Molecular Genetic Demonstration of the Evolution of Transformed Mycosis Fungoides: A Clinicopathological and Molecular Case Study

Large cell transformation (LCT) in mycosis fungoides (MF) is thought to represent the clonal evolution of a single clone and is associated with aggressive clinical behavior and poor outcome not overcome by aggressive treatment regimens. The tumor dynamics leading to LCT-MF are poorly understood and previously determined genetic alterations in MF do not explain nor can predict disease progression and/or transformation, although implicating driver mutations have been identified. Our aim is to describe a distinct case of MF and the evolution of a genomic signature after LCT. This brief report highlights the evolution of genetic mutations seen in a 30-year-old Caucasian female with MF, folliculotropic type, who failed multiple treatment regimens and ultimately progressed with histologically confirmed LCT. The genomic analysis of five separate tumor samples, which originally harbored NRAS and PLCG1, showed molecular evolution with new somatic mutations in ATM, CARD11, TET2, TP53, U2AF1, and copy number variation including amplification of CDK6 and EIF4E, loss of CDKN2A, CDKN2B, and IKZF1 oncogenic isoform and high tumor burden, which were not seen in samples prior to LCT. The new somatic alterations seen with the clinical progression of LCT suggest evolution of the molecular tumor environment. Many of the mutations described implicate driver mutations in advanced-stage MF and have been associated with poor survival. While there is no evidence suggesting a singular mutation for the pathogenesis of LCT, the constellation of mutations may be responsible for histologic progression to LCT.