<aside> 💡 Typically express CD10, CD19, CD20, CD22, CD79α, surface Ig, BCL-2, and BCL-6, with CD23+/-, CD43-, and CD5-. Rare cases may be CD10- or BCL2-. t(14;18)(q32,q21) → IGH-BCL2 translocation (85~90%)

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Epidemiology

• FL is the most common type of indolent lymphoma, accounting for approximately 60% of low-grade lymphomas and roughly 25% of all NHL.
  • Less common in black and Asian populations.
  • ~10% of all lymphomas in Taiwan (less than NK/T).
• The peak incidence is in the fifth and sixth decades, and is rare under the age of 20.

Genetics

• Cytogenetic changes involving the BCL2 gene locus, most commonly t(14;18)(q32;q21) (~85%), result in overexpression of the anti-apoptotic BCL-2 protein, contributing to overexpression of the antiapoptotic protein BCL2.
  • Nearly 30% of grade 3A and a majority of grade 3B FLs are t(14;18) negative.

• Translocations involving the minor cluster region 30 kb downstream of the BCL2 gene occur in only 11% of cases but are associated with 95% failure-free survival (FFS) at 3 years.
• Translocations involving the major breakpoint region in the 3′ untranslated region of the BCL2 gene occur in 71% of cases and are associated with 76% 3 year FFS.
• 1p36 deletions have a predominant diffuse pattern in inguinal nodes, large localized mass, CD23+, typically grade 1-2 and have a good prognosis.

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Model of FL pathogenesis

Naive B cells in the bone marrow (BM) acquire the t(14;18) translocation due an error in V(D)J recombination and subsequently home to B-cell follicles where they undergo the GC reaction. In the dark zone of the GC, the B cells proliferate as centroblasts and undergo somatic hypermutation (SHM) and class switching of their BCRs. Centroblasts then become smaller centrocytes and migrate to the light zone of the GC where they interact with follicular dendritic cells (FDCs) and are selected to either undergo apoptosis or rescue by follicular helper T cells (TFH) based on antigen (Ag) affinity of their BCRs. Ectopic expression of BCL2 provides mutant B cells with t(14;18) an avenue to escape apoptosis, independent of BCR affinity. These FL-like B cells then exit the GC and enter the circulation where they might be prone to traffic between follicles and/or the BM and have the opportunity to acquire additional genetic changes necessary for transformation to FL. CSR, class switching recombination.

Clinical Presentations

• Commonly presents as asymptomatic lymphadenopathy, with a quarter of patients experiencing B symptoms.
  • A long history of having noted painless increased lymph nodes in one or more sites over a number of years before presentation.
  • Lymphadenopathy may wax and wane and spontaneous remissions can occur, albeit rarely.
• Extranodal disease is relatively common and can affect any organ.
• The most common sites of extranodal disease include the BM, skin, gastrointestinal tract, and bone.
  • Bone marrow involvement is common (30%-60%); only about one-third of patients will present with stage I/II disease.
• Cytologic examination by light microscopy classifies FL into grades based on the number of centrocytes per high power field.
  • Grades 1 and 2 are considered to be indolent disease.
  • Grade 3 (>15 centroblasts/hpf) is an area of controversy. The distinction between follicular grade 3a and 3b is based on the presence or absence of centrocytes in the background.
  • Some may treat FL grade 3a as follicular lymphoma and others may treat it as diffuse large B-cell lymphoma (DLBCL).
  • The pathogenesis of most cases of FL grade 3B differs from that of FL grades 1–2/3A, in lacking the BCL2/IGH, but also differs from diffuse large B-cell lymphoma, in having a low incidence of BCL6 aberrations.
  • Discordant low-grade, high Ki-67 (>30%) occurred in 18% of cases in one study and had more aggressive clinical behavior as compared to low-grade, low Ki-67.

Prognosis