EBV相关淋巴组织增生性疾病的分类进展（2）

（2）急性传染性单核细胞增多症
定义和临床特征：
This infectious disorder is characterized by sore throat, fever, markedly enlarged tonsils, and lymphadenopathy, particularly cervical lymph nodes.	这种感染性疾病的特点是咽喉痛、发烧、扁桃体明显肿大、淋巴结肿大，特别是颈部淋巴结。
Most initial infections occur asymptomatically in children less than 5 years of age but symptomatic infectious mononucleosis occurs in all age groups except childhood.	大多数发生5岁以下儿童的初始感染无症状，但有症状的传染性单核细胞增多症在除儿童外的所有年龄组中都发生。
The disorder is usually suspected clinically and lymphocytosis with 10% to 20% atypical lymphocytes is usually noted on examination of the peripheral blood smear. The diagnosis is confirmed serologically by the Monospot test or by the more specific EBV antibody titer studies. In addition to the peripheral blood findings, the bone marrow is often involved, although not frequently sampled.	当外周血涂片检查常发现10%至20%不典型淋巴细胞的淋巴细胞增多时临床常怀疑为该病。诊断通过血清学的单点试验或更特异的EBV抗体滴度研究得到证实。除了外周血象外，骨髓也常受累，尽管不常取样。
形态学特点：
An immunoblastic proliferation is the characteristic feature, accompanied by reactive follicular hyperplasia. Foci of monocytoid B-cell hyperplasia may be present or may precede the immunoblastic proliferation. Abundant plasma cells are usually seen and foci of necrosis may be present. Most of the proliferating immunoblasts are CD30 positive. The exuberant immunoblastic proliferation and architectural distortion seen in some cases can lead to misdiagnosis of infectious mononucleosis as a lymphoma,especially diffuse large B-cell lymphoma.	以免疫母细胞增生为特征，伴有反应性滤泡增生。单核细胞样B细胞增生灶可能存在或先于免疫母细胞增殖。通常可见大量浆细胞，并可出现坏死灶。大多数增生的免疫母细胞呈CD30阳性。在某些病例中，免疫母细胞的大量增生和结构的扭曲可导致传染性单核细胞增多症误诊为淋巴瘤，尤其是弥漫大B细胞淋巴瘤（DLBCL）。
Hodgkin lymphoma is often included in the differential diagnosis because Reed-Sternberg–like cells are often seen in infectious mononucleosis; however, most of the large, EBV-infected cells resemble immunoblasts rather than Reed-Sternberg cells and variants.	霍奇金淋巴瘤常被列入鉴别诊断，因为传染性单核细胞增多症常可见Reed-Sternberg样细胞；然而，大多数感染EBV的大细胞类似于免疫母细胞，而不是里R-S及变异细胞。
The localization of the lesion to the tonsils or cervical lymph nodes in a young patient, the heterogeneity of the cellular infiltrate, and the presence of few residual hyperplastic germinal centers and distended sinuses are factors that support a diagnosis of infectious mononucleosis, but the main distinction can be achieved by in situ hybridization.	年轻患者出现扁桃体或颈部淋巴结的病变，细胞浸润的异质性，以及少量残存的增生的生发中心和扩张淋巴窦的存在是支持传染性单核细胞增多症诊断的要素，但主要的区别可以通过原位杂交来实现。
FIG.1 Infectious mononucleosis, There are small foci in which numerous large cells are present outside of follicles. 图1：传染性单核细胞增生症中在滤泡外可见较多小灶状大细胞；
发病机制（Pathogenesis）：
The lytic cycle of EBV infection and the profound cellular immune response leads to destruction of virus-infected cells and the eventual release of inflammatory cytokines, which are the main cause of symptoms.	EBV感染的溶解期和巨大的细胞免疫反应导致病毒感染细胞的破坏，最终释放炎症细胞因子，这是引起症状的主要原因。
临床病程与预后：
This condition is self-limiting in immunocompetent patients, although persistence into chronic active EBV disease can occur and progression to fatal sporadic infectious mononucleosis may occur, which is now classified under the systemic EBV positive T-cell lymphoma of childhood category in the 2016 World Health Organization (WHO) classification.	在免疫能力强的患者中这是自限性疾病，尽管可能会持续发生慢性活动性EBV疾病，并可能发展为致命的散发性传染性单核细胞增多症，该病现在被归入2016年世界卫生组织（WHO）分类中的儿童系统性EBV阳性T细胞淋巴瘤。
EBV原位杂交染色模式（EBER）：
This expression pattern is characteristic of EBV, with many EBV-positive small and large cells present, mainly in the paracortical area, but scattered cells are usually present in the germinal centers and the monocytoid B-cell areas. Many negative cells are also present. This pattern contrasts with EBV positive lymphomas, which usually have a much higher proportion and uniformity of EBV positive cells, mainly large. Most of the EBV positive cells represent B cells with a low proportion of the cells (<10%) representing T and NK cells.	这一表达模式是EBV的特征：存在较多EBV阳性的小和大细胞，主要分布于副皮质区，但也有散在分布于生发中心和单核B细胞区。许多阴性细胞也存在。这种模式与EBV阳性淋巴瘤相比，EBV阳性淋巴瘤中EBV阳性细胞的比例和均匀性要高得多，且以大细胞为主。EBV阳性细胞多为B细胞，T细胞和NK细胞所占比例较低（<10%）。

（3）EBV阳性噬血细胞淋巴组织细胞增多症 EBV–Positive Hemophagocytic Lymphohistiocytosis
定义和临床特征：
In the absence of primary genetic aberrations, EBV-positive hemophagocytic lymphohistiocytosis (HLH) usually occurs in young children, mainly Asian, with a median age of 4 years.	在没有原发性遗传异常的情况下，EBV阳性的噬血细胞淋巴组织细胞增多症（HLH）好发于亚洲儿童，中位年龄4岁。
These patients usually have a high EBV viral load in the blood. The diagnosis of HLH can be established on a molecular basis or by the presence of 5 of the 8 clinical criteria: fever, splenomegaly, cytopenias affecting at least 2 lineages, hypertriglyceridemia or hypofibrinogenemia, morphologic evidence of hemophagocytosis, low or absent NK-cell activity, increased ferritin level, and increased soluble CD25 level.	这些患者血液中的EBV病毒载量通常很高。HLH的诊断可建立在分子基础上，或通过8个临床标准中的5个来确定：发热、脾肿大、至少影响2个谱系的血细胞减少、高甘油三酯或低纤维蛋白原血症、嗜血细胞的形态学证据、NK细胞活性低或缺失、铁蛋白升高和可溶性CD25水平升高。
形态学特点：
The affected organs show an infiltration of benign appearing histiocytes with hemophagocytosis, predominantly of red blood cells and neutrophils.	受影响的器官呈嗜血细胞的良性组织细胞浸润，主要是红细胞和中性粒细胞。
T-cell receptor gene clonality may be detected in EBV-positive HLH but it does not necessarily indicate an underlying T-cell lymphoma.	在EBV阳性HLH中可检测到T细胞受体基因的克隆性，但并不一定提示潜在的T细胞淋巴瘤。
Figure. Lymph node from a patient with hemophagocytic lymphohistiocytosis. The distended sinus contains histiocytes engorged with phagocytized red blood cells. 图 噬血细胞淋巴组织细胞增多症患者的淋巴结：扩张的窦可见吞噬红细胞的组织细胞。
发病机制（Pathogenesis）：
This condition represents an exaggerated immune response secondary to acute EBV infection in most cases. EBV can infect B cells but mainly infects T and NK cells in this disorder, and infection of CD81 T cells results in a cytokine storm with increased levels of tumor necrosis factor and interferon leading to secondary and systemic activation of histiocytes and macrophages.	在大多数病例中，这种情况代表了继发于急性EBV感染的过度免疫反应。EBV可感染B细胞，但主要感染T细胞和NK细胞，CD81 T 细胞的感染导致细胞因子风暴，肿瘤坏死因子和干扰素水平升高，导致组织细胞和巨噬细胞的继发性和系统性激活。
临床病程与预后：
The HLH 2004 treatment is effective in most cases, with remissions achieved in many cases.	HLH 2004治疗大多数病例是有效的，许多病例可以达到缓解。
EBV原位杂交染色模式（EBER）：
EBV is detected mainly in T cells, usually in an interstitial pattern with scattered positive bystander B cells. The EBV-positive cells are mainly small and lack any atypical features.	EBV阳性细胞主要为T细胞，通常为间质型，周围B细胞呈散在阳性。EBV阳性细胞以小细胞为主，缺乏任何非典型特征。

REACTIVE PROLIFERATIONS WITH VARIED MALIGNANT POTENTIAL	不同恶性潜能的反应性增生
（1）慢性活动性EBV疾病
定义和临床特征：
This condition is a rare systemic entity related to persistent EBV infection (>3 months) that is usually preceded by an acute EBV infection in patients without known immunodeficiency.	这种疾病是一种少见的持续性EBV感染（大于3个月）相关的全身性疾病，通常在无已知免疫缺陷患者中出现急性EBV感染。
Patients usually show markedly increased EBV DNA levels or antibodies to EBV in the peripheral blood; show EBV-positive cells in tissues; and clinically present with fever, lymphadenopathy, and hepatosplenomegaly.	患者外周血中EBV-DNA水平或EBV抗体明显升高；组织中出现EBV阳性细胞；临床表现为发热、淋巴结肿大和肝脾肿大。
Occurrence of hemophagocytic syndrome as a secondary finding may occur in some patients and progressive loss of B cells leading to hypogammaglobulinemia can occur in a subset of the patients.	噬血细胞综合征的发生可能是某些患者继发表现，B细胞的进行性丢失可导致部分患者出现低丙种球蛋白血症。
Although EBV usually resides in B cells in healthy individuals, most chronic active EBV (CAEBV) cases (mainly from Japan and other Asian countries, as well as in Native Americans) have EBV detected in T and NK cells (T/NK-cell type) but cases with EBV detected in B cells (B-cell type) are more common in the United States and occur rarely in Japan.	虽然EBV常存在于健康人的B细胞中，但大多数慢性活动性EBV病例（主要来自日本和亚洲其他国家，以及美洲土著居民）的阳性细胞为T/NK细胞，但是在B细胞中检测到EBV的病例在美国更为常见，在日本很少发生。
形态学特点：
For CAEBV of T/NK-cell type, a T/NK-cell infiltrate (more commonly T cells) is noted, which is usually sinusoidal in the liver and spleen, sinusoidal/interstitial in the bone marrow, and interstitial/diffuse in the paracortical areas of the lymph nodes.	对于T/NK细胞型的CAEBV，T/NK细胞浸润（更常见的是T细胞），通常在肝和脾窦，在骨髓呈窦/间质性，在淋巴结的副皮质区呈间质/弥漫性。
The architecture of the affected tissue is usually preserved and cytologic atypia is absent within the EBV-positive cells.	在EBV阳性细胞中，受感染组织的结构通常存在，并且没有细胞学上的异型性。
Hemophagocytosis is commonly seen and the expanded activated histiocytes alter the histologic picture in some cases.	在一些病例中，噬血细胞是常见的，增加的活化组织细胞改变了组织学图像。
For CAEBV of B-cell type, it morphologically shows a PTLD-like picture but with an increased number of proliferating immunoblasts, plasma cells, occasional Reed-Sternberg-like cells, and paracortical hyperplasia.	对于B细胞型CAEBV，其形态学表现为PTLD样改变，但出现免疫母细胞和浆细胞增多、偶尔出现的Reed-Sternberg样细胞和副皮质增生。
发病机制（Pathogenesis）：
This condition likely involves a cellular immune defect that failed to control the proliferation of EBV latently infected lymphocytes with expression of viral lytic proteins and the subsequent production of antibodies to these proteins.	这种疾病可能涉及一种细胞免疫缺陷，这种缺陷无法通过表达病毒裂解蛋白和随后产生的抗体来控制EBV潜伏感染的淋巴细胞的增生。
临床病程与预后：
CAEBV can be polyclonal, oligoclonal, or monoclonal, and clonality can be used as a prognostic factor and for subclassification purposes. Allogeneic stem cell transplant can be curative for CAEBV disease if considered early in the course of the disease. Some patients respond temporarily to immunomodulating agents, immunosuppressive therapy, or cytotoxic chemotherapy, but these treatments are not curative, and most patients succumb to their disease.	CAEBV可以是多克隆、寡克隆或单克隆，克隆性可以作为一个预后因素和亚分类的目的。同种异体干细胞移植可以治疗CAEBV疾病，如果考虑在疾病的早期。有些病人对免疫调节剂、免疫抑制疗法或细胞毒性化疗有暂时的反应，但这些方法没有疗效，大多数病人死于该疾病。
EBV原位杂交染色模式（EBER）：
For CAEBV of T/NK-cell type, EBV is uniformly expressed in many cytotoxic T cells in most cases. For CAEBV of B-cell type, the EBV expression pattern is similar to infectious mononucleosis, in which many small and large EBV-positive cells are identified with many EBV-negative cells present.	对于T/NK细胞型CAEBV，在多数病例，EBV一致地表达于多数细胞毒性T细胞。对于B细胞型CAEBV，EBV的表达模式与传染性单核细胞增多症相似，在传染性单核细胞增多症中，存在许多小和大的EBV阳性细胞和许多EBV阴性细胞。

参考文献:

[1] EBV-Associated Lymphoproliferative Disorders:Update in Classification.2019.