2011. Acad Dermatol 19: 854-858, 1988. 6. Cheng S, Edmonds E, Ben-Gashir M, Yu RC. Subcorneal pustular 16. Agarwal A, Shivaswamy KN, Raja B, Thappa DM, Verma SK. dermatosis: 50 years on. Clin Exp Dermatol 33: 229-233, 2008. Subcorneal pustlar dermatosis and thymoma: an association or co- 7. Atukorala DN, Joshi RK, Abanmi A, Jeha MT. Subcorneal pustu- incidence? Indian J Dermatol 51: 272-274, 2006. lar dermatosis and IgA myeloma. Dermatology 187: 124-126, 17. Therasse P, Arbuck SG, Eisenhauer EA, et al. New guidelines to 1993. evaluate the response to treatment in solid tumors. European Or- 8. Lautenschlager S, Itin PH, Hirsbrunner P, Buchner SA. Subcorneal ganization for Research and Treatment of Cancer, National Cancer pustular dermatosis at the injection site of recombinant human Institute of the United States, National Cancer Institute of Canada. granulocyte-macrophage colony-stimulating factor in a patient J Natl Cancer Inst 92: 205-216, 2000. with IgA myeloma. J Am Acad Dermatol 30: 787-789, 1994. 18. Akaza H, Tsukamoto T, Murai M, Nakajima K, Naito S. Phase II 9. Butt A, Burge SM. Sneddon-Wilkinson disease in association with study to investigate the efficacy, safety, and pharmacokinetics of rheumatoid arthritis. Br J Dermatol 132: 313-315, 1995. sorafenib in Japanese patients with advanced renal cell carcinoma. 10. Iobst W, Ingraham K. Sneddon-Wilkinson disease in a patient Jpn J Clin Oncol 37: 755-762, 2007. with rheumatoid arthritis. Arthritis Rheum 52: 3771, 2005. 19. Sneddon IB, Wilkinson DS. Subcorneal pustular dermatosis. Br J 11. Delaporte E, Colombel JF, Nguyen-Mailfer C, Piette F, Cortot A, Dermatol 68: 385-394, 1956. Bergoend H. Subcorneal pustular dermatosis in a patient with 20. Grob JJ, Mege JL, Capo C, et al. Role of tumor necrosis factor- Crohn’s disease. Acta Derm Venereol 72: 301-302, 1992. alpha in Sneddon-Wilkinson subcorneal pustular dermatosis. A 12. Tsuruta D, Matsumura-Oura A, Ishii M. Subcorneal pustular der- model of neutrophil priming in vivo. J Am Acad Dermatol 25: matosis and Sjögren’s syndrome. Int J Dermatol 44: 955-957, 944-947, 1991. 2005. 21. Takematsu H, Tagami H. Quantification of chemotactic peptides 13. Buchet S, Humbert P, Blanc D, et al. [Subcorneal pustular derma- (C5a anaphylatoxin and IL-8) in psoriatic lesional skin. Arch Der- tosis associated with epidermoid carcinoma of the lung]. Ann Der- matol 129: 74-80, 1993. matol Venereol 118: 125-128, 1991 (in French). 22. Maki N, Komine M, Takatsuka Y, Maekawa T, Murata S, Ohtsuki 14. Villey MC, Ehrsam E, Marrakchi S, Colombel JF, Thomas P. Apu- M. Pustular eruption induced by sorafenib in a case of psoriasis doma and subcorneal pustular dermatosis (Sneddon-Wilkinson dis- vulgaris. J Dermatol 40: 299-300, 2013. ease). Dermatology 185: 269-271, 1992. 23. Jain L, Gardner ER, Figg WD, Chernick MS, Kong HH. Lack of 15. Kasha EE, Epinette WW. Subcorneal pustular dermatosis association between excretion of sorafenib in sweat and hand-foot (Sneddon-Wilkinson disease) in association with a monoclonal skin reaction. Pharmacotherapy 30: 52-56, 2010.

600