Genetic heterogeneity highlighted by differential FDG-PET response in diffuse large B-cell lymphoma

Intratumor heterogeneity (ITH) has emerged as a key theme to understanding the mechanisms driving treatment failure and relapse. Studies in many different cancers have revealed varying degrees of molecular heterogeneity both within and between biopsies taken from different sites of disease in the same patient. In practice, the rarity of multi-site sampling in diffuse large B-cell lymphoma (DLBCL) has restricted studies to single biopsies at the time of diagnosis and these have been highly informative in characterizing unique molecular subtypes, based on the gene expression-derived cell-of-origin (COO) (activated B-cell [ABC], germinal center B-cell [GCB]) or distinct molecular subgroups that demonstrate a differential response to immuno-chemotherapy. In this study we had an opportunity to examine both spatial and temporal heterogeneity, performing whole exome sequencing on four tumors from the same patient that demonstrated a discordant response to immunochemotherapy, providing a unique insight into the relationship between ITH and treatment response. A 50-year-old female presented with rapidly growing lymphadenopathy including a left inguinal mass (9.7x11.2 cm) and a left mediastinal mass (3.9x3.3 cm) without organomegaly or B-symptoms (Figure 1A). An inguinal biopsy (ING) revealed the diagnosis of DLBCL and imaging showed stage III disease with an International Prognostic Index (IPI) score of 2 (raised lactate dehydrogenase [LDH] 349 U/L). Immunohistochemical staining of the inguinal biopsy demonstrated; CD10, BCL6 and MUM1 disease; consistent with GCB classification according to Hans’ criteria (Figure 1B). The patient was enrolled into the REMoDL-B trial and randomized to the experimental arm with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone) and bortezomib from the second cycle. After six cycles of treatment, a