Follicular Lymphoma in the 5th Edition of the WHO-Classification of Haematolymphoid Neoplasms-Updated Classification and New Biological Data

Abstract

The conceptual description of Follicular lymphoma (FL) in the 5th edition of the World Health Organization (WHO) classification of haematolymphoid tumors (WHO-HAEM5) has undergone significant revision. The vast majority of FL (85%) with a follicular growth pattern are composed of centrocytes and centroblasts, harbor the t(14;18)(q32;q21) translocation and are now termed classic FL (cFL). They are set apart from three related subtypes, FL with predominantly follicular growth pattern, FL with unusual cytological features (uFL) and follicular large B-cell lymphoma (FLBCL). In contrast to the revised 4th edition of the WHO classification of haematolymphoid tumors (WHO-HAEM4R), grading of cFL is no longer mandatory. FL with a predominantly diffuse growth pattern had been previously recognized in WHO-HAEM4R. It frequently occurs as a large tumor in the inguinal region and is associated with CD23 expression. An absence of the IGH::BCL2 fusion and frequent STAT6 mutations along with 1p36 deletion or TNFRSF14 mutation is typical. The newly introduced subtype of uFL includes two subsets that significantly diverge from cFL: one with "blastoid" and one with "large centrocyte" variant cytological features. uFL more frequently displays variant immunophenotypic and genotypic features. FLBCL is largely identical to WHO-HAEM4R FL grade 3B and renaming was done for reasons of consistency throughout the classification. In-situ follicular B-cell neoplasm, pediatric-type FL, duodenal-type FL and primary cutaneous follicle center lymphoma are categorized as discrete entities. In addition, novel findings concerning underlying biological mechanisms in the pathogenesis of early and systemic follicular lymphoma will be presented.

Keywords: BCL2 translocation; WHO-HAEM5; classic FL (cFL); classification; follicular lymphoma (FL); localized stage FL (lFL); systemic FL (sFL).

Figure 1

In-situ follicular B-cell neoplasm (H&E ×100). This photomicrograph illustrates strong aberrant reactivity for BCL2 in two germinal centers showing a slightly stronger staining than the surrounding marginal zone B- and T-cells. The overall nodal architecture is well preserved.

Figure 2

Classic follicular lymphoma (cFL) (H&E ×400). (A) This is a typical example of classic FL (FL grade 1/2 according to WHO-HAEM4R) with a predominance of centrocytes (red arrows) and only a few interspersed centroblasts (black arrows). (B) In this example, the number of large, transformed cells (centroblasts, black arrows) is distinctly higher (>15 centroblasts per high-power-field (FL grade 3A according to WHO-HEAM4R), however, centrocytes (red arrows) are still present.

Figure 3

A schematic overview on the evolution of follicular lymphoma. The t(14;18) arose in pre-B- cells during failures in VDJ joining and leads to the generation of long-lived FL-like B-cells. Via several re-entries into germinal centers, these t(14;18)-positive B-cells acquire additional mutations enabling them to be founders of ISFN or manifest lymphoma. Orange cells and green stars represent T-cells and follicular dendritic cells, respectively. Under physiological conditions germinal center B-cells undergo apoptosis, while this process is inhibited in FL (marked by X).

Figure 4

Follicular lymphoma with unusual cytological features (H&E ×400). In this example of a neoplasm growing in follicular structures, there is a predominance of small to medium-sized blastoid cells with round nuclei, finely dispersed chromatin and in part small nucleoli. Note the increased number of mitotic figures. This case had a proliferation index of 80%.

Figure 5

Predominantly diffuse FL. (A) Low magnification shows a preserved subcapsular rim of preserved reactive lymphatic tissue to the left and an ill-defined lymphomatous infiltration to the right (H&E ×40). (B) Higher magnification reveals an entirely diffuse growth pattern (H&E ×100).

Figure 6

Follicular large B-cell lymphoma. (A) There is a clearly discernible follicular growth pattern (H&E ×40). (B) On high magnification, the neoplastic follicles are composed of large, transformed cells (centroblasts) exclusively, without an admixture of (typical) centrocytes (H&E ×400).

Figure 7

Pediatric-type follicular lymphoma (PTFL) (H&E ×100). In PTFL, there is an intriguing proliferation of large follicles, often lacking mantle zones, and that are large and expansile, often with a “serpiginous” growth pattern.

Figure 8

Duodenal-type follicular lymphoma (H&E ×40). Low magnification shows large, atypical nodules/follicles occupying the mucosa and extending into the upper part of the submucosa in this duodenal resection specimen. There is an absence of polarization of the follicles that are composed nearly exclusively of small centrocytes.

Figure 9

Primary cutaneous follicle center lymphoma (H&E ×20). This example shows atypical follicular structures occupying the dermal portions of the skin underneath an intact epidermis.