Summary
Palmoplantar keratodermas comprise a diverse group of acquired and hereditary disorders marked by excessive thickening of the epidermis of palms and soles. Early onset and positive family history suggest a genetic cause. While hereditary forms of palmoplantar keratoderma (PPK) may represent the sole or dominant clinical feature, they may also be associated with other ectodermal defects or extracutaneous manifestations. In recent years, much progress has been made in deciphering the genetic basis of PPK, which has led to the emergence of new disorders and syndromes. The elucidation of disease mechanisms has opened new avenues for specific therapies, increasingly sparking interest in this field. Given the high heterogeneity with respect to clinical features, genetic defects, and disease mechanisms, the classification of PPK is based on various criteria. These include extent of disease manifestations, morphology of palmoplantar skin involvement, inheritance patterns, and molecular pathogenesis. Though not always feasible, the clinical distinction of various PPK entities is based on fine‐tuned criteria or clues. Remarkably, apparently distinct disorders have been shown to be allelic, as they are caused by mutations in the same gene. By contrast, similar clinical pictures may result from mutations in different genes. Because of this complexity, mutation analysis is required to determine the precise type of PPK. The best‐defined entities are described in this review.
The enzyme indoleamine 2,3-dioxygenase (IDO) is emerging as a facilitator of cancer development through its effects on cancer-associated inflammation. Recent studies report a significant improvement of the response rates in melanoma patients to PD-1 antibodies when IDO inhibitors were added to the regimen. Data on IDO expression in primary human melanomas are, however, incomplete and conflicting. Here, we show that the level of IDO expression in primary human melanoma cells significantly correlates with Breslow thickness (P = 0.003), the presence of tumor-infiltrating lymphocytes (P = 0.029), and the intensity of the peritumoral inflammatory infiltrate (P = 0.001). The expression of IDO in melanoma cells predicted independently of Breslow thickness and tumor stage (P = 0.04). We further show that CD11c dendritic cells and CD68 macrophages in the microenvironment of melanomas express IDO. The level of IDO expression in antigen-presenting cells correlated positively to peritumoral inflammation (P = 0.001) but not to tumor-infiltrating lymphocytes. Significant negative correlation with progression-free survival was found for patients for whom antigen-presenting cells were very strongly IDO positive. These results suggest that IDO induction within melanoma cells may directly reflect tumor progression, whereas IDO in antigen-presenting cells may determine immune surveillance with impact on local and systemic tolerance.
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