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Abstract：
BACKGROUND: Follicular lymphoma (FL) is characterized by t(14;18)(q32;q21) involving the IGH and BCL2 genes. However, 10-15% of FLs lack the BCL2 rearrangement. These BCL2-rearrangement-negative FLs are clinically, pathologically, and genetically heterogeneous. The biological behavior and histological transformation of such FLs are not adequately characterized. Here, we report the first case of t(14;18)-negative FL that rapidly progressed to plasmablastic lymphoma (PBL).
METHODS: A previously healthy 51-year-old man presented with leg swelling. Computed tomography (CT) showed enlarged lymph nodes (LNs) throughout the body, including both inguinal areas. Needle biopsy of an inguinal LN suggested low-grade B-cell non-Hodgkin lymphoma. Excisional biopsy of a neck LN showed proliferation of centrocytic and centroblastic cells with follicular and diffuse growth patterns. Immunohistochemical analysis showed that the cells were positive for CD20, BCL6, CD10, and CD23. BCL2 staining was negative in the follicles and weak to moderately positive in the interfollicular areas. BCL2 fluorescence in situ hybridization result was negative. Targeted next-generation sequencing (NGS) revealed mutations in the TNFRSF14, CREBBP, STAT6, BCL6, CD79B, CD79A, and KLHL6 genes, without evidence of BCL2 or BCL6 rearrangement. The pathologic and genetic features were consistent with t(14;18)-negative FL. Two months after one cycle of bendamustine and rituximab chemotherapy, the patient developed left flank pain. Positron emission tomography/CT showed new development of a large hypermetabolic mass in the retroperitoneum. Needle biopsy of the retroperitoneal mass demonstrated diffuse proliferation of large plasmablastic cells, which were negative for the B-cell markers, BCL2, BCL6, and CD10; they were positive for MUM-1, CD138, CD38, and C-MYC. The pathologic findings were consistent with PBL. The clonal relationship between the initial FL and subsequent PBL was analyzed via targeted NGS. The tumors shared the same CREBBP, STAT6, BCL6, and CD79B mutations, strongly suggesting that the PBL had transformed from a FL clone. The PBL also harbored BRAF V600E mutation and IGH::MYC fusion in addition to IGH::IRF4 fusion.
CONCLUSIONS: We propose that transformation or divergent clonal evolution of FL into PBL can occur when relevant genetic mutations are present. This study broadens the spectrum of histological transformation of t(14;18)-negative FL and emphasizes its biological and clinical heterogeneity.
METHODS: A previously healthy 51-year-old man presented with leg swelling. Computed tomography (CT) showed enlarged lymph nodes (LNs) throughout the body, including both inguinal areas. Needle biopsy of an inguinal LN suggested low-grade B-cell non-Hodgkin lymphoma. Excisional biopsy of a neck LN showed proliferation of centrocytic and centroblastic cells with follicular and diffuse growth patterns. Immunohistochemical analysis showed that the cells were positive for CD20, BCL6, CD10, and CD23. BCL2 staining was negative in the follicles and weak to moderately positive in the interfollicular areas. BCL2 fluorescence in situ hybridization result was negative. Targeted next-generation sequencing (NGS) revealed mutations in the TNFRSF14, CREBBP, STAT6, BCL6, CD79B, CD79A, and KLHL6 genes, without evidence of BCL2 or BCL6 rearrangement. The pathologic and genetic features were consistent with t(14;18)-negative FL. Two months after one cycle of bendamustine and rituximab chemotherapy, the patient developed left flank pain. Positron emission tomography/CT showed new development of a large hypermetabolic mass in the retroperitoneum. Needle biopsy of the retroperitoneal mass demonstrated diffuse proliferation of large plasmablastic cells, which were negative for the B-cell markers, BCL2, BCL6, and CD10; they were positive for MUM-1, CD138, CD38, and C-MYC. The pathologic findings were consistent with PBL. The clonal relationship between the initial FL and subsequent PBL was analyzed via targeted NGS. The tumors shared the same CREBBP, STAT6, BCL6, and CD79B mutations, strongly suggesting that the PBL had transformed from a FL clone. The PBL also harbored BRAF V600E mutation and IGH::MYC fusion in addition to IGH::IRF4 fusion.
CONCLUSIONS: We propose that transformation or divergent clonal evolution of FL into PBL can occur when relevant genetic mutations are present. This study broadens the spectrum of histological transformation of t(14;18)-negative FL and emphasizes its biological and clinical heterogeneity.
摘要：
背景：滤泡性淋巴瘤（FL）的特征在于涉及IGH和BCL2基因的t（14;18）（q32;q21）。然而,10-15%的FL缺乏BCL2重排。这些BCL2重排阴性FL是临床上的，病理上,和遗传异质性。此类FL的生物学行为和组织学转化未得到充分表征。这里,我们报告了首例t（14;18）阴性FL迅速发展为浆细胞母细胞淋巴瘤（PBL）。
方法：一名先前健康的51岁男性出现腿部肿胀。计算机断层扫描（CT）显示全身淋巴结肿大，包括两个腹股沟区域。腹股沟LN的穿刺活检提示低度B细胞非霍奇金淋巴瘤。颈部LN的切除活检显示中心细胞和中心母细胞增殖，具有滤泡和弥漫性生长模式。免疫组织化学分析显示细胞CD20、BCL6、CD10和CD23呈阳性。BCL2染色在卵泡中为阴性，而在卵泡间区域为弱至中度阳性。BCL2荧光原位杂交成果为阴性。靶向下一代测序(NGS)揭示了TNFRSF14、CREBBP、STAT6,BCL6,CD79B,CD79A,和KLHL6基因，没有BCL2或BCL6重排的证据。病理和遗传特征与t（14;18）阴性FL一致。苯达莫司汀和利妥昔单抗化疗一个周期后两个月，患者出现左侧腹部疼痛。正电子发射断层扫描/CT显示腹膜后大的高代谢性物质的新发展。腹膜后肿块的穿刺活检显示大浆细胞的弥漫性增殖，B细胞标记为阴性，BCL2、BCL6和CD10；它们对MUM-1、CD138、CD38和C-MYC呈阳性。病理结果与PBL一致。通过靶向NGS分析初始FL和随后的PBL之间的克隆关系。肿瘤有相同的CREBBP,STAT6、BCL6和CD79B突变，强烈表明PBL是从FL克隆转化的。除了IGH::IRF4融合之外,PBL还具有BRAFV600E突变和IGH::MYC融合。
结论：我们提出，当存在相关的基因突变时，可以发生FL向PBL的转化或不同的克隆进化。这项研究拓宽了t（14;18）阴性FL的组织学转变范围，并强调了其生物学和临床异质性。
方法：一名先前健康的51岁男性出现腿部肿胀。计算机断层扫描（CT）显示全身淋巴结肿大，包括两个腹股沟区域。腹股沟LN的穿刺活检提示低度B细胞非霍奇金淋巴瘤。颈部LN的切除活检显示中心细胞和中心母细胞增殖，具有滤泡和弥漫性生长模式。免疫组织化学分析显示细胞CD20、BCL6、CD10和CD23呈阳性。BCL2染色在卵泡中为阴性，而在卵泡间区域为弱至中度阳性。BCL2荧光原位杂交成果为阴性。靶向下一代测序(NGS)揭示了TNFRSF14、CREBBP、STAT6,BCL6,CD79B,CD79A,和KLHL6基因，没有BCL2或BCL6重排的证据。病理和遗传特征与t（14;18）阴性FL一致。苯达莫司汀和利妥昔单抗化疗一个周期后两个月，患者出现左侧腹部疼痛。正电子发射断层扫描/CT显示腹膜后大的高代谢性物质的新发展。腹膜后肿块的穿刺活检显示大浆细胞的弥漫性增殖，B细胞标记为阴性，BCL2、BCL6和CD10；它们对MUM-1、CD138、CD38和C-MYC呈阳性。病理结果与PBL一致。通过靶向NGS分析初始FL和随后的PBL之间的克隆关系。肿瘤有相同的CREBBP,STAT6、BCL6和CD79B突变，强烈表明PBL是从FL克隆转化的。除了IGH::IRF4融合之外,PBL还具有BRAFV600E突变和IGH::MYC融合。
结论：我们提出，当存在相关的基因突变时，可以发生FL向PBL的转化或不同的克隆进化。这项研究拓宽了t（14;18）阴性FL的组织学转变范围，并强调了其生物学和临床异质性。
