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Journal of Peking University (Health Sciences) ›› 2023, Vol. 55 ›› Issue (3): 521-529. doi: 10.19723/j.issn.1671-167X.2023.03.019

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Analysis of clinicopathological and molecular abnormalities of angioimmunoblastic T-cell lymphoma

Yun-fei SHI1,Hao-jie WANG2,Wei-ping LIU3,Lan MI3,Meng-ping LONG1,Yan-fei LIU3,Yu-mei LAI1,Li-xin ZHOU1,Xin-ting DIAO1,Xiang-hong LI1,*()   

  1. 1. Department of Pathology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing 100142, China
    2. Central Laboratory, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing 100142, China
    3. Department of Lymphoma, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing 100142, China
  • Received:2022-09-22 Online:2023-06-18 Published:2023-06-12
  • Contact: Xiang-hong LI E-mail:kxhli72@163.com

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Abstract:

Objective: To analyze the clinicopathological features, molecular changes and prognostic factors in angioimmunoblastic T-cell lymphoma (AITL). Methods: Sixty-one cases AITL diagnosed by Department of Pathology of Peking University Cancer Hospital were collected with their clinical data. Morphologically, they were classified as typeⅠ[lymphoid tissue reactive hyperplasia (LRH) like]; typeⅡ[marginal zone lymphoma(MZL)like] and type Ⅲ [peripheral T-cell lymphoma, not specified (PTCL-NOS) like]. Immunohistochemical staining was used to evaluate the presence of follicular helper T-cell (TFH) phenotype, proliferation of extra germinal center (GC) follicular dendritic cells (FDCs), presence of Hodgkin and Reed-Sternberg (HRS)-like cells and large B transformation. The density of Epstein-Barr virus (EBV) + cells was counted with slides stained by Epstein-Barr virus encoded RNA (EBER) in situ hybridization on high power field (HPF). T-cell receptor / immunoglobulin gene (TCR/IG) clonality and targeted exome sequencing (TES) test were performed when necessary. SPSS 22.0 software was used for statistical analysis. Results: Morphological subtype (%): 11.4% (7/61) cases were classified as type Ⅰ; 50.8% (31/61) as type Ⅱ; 37.8% (23/61) as type Ⅲ. 83.6% (51/61) cases showed classical TFH immunophenotype. With variable extra-GC FDC meshwork proliferation (median 20.0%); 23.0% (14/61) had HRS-like cells; 11.5% (7/61) with large B transformation. 42.6% (26/61) of cases with high counts of EBV. 57.9% (11/19) TCR+/IG-, 26.3% (5/19) TCR+/IG+, 10.5% (2/19) were TCR－/IG－, and 5.3% (1/19) TCR－/IG+. Mutation frequencies by TES were 66.7% (20/30) for RHOA, 23.3% (7/30) for IDH2 mutation, 80.0% (24/30) for TET2 mutation, and 33.3% (10/30) DNMT3A mutation. Integrated analysis divided into four groups: (1) IDH2 and RHOA co-mutation group (7 cases): 6 cases were type Ⅱ, 1 case was type Ⅲ; all with typical TFH phenotype; HRS-like cells and large B transformation were not found; (2) RHOA single mutation group (13 cases): 1 case was type Ⅰ, 6 cases were type Ⅱ, 6 cases were type Ⅲ; 5 cases without typical TFH phenotype; 6 cases had HRS-like cells, and 2 cases with large B transformation. Atypically, 1 case showed TCR－/IG－, 1 case with TCR－/IG+, and 1 case with TCR+/IG+; (3) TET2 and/or DNMT3A mutation alone group (7 cases): 3 cases were type Ⅱ, 4 cases were type Ⅲ, all cases were found with typical TFH phenotype; 2 cases had HRS-like cells, 2 cases with large B transformation, and atypically; (4) non-mutation group (3 cases), all were type Ⅱ, with typical TFH phenotype, with significant extra-GC FDC proliferation, without HRS-like cells and large B transformation. Atypically, 1 case was TCR－/IG－. Univariate analysis confirmed that higher density of EBV positive cell was independent adverse prognostic factors for both overall survival (OS) and progression free survival(PFS), (P=0.017 and P=0.046). Conclusion: Pathological diagnoses of ALTL cases with HRS-like cells, large B transformation or type Ⅰ are difficult. Although TCR/IG gene rearrangement test is helpful but still with limitation. TES involving RHOA, IDH2, TET2, DNMT3A can robustly assist in the differential diagnosis of those difficult cases. Higher density of EBV positive cells counts in tumor tissue might be an indicator for poor survival.

Key words: T cell, Lymphoma, Pathology, Gene mutation, Prognosis

CLC Number: 

  • R732.2

Table 1

Details in primary antibodies in immunohistochemical staining"

Primary antibody Clone Manufacturer Specified target Location Dilution
BCL6 ZR280 Beijing Xiya Golden Bridge Biotechnology TFH cell or tumor cell Cell nuclear 1:50
CD3ε A0452 Dako, Agilent Technologies, Santa Clara, USA T cell or tumor cell Cytoplasm 1:50
CD10 56C6 Dako, Agilent Technologies, Santa Clara, USA TFH cell or tumor cell Cell membrane 1:50
CD20 L26 Dako, Agilent Technologies, Santa Clara, USA B cell Cell membrane 1:50
CD21 EP64 Beijing Zhongshan Golden Bridge Biotechnology FDC cell Cell membrane 1:50
CD30 JCM182 Novocastra, Leica Biosystems, UK Immunoblastic cell Cell membrane or cytoplasm 1:50
CD4 UMAB64 Beijing Xiya Golden Bridge Biotechnology T helper cell or tumor cell Cell membrane 1:50
CXCL13 53610 R&D Systems TFH cell or tumor cell Cytoplasm 1:50
Ki67 MIB1 Dako, Agilent Technologies, Santa Clara, USA Tumor cell Cell nuclear 1:50
PD1 UMAB199 Beijing Zhongshan Golden Bridge Biotechnology TFH cell or tumor cell Cell membrane 1:50

Table 2

The clinical and pathological characteristics and outcomes of the angioimmunoblastic T-cell lymphoma (AITL) patients"

Characteristics n(%)
Age, ＞60 years 27 (44.3)
Gender, male 39 (63.9)
Ann arbor stage, Ⅲ-Ⅳ 59 (96.7)
B symptoms, yes 28 (45.9)
Skin rash, yes 19 (31.1)
IPI score, high risk (3-5) 27 (44.3)
PIT score, high risk (2-3) 32 (52.5)
ECOG score, ＞1 7 (11.5)
Nodal areas involved, ＞5 44 (72.1)
Extranodal involvement, ＞1 18 (29.5)
Bone marrow involvement, yes 13 (21.3)
LDH elevated 29 (47.5)
β2-MG elevated 40 (30.5)
Treatment
  CHOP-like 24 (39.3)
  CHOEP-like 26 (42.6)
  CHOEPG-like 10 (16.4)
  Prednisone mono-therapy 1 (1.6)
Response
  CR 27 (44.3)
  ORR 38 (62.3)
  NA 3 (4.9)
Transplant AHSCT 13 (21.3)
Histology pattern
  Pattern Ⅰ 7 (11.4)
  Pattern Ⅱ 31 (50.8)
  Pattern Ⅲ 23 (37.8)
HRS-like cell present, yes 14 (23.0)
Large B cell transformation, yes 7 (11.5)
TFH phenotype, typical 51 (83.6)
Extra FDC (CD21), ≥20% 35 (57.4)
EBV positive cell, >10/HPF 26 (42.6)
Ki67, ≥60% 24 (39.3)

Figure 1

Representative images of morphological patterns in angioimmunoblastic T-cell lymphoma (AITL) A, a case with type Ⅰ pattern: follicular hyperplasia / reactive hyperplasia, LRH-like); B, a case with type Ⅱ pattern (follicular atrophy with paracortical expansion, MZL-like); C, a case with type Ⅲ (disappearance of follicles with significant expansion of paracortical area or diffuse tumor invasion, PTCL-NOS like)."

Figure 2

Representative images of CD10, BCL6, PD1 and CXCL13 expression in the same AITL case A, strong membrane staining with CD10; B, nuclear staining with BCL6; C, bright membrane staining of PD1; D, cytoplasmic staining of CXCL13."

Figure 3

Representative images of the expanded follicular dendritic cell meshwork, HRS-like cells, large B transformation component, and EBER status in relative angioimmunoblastic T-cell lymphoma (AITL) cases A, highly expanded extra follicular FDC meshwork; B, Hodgkin and Read-Sternberg (HRS)-like cells in the canter of the picture; C, large B transformation component at low-power field(indicated by black circle); D, transformed large B cells at high-power field; E, the status of Epstein-Barr virus encoded RNA (EBER) positive cells in tumor tissue were classified as high density; F, the status of EBER positive cells in tumor tissue were classified as low density."

Figure 4

Overview of clinical, pathological and molecular genetic findings in 30 AITL cases Each column of the heat map represents one angioimmunoblastic T-cell lymphoma (AITL) case and each line the specific analysis. HRS, Hodgkin and Reed-Sternberg-like; NGS, next-generation sequencing; IHC, Immunohistochemistry; EBER, Epstein-Barr virus-encoded RNA; TFH, follicular T helper cell; EBV, Epstein-Barr virus; TCR, T cell receptor; IG, immunoglobulin; NGS, next-generration sequencing."

Figure 5

EBER status (n=61) and the mutation status of IDH2 and RHOA (n=30)in AITL tumor tissue were found associated with clinical outcomes A, patients with Epstein-Barr virus encoded RNA (EBER) positive status rated as high (>10% cell/high power field) exhibited shortened overall survival (OS); B, patients with EBER positive status rated as high (>10% cell/high power field) exhibited shortened progression free survival (PFS); C, patients with IDH2 mutation showed better prognosis in terms of OS; D, those patients with mutated RHOA related to significant prolonged PFS. Log-rank P values and number of cases analyzed were all provided. By univariate (Kaplan-Meier estimations) with the log rank test for OS in AITL patients."

Table 3

Prognostic parameters analysis for angioimmunoblastic T-cell lymphoma (AITL) (n=61)"

Characteristics OS PFS
Univariate analysis Univariate analysis
HR(95%CI) P value HR(95%CI) P value
EBV grade 2.526 (1.144-5.577) 0.022 1.873 (1.000-3.509) 0.050
Large B transformation 0.830 (0.248-2.774) 0.762 0.902 (0.351-2.317) 0.831
TFH phenotype 0.516 (0.192-1.385) 0.189 0.493 (0.205-1.186) 0.114
HRS cell 0.813 (0.324-2.036) 0.658 0.827 (0.410-1.668) 0.596
Gender 0.984 (0.426-2.272) 0.970 1.297 (0.663-2.536) 0.448
Age(>60 years) 1.664 (0.7547-3.670) 0.207 1.528 (0.817-2.855) 0.184
Skin rash 0.579 (0.232-1.446) 0.242 0.845 (0.421-1.697) 0.637
IPI (score 3-5) 2.114 (0.969-4.614) 0.060 1.365 (0.731-2.550) 0.328
PIT(score 2-3) 1.087 (0.502-2.354) 0.833 1.136 (0.607-2.126) 0.690
β2-MG elevated 2.338 (1.035-5.281) 0.041 1.948 (1.032-3.676) 0.040
Nodal areas involved >5 56.392 (2.171-1 464.673) 0.015 3.187 (1.453-6.990) 0.004
Transplant 0.191 (0.045-0.813) 0.025 0.195 (0.069-0.554) 0.002
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