The clinical and molecular taxonomy of t(14;18)-negative follicular lymphomas

Abstract

Follicular lymphoma (FL) is a neoplasm derived from germinal center B cells, composed of centrocytes and centroblasts, with at least a focal follicular growth pattern. The t(14;18) translocation together with epigenetic deregulation through recurrent genetic alterations are now recognized as the hallmark of FL. Nevertheless, FL is a heterogeneous disease, clinically, morphologically, and biologically. The existence of FL lacking the t(14;18) chromosomal alteration highlights the complex pathogenesis of FL, and indicates that there are alternative pathogenetic mechanisms that can induce a neoplasm with follicular center B-cell phenotype. Based on their clinical presentation, t(14;18)-negative FLs can be divided into 3 broad groups: nodal presentation, extranodal presentation, and those affecting predominantly children and young adults. Recent studies have shed some light into the genetic alterations of t(14;18)-negative FL. Within the group of t(14;18)-negative FL with nodal presentation, cases with STAT6 mutations are increasingly recognized as a distinctive molecular subgroup, often cooccurring with CREBBP and/or TNFRSF14 mutations. FL with BCL6 rearrangement shows clinicopathological similarities to its t(14;18)-positive counterpart. In contrast, t(14;18)-negative FL in extranodal sites is characterized mainly by TNFRSF14 mutations in the absence of chromatin modifying gene mutations. FL in children have a unique molecular landscape when compared with those in adults. Pediatric-type FL (PTFL) is characterized by MAP2K1, TNFRSF14, and/or IRF8 mutations, whereas large B-cell lymphoma with IRF4 rearrangement is now recognized as a distinct entity, different from PTFL. Ultimately, a better understanding of FL biology and heterogeneity should help to understand the clinical differences and help guide patient management and treatment decisions.

Graphical abstract

Figure 1.

Morphological and immunophenotypic features of nodal t(14;18)-positive and t(14;18)-negative FLs. (A) t(14;18)-positive FL showing a nodular growth pattern, with follicles growing back to back and the lack of a defined mantle zone, (original magnification ×50; hematoxylin and eosin [H&E] stain). (B) Higher magnification demonstrates the presence of predominantly centrocytes with few intermingled centroblasts in the follicles characteristic of FL grade 1/2, (original magnification ×400; H&E stain). (C-D) BCL2-R–neg CD23⁺ FCL with diffuse growth pattern. (C) The H&E stain shows an inguinal lymph node with partial involvement of a diffuse lymphoid infiltration that leaves a rim of normal lymph node in the periphery. (D) The tumor cells are strongly CD23⁺. Note that in the periphery of the lymph node there are residual normal GCs and the CD23 stain highlights the follicular dendritic cells. (E) The tumor cells are also strongly positive for CD10. The residual normal GCs are CD10⁺. (Snapshot of scanned slides, ×10). (F-G) BCL2-R–neg CD23⁺ FCL with follicular growth pattern. (F) The H&E stain shows an axillary lymph node with involvement of a lymphoid proliferation with follicular growth pattern (original magnification ×40; H&E stain). (G) The tumor cells are CD23⁺ (original magnification ×40; immunohistochemistry). (H) The tumor cells are BCL2⁻. Note that the B cells in the attenuated mantle zone are BCL2⁺. (original magnification ×400; immunohistochemistry). (I) The neoplastic cells in the follicles are CD23⁺, (original magnification ×400; immunohistochemistry).

Figure 2.

Alternative forms of t(14;18)-negative FL. The cases are classified per site of presentation; nodal vs extranodal, and those cases presenting mainly in children and young adults.

Figure 3.

Comparison of mutational landscape between t(14;18)-positive and t(14;18)-negative FL entities. Frequencies of recurrently mutated genes in 100 t(14;18)-positive FL (BCL2-pos FL), 31 duodenal-type FL (DTFL), 74 nodal t(14;18)-negative cases,^,, , 31 PCFCL,^, 10 lower female genital tract (LFGT) FL, 7 thyroid BCL2-neg FL, 81 PTFL,, , and 17 LBCL-IRF4. Color gradient depicted per the percentage of mutated cases for each gene: dark red, 100%: dark green, 0%. neg, negative; mut, mutated; n.a.: not available.

Figure 4.

Different genetic clusters of nodal t(14;18)-negative FL. Comparison of 2 studies that identified a distinct molecular cluster characterized by STAT6 mutations.^, The 2 studies highlight the frequent cooccurrence of STAT6 and CREBBP mutations.

Figure 5.

Model of mutated STAT6 (STAT6^mut)–mediated pathogenesis in FL. Left panel: FL with wild-type STAT6. FL is characterized by increased numbers of TFH cells, which are the main source of IL-4 production that initiates the cascade of IL-4–STAT6 pathway with activation of STAT6 and induction of STAT6-dependent genes including FCER2 (CD23), CCL17, and CCL22. In some t(14;18)-positive FL cases this might induce the expression of CD23 in the absence of STAT6 mutation. Right panel: FL with activating mutations of STAT6. STAT6 mutations amplify IL-4–induced STAT6-dependent gene activation via an intracellular self-reinforcing regulatory microcircuit that involves aberrantly increased PARP14 levels. The increased expression of cytokines CCL17 and CCL22 contribute to re-educate the TME, with further recruitment of IL-4–producing TFH cells. STAT6^mut in FL cells cooccurred either with CREBBP mutations and/or TNFRSF14 mutations.^,,CREBBP mutations favor immune evasion and precludes apoptosis by inhibiting the acetylation of CREBBP target genes, BCL6 and TP53.^,TNFRSF14 mutations help to re-educate the TME and enhance lymphoma cell survival by disrupting the BTLA–TNFRSF14 pathway. Figure created with BioRender.com.

Figure 6.

Genetic alterations and model of IRF4^mut-mediated pathogenesis in LBCL-IRF4. (A) Fluorescence in situ hybridization with IRF4 break-apart probe shows a signal constellation of 1 colocalization (yellow arrow) and 1 split signal (red and green arrows) consistent with the gene rearrangement in a case with LBCL-IRF4 with pure FL morphology. (B) A diagram of the relative positions of IRF4 mutations in cases with LBCL-IRF4 (A Colmenero, I Salaverria, unpublished data, March 2023). x-axis indicates amino acid position. IRF4 domains: DBD, DNA binding domain; LKD, linker domain; IAD, IRF association domain; and AR, autoinhibitory region. (C) Schematic overview of B-cell differentiation deregulation by constitutive activation of IRF4 and/or NF-κB, which induces the oncogenic transcription program in LBCL-IRF4.