Abstract：
Primary cutaneous peripheral T-cell lymphomas with a T-follicular helper phenotype (pcTFH-PTCL) are poorly characterized, and often compared to, but not corresponding with, mycosis fungoides (MF), Sézary syndrome, primary cutaneous CD4+ lymphoproliferative disorder, and skin manifestations of angioimmunoblastic T-cell lymphomas (AITL).
We describe the clinicopathological features of pcTFH-PTCL in this original series of 23 patients, and also characterize these cases molecularly.
Clinical and histopathological data of the selected patients were reviewed. Patient biopsy samples were also analysed by targeted next-generation sequencing.
All patients (15 men, eight women; median age 66 years) presented with skin lesions, without systemic disease. Most were stage T3b, with nodular (n = 16), papular (n = 6) or plaque (atypical for MF, n = 1) lesions. Three (13%) developed systemic disease and died of lymphoma. Nine (39%) patients received more than one line of chemotherapy. Histologically, the lymphomas were CD4+ T-cell proliferations, usually dense and located in the deep dermis (n = 14, 61%), with the expression of at least two TFH markers (CD10, CXCL13, PD1, ICOS, BCL6), including three markers in 16 cases (70%). They were associated with a variable proportion of B cells. Eight patients were diagnosed with an associated B-cell lymphoproliferative disorder (LPD) on biopsy, including Epstein-Barr virus (EBV)-positive diffuse large B-cell lymphoma (n = 3), EBV+ LPD (n = 1) and monotypic plasma cell LPD (n = 4). Targeted sequencing showed four patients to have a mutated TET2-RHOAG17V association (as frequently seen in AITL) and another a TET2/DNMT3A/PLCG1/SETD2 mutational profile. The latter patient, one with a TET2-RHOA association, and one with no detected mutations, developed systemic disease and died. Five other patients showed isolated mutations in TET2 (n = 1), PLCG1 (n = 2), SETD2 (n = 1) or STAT5B (n = 1).
Patients with pcTFH-PTCL have pathological and genetic features that overlap with those of systemic lymphoma of TFH derivation. Clinically, most remained confined to the skin, with only three patients showing systemic spread and death. Whether pcTFH-PTCL should be integrated as a new subgroup of TFH lymphomas in future classifications is still a matter of debate. What is already known about this topic? There is a group of cutaneous lymphomas that express T-follicular helper (TFH) markers that do not appear to correspond to existing World Health Organization diagnostic entities. These include mycosis fungoides, Sézary syndrome, or primary cutaneous CD4+ small/medium-sized T-cell lymphoproliferative disorder or cutaneous extensions of systemic peripheral T-cell lymphomas (PTCL) with TFH phenotype. What does this study add? This is the first large original series of patients with a diagnosis of primary cutaneous PTCL with a TFH phenotype (pcTFH-PTCL) to be molecularly characterized. pcTFH-PTCL may be a standalone group of cutaneous lymphomas with clinicopathological and molecular characteristics that overlap with those of systemic TFH lymphomas, such as angioimmunoblastic T-cell lymphoma, and does not belong to known diagnostic groups of cutaneous lymphoma. This has an impact on the treatment and follow-up of patients; the clinical behaviour needs to be better clarified in further studies to tailor patient management.
We describe the clinicopathological features of pcTFH-PTCL in this original series of 23 patients, and also characterize these cases molecularly.
Clinical and histopathological data of the selected patients were reviewed. Patient biopsy samples were also analysed by targeted next-generation sequencing.
All patients (15 men, eight women; median age 66 years) presented with skin lesions, without systemic disease. Most were stage T3b, with nodular (n = 16), papular (n = 6) or plaque (atypical for MF, n = 1) lesions. Three (13%) developed systemic disease and died of lymphoma. Nine (39%) patients received more than one line of chemotherapy. Histologically, the lymphomas were CD4+ T-cell proliferations, usually dense and located in the deep dermis (n = 14, 61%), with the expression of at least two TFH markers (CD10, CXCL13, PD1, ICOS, BCL6), including three markers in 16 cases (70%). They were associated with a variable proportion of B cells. Eight patients were diagnosed with an associated B-cell lymphoproliferative disorder (LPD) on biopsy, including Epstein-Barr virus (EBV)-positive diffuse large B-cell lymphoma (n = 3), EBV+ LPD (n = 1) and monotypic plasma cell LPD (n = 4). Targeted sequencing showed four patients to have a mutated TET2-RHOAG17V association (as frequently seen in AITL) and another a TET2/DNMT3A/PLCG1/SETD2 mutational profile. The latter patient, one with a TET2-RHOA association, and one with no detected mutations, developed systemic disease and died. Five other patients showed isolated mutations in TET2 (n = 1), PLCG1 (n = 2), SETD2 (n = 1) or STAT5B (n = 1).
Patients with pcTFH-PTCL have pathological and genetic features that overlap with those of systemic lymphoma of TFH derivation. Clinically, most remained confined to the skin, with only three patients showing systemic spread and death. Whether pcTFH-PTCL should be integrated as a new subgroup of TFH lymphomas in future classifications is still a matter of debate. What is already known about this topic? There is a group of cutaneous lymphomas that express T-follicular helper (TFH) markers that do not appear to correspond to existing World Health Organization diagnostic entities. These include mycosis fungoides, Sézary syndrome, or primary cutaneous CD4+ small/medium-sized T-cell lymphoproliferative disorder or cutaneous extensions of systemic peripheral T-cell lymphomas (PTCL) with TFH phenotype. What does this study add? This is the first large original series of patients with a diagnosis of primary cutaneous PTCL with a TFH phenotype (pcTFH-PTCL) to be molecularly characterized. pcTFH-PTCL may be a standalone group of cutaneous lymphomas with clinicopathological and molecular characteristics that overlap with those of systemic TFH lymphomas, such as angioimmunoblastic T-cell lymphoma, and does not belong to known diagnostic groups of cutaneous lymphoma. This has an impact on the treatment and follow-up of patients; the clinical behaviour needs to be better clarified in further studies to tailor patient management.
摘要：
具有T滤泡辅助表型的原发性皮肤外周T细胞淋巴瘤（pcTFH-PTCL）的特征不明确，经常与之比较，但不符合，霉菌病（MF），Sézary综合征,原发性皮肤CD4+淋巴增殖性疾病，血管免疫母细胞性T细胞淋巴瘤（AITL）的皮肤表现。
我们描述了pcTFH-PTCL在23例患者中的临床病理特征，并在分子上表征这些病例。
对所选患者的临床和组织病理学数据进行了回顾。还通过靶向下一代测序分析患者活检样品。
所有患者（15名男性，八名妇女；中位年龄66岁）出现皮肤病变，没有全身性疾病。大多数是T3b阶段，结节（n=16），丘疹（n=6）或斑块（不典型的MF，n=1)病变。3人（13％）发展为全身性疾病并死于淋巴瘤。9例（39%）患者接受了一种以上的化疗。组织学上,淋巴瘤是CD4+T细胞增殖，通常致密，位于真皮深处（n=14，61%），具有至少两种TFH标志物(CD10，CXCL13，PD1，ICOS，BCL6),16例(70%)中包括三个标志物。它们与可变比例的B细胞相关。8例患者在活检时被诊断为相关的B细胞淋巴增生性疾病（LPD），包括EB病毒（EBV）阳性的弥漫性大B细胞淋巴瘤（n=3），EBV+LPD(n=1)和单型浆细胞LPD(n=4)。靶向测序显示四名患者具有突变的TET2-RHOAG17V关联（如在AITL中常见）和另一个TET2/DNMT3A/PLCG1/SETD2突变谱。后者的病人,一个有TET2-RHOA协会的，一个没有检测到突变的，发展为全身性疾病并死亡。另外五名患者在TET2（n=1）中显示出孤立的突变，PLCG1（n=2），SETD2(n=1)或STAT5B(n=1)。
pcTFH-PTCL患者具有与TFH衍生的系统性淋巴瘤重叠的病理和遗传特征。临床上,大多数仍然局限于皮肤，只有三名患者表现出全身扩散和死亡。在未来的分类中，是否应将pcTFH-PTCL整合为TFH淋巴瘤的新亚组仍存在争议。关于这个主题已经知道什么？有一组表达T滤泡辅助（TFH）标记的皮肤淋巴瘤似乎与现有的世界卫生组织诊断实体不符。这些包括真菌肉芽肿,Sézary综合征,或原发性皮肤CD4+小/中型T细胞淋巴增殖性疾病或具有TFH表型的全身性外周T细胞淋巴瘤（PTCL）的皮肤扩张。这项研究增加了什么？这是第一个大型原始系列的患者，诊断为具有TFH表型的原发性皮肤PTCL（pcTFH-PTCL）进行分子表征。pcTFH-PTCL可能是一组独立的皮肤淋巴瘤，其临床病理和分子特征与系统性TFH淋巴瘤重叠，如血管免疫母细胞性T细胞淋巴瘤，并且不属于已知的皮肤淋巴瘤诊断组。这对患者的治疗和随访有影响；需要在进一步的研究中更好地阐明临床行为，以定制患者管理。
我们描述了pcTFH-PTCL在23例患者中的临床病理特征，并在分子上表征这些病例。
对所选患者的临床和组织病理学数据进行了回顾。还通过靶向下一代测序分析患者活检样品。
所有患者（15名男性，八名妇女；中位年龄66岁）出现皮肤病变，没有全身性疾病。大多数是T3b阶段，结节（n=16），丘疹（n=6）或斑块（不典型的MF，n=1)病变。3人（13％）发展为全身性疾病并死于淋巴瘤。9例（39%）患者接受了一种以上的化疗。组织学上,淋巴瘤是CD4+T细胞增殖，通常致密，位于真皮深处（n=14，61%），具有至少两种TFH标志物(CD10，CXCL13，PD1，ICOS，BCL6),16例(70%)中包括三个标志物。它们与可变比例的B细胞相关。8例患者在活检时被诊断为相关的B细胞淋巴增生性疾病（LPD），包括EB病毒（EBV）阳性的弥漫性大B细胞淋巴瘤（n=3），EBV+LPD(n=1)和单型浆细胞LPD(n=4)。靶向测序显示四名患者具有突变的TET2-RHOAG17V关联（如在AITL中常见）和另一个TET2/DNMT3A/PLCG1/SETD2突变谱。后者的病人,一个有TET2-RHOA协会的，一个没有检测到突变的，发展为全身性疾病并死亡。另外五名患者在TET2（n=1）中显示出孤立的突变，PLCG1（n=2），SETD2(n=1)或STAT5B(n=1)。
pcTFH-PTCL患者具有与TFH衍生的系统性淋巴瘤重叠的病理和遗传特征。临床上,大多数仍然局限于皮肤，只有三名患者表现出全身扩散和死亡。在未来的分类中，是否应将pcTFH-PTCL整合为TFH淋巴瘤的新亚组仍存在争议。关于这个主题已经知道什么？有一组表达T滤泡辅助（TFH）标记的皮肤淋巴瘤似乎与现有的世界卫生组织诊断实体不符。这些包括真菌肉芽肿,Sézary综合征,或原发性皮肤CD4+小/中型T细胞淋巴增殖性疾病或具有TFH表型的全身性外周T细胞淋巴瘤（PTCL）的皮肤扩张。这项研究增加了什么？这是第一个大型原始系列的患者，诊断为具有TFH表型的原发性皮肤PTCL（pcTFH-PTCL）进行分子表征。pcTFH-PTCL可能是一组独立的皮肤淋巴瘤，其临床病理和分子特征与系统性TFH淋巴瘤重叠，如血管免疫母细胞性T细胞淋巴瘤，并且不属于已知的皮肤淋巴瘤诊断组。这对患者的治疗和随访有影响；需要在进一步的研究中更好地阐明临床行为，以定制患者管理。
