Follicular lymphoma and marginal zone lymphoma: how many diseases?

Abstract

Follicular lymphoma (FL) and marginal zone lymphoma (MZL) are indolent mature B-cell neoplasms with variable clinical presentation and distinct histopathologic features. Recent advances in the biology and molecular characteristics of these lymphomas have further expanded our understanding of the heterogeneous nature of these lymphomas, with increasing recognition of specific disease entities within the broader categories of FL and MZL. Here, we discuss the conclusions of the 2022 International Consensus Classification of Mature Lymphoid Neoplasms (2022 ICC) dealing with FL, and review differences with the proposed WHO 5th Edition classification. We review issues related to grading and alternative forms of FL especially those lacking the genetic hallmark of FL, the t(14;18) chromosomal alteration. Among them, t(14;18)-negative CD23⁺ follicle center lymphoma has been proposed by the 2022 ICC as a provisional entity. Other follicle center-derived lymphomas such as pediatric-type follicular lymphoma, testicular follicular lymphoma, primary cutaneous follicle center lymphoma, and large B-cell lymphoma with IRF4 rearrangement are considered distinct entities separate from conventional FL. Importantly, large B-cell lymphoma with IRF4 rearrangement introduced as a provisional entity in the WHO 2017 is upgraded to a definite entity in the 2022 ICC. We also discuss diagnostic strategies for recognition of MZLs including splenic MZL, extranodal MZL (MALT lymphoma), and primary nodal MZL. The importance of molecular studies in the distinction among marginal zone lymphoma subtypes is emphasized, as well as their value in the differential diagnosis with other B-cell lymphomas.

Keywords: 2022 ICC; 5th WHO; Classification; Follicular lymphoma; Marginal zone lymphoma; Morphological variants and distinct entities.

Fig. 1

BCL2-R-negative CD23⁺ follicle center lymphoma with predominant diffuse growth pattern. Inguinal lymph node with effaced architecture by an atypical lymphoid infiltration with diffuse pattern (A, H&E). Tumors cells are CD20-positive (B), CD10-negative (C), BCL2-negative (D), and CD23-positive (E). CD21 shows no FDC meshwork (F). Interphase fluorescence in situ hybridization (FISH) using BCL2 (G; inset × 6000) and BCL6 (H; inset × 6000) break apart probes are negative

Fig. 2

Large B-cell lymphoma with IRF4 rearrangement. A H&E stain of a tonsil of a 37-year-old woman in clinical stage 1 disease at low magnification showing a vaguely nodular lymphoid proliferation (A, × 400; inset: centroblast-like cells comprise the dominant cell type). B The cells are CD20-positive. Note the vaguely nodular growth pattern. C CD10 is positive. D MUM1/IRF4 is strongly and homogeneous positive in the tumor cells. Inset: interphase fluorescence in situ hybridization (FISH) analysis using an IRF4 break apart probe. The cell depicted show one allele with a normal colocalized signal (yellow arrow) and the second allele with a split red and green signals (green and yellow arrows) indicating a rearrangement

Fig. 3

Splenic marginal zone lymphoma. On gross examination, the splenic parenchyma shows increased and expanded white pulp nodules (A). On H&E sections, the splenic parenchyma shows increased numbers of white pulp nodules (B), which are typically composed of central cores containing small lymphocytes with scant cytoplasm and a peripheral zone of marginal zone cells with more abundant cytoplasm (C, H&E). In the peripheral blood, the neoplastic cells are small, often with a somewhat plasmacytoid appearance, and, in some cases, cytoplasmic projections may be seen (D, Wright’s stain). In trephine biopsy samples, interstitial lymphoid aggregates are present (E, H&E) with numerous small B-cells seen within the aggregate (F, CD20). Often, at least focal areas will display an intrasinusoidal growth pattern of small B-cells (inset, F)

Fig. 4

Extranodal marginal zone lymphoma. In gastric MALT lymphoma, the mucosa contains a dense infiltrate of small lymphocytes and germinal centers (A, H&E). The small lymphocytes form desctructive lymphoepithelial lesions (B, H&E). In this salivary gland MALT lymphoma (C, H&E), the lymphoid proliferation contains germinal centers (lower left) and prominent lymphoepithelial lesions (upper right). In thyroid MALT lymphomas (D, H&E), lymphoepithelial lesions consist of small lymphocytes within glandular lumens (so-called MALT balls)

Fig. 5

Nodal marginal zone lymphoma. The histologic appearance of NMZL is variable: Panel A (H&E) shows a NMZL with a diffuse growth pattern and predominantly small lymphocytes with little cytoplasm, while the NMZL in panel B (H&E) displays abundant pale cytoplasm and a nodular appearance with colonized germinal centers