Hand-Foot and Stump Syndrome to Sorafenib
Authors: Susan E. Lai, Timothy Kuzel, Mario E. Lacouture
Journal: Journal of Clinical Oncology (2007)

Hand-Foot and Stump Syndrome to SorafenibA 47-year-old white man, who had an above-the-knee amputation of his left leg, was treated with single-agent sorafenib 400 mg orally twice daily for metastatic renal cell carcinoma.The patient regularly wore a prosthesis that encases his left stump.After approximately 8 weeks on sorafenib, the patient developed a tingling sensation of bilateral hands, his right sole, and his left stump.These quickly progressed to well-demarcated, tender, erythematous, scaling lesions on his palms, right sole (Fig 1) and left stump (Fig 2).Painless distal subungual splinter hemorrhages were also seen in all of his fingernails.Based on clinical findings and history, a diagnosis of hand-foot and stump syndrome (HFSS) secondary to sorafenib therapy was made.Like hand-foot syndrome, the mechanism by which sorafenib induces the HFSS variant remains only speculative.However, the observed results of this case indicate a possible relationship between the direct toxic effect of the chemotherapeutic drug delivered by the high concentration of eccrine glands in the palms and right sole, and the hyperhidrosis of the encased left stump, which may have contributed to the development of the HFSS on these sites and supporting the notion of anticancer agents in eccrine sweat leading to alterations in skin. 1 Features of the acral skin, such as the temperature gradient, the vascular anatomy, the rapidly dividing epidermis, and the highest number of eccrine sweat glands, favor such a hypothesis. 2,3In a study looking at 10 patients treated with doxorubicin, a well described culprit for HFS, Jacobi et al 5 measured the fluorescence of the drug qualitatively using a dermatologic laser scanning microscope in one male patient before and after intravenous treatment of doxorubicin on several body surface areas. 4Doxorubicin fluorescence was detected in the uppermost part of the skin on the palmar-plantar surfaces, deep in sweat ducts, and around their openings in the upper skin layers. 4his result suggests that the chemotherapeutic agent was delivered by the sweat to the skin surface.Other cutaneous adverse effects that can be caused by sorafenib warrant attention, including a seborrheic dermatitis-like rash, alopecia, stomatitis, splinter hemorrhages, and inflammation of actinic keratoses. 5The splinter hemorrhages may possibly be explained by the blockade of the vascular endothelial growth factor receptor, which might impair the intrinsic repair mechanisms of delicate injury-prone spiral capillaries. 6Depigmentation of terminal hairs has also been witnessed in clinical practice, occurring in as few as 8 weeks.In mice, blockade of c-kit signaling leads to complete but reversible hair depigmentation with inhibition of melanocyte proliferation and differentiation. 7ultitargeted tyrosine kinase inhibitors can induce a variety of dermatologic adverse events, which require early recognition and effective management, 8 in order to ensure continued lifesaving antineoplastic therapy.It is anticipated that observations such as the one described here, will contribute to a better understanding and further investigations towards the optimization of multitargeted therapies.