Objective: To investigate the clinical, pathological and immunophenotypic features, and differential diagnosis of angioimmunoblastic T-cell lymphoma (AITL) with B-cell proliferation or neoplasms. Methods: Eight qualified cases were collected from the Department of Pathology, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China from January 2019 to July 2023. One case was diagnosed with AITL and diffuse large B-cell lymphoma (DLBCL) and the other seven cases were diagnosed with AITL and B-cell proliferation. Clinical characteristics and pathological morphology were summarized. Immunohistochemical analysis, fluorescence in situ hybridization and gene rearrangement detection were performed. Results: The patients\' average age was 58 years. Five of them were male. Biopsies of the enlarged cervical lymph nodes showed structural destruction and exhibited various histologic patterns. Some cases revealed Burkitt-like morphology, a moderate tumor volume and slightly irregular nuclei. Some cases showed prominent nucleoli. High endothelial venules and expanded follicular dendritic cells were detected. Tumor cells derived from T-follicular helper (TFH) cells were positive for two or more TFH biomarkers. Nodular or diffuse patchy proliferation of B cells was noted around the tumor tissue, which was initially considered as B-cell lymphoma. All of the 8 cases showed monoclonal rearrangements of the T-cell receptor genes while 5 of them also showed clonal rearrangements of the Ig genes. Seven of the 8 cases were subject to the detection of C-MYC gene breakage and were all negative. EBV-positive cells were seen in 6 cases. Neoplastic B cells were positive for C-MYC (>40%), while proliferative B cells were negative for C-MYC (<40%). Conclusions: The histological morphology of AITL with B-cell proliferation or lymphoma may be different from AITL. An integrated analysis, incorporating clinical, morphologic, immunophenotypic, and molecular assessment, helps reach an accurate diagnosis. This group of cases demonstrated the clinical and pathological characteristics of AITL accompanied by B-cell proliferation and B-cell lymphoma. The findings suggest that C-MYC maybe a feasible indicator for distinguishing B-cell proliferation from B-cell lymphoma, and provide a simple and feasible immunohistochemical marker for the diagnosis and research of composite lymphoma.
目的： 探讨血管免疫母细胞性T细胞淋巴瘤（AITL）伴B细胞增生或肿瘤的临床特征、病理形态、免疫表型、分子生物学特点和鉴别诊断。 方法： 收集中山大学附属第一医院病理科2019年1月至2023年7月诊断的8例AITL伴B细胞增生或肿瘤病例，分别为AITL伴弥漫大B细胞淋巴瘤（DLBCL）1例及AITL伴B细胞增生7例，对其临床与病理组织学特征进行回顾性分析，并行免疫组织化学染色、荧光原位杂交及基因重排检测。 结果： 8例AITL患者中，男性5例，女性3例，年龄52~61岁，平均年龄为58岁；取颈部肿大淋巴结活检，镜下均可见淋巴结结构破坏，但组织学形态不一；部分病例具Burkitt样形态，肿瘤细胞胞体中等大，核略不规则；部分病例核仁明显，局部伴高内皮小静脉增生，伴有滤泡树突细胞（FDC）网架增生并破坏；肿瘤细胞起源于生发中心辅助T细胞，表达2个以上滤泡辅助T细胞标志物，肿瘤组织周围尚可见呈结节状或弥漫片状增殖的B细胞，初诊时易被考虑为B细胞淋巴瘤。8例AITL病例的T细胞受体（TCR）克隆性基因重排检测结果均为阳性，其中5例伴有免疫球蛋白重链基因（IgH）重排阳性，8例中有7例行C-MYC基因断裂检测，均为阴性。8例中有6例免疫母细胞样B细胞EB病毒编码的RNA（EBER）原位杂交检测呈阳性。在AITL伴DLBCL病例中，肿瘤性B细胞C-MYC呈阳性表达（阳性率>40%），而AITL伴B细胞增生的7例中，增生性B细胞C-MYC为阴性（阳性率<40%）。 结论： AITL伴B细胞增生或肿瘤的病理形态不典型，诊断需要结合临床、病理形态、免疫表型及分子检测结果综合分析，容易误诊、漏诊。C-MYC或可作为鉴别B细胞增生与肿瘤的可行性指标，为复合性淋巴瘤的诊断和研究提供简便可行的免疫标志物。.

In order to explore a new mode for the diagnosis of angioimmunoblastic T-cell lymphoma (AITL), 31 cases of AITL and 28 cases of peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) were used as the study subjects. Identifying T follicular helper (TFH) cells with CD4, CD10, Bcl-6, and PD-1, identifying proliferative B cells with CD20 and EZH2, identifying proliferative follicular dendritic cells (FDCs) with CD21 and CD23, and analyzing the value of TFH/B/FDC proliferation and immunolocalization in the diagnosis of AITL. (1) Outside the inherent lymphoid follicles, simultaneous proliferation of TFH/B/FDC (a new diagnostic mode) were observed in AITL [83.87%; 26/31], with their immunolocalizations in the same site [83.87%; 26/31], while this phenomenon was not observed in 28 cases of PTCL-NOS (P<0.05). (2) The sensitivity and specificity of using this new mode to diagnose AITL were both high (83.87%, 100%), which was superior to CD2 (100%, 0%), CD3 (100%, 0%), CD4 (100%, 32.14%), CD5 (100%, 25%), CD10 (61.9%, 100%), Bcl-6 (42.86%, 100%), PD-1 (83.87%, 96.43%), and its Youden Index (0.84) was the highest. The areas under the curve (AUC) of CD10, Bcl-6, PD-1, and new mode to diagnosis AITL were 0.81, 0.71, 0.90, and 0.92, respectively, while the new mode had the highest AUC. The simultaneous proliferation of TFH/B/FDC cells outside the inherent lymphoid follicles can be used to assist in the diagnosis of AITL, and the simultaneous spatiotemporal proliferation of TFH/B/FDC cells is a specific immunomorphology of AITL.

OBJECTIVE: To explore the clinicopathologic features, treatment, and survival outcomes of angioimmunoblastic T-cell lymphoma (AITL) involving the nasopharynx.
METHODS: We retrospectively analyzed 73 cases of AITL. Among them, 64 cases with complete pre-treatment 18F-FDG positron emission tomography/computed tomography (PET/CT) images were integrated into the analysis of clinical characteristics and PET/CT findings of AITL involving the nasopharynx; 14 cases with both biopsies from lymph node and nasopharynx were included in the comparison of pathological characteristics of AITL in the two areas. Forty-six of the 73 patients who received first-line systemic treatment at our institute were included in the treatment efficacy and survival analyses.
RESULTS: Nasopharyngeal involvement was seen in 44/64 (68.8%) patients. Histologically, lymph node and nasopharyngeal biopsies in 14 patients both showed small to medium-sized tumor cells, complex inflammatory infiltration, and Reed-Sternberg-like cells or B immunoblasts. However, tumor cells with clear cytoplasm, significant high endothelial venule (HEV) hyperplasia, and perivascular infiltration were observed in 5/14, 3/14, and 2/14 nasopharyngeal biopsies, respectively, but in all fourteen lymph node biopsies (P < 0.05). Immunophenotypic profiles and gene rearrangements were highly concordant. Treatment efficacy and survival were similar between patients with nasopharyngeal involvement and those without (P > 0.05), indicating nasopharyngeal involvement is not a prognostic factor for AITL patients.
CONCLUSIONS: Nasopharyngeal involvement is common in AITL but can be easily misdiagnosed because of its atypical pathologic pattern, especially when a lymph node biopsy is unavailable. However, the patient\'s clinical presentation, PET/CT manifestations, the typical immunophenotype, and gene rearrangements help the diagnosis.

Objective: To investigate the characteristics of gene mutations in angioimmunoblastic T-cell lymphoma (AITL). Methods: Seventy-five AITL cases diagnosed at the Department of Pathology, Ruijin Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China from June 2021 to June 2023 were included. Their formalin-fixed and paraffin-embedded or fresh tissues were subject to targeted next generation sequencing (NGS). The sequencing data was collected, and the distribution and type of gene mutations were analyzed. Results: 492 potential driver mutations were identified in 74 out of the 84 genes. Targeted sequencing data for the 75 AITL patients showed that the genes with mutation frequencies of ≥10% were TET2 (89.3%), RHOA (57.3%), IDH2 (37.3%), DNMT3A (36.0%), KMT2C (21.3%), PLCG1 (12.0%), and KDM6B (10.7%). There were significant co-occurrence relationships between TET2 and RHOA, TET2 and IDH2, and RHOA and IDH2 gene mutations (P<0.05), respectively, while TET2 and KDM6B gene mutations were mutually exclusive (P<0.05). Conclusions: The study reveals the mutational characteristics of AITL patients using NGS technology, which would provide insights for molecular diagnosis and targeted therapy of AITL.
目的： 探讨血管免疫母细胞性T细胞淋巴瘤（angioimmunoblastic T-cell lymphoma，AITL）的基因突变特征。 方法： 收集2021年6月至2023年6月经上海交通大学医学院附属瑞金医院病理科诊断为AITL，并用石蜡包埋组织或新鲜组织进行靶向测序检测的75例病例资料，分析AITL患者的突变基因分布和突变类型。 结果： 在75例AITL标本中均检测出基因突变，共检测到492个变异位点，分别位于84个基因列表中的74个基因。在≥10%的AITL病例中检测到的突变基因依次是TET2（89.3%）、RHOA（57.3%）、IDH2（37.3%）、DNMT3A（36.0%）、KMT2C（21.3%）、PLCG1（12.0%）和KDM6B（10.7%）。TET2和RHOA、TET2和IDH2、RHOA和IDH2基因突变之间均具有显著的共现关系（P<0.05），TET2和KDM6B基因突变之间具有显著的互斥关系（P<0.05）。 结论： 应用二代测序技术可揭示AITL基因突变的独特特征，为AITL的诊断和靶向治疗提供参考依据。.

暂无摘要。

Objective: To investigate the clinicopathologic features of progressively transformed germinal center-like follicular T-cell lymphoma (PTGC-like FTCL). Methods: The clinicopathologic data of 14 PTGC-like FTCL cases that were diagnosed at the Beijing Friendship Hospital Affiliated to the Capital Medical University from January 2017 to January 2022 were retrospectively collected. Clinicopathological features, immunophenotype, and Epstein-Barr virus (EBV) infection status were analyzed in these cases. Polymerase chain reaction (PCR) was performed to detect the clonal gene rearrangements of T cell receptor (TCR) and the immunoglobulin (Ig) in 10 and 8 cases, respectively. Results: The male to female ratio was 5∶2. The median age was 61 years (range 32-70 years). All patients had lymphadenopathy at the time of diagnosis. By using the Ann Arbor system staging, seven cases were classified as stage Ⅰ-Ⅱ, and seven cases as stage Ⅲ-Ⅳ. Seven cases had B symptoms, four cases had splenomegaly, and two cases had skin rash and pruritus. Previously, three cases were diagnosed as classic Hodgkin\'s lymphoma, three cases as small B-cell lymphoma, two cases as atypical lymphoid hyperplasia unable to exclude angioimmunoblastic T-cell lymphoma (AITL), one case as EBV-associated lymphoproliferative disorder, and one case as peripheral T-cell lymphoma (PTCL) associated with the proliferation of B cells. All the 14 cases showed that the large nodules were composed of mature CD20+, IgD+B lymphocytes admixed with small aggregates of neoplastic cells with pale to clear cytoplasm. Moreover, hyperplastic germinal centers (GCs) and Hodgkin/Reed-Sternberg-like (HRS-like) cells were seen within these nodules in two and five cases, respectively. The neoplastic cells expressed CD3 (14/14), CD4 (14/14), PD1 (14/14), ICOS (14/14), CD10 (9/14), bcl-6 (12/14), CXCL13 (10/14), and CD30 (10/14). The HRS-like cells in five cases expressed CD20 (2/5), PAX5 (5/5), CD30 (5/5), CD15 (2/5), LCA (0/5), OCT2 (5/5) and BOB1 (2/5). Moreover, neoplastic T cells formed rosettes around HRS-like cells. EBV-encoded RNA (EBER) in situ hybridization showed scattered, small, positive bystander B lymphocytes in 8/14 cases, including 3/5 cases containing HRS-like cells. All tested cases (including five with HRS-like cells) showed monoclonal TCR gene rearrangement and polyclonal Ig gene rearrangement. Conclusions: PTGC-like FTCL is a rare tumor originated from T-follicular helper cells. It could be distinguished from angioimmunoblastic T-cell lymphoma by the formation of follicular structure, and lack of follicular dendritic cell proliferation outside the follicles and the polymorphous inflammatory background. In addition, it should be differentiated from lymphocyte-rich classical Hodgkin\'s lymphoma and low-grade B cell lymphoma.
目的： 探讨进行性转化生发中心样滤泡T细胞淋巴瘤（PTGC样FTCL）的临床病理学特征。 方法： 收集首都医科大学附属北京友谊医院病理科2017年1月至2022年1月14例PTGC样FTCL，分析其临床特征、病理形态、免疫表型及EB病毒感染状态。对10例行T细胞受体基因检测，对8例行免疫球蛋白（Ig）基因克隆性检测。 结果： （1）患者男性10例，女性4例，男女比为5∶2，发病年龄32~70岁，中位年龄61岁，起病时均有淋巴结肿大，按Ann Arbor系统分期，Ⅰ~Ⅱ期7例，Ⅲ~Ⅳ期7例，有B症状者7例，脾肿大者4例，伴皮疹及皮肤瘙痒者2例。10例获得原单位病理报告，3例诊断为小B细胞淋巴瘤，3例诊断为经典霍奇金淋巴瘤，2例诊断为不除外血管免疫母细胞性T细胞淋巴瘤（AITL），1例诊断为EB病毒相关淋巴组织增生性病变，1例诊断为外周T细胞淋巴瘤（PTCL）伴多量B细胞反应。（2）形态学显示由形态成熟的小淋巴细胞构成的深染大结节，结节内可见散在及灶状分布的异型瘤细胞，胞质淡染或透明。2例在深染结节内见增生的生发中心。5例在结节内还见到散在霍奇金（HRS）样大细胞。（3）免疫组织化学染色结果显示构成深染大结节的小淋巴细胞表达CD20、PAX5和IgD，胞质淡染或透明的异型细胞表达CD3（14/14）、CD4（14/14）、PD1（14/14）、ICOS（14/14）、CD10（9/14）、bcl-6（12/14）和CXCL13（10/14）；10例（10/14）瘤细胞表达CD30。5例有HRS样大细胞的病例，HRS样大细胞不表达CD3和白细胞共同抗原（LCA），表达CD20（2/5）、PAX5（5/5）、CD30（5/5）、CD15（2/5）、OCT2（5/5）及BOB1（2/5），并见肿瘤性滤泡辅助T细胞包绕HRS样细胞形成花环结构。（4）EB病毒编码的RNA（EBER）原位杂交显示14例中8例见散在较小的B细胞阳性，包括3/5例具有HRS样大细胞的病例，同时显示HRS样细胞阳性。（5）10例病例（包括5例有HRS样大细胞的病例）行T细胞受体基因重排检测均呈单克隆性，8例（包括5例有HRS样大细胞的病例）行Ig基因重排检测均呈多克隆性重排。 结论： PTGC样FTCL是少见的起源于滤泡辅助T细胞的肿瘤，和AITL的鉴别在于前者形成滤泡结构，缺乏滤泡外的滤泡树突细胞网增生和多形性浸润。该病还需和淋巴细胞丰富的经典霍奇金淋巴瘤及低级别B细胞淋巴瘤鉴别。.

Angioimmunoblastic T-cell lymphoma (AITL) is an aggressive subtype of peripheral T-cell lymphomas with its cell origin determined to be follicular helper T-cells. AITL is characterized by a prominent tumor microenvironment involving dysregulation of immune cells, signaling pathways, and extracellular matrix. Significant progress has been made in the molecular pathophysiology of AITL, including genetic mutations, immune metabolism, hematopoietic-derived microenvironment, and non-hematopoietic microenvironment cells. Early diagnosis, detection of severe complications, and timely effective treatment are crucial for managing AITL. Treatment typically involves various combination chemotherapies, but the prognosis is often poor, and relapsed and refractory AITL remains challenging, necessitating improved treatment strategies. Therefore, this article provides an overview of the pathogenesis and latest advances in the treatment of AITL, with a focus on potential therapeutic targets, novel treatment strategies, and emerging immunotherapeutic approaches.

Molecular and clinical stratification of patients with angioimmunoblastic T-cell lymphoma (AITL) is unsatisfactory, which hinders the development of personalized therapies. This study aimed to identify molecular biomarkers for AITL based on peripheral cell-free DNA (cfDNA) that could be used to predict prognosis and guide treatment non-invasively. A customized panel containing 46 genes was used to study pretreatment cfDNA and paired tumour tissues in 64 Chinese AITL patients from three clinical centres, and gene mutations in cfDNA and tumour tissue were assessed for concordance (34 paired samples). Then, the association of gene mutations and prognosis was analysed, and a functional enrichment analysis was performed. The sequencing results showed good consistency between cfDNA samples and paired tissue samples. KDM5A, STAT1, FANCM, ERBB4, PIK3R5 and NSD1 were identified as novel recurrent mutations. Mutations in FANCM or combinations of RHOA, KDM5A and FAT1 were associated with poor prognosis. Additionally, functional analysis revealed that RHOAG17 might serve as a predictive biomarker of PD-1 blockade respondence. Our findings confirmed the role of cfDNA as a liquid biopsy in AITL, and revealed novel molecular determinants that can stratify patients and guide treatment options.

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).
CONCLUSIONS: 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.

BACKGROUND: The prognosis of patients with angioimmunoblastic T cell lymphoma (AITL) remains dismal, with their 5-year overall survival (OS) and progression-free survival (PFS) rates of 32-41% and 18-38%, respectively. Spleen involvement occurs in a proportion of patients with AITL. But still, it is unclear whether spleen involvement impacts the prognosis of AITL patients. In this study, we aim to establish new prognostic indicators for the identification of high-risk patients to draft optimal treatment regimens.
METHODS: We collected and counted the clinical data of 54 patients with AITL treated with CHOP-based first-line chemotherapy regimen between 2010 and 2021 at Hubei Cancer Hospital and Hunan Cancer Hospital. In addition, all patients received PET-CT scan prior to receiving treatment. We performed univariate and multivariate analyses to assess the predictive role of tumor characteristics, laboratory, and radiographic data for the prognosis of AITL.
RESULTS: We observed that PFS and OS are worse in patients with high ECOG scores, spleen involvement, and low serum albumin levels in patients with AITL. In univariate analysis, stage (HR 3.515 [1.142-10.822], p = 0.028) and spleen involvement (HR 8.378 [1.085-64.696, p = 0.042) were correlated with PFS in patients with AITL. Besides, stage (HR 3.439 [1.108-10.674], p = 0.033) and spleen involvement (HR 11.002 [1.420-85.254], p = 0.022) were significantly correlated with OS. Consistently, spleen involvement was correlated with OS (HR 16.571 [1.350-203.446], p = 0.028) and PFS (HR 10.905 [1.037-114.690], p = 0.047) in AITL patients in a multivariate analysis.
CONCLUSIONS: This study demonstrates that spleen involvement might be used as a prognostic indicator for AITL patients.