目的: 分析血管免疫母细胞性T细胞淋巴瘤(angioimmunoblastic T-cell lymphoma，AITL)病理学特征、基因改变及预后的影响因素。方法: 选择北京大学肿瘤医院病理科2007年6月至2021年11月明确诊断且有完整随访信息的AITL患者病例资料进行回顾性分析，对病例进行形态学分型[Ⅰ型：淋巴结反应性增生(lymphoid tissue reactive hyperplasia，LRH)样；Ⅱ型：边缘区淋巴瘤(marginal zone lymphoma，MZL)样；Ⅲ型：外周T细胞淋巴瘤非特指型(peripheral T-cell lymphoma, not specified，PTCL-NOS)样]。结合免疫组化染色评估肿瘤有无滤泡辅助T细胞(follicular helper T cell，TFH)表型，生发中心(germinal center，GC)外滤泡树突细胞(follicular dendritic cells，FDC)增生，Hodgkin和Reed-Sternberg (HRS)样细胞及大B(细胞淋巴瘤)转化；计数每个高倍视野(high power field，HPF)Epstein-Barr病毒(Epstein-Barr virus，EBV)阳性细胞含量；按需要完善T细胞受体(T-cell receptor，TCR) / 免疫球蛋白(immunoglobulin，IG)基因重排检测和靶向外显子二代测序(targeted exome sequencing，TES)检测。结果: 共收集患者61例，形态分型Ⅰ型7例(11.4%)、Ⅱ型31例(50.8%)、Ⅲ型23例(37.8%)，51例(83.6%)具有明确TFH表型，有不同程度GC外FDC网架增生(中位20.0%)，14例(23.0%)有HRS样细胞，7例(11.5%)有大B转化。42.6%(26/61)的病例属于EBV高含量(＞10个/HPF)。TCR/IG重排分析57.9%TCR⁺/IG^-(11/19)，26.3%TCR⁺/IG⁺(5/19)，10.5%TCR^-/IG^-(2/19)，5.3%TCR^-/IG⁺(1/19)。TES检测RHOA突变66.7%(20/30)，IDH2突变23.3%(7/30)，TET2突变80.0%(24/30)，DNMT3A突变33.3%(10/30)。TES检测30例患者分为(1)IDH2和RHOA共突变组(7例)：Ⅱ型6例，Ⅲ型1例，具典型TFH表型，未见HRS细胞和大B转化；(2)单RHOA突变组(13例)：Ⅰ型1例，Ⅱ型6例，Ⅲ型6例，不具典型TFH表型5例，伴HRS细胞6例，伴大B转化2例，TCR^-/IG^- 1例, TCR^-/IG⁺ 1例，TCR⁺/IG⁺ 1例；(3)仅TET2和/或DNMT3A突变组(7例)：Ⅱ型3例，Ⅲ型4例，均具典型TFH表型，伴HRS细胞2例，伴大B转化2例；(4)无突变组(3例)，均为Ⅱ型，TFH表型典型，FDC网架增生，TCR^-/IG^- 1例。单因素生存分析证实EBV阳性细胞含量高为总生存和无进展生存的不良预后因素(P=0.017及P=0.046)。结论: AITL组织病理学难以诊断主要见于形态Ⅰ型，伴HRS样细胞，大B转化；此时TCR/IGH重排检测对诊断有帮助但价值有限；增加TES检测RHOA、IDH2、TET2、DNMT3A等基因突变可有效辅助AITL疑难病例的组织病理学诊断。肿瘤组织中EBV阳性细胞含量升高提示预后不良。

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.