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The Ras-Raf-MEK-ERK signalling pathway is frequently dysregulated in human malignancies, as is angiogenesis and the vascular endothelial growth factor receptor (VEGF/VEGFR) pathway. These kinases are therefore important anticancer targets. The novel, oral treatment sorafenib (BAY 43-9006), has been shown to be an inhibitor of VEGFR, Raf and platelet-derived growth factor in clinical trials against a variety of cancers, with the greatest activity to date observed in metastatic renal cancer. Although side-effects with this targeted therapy are usually not dose-limiting, they frequently involve the skin, and consist of a maculopapular rash, palmar-plantar dysaesthesia, alopecia and xerosis. In this report, we present two patients in whom treatment with sorafenib resulted in inflammation of actinic keratosis, which in some cases progressed to invasive squamous cell carcinoma. This side-effect is of clinical importance, as early recognition is critical for early treatment and may represent a source of additional morbidity to these patients.

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Hypopigmented mycosis fungoides is an uncommon clinical variant of cutaneous T-cell lymphoma. We hypothesized that hypomelanosis in hypopigmented mycosis fungoides may have a similar mechanism as in vitiligo, a condition in which it is believed that alterations in expression of CD117 (stem cell factor receptor/KIT protein) on epidermal melanocytes and abnormal interactions between melanocytes and surrounding keratinocytes may play a pathogenic role. To test the hypothesis that similar mechanisms might also explain hypopigmentation in hypopigmented mycosis fungoides, skin specimens from five cases each of hypopigmented mycosis fungoides and vitiligo were studied immunohistochemically for immunophenotype of the infiltrating cells, CD117 (expressed by epidermal melanocytes), and pan melanoma cocktail of antigens (gp100, tyrosinase, and MART-1) expression; cases of conventional mycosis fungoides and normal skin were studied in parallel as controls. Our findings confirm a predominance of CD8 þ neoplastic T cells in hypopigmented mycosis fungoides. Similarly, the epidermal lymphocytic infiltrate in vitiligo was also composed of CD8 þ cytotoxic T cells, in contrast to an epidermal infiltrate composed of CD4 þ T cells in conventional mycosis fungoides. The average number of epidermal CD117 expressing cells followed the same pattern of decreased expression in hypopigmented mycosis fungoides as in vitiligo, whereas the levels in conventional mycosis fungoides were higher, and similar to that observed in normal skin. Furthermore, a decreased number of melanocytes per high-power field of the length of the biopsy was present in hypopigmented mycosis fungoides and vitiligo, as compared with either conventional mycosis fungoides or normal skin, suggesting a correlation between decreased expression of CD117 and decreased number of melanocytes. We propose that decreased expression of CD117 and its downstream events in melanocytes may be initiated by cytotoxic effects of melanosomal-antigen-specific CD8 þ neoplastic T lymphocytes, resulting in destabilization of CD117 and leading to dysfunction and/or loss of melanocytes in the epidermis of hypopigmented mycosis fungoides.