Objective: To investigate the clinicopathological features and misdiagnosis factors of ALK positive large B-cell lymphoma (ALK+LBCL). Methods: The clinicopathological data of 3 patients with ALK+LBCL in the Department of Pathology, the Affiliated Hospital of Xuzhou Medical University from 2010 to 2021 were collected retrospectively. Immunohistochemistry (IHC) was used for immunophenotyping, in-situ hybridization (ISH) for EBV-encoded RNA (EBER) detection, in-situ fluorescence hybridization (FISH, break-apart probes) for ALK, MYC, and CCND1 translocations. Next-generation sequencing (NGS) was used for the detection of gene fusions and mutations. And clinicopathological features and prognosis of patients were analyzed. Results: Among the 3 ALK+LBCL patients, there were 2 males and 1 female, aged 42, 59, and 39 years, respectively, none of which presented with B symptoms. Case 1 showed systemic lymphadenopathy with elevated serum EBV DNA loading, while cases 2 and 3 presented with extranodal lesions in the nasal and hard palate, respectively. Bone marrow biopsies were performed in cases 1 and 3, and neither showed involvement. Case 1 was at clinical stage Ⅲ while both cases 2 and 3 were at stage Ⅰ, and IPI score ranged 0-1 in all cases. The morphology of these cases was similar. The architecture was effaced by sheets of cohesive large cells growing in extensive infiltration and intra-sinus growth pattern. The neoplastic cells showed immunoblastic or plasmablastic morphology, and large anaplastic cells were easily found. The tumor cells expressed ALK protein cytoplasmically in almost all cells, with ALK gene translocations detected by FISH. Common B-cell and T-cell markers, including CD20, PAX5, CD19, CD2, CD3, CD5, CD7, CD43, CD56, and bcl-2, were negative, while plasmacytic differentiation markers, including CD138, CD38, and MUM1, were positive; CD22, BOB1 and OCT2 were variably expressed. CD10 was strongly expressed only in case 3. All cases were negative for bcl-6 but positive for CD4, perforin, CD30 (partial cells), pSTAT3 (diffusely), and MYC (40%-50%). The Ki-67 index was ranged 60%-70%. MYC translocation was not detected in any case by FISH. In case 1, EBER was strongly positive in>90% of tumor cells. Case 3 was diffusely positive for cyclin D1 but negative for SOX11 expression and CCND1 translocation. All cases harbored ALK fusion genes detected by NGS. In case 1, the fusion partner was TFG, which had not been reported in DLBCL, while in the other 2 cases, ALK fused with the CTCL gene, which was commonly seen in ALK+LBCL. Cases 1 and 3 were treated with ECHOP-based chemotherapy for six cycles and were followed up for 70 and 27 months, respectively, and both achieved complete remission. Conclusions: ALK+LBCL cases with diffuse EBER-positivity reported in this study show TGF as a new fusion partner of ALK in DLBCL, together with cyclin D1 expression. These rare cases are easily confused with EBV positive diffuse large B-cell lymphoma, not otherwise specified (EBV+DLBCL, NOS), cyclin D1 positive diffuse large B-cell lymphoma (cyclin D1+DLBCL) and ALK positive anaplastic large cell lymphoma (ALK+ALCL), resulting in misdiagnosis. Being aware of these rare phenotypes is essential for pathologists to diagnose ALK+LBCL and guide appropriate treatment accurately.
目的： 探讨间变性淋巴瘤激酶（ALK）阳性大B细胞淋巴瘤（ALK-positive large B-cell lymphoma，ALK+LBCL）的临床病理特征及其易误诊因素。 方法： 回顾性收集徐州医科大学附属医院病理科2010年至2021年共3例ALK+LBCL患者的临床病理资料，行免疫组织化学染色，原位杂交检测EB病毒编码的RNA（EBER），荧光原位杂交（FISH）检测ALK、MYC、CCND1基因易位（断裂探针），二代测序检测多基因遗传异常，收集并分析相关的临床病理特征和预后。 结果： 3例ALK+LBCL患者中，男性2例，女性1例，年龄分别为42、59、39岁，均无B症状。例1全身淋巴结肿大，外周血EBV DNA载量增高，例2、3为结外局限性病灶（发生于鼻腔、硬腭）。例1、3行骨髓活检均未见累及，例1为临床Ⅲ期，例2、3均为Ⅰ期，国际预后指数（IPI）评分均为0~1分。3例形态类似：结构破坏，大细胞片状生长，弥漫浸润伴显著窦内生长模式；瘤细胞呈免疫母或浆母细胞样形态，间变性大细胞易见。3例瘤细胞均弥漫强表达ALK，且均ALK基因易位阳性，均不表达常用B、T细胞标志物（CD20、PAX5、CD19、CD2、CD3、CD5、CD7、CD43、CD56、bcl-2），但表达浆样分化标志物（CD138、CD38、MUM1），可见表达CD22、BOB.1、OCT2。生发中心标志物bcl-6均阴性，CD10仅例3强表达。均表达CD4、穿孔素，CD30部分细胞表达，均表达pSTAT3（弥漫）及MYC（40%~50%），但不伴MYC基因易位，Ki-67阳性指数较高（60%~70%）。例1 >90%的瘤细胞EBER强阳性，例3 cyclin D1弥漫阳性，但SOX11阴性，CCND1基因易位阴性。二代测序检测3例均见ALK基因融合，其中例1融合伴侣为TFG，另2例融合伴侣为CLTC。例1、3以ECHOP（依托泊苷+长春地辛+吡柔比星+氢化泼尼松+环磷酰胺）为主的方案化疗6个疗程，分别随访70、27个月，达完全缓解。 结论： ALK+LBCL伴有弥漫EBER表达，极易与EBV阳性弥漫性大B细胞淋巴瘤，非特指、cyclin D1阳性弥漫性大B细胞淋巴瘤和ALK阳性间变性大细胞淋巴瘤等混淆，从而造成误诊，了解这些罕见表型有助于建立正确的诊断从而选择合理的治疗。.