Lymphoma Disease Discovery and Defintion

我们继续研究儿童年龄组的淋巴瘤，以及它们的特点。滤泡性淋巴瘤（FL）是一种常见的成人淋巴瘤，很少发生在儿童和青年患者中。区分儿童型滤泡性淋巴瘤和成人型滤泡性淋巴瘤的标准还没有很好的定义。我们对30岁以下的FL患者进行了一项研究。我们鉴定了63例病例，通过形态学、免疫组织化学和聚合酶链反应分析igh@igk@克隆性。这些数据与临床表现相关，包括分期、治疗和结果。在63例病例中，34例被归类为FL的儿童变体，22例出现在淋巴结，8例出现在Waldeyer环，4例出现在睾丸。在97%的PFL病例中检测到克隆性免疫球蛋白基因重排，但荧光原位杂交分析显示，在所有检测病例中都没有BCL2/ ight @易位。29例为普通FL，其中28例表现于淋巴结。结性儿童肿瘤仅在男性患者中观察到，包括儿童和年轻人，中位年龄为15岁。他们表现出明显的头颈部病变，具有增殖率高的囊胚细胞学特征，缺乏BCL2蛋白和t(14;18)，发病时临床分期低，预后好。涉及Waldeyer环的儿童fl通过MUM1表达来区分，其中50%（3/6）携带IRF4断裂。在没有BCL2/ ight @易位的情况下，BCL2的表达是常见的（63%）。通常的fl在女性患者中更为常见，仅在年轻人（中位年龄为24岁）中，18岁以下患者无病例报告。1 ~ 2级25例，3A级4例。他们在发病时表现出较高的临床阶段。83%的人表达BCL2。我们的研究结果表明，组织学和免疫表型标准可以可靠地将小儿型滤泡性淋巴瘤与成人型滤泡性淋巴瘤区分开来，并且在儿童年龄组中，普通滤泡性淋巴瘤非常罕见。此外，淋巴结肿瘤与表现部位有生物学相关性，淋巴结肿瘤不同于表现于睾丸或瓦尔德耶氏环的肿瘤。我们的研究还表明，许多患者可以保守治疗，可能不需要化疗。（1,2）在2013年发表的另一项研究中，我们对是否存在t细胞形式的经典霍奇金淋巴瘤（CHL）的争论提供了新的见解。经典霍奇金淋巴瘤（cHL）的HRS细胞很少表达t细胞相关抗原，但这一发现的临床意义尚不确定，也不清楚这些t细胞抗原阳性的肿瘤是否真的是t细胞衍生的。在两个队列（National Cancer Institute, n = 38; Basel, n = 12）中鉴定了50例在HRS细胞上表达任何t细胞相关抗原的chl。在所有病例中检查诊断病理学数据，并在一部分病例中使用额外的t细胞受体γ重排（TRG@）聚合酶链反应（PCR）。结果数据与t细胞相关抗原阴性chl队列（n = 272）进行比较。检查的主要终点是无事件生存期（EFS）和总生存期（OS）。t细胞抗原阳性组的中位年龄为40岁（范围10-85岁）。70%的病例表现为低阶段（I/II期），结节性硬化症（NS）组织学占80%。在表达的抗原中，CD4和CD2最为常见，分别占80.4%和77.4%。31例中29例克隆重排阴性。几乎所有病例均表达b细胞相关转录因子PAX5。因此，在b细胞源性肿瘤中所见的t细胞抗原表达异常。在中位随访113个月期间，t细胞抗原表达预测更短的OS(校正风险比[HRadj] = 3.32[95%可信区间（CI）： 1.61, 6.84]；P = .001)和EFS （HRadj = 2.55 [95% CI: 1.45, 4.49]; P = .001）。与缺乏t细胞抗原的霍奇金淋巴瘤相比，携带t细胞抗原的CHL患者通常表现为NS组织学，缺乏t细胞基因型，并且与明显较短的OS和EFS独立相关。(3)我们还对t滤泡辅助细胞（TFH）起源的外周t细胞淋巴瘤提供了新的见解。外周t细胞淋巴瘤（PTCLs）在功能和形态上都很复杂。Epstein-Barr病毒（EBV）阳性的B细胞在血管免疫母细胞淋巴瘤（AITL）和其他ptcl中有报道，并且可能模拟霍奇金/里德-斯滕伯格（HRS）细胞，但EBV阴性的HRS样B细胞尚未被描述。我们希望评估与hrs样细胞相关的PTCL的性质，并确定是否可以看到ebv阴性的hrs样细胞。我们发现57例PTCL病例报告含有hrs样细胞。其中包括32例AITL， 19例PTCL，无其他特异性（NOS）， 3例PTCL-NOS，滤泡变异，1例PTCL-NOS， t区变异，2例成人t细胞白血病/淋巴瘤。所有患者均为成人，中位年龄63岁，表现为淋巴结病。男女比例为31:26（1.2:1）。克隆性TRG重排46/53例。38例中有6例伴有克隆性免疫球蛋白基因重排。52/57例HRS细胞EBV阳性。5例患者，3例为AITL， 2例为PTCL-NOS，滤泡型变异，含有EBV阴性的rs样细胞。所有具有ebv阴性HRS细胞的PTCLs均具有T滤泡辅助细胞免疫表型。肿瘤T细胞表达CD3、CD4和PD-1，并在hrs样细胞周围形成莲座。hrs样细胞CD20（可变强度）、PAX5、CD30、CD15阳性（4/5）。我们得出结论，ebv阳性和ebv阴性的hr样B细胞都可能出现在PTCL的背景下；需谨慎避免误诊为经典霍奇金淋巴瘤。hrs样细胞和聚集的pd -1阳性T细胞之间的密切相互作用提示了这种现象可能的发病作用，并为TFH恶性肿瘤中发生的异常b细胞增殖提供了新的见解。（4,5）关键参考文献：刘强，刘春华，刘春华，等。滤泡性淋巴瘤在儿童和年轻人：儿童变异与正常滤泡性淋巴瘤的比较。美国外科病理学杂志。2013; 37:333 - 343。2. Jaffe ES。滤泡性淋巴瘤：一幅由普通和对比线组成的挂毯。Haematologica。2013;98:1163 - 1165。3. 张建军，张建军，张建军，等。经典霍奇金淋巴瘤中异常t细胞抗原表达与无事件生存期和总生存期降低相关。血。2013;121:1795 - 1804。4. 张建军，张建军，张建军，等。与b细胞谱系的霍奇金/里德-斯滕伯格细胞衍生的滤泡t辅助细胞衍生的周围t细胞淋巴瘤：ebv阳性和ebv阴性变体均存在。美国外科病理学杂志。2013; 37:816 - 826。5. Huppmann AR, Roullet MR, Raffeld M，等。血管免疫母细胞t细胞淋巴瘤部分被eb病毒阴性克隆浆细胞增殖掩盖。中华临床医学杂志，2013;31(1):28-30。

We have continued our work on lymphomas in the pediatric age group, and their often distinctive features. Follicular lymphoma (FL), a common lymphoma in adults, occurs rarely in pediatric and young adult patients. The criteria to distinguish the pediatric variant of FL from usual FL seen in adults are not well defined. We undertook a study of FL in patients under the age of 30. We identified 63 cases, which were analyzed by morphology, immunohistochemistry, and polymerase chain reaction analysis of IGH@ and IGK@ clonality. These data were correlated with clinical findings including stage, treatment, and outcome. Among the 63 cases, 34 cases were classified as the pediatric variant of FL, 22 presenting in lymph nodes, 8 in the Waldeyer ring, and 4 in the testis. Clonal immunoglobulin gene rearrangement was detected in 97% of PFL cases, but fluorescence in situ hybridization analysis showed an absence of the BCL2/IGH@ translocation in all cases tested. Twenty-nine cases were classified as usual FL, 28 of which presented in lymph nodes. The nodal pediatric tumors were observed exclusively in male patients in both children and young adults with a median age of 15 years. They showed marked head/neck predilection, blastoid cytologic features with a high proliferation rate, lack of BCL2 protein and t(14;18), low clinical stage at presentation, and good prognosis. Pediatric FLs involving the Waldeyer ring were distinguished by MUM1 expression, 50% (3/6) of which carried IRF4 breaks. BCL2 expression was common (63%) in the absence of BCL2/IGH@ translocation. Usual FLs were more common in female patients, exclusively in young adults (median age, 24 y), with no cases reported in patients under the age of 18. Twenty-five of 29 cases were of grade 1-2, and 4 cases were classified as grade 3A. They exhibited a higher clinical stage at presentation. Eighty-three percent expressed BCL2. Our results showed that histologic and immunophenotypic criteria can reliably separate the pediatric variant of FL the usual adult form, and that usual FL is exceptionally rare in the pediatric age group. Additionally, there are biological correlates with the site of presentation, and nodal tumors differ from those presenting in testis or Waldeyer's ring. Our studies also showed that many of these patients can be managed conservatively, and may not require chemotherapy.(1, 2) In an separate study published in 2013, we provided new insight into an ongoing debate as to whether there is a T-cell form of classical Hodgkin lymphoma (CHL). Hodgkin/Reed-Sternberg (HRS) cells of classical Hodgkin lymphoma (cHL) rarely express T-cell-associated antigens, but the clinical significance of this finding is uncertain, and has not been clear whether these tumors positive for T-cell antigens were truly of T-cell derivation. Fifty cHLs expressing any T-cell associated antigen on the HRS cells were identified in two cohorts (National Cancer Institute, n = 38; Basel, n = 12). Diagnostic pathology data were examined in all cases with additional T-cell receptor gamma rearrangements (TRG@) polymerase chain reaction (PCR) in a subset of cases. The outcome data were compared with a cohort of cHLs negative for T-cell associated antigens (n = 272). Primary end points examined were event-free survival (EFS) and overall survival (OS). The median age in the T-cell antigen positive group was 40 years (range, 10-85 years). Seventy percent presented in low stage (stage I/II) at presentation with nodular sclerosis (NS) histology predominating in 80% of cases. Among the antigens expressed, CD4 and CD2 were most commonly, seen in 80.4% and 77.4% of cases, respectively. TRG@ PCR was negative for clonal rearrangements in 29 of 31 cases. Nearly all cases expressed the B-cell associated transcription factor PAX5. Thus, the T-cell antigen expression seen is an aberrancy in a neoplasm of B-cell origin. During a median follow up of 113 months, T-cell antigen expression predicted shorter OS (adjusted hazard ratio [HRadj] = 3.32 [95% confidence interval (CI): 1.61, 6.84]; P = .001) and EFS (HRadj = 2.55 [95% CI: 1.45, 4.49]; P = .001). Cases of CHL with T-cell antigens often display NS histology, lack T-cell genotype, and are independently associated with significantly shorter OS and EFS compared with cases of Hodgkin lymphoma lacking T-cell antigens.(3) We also provided new insights into peripheral T-cell lymphomas of T-follicular helper cell (TFH) origin. Peripheral T-cell lymphomas (PTCLs) are functionally and morphologically complex. Epstein-Barr virus (EBV)-positive B cells have been reported in angioimmunoblastic T-cell lymphoma (AITL) and other PTCLs and may mimic Hodgkin/Reed-Sternberg (HRS) cells, but EBV-negative HRS-like B cells have not been described. We wished to assess the nature of the PTCL associated with HRS-like cells and to determine whether EBV-negative HRS-like cells may be seen. We identified 57 PTCL cases reported as containing HRS-like cells. These included 32 AITL, 19 PTCL, not otherwise specified (NOS), 3 PTCL-NOS, follicular variant, 1 PTCL-NOS, T-zone variant, and 2 adult T-cell leukemia/lymphoma cases. All patients were adults with a median age of 63 and presented with lymphadenopathy. The male:female ratio was 31:26 (1.2:1). Clonal TRG rearrangement was detected in 46/53 cases. Six of 38 cases had a concomitant clonal immunoglobulin gene rearrangement. In 52/57 cases the HRS cells were positive for EBV. Five cases, 3 classified as AITL and 2 as PTCL-NOS, follicular variant, contained HRS-like cells negative for EBV. All PTCLs with EBV-negative HRS cells had a T follicular helper cell immunophenotype. The neoplastic T cells expressed CD3, CD4, and PD-1 and formed rosettes around the HRS-like cells. The HRS-like cells were positive for CD20 (variable intensity), PAX5, CD30, and CD15 (4/5). We conclude that both EBV-positive and EBV-negative HRS-like B cells may occur in the background of PTCL; caution is needed to avoid misdiagnosis as classical Hodgkin lymphoma. The close interaction between the HRS-like cells and the rosetting PD-1-positive T cells suggests a possible pathogenetic role in this phenomenon and provides new insights into the abnormal B-cell proliferations that occur in the context of TFH malignancies.(4, 5) Key references: 1. Liu Q, Salaverria I, Pittaluga S, et al. Follicular lymphomas in children and young adults: a comparison of the pediatric variant with usual follicular lymphoma. The American journal of surgical pathology. 2013;37:333-343. 2. Jaffe ES. Follicular lymphomas: a tapestry of common and contrasting threads. Haematologica. 2013;98:1163-1165. 3. Venkataraman G, Song JY, Tzankov A, et al. Aberrant T-cell antigen expression in classical Hodgkin lymphoma is associated with decreased event-free survival and overall survival. Blood. 2013;121:1795-1804. 4. Nicolae A, Pittaluga S, Venkataraman G, et al. Peripheral T-cell Lymphomas of Follicular T-Helper Cell Derivation With Hodgkin/Reed-Sternberg Cells of B-cell Lineage: Both EBV-positive and EBV-negative Variants Exist. The American journal of surgical pathology. 2013;37:816-826. 5. Huppmann AR, Roullet MR, Raffeld M, et al. Angioimmunoblastic T-cell lymphoma partially obscured by an Epstein-Barr virus-negative clonal plasma cell proliferation. J Clin Oncol. 2013;31:e28-30.