Follicular lymphoma: updates for pathologists

Abstract

Follicular lymphoma (FL) is the most common indolent B-cell lymphoma and originates from germinal center B-cells (centrocytes and centroblasts) of the lymphoid follicle. Tumorigenesis is believed to initiate early in precursor B-cells in the bone marrow (BM) that acquire the t(14;18)(q32;q21). These cells later migrate to lymph nodes to continue their maturation through the germinal center reaction, at which time they acquire additional genetic and epigeneticabnormalities that promote lymphomagenesis. FLs are heterogeneous in terms of their clinicopathologic features. Most FLs are indolent and clinically characterized by peripheral lymphadenopathy with involvement of the spleen, BM, and peripheral blood in a substantial subset of patients, sometimes accompanied by constitutional symptoms and laboratory abnormalities. Diagnosis is established by the histopathologic identification of a B-cell proliferation usually distributed in an at least partially follicular pattern, typically, but not always, in a lymph node biopsy. The B-cell proliferation is biologically of germinal center cell origin, thus shows an expression of germinal center-associated antigens as detected by immunophenotyping. Although many cases of FLs are typical and histopathologic features are straightforward, the biologic and histopathologic variability of FL is wide, and an accurate diagnosis of FL over this disease spectrum requires knowledge of morphologic variants that can mimic other lymphomas, and rarely non-hematologic malignancies, clinically unique variants, and pitfalls in the interpretation of ancillary studies. The overall survival for most patients is prolonged, but relapses are frequent. The treatment landscape in FL now includes the application of immunotherapy and targeted therapy in addition to chemotherapy.

Keywords: Cytogenetics; Follicular lymphoma; Immunohistochemistry; Molecular; Prognosis; Treatment.

Fig. 1.

Follicular lymphoma, low-grade. A representative case of follicular lymphoma, low-grade. H&E-stained excisional biopsy (A–D) and immunohistochemical stains (C inset, E–I) show classic morphology of follicular lymphoma cells, with increased, monotonous appearing neoplastic follicles in an excisional biopsy of the lymph node. The borders of the follicles are ill-defined and lack well-preserved mantle zones. Foci of sclerosis are identified (A). The neoplastic follicles are expansile and arranged in a back-to-back fashion. The neoplasm extends into perinodal fat (B) and has attenuated to absent mantle zones (C). Immunostain for CD21 highlights follicular dendritic cell meshworks within neoplastic follicles, which is useful in establishing the presence of lymphoid follicles (C, inset). The neoplastic follicle comprises numerous centrocytes and fewer centroblasts, compatible with grade 1–2 of 3 (D). Immunostain for CD20 highlights B lymphocytes in neoplastic follicles and interfollicular (diffuse) areas (E). Immunostain for CD3 highlights reactive T-cells in follicular lymphoma. The pattern of CD3, accumulating around neoplastic follicles, can be used to highlightthe nodulardistribution of lymphoma cells (F). Immunostain for CD10 confirms that the neoplastic cells are of germinal center origin (lymphoma cells are positive within neoplastic follicles). Scattered interfollicular neoplastic cells are weakly stained with CD10. The reactivity is stronger in germinal centers than in interfollicular regions (G). Immunostain for BCL-6 highlights neoplastic lymphoma cells of germinal center origin within neoplastic follicles (H). Immunostain for BCL2 is positive in neoplastic Blymphocytes (I).

Fig. 2.

Follicular lymphoma, high-grade morphology. A representative case of follicular lymphoma, high-grade (grade 3B). H&E-stained excisional biopsy (A, B). The neoplastic follicles are composed of a homogeneous population of large lymphoma cells. High power magnification shows a neoplastic follicle of FL, grade 3B. Most cells in this follicle are large centroblasts without intervening centrocytes.

Fig. 3.

Duodenal-type follicular lymphoma. A representative case of duodenal-type follicular lymphoma. H&E-stained biopsy (A, B) and immunohistochemical stains (C–I) show intramucosal follicular lymphoma, grade 1, forming polyps in the mucosa of the small intestine (A). The neoplastic follicles are partially surrounded by a thin layer of mantle cells (arrow) (B). Neoplastic lymphocytes are positive for CD20 (C) with the germinal center marker CD10 (D), and BCL6 (H) co-expression. CD10 also highlights the intestinal absorptive epithelium, which is internal control. The neoplastic lymphocytes co-express BCL2 (E, G), supporting follicular lymphoma diagnosis. CD21 confirms that the follicular dendritic meshwork is located at the periphery of the neoplastic follicle (F). Ki-67 proliferation index is not increased (I).

Fig. 4.

Follicular lymphoma, fine-needle aspirate smear. Paratrabecular pattern of involvement in the bone marrow and peripheral blood smear involvement. Wright-Giemsa-stained smears (A, D, E), H&E-stained slide (B), and immunohistochemical stain (C). Fine-needle aspiration of a lymph node from a patient with FL, grade 1–2, demonstrates a mixture of centrocytes and centroblasts (A). Bone marrow core biopsy specimen involved by follicular lymphoma is shown. The neoplasm has a paratrabecular pattern of distribution (B). PAX-5 highlights neoplastic B-cells (C). Peripheral blood smear from a patient with follicular lymphoma demonstrates leukemic involvement by centrocytes (D) with deeply cleaved nuclei (E).

Fig. 5.

A representative case of the flow cytometric immunophenotype of follicular lymphoma. Flow cytometry immunophenotyping of a lymph node fine-needle aspirate specimen from a patient with follicular lymphoma confirms that the lymphoma cells, gated by expression of CD45, co-express CD20 and CD10, with surface light chain restriction for lambda.

Fig. 6.

IGH/BCL2 dual-color fluorescent in-situ hybridization (FISH). FISH on a fixed, paraffin-embedded tissue section of follicular lymphoma using dual-fusion probes for BCL2 (red) and IGH (green). The t(14;18)(q32;q21) IGH/BCL2 fusion gene is a yellow signal.

Fig. 7.

Floral variant of follicular lymphoma. H&E-stained excisional biopsy (A, B) shows the morphology of follicular lymphoma with large and lobulated follicles, in some areas resembling flower petals (A). The darker mantle zone lymphocytes are infiltrating the pale follicular lymphoma cells (B).