Follicular Lymphoma Follicular Lymphoma Pathophysiology Follicular Lymphoma (FL) is one of the most common B-cell lymphoma subtypes. Pathological grading is dependent on the number of centroblasts (rapidly dividing B cells with a noncleaved nucleus) and in considered to be a clinical predictor of outcome.1,2 Lymphocytes originate from a common progenitor cell located in the bone marrow.3 Differentiation consists of DNA recombination creating immunoglobulins or T-cell receptors.3 Interaction with T cells normally regulates the proliferation of B cells that undergo affinity mutation of their Ig genes.2,4 In the case of FL, this process is disrupted, leading to unregulated B cell proliferation. The link to the immune system stems from the large presence of infiltrating T cells and B cells.4 Though initial response to therapy is frequent, relapse is associated with an increased risk of eventual histological transformation to a higher grade.4 The genetic hallmark of FL is present in 80-90% of tumors.4,5 Interestingly, this hallmark (“B-cell leukemia/lymphoma 2 (BCL2) oncogene under control of the Ig heavy chain enhancer”) is also found in healthy individuals, albeit rarely, but indicative that additional understanding is necessary to reveal the drivers of clinical disease.4,5 Essential workup procedures for patients with FL includes a complete physical exam (paying close attention to node bearing areas and the size of the liver and spleen), symptoms, performance status, laboratory studies (including CBC, Sr LDH, Hep B, metabolic panel, and CT with oral and IV contrast).1 Bone marrow biopsy with or without aspirate is crucial for all patients considering treatment, though there are cases where it may be deferred.1 Genetic alterations, epigenetic mechanism and microenvironment signals contribute to FL transformation, an event resulting from characteristic aggression.5 Some genetic alterations that are associated with FL transformation, include5: TP53 mutation MYC rearrangement REL amplification CDKN2A/CDKN2B deletion While the full underlying pathway supporting transformation are still being explored, research has lead to potential drug targets such as BCL2, EZH2, CTLA4 and BCR signaling via BTK.6 References: National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®). B- Cell Lymphomas. Version 4.2018 – May 15,2018 Lenz G, Staudt LM. Aggressive Lymphomas. NEJM. 2010; 362:1417-1429 Maloney DG. Anti-CD20 Antibody Therapy for B-Cell Lymphomas. NEJM. 2012. 366:2008-2016 Green MR, Kihira S, et al. Mutations in early follicular lymphoma progenitors are associated with suppressed antigen presentation. 2014. PNAS Plus. pnas.org/cgi/doi/10.1073/pnas.1501199112 Bisikirska B, Bansal M, et al. Elucidation and pharmacological targeting of novel molecular drivers of follicular lymphoma progression. Cancer Res. 2016; 76(3): 664–674. doi:10.1158/0008-5472.CAN-15-0828 Schatz JH, Oricchio E, Puvvada SD, Wendel HG. Progress Against Follicular Lymphoma. Curr Opin Hematol. 2013;20(4): 10.1097/MOH.0b013e3283622ed6.