Pigmentary Changes Reported with Tyrosine Kinase Inhibitors: A Narrative Review of Mechanisms and Clinical Implications.

Abstract

Tyrosine kinase inhibitors are widely used targeted anti-cancer agents. They may induce pigmentary alterations that, although often benign, can have meaningful clinical and psychosocial implications. This study aimed to investigate pigmentation changes in the use of all tyrosine kinase inhibitors and to explain their underlying mechanisms. This narrative review is based on studies identified through searches of PubMed, Scopus, and Web of Science up to 1 September, 2025, encompassing clinical trials, case reports, original research articles, and relevant review articles on tyrosine kinase inhibitor-associated pigmentary changes. Tyrosine kinase inhibitor therapy was associated with a wide spectrum of pigmentary outcomes. Skin hypopigmentation and hair depigmentation were more frequently observed, largely attributed to direct inhibition of stem cell factor/c-Kit signaling and its downstream mitogen-activated protein kinase/extracellular signal-regulated kinase and phosphoinositide 3-kinase/protein kinase B pathways, leading to reduced melanocyte survival and function. Conversely, hyperpigmentation, though rare and unpredictable, was reported in association with paradoxical mitogen-activated protein kinase activation, melanocortin 1 receptor reactivation, or drug-melanin-iron complex formation. Patient-specific factors, including genetic polymorphisms (c-KIT, melanocortin 1 receptor, microphthalmia-associated transcription factor), immune and cytokine milieu, ethnicity, and concomitant therapies, were identified as modifiers of clinical outcomes. Pigmentary alterations induced by tyrosine kinase inhibitors are multifactorial, patient dependent, and reflect the interplay of genetic, immunologic, environmental, and pharmacologic factors. While hypopigmentation predominates, hyperpigmentation remains an uncommon but clinically relevant phenomenon. Larger multicenter studies, functional experimental models, and pharmacogenetic investigations are needed to elucidate predictive factors, clarify molecular mechanisms, and develop preventive or therapeutic strategies. Understanding these pigmentary changes may also provide valuable insights into drug activity and pave the way toward personalized medicine.