Independent evolution of cutaneous lymphoma subclones in different microenvironments of the skin

A characteristic but poorly studied feature of Mycosis Fungoides (MF) is epidermotropism, the tendency to infiltrate skin epithelial layer (epidermis) in addition to the vascularized dermis. By sequencing the exomes of the microdissected clusters of lymphoma cells from the epidermis and the dermis, we found that those microenvironments comprised different malignant clonotypes. Subclonal structure witnessed the independent mutational evolution in the epidermis and dermis. Malignant cells in epidermal and dermal niches exhibited different patterns of driver gene mutations. Thus, the epidermal involvement in MF could not be explained by gradual infiltration from the dermis but was caused by a separate seeding process. Since Intra Tumor Heterogeneity (ITH) adversely affects cancer prognosis, targeting the microenvironment may present therapeutic opportunities in MF and other cancers.