The t(14;18) occurs in a precursor B cell in the bone marrow. B cells carrying the t(14; 18) can be detected at very low levels in the peripheral blood of >50% of healthy adults. These cells have undergone somatic hypermutation (SHM), and class switch recombination (CSR), indicative of transit through the germinal center. They are prone to intense trafficking, with multiple episodes of germinal center reentry. However, <0.01% of patients with FL-like B cells in the peripheral blood subsequently develop FL. Expansion of FL-like B cells, in either the intestine or the lymph node, lead to 2 early lesions, duodenal-type FL, and ISFN. ISFN can be identified in ∼2% to 3% of unselected lymph node biopsies. Both duodenal-type FL and ISFN progress to systemic FL in only 2% to 3% of cases. These early lesions have a low level of copy number aberrations (CNAs), but share many genetic features with conventional FL, including the t(14;18), and mutations in CREBBP, TNFRSF14, and EZH2. However, multiple mutations in KMT2D may be a later event, associated with more advanced disease. Microenvironmental influences may drive colonization of the intestine, independent of the genetic profile. All tissue sections illustrated are stained for BCL2 by immunohistochemistry, original magnification ×40. Peripheral smear, Wright-Giemsa stain, original magnification ×1000. GC, germinal center.