Neoplasms of follicular helper T-cells: an insight into the pathobiology

Abstract

T-follicular helper cells (TFH) are a unique subset of T-cells with varied transcriptional profiles and functions. In the last 2016 WHO classification, lymphomas arising from TFH were included as a broad category and emphasis was given to separating them from other peripheral T cell lymphomas. The neoplasms derived from these mainly comprise angioimmunoblastic T-cell lymphoma, peripheral T-cell lymphoma with T-follicular helper cell phenotype, follicular T-cell lymphoma, and cutaneous CD4+ small-medium sized lymphoproliferative disorders. The TFH lymphomas comprise both indolent and aggressive forms. Additional immunohistochemistry to identify TFH cells like CD10, BCL6, ICOS, PD1, CXCL13 and mutations like RHOA, IDH2 is required for diagnosis and prognostication. The understanding of these has evolved over the years, and currently we review the updates and pathobiology of the above.

Keywords: AITL; Follicular helper T-cells; PTCL; follicular T helper cell lymphoma.

Figure 1

Development of T-follicular helper cells: Artwork shows TFH cell development in the lymphoid follicle. Interaction of naïve T-cell and dendritic cells in the outer T-cell zone prime the lymphocytes which in the respective cytokine milieu mature into the T-lymphocyte subsets. Activated T-cell with CXCR5 upon interaction with B-cell in the lymphoid follicle mature into the TFH cell and share a symbiotic relationship with B-cells.

Figure 2

Characteristic immunophenotype of TFH: Microphotograph shows secondary follicle CD3 [A ×200] highlighting Follicular T helper (TFH) cell, CD10 [B ×200], PD1 [C ×200], ICOS [D ×200] and BCL6 [E ×200]. The right panel shows lymphoma arises from TFH cell.

Figure 3

Pathogenesis of AITL: Art work shows TFH cells (Blue colour) interact with B-cells (Green colour) via PD1-PDL1, CD40L-CD40 and ICOSL-ICOS which leads to B-cell survival and proliferation. ICOS axis leads to TFH cell proliferation via p13AKT and mTOR pathway. Follicular dendritic cells secrete CXCL13, IL6, and IL2 creating conducive environment for proliferation of T-cells and in turn TFH cells produce VEGF which causes high endothelial venule proliferation (red colour circle). Eosinophils are recruited by IL5 secreted by TFH cells. EBV (small yellow circle with green spikes) infects the B-cells and further leads to T-cell proliferation and B-cell lymphomas rarely with gain of B-cell receptor, Tet2 mutations. Immunodeficiency is also caused by the virus. Increase in plasma cells and autoimmune haemolytic phenomenon can be associated with the B-cell proliferation associated. RHOA acts via the VAV-KRAS-MAPK and ROCK-NFkB pathway and affects the TFH cell differentiation and survival. Clonal haematopoiesis with various mutations can cause unregulated proliferation of the tumor cells.

Figure 4

Microphotograph shows: Diffuse effacement of architecture with paracortical expansion [A: H&E ×16] Presence of patent marginal sinus [B: H&E ×100] Intermediate sized atypical lymphoid cells having clear cytoplasm [C: H&E ×100] Polymorphous population with predominant eosinophil population [D: H&E x100] AITL with predominant lymphocyte population [E: H&E ×200] Polymorphous population with predominant plasma cells and Russel bodies [F: H&E ×100] Increased high endothelial venules [G: H&E ×100]. Eosinophilic hyaline material deposition [H: H&E ×100].

Figure 5

Immunophenotype of AITL: Microphotograph shows atypical lymphoid cells immunopositive for CD3 [A ×100] CD21 highlighting the expanded dendritic meshwork [B ×16] Loss of CD7 in the atypical lymphoid cells [C ×100] Characteristic immunophenotype of TFH atypical lymphoid cells PD1 [D ×100], Bcl6 [E ×100], ICOS [F ×100], CD10 [G ×100]. EBER ISH highlights the large atypical lymphoid cells [H ×100].

Figure 6

PTCL with TFH phenotype: Microphotograph shows effacement of lymph nodal architecture [H&E A ×100]. The cells are of intermediate size with mild nuclear irregularity [H&E B ×100]. The cells are immunopositive for CD3 [C ×100], BCL6 [D ×200] while negative for CD20 [E ×100]. CD23 shows loss of dendritic cell meshwork [F ×100].

Figure 7

Follicular T-cell lymphoma: Microphotograph shows effacement of lymph nodal architecture by monomorphic nodules [H&E A ×100]. The nodule comprises small to intermediate size cells [H&E B ×100]. The cells are immunopositive for CD3 [C ×100], CD4 [E ×100], CD5 [G ×100], BCL6 [I ×100] while negative for CD20 [D ×100] and CD8 [F ×100]. CD23 shows mild expansion of dendritic cell meshwork [H ×100].