Clonal Transdifferentiation from Follicular Lymphoma to Langerhans Cell Histiocytosis: Diagnostic Challenges, Molecular Insights, and the Role of Skin as a Diagnostic Window

Summary: Transdifferentiation from follicular lymphoma (FL) to Langerhans cell histiocytosis (LCH) presents diagnostic and therapeutic challenges. The skin acts as a crucial window for systemic diseases, offering an accessible site for biopsy and detection of lineage transformations. Pathologists play vital roles in identifying cutaneous manifestations signifying transdifferentiation. 
A 72-year-old male with FL (grade 1-2 of 3, stage III) diagnosed in 2014 was treated with rituximab monotherapy, followed by obinutuzumab-bendamustine in 2017 for progression. By 2022, lymphadenopathy progressed, and a tonsillar biopsy (12/2022) revealed FL (~5%), LCH (~50%), and necrosis (~45%). Retroperitoneal biopsy (1/2023): FL (50%) and LCH (50%); Lung and neck skin (3/2023): Pure LCH, confirming systemic transformation. PCR for IGH rearrangement and FISH studies demonstrated clonal relatedness of FL and LCH. Molecular analysis identified KRAS (p.Q61R) and TNFRSF14 (p.Q130*) mutations, driving aggressive behavior through oncogenic and immune dysregulation pathways. Moderate tumor mutational burden suggested additional contributions to tumor progression. Despite aggressive therapy, the patient developed pancytopenia and septic shock, passing in April 2023.

 The skin biopsy provided a vital clue to systemic lineage transformation and emphasized the importance of accessible diagnostic sites. Molecular analyses are essential for confirming clonal transdifferentiation and guiding therapeutic strategies for these rare and aggressive malignancies.