Pathologic and molecular insights in nodal T-follicular helper cell lymphomas

Abstract

T-follicular helper (TFH) cells are one of the T-cell subsets with a critical role in the regulation of germinal center (GC) reactions. TFH cells contribute to the positive selection of GC B-cells and promote plasma cell differentiation and antibody production. TFH cells express a unique phenotype characterized by PD-1^hi, ICOS^hi, CD40L^hi, CD95^hi, CTLA^hi, CCR7^lo, and CXCR5^hi . Three main subtypes of nodal TFH lymphomas have been described: 1) angioimmunoblastic-type, 2) follicular-type, and 3) not otherwise specified (NOS). The diagnosis of these neoplasms can be challenging, and it is rendered based on a combination of clinical, laboratory, histopathologic, immunophenotypic, and molecular findings. The markers most frequently used to identify a TFH immunophenotype in paraffin-embedded tissue sections include PD-1, CXCL13, CXCR5, ICOS, BCL6, and CD10. These neoplasms feature a characteristic and similar, but not identical, mutational landscape with mutations in epigenetic modifiers (TET2, DNMT3A, IDH2), RHOA, and T-cell receptor signaling genes. Here, we briefly review the biology of TFH cells and present a summary of the current pathologic, molecular, and genetic features of nodal lymphomas. We want to highlight the importance of performing a consistent panel of TFH immunostains and mutational studies in TCLs to identify TFH lymphomas.

Keywords: angioimmunoblastic T cell lymphoma; follicular T helper; molecular and genetic profiling; next-generation sequencing; peripheral T cell lymphomas.

Figure 1

Histopathologic features of nodal T-follicular helper (TFH) cell lymphoma, angioimmunoblastic-type. (A, B) Hematoxylin & Eosin (H&E) shows that the neoplasm completely effaces the nodal architecture (A); the neoplasm is diffuse and composed of a heterogeneous cell infiltrate associated with numerous high endothelial venules (HEVs), inflammatory cells, and clusters of small lymphocytes with clear cytoplasm (B) (2x and 40x); (C) CD3 shows that most of the cells in the infiltrate are T-cells. Some of the T-cells are intermediate in size with irregular nuclear contours (40x); (D-H) The tumor cells are positive for CD10 (D), BCL6 (E), ICOS (F), CXCL13 (G) and PD-1 (H) supporting a TFH immunophenotype (all 40x). Note the clustering of the tumor cells around the HEVs. (I) CD21 highlights focally expanded follicular dendritic cell meshworks surrounding HEVs (20x).

Figure 2

Histopathologic features of nodal T-follicular helper (TFH) cell lymphoma, follicular-type. (A) This case shows a predominantly follicular growth pattern, simulating follicular lymphoma, with the neoplastic follicles composed of small to medium-sized atypical lymphocytes admixed with scattered large cells (20x); (B) PD-1 shows that the tumor cells form solid clusters inside the nodules with residual B-cells pushed to the periphery of the follicles (not shown) (20x); (C) This other case shows that the neoplastic nodules have features of progressive transformation of germinal centers (PTGC). The nodules display a ‘moth-eaten’ appearance with aggregates of neoplastic T-cells surrounded by small B-cells (20x); (D) The neoplastic cells are positive for PD-1 in addition to other TFH markers (not shown) (20x).

Figure 3

Histopathologic features of nodal TFH cell lymphoma, not otherwise specified (NOS). (A) In the case shown, the neoplasm is diffuse and composed predominantly of intermediate atypical lymphoid cells (40x); Features of AITL were not seen. (B) The tumor cells are positive for CD3 (40x); (C-E) BCL6 (C), ICOS (D), and PD-1 (E) are also variably positive in the neoplastic cells (40x); (F) Epstein-Barr virus-encoded small RNAs (EBER) shows positivity in scattered cells (20x).