J Pathol Transl Med.  2024 Mar;58(2):59-71. 10.4132/jptm.2024.01.04.

Clinicopathological implications of immunohistochemical expression of TBX21, CXCR3, GATA3, CCR4, and TCF1 in nodal follicular helper T-cell lymphoma and peripheral T-cell lymphoma, not otherwise specified

• Han B
• Lim S
• Yim J
• Song YK
• Koh J
• Kim S
• Lee C
• Kim YA
• Jeon YK

• KMID: 2553473
• DOI: http://doi.org/10.4132/jptm.2024.01.04

Abstract

Background
The classification of nodal peripheral T-cell lymphoma (PTCL) has evolved according to histology, cell-of-origin, and genetic alterations. However, the comprehensive expression pattern of follicular helper T-cell (Tfh) markers, T-cell factor-1 (TCF1), and Th1- and Th2-like molecules in nodal PTCL is unclear.
Methods
Eighty-two cases of nodal PTCL were classified into 53 angioimmunoblastic T-cell lymphomas (AITLs)/nodal T-follicular helper cell lymphoma (nTFHL)-AI, 18 PTCLs-Tfh/nTFHL–not otherwise specified (NOS), and 11 PTCLs-NOS according to the revised 4th/5th World Health Organization classifications. Immunohistochemistry for TCF1, TBX21, CXCR3, GATA3, and CCR4 was performed.
Results
TCF1 was highly expressed in up to 68% of patients with nTFHL but also in 44% of patients with PTCL-NOS (p > .05). CXCR3 expression was higher in AITLs than in non-AITLs (p = .035), whereas GATA3 expression was higher in non-AITL than in AITL (p = .007) and in PTCL-Tfh compared to AITL (p = .010). Of the cases, 70% of AITL, 44% of PTCLTfh/ nTFHL-NOS, and 36% of PTCL-NOS were subclassified as the TBX21 subtype; and 15% of AITL, 38% of PTCL-Tfh/nTFHL-NOS, and 36% of PTCL-NOS were subclassified as the GATA3 subtype. The others were an unclassified subtype. CCR4 expression was associated with poor progression-free survival (PFS) in patients with PTCL-Tfh (p < .001) and nTFHL (p = .023). The GATA3 subtype showed poor overall survival in PTCL-NOS compared to TBX21 (p = .046) and tended to be associated with poor PFS in patients with non-AITL (p = .054).
Conclusions
The TBX21 subtype was more prevalent than the GATA3 subtype in AITL. The GATA3 subtype was associated with poor prognosis in patients with non-AITL and PTCL-NOS.

Keyword

Angioimmunoblastic T-cell lymphoma; Nodal peripheral T-cell lymphoma of TFH phenotype; Nodal T-follicular helper (TFH) cell lymphoma; angioimmunoblastic-type; Nodal T-follicular helper (TFH) cell lymphoma; not otherwise specified; Peripheral T-cell lymphoma; not otherwise specified

Figure

• 

  Fig. 1 Representative immunostaining for TBX21, CXCR3, GATA3, and CCR4 within TBX21 and GATA3 subtypes in three PTCL entities. Hematoxylin and eosin and TBX21, CXCR3, GATA3, and CCR4 immunostaining within the TBX21 subtype in AITL (A), GATA3 subtype in AITL (B), TBX21 subtype in PTCL-Tfh (C), GATA3 subtype in PTCL-Tfh (D), TBX21 subtype in PTCL-NOS (E), and GATA3 subtype in PTCL-NOS (F). AITL, angioimmunoblastic T-cell lymphoma; CCR4, C-C motif chemokine receptor 4; CXCR3, C-X-C motif chemokine receptor 3; GATA3, GATA binding protein 3; PTCL, peripheral T-cell lymphoma; PTCL-Tfh, peripheral T-cell lymphoma of follicular helper T-cell phenotype; PTCL-NOS, peripheral T-cell lymphoma, not otherwise specified; TBX21, T-box transcription factor 21.

• 

  Fig. 2 Expression and distribution of IHC staining in patients with three PTCL entities. The heatmap presents the distribution of IHC markers related to Tfh (CD10, BCL6, PD-1, CXCR5, and ICOS), TCF1, and classifications (TBX21, CXCR3, GATA3, and CCR4) across three PTCL entities and subtypes (A). Correlation between TBX21 and CXCR3 (B), and GATA3 and CCR4 (C). Expression patterns for TBX21 (D), CXCR3 (E), GATA3 (F), and CCR4 (G) in three PTCL entities. AITL, angioimmunoblastic T-cell lymphoma; CCR4, C-C motif chemokine receptor 4; CXCR5, C-X-C motif chemokine receptor 5; GATA3, GATA binding protein 3; ICOS, inducible T cell costimulatory; IHC, immunohistochemistry; PD-1, programmed death-1; PTCL, peripheral T-cell lymphoma; PTCL-NOS, peripheral T-cell lymphoma, not otherwise specified; PTCL-Tfh, peripheral T-cell lymphoma of follicular helper T-cell phenotype; TBX21, T-box transcription factor 21; TCF1, T-cell factor-1. *p < .05, **p < .01, ***p < .001.

• 

  Fig. 3 Survival analysis of progression-free survival in patients with nodal peripheral T-cell lymphoma according to Th2-like markers and TCF1. Kaplan-Meier curves display progression-free survival according to GATA3, CCR4, and TCF1 in AITL (A–C), PTCL-Tfh (D–F), nTFHL (G–I), PTCL-NOS (J–L), and non-AITL (M–O). AITL, angioimmunoblastic T-cell lymphoma; CCR4, C-C motif chemokine receptor 4; GATA3, GATA binding protein 3; nTFHL, nodal T-follicular helper cell lymphoma; PTCL-NOS, peripheral T-cell lymphoma, not otherwise specified; PTCL-Tfh, peripheral T-cell lymphoma of follicular helper T-cell phenotype; TCF1, T-cell factor-1. *p < .05, **p < .01, ***p < .001.

• 

  Fig. 4 Survival analysis of patients with nodal peripheral T-cell lymphoma according to TBX21 and GATA3 subtype classification. Kaplan-Meier curves displays overall survival and progression-free survival according to classification in AITL (A, B), PTCL-Tfh (C, D), nTFHL (E, F), PTCL-NOS (G, H), and non-AITL (I, J). AITL, angioimmunoblastic T-cell lymphoma; GATA3, GATA binding protein 3; nTFHL, nodal T-follicular helper cell lymphoma; PTCL-Tfh, peripheral T-cell lymphoma of follicular helper T-cell phenotype; PTCL-NOS, peripheral T-cell lymphoma, not otherwise specified; TBX21, T-box transcription factor 21. *p < .05, **p < .01.

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