伯基特淋巴瘤

伯基特氏淋巴瘤、伯基特淋巴瘤（Burkitt lymphoma）是淋巴系统生长中心的B淋巴球癌症，是一种非常迅速的非霍奇金淋巴瘤。以爱尔兰外科医生丹尼斯·帕森斯·伯基特命名，他于1958年赤道非洲首次描述了这疾病。发达国家伯基特淋巴瘤的总体治愈率约为90%。不常见于成人，但见于成人情况预后更糟。

## 分类

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可分为三种主要的临床变异：地方性、散发性、免疫缺陷相关变异。在形态学微观外观、免疫表型、遗传学，伯基特淋巴瘤的变种是相似的。

- “地方性变种”（也称为“非洲变种”）最常见于生活在世界疟疾流行地区（例如，赤道非洲、巴西、巴布亚新几内亚）人类疱疹病毒第四型（EBV）感染几乎在所有患者中发现。慢性疟疾被认为会降低对EBV的抵抗力。该疾病的特点是涉及下颌或其他面部骨骼、回肠、盲肠、卵巢、肾脏、乳房。
- “散发性变种”（也称为“非非洲变种”）是在疟疾不流行的地方（例如北美、欧洲）发现的最常见的变种。肿瘤细胞具有与经典地方性伯基特淋巴瘤的癌细胞相似的外观。散发性淋巴瘤很少与EBV相关。颌骨较少参与这种变体。腹部区域是常见的受累部位。
- 免疫缺陷相关，通常与HIV感染有关，但也可能发生在移植后患者的环境中。

伯基特淋巴瘤通常与人类疱疹病毒第四型（EBV）感染B淋巴球有关，在这些情况下被认为是人类疱疹病毒第四型病毒相关的淋巴组织增生性疾病。

伯基特淋巴瘤的地方性变异几乎在所有病例中都与EBV感染有关。一些伯基特淋巴瘤病例不涉及EBV的事实允许许多疾病病例不是由 EBV 引起和/或促进的，即在这些病例中病毒可能是无辜的乘客病毒。然而，该病毒在伯基特淋巴瘤的地方性变体中几乎无处不在，这表明它有助于该变体的发展和或进展。最近发现伯基特淋巴瘤的突变在有没有EBV感染肿瘤间存在差异，这进一步加强了病毒在疾病起源中的作用。

## 病理生理学

### 遗传学

All types of Burkitt lymphoma are characterized by dysregulation of the c-myc gene by one of three chromosomal translocations. This gene is found at 8q24.

- The most common variant is t(8;14)(q24;q32), which accounts for about 85% of cases. This involves c-myc and IGH@. A variant of this, a three-way translocation, t(8;14;18), has also been identified.
- A rare variant is at t(2;8)(p12;q24). This involves IGK@ and c-myc.
- Another rare variant is t(8;22)(q24;q11). This involves IGL@ and c-myc.

Combined, the two less-common translocations, t(2;8)(p12;q24) and t(8;22)(q24;q11), account for the remaining 15% of cases not due to the t(8;14)(q24;q32) translocation.

The c-myc gene found on chromosome 8 is part of the Myc family of genes that serve as regulators of cellular transcription and is associated with Burkitt lymphoma. Expression of the c-myc gene results in the synthesis of transcriptional factors that increase the expression of other genes involved in aerobic glycolysis. Ultimately, an increase in aerobic glycolysis plays a role in providing the necessary energy for cellular growth to occur. The translocation of the c-myc gene to the IGH, IGK, or IGL region moves the gene to a location in the genome near immunoglobulin enhancers which increases the expression of the c-myc gene. Overall, this translocation leads to increased cellular proliferation that is found in Burkitt lymphoma. Point mutations can also be present in the translocated c-myc gene resulting in the expressed c-myc protein being overactive. Other mutations found include the TCF transcription factor mutation, which increases cellular proliferation via the increased expression of other genes. Along with mutations that support cell proliferation, Burkitt lymphoma has been found to also harbor mutations in the TP53 gene that is a tumor suppressor and would normally function to limit cellular growth.

### 病毒学

The complete role of EBV in the pathogenesis of endemic Burkitt lymphoma is not completely elucidated, but it has been shown to cause DNA damage, dysfunction of telomeres, and genome instability. B cell infection with EBV is latent, and the virus does not undergo replication. These latently infected B cells can then go on to produce proteins that function to promote cellular growth through modification of normal signaling pathways. EBV promotes the development of malignant B cells via proteins that limit apoptosis in cells that had the c-myc translocation. Apoptosis is limited by EBV through various means such as the EBNA-1 protein, BHF1 protein, EBER transcripts, vIL-10 gene, BZLF1, and LMP1. Malaria has been found to cause genomic instability in endemic Burkitt lymphoma. Malaria can lead to the reactivation of latent EBV and also MYC translocations via activation of the toll-like receptor 9. Malaria also promotes B-cell proliferation by altering the regular immune response. The immune system targets antigens (e.g., EBNA2 and LMP-1) and eliminates most B cells infected with EBV. Downregulation of antigens targeted by the immune system leads to the development of persistent B cells. These B cells can then undergo further mutations (e.g., c-myc translocation) that promote cancer development.

### 免疫学

伯基特淋巴瘤细胞正常表达HLA I类分子，以及一些HLA II类复合物；然而，CD4+ T 细胞没有被正确激活。伯基特淋巴瘤细胞仅表达EBNA1，一种抗原性较差的EBV相关抗原，能够逃避HLA I类呈递，从而逃避免疫反应。EBNA 1可通过HLA II类分子呈递，但HLA II类途径无法激活CD4+T细胞。

## 诊断

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### 恶性B淋巴球特征

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### 显微镜特征

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肿瘤由单调（即大小和形态相似）的中等大小的淋巴细胞群组成，具有高增殖和凋亡活性。

### 免疫组织化学特征

肿瘤细胞通常强烈表达B淋巴球分化标志物（CD20、CD22、CD19）以及CD10和BCL6。肿瘤细胞通常对BCL2和TdT呈阴性。近100%染色阳性细胞Ki67证实了伯基特淋巴瘤有高有丝分裂活性。

## 治疗

一般来说，伯基特淋巴瘤的一线治疗是化疗。其中一些方案是：GMALL-B-ALL/NHL2002方案、改良Magrath方案 (R-CODOX-M/IVAC)。COPADM, hyper-CVAD,以及癌症和白血病B组 (CALGB) 8811 方案；这些可能与利妥昔单抗有关。在老年患者中，可以使用利妥昔单抗调整剂量EPOCH (化疗)。

化疗

- 环磷酰胺
- 阿霉素
- 长春新碱
- 甲氨蝶呤
- 阿糖胞苷
- 异环磷酰胺
- 依托泊苷
- 利妥昔单抗

其他治疗方法包括免疫疗法、骨髓移植、干细胞移植、手术去除肿瘤、放射疗法。

## 预后

伯基特淋巴瘤预后在儿童中较好，年龄增加则反之。

发达国家散发性伯基特淋巴瘤的总体治愈率约为90%。在成人中，伯基特淋巴瘤并不常见且预后不佳。

用环磷酰胺、长春新碱、泼尼松龙治疗伯基特淋巴瘤初始反应不令人满意表明预后不良。

```
Furthermore, failed initial treatment and return of Burkitt lymphoma after a six-month stint of time serve as a poor prognostic indicator.<ref name=":0" /> The adequate utilization of therapeutic drugs during initial treatment limits additional treatment options following the return of the disease.<ref name=":0" /> Notably, in areas of the world where the initial treatment of Burkitt lymphoma is inadequate further treatment options may remain for cases when the disease returns.<ref name=":0" /> Laboratory studies such as [[lactate dehydrogenase]] (LDH), CD4 count, and other cytogenetic studies are also prognostic indicators.<ref name=":0" /> Unsatisfactory outcomes have been associated with an LDH that is found to be two times above the upper limit of normal.<ref name=":0" /> Specifically, there is a poor prognosis associated with a CD4 count that is decreased in the immunodeficiency-associated variant of Burkitt lymphoma.<ref name=":0" /> Genetic mutations extending beyond the previously described MYC translocation may also serve as negative prognostic indicators.<ref name=":0" /> Some notable genetic findings that may be associated with poor outcomes include: 13q deletion, 7q gain, ID3 and CCND3 double-hit mutations, and 18q21 CN-LOH mutations.<ref name=":0" /> The prognosis for Burkitt lymphoma can be better determined following staging utilizing imaging modalities such as [[positron emission tomography]] and [[CT scan|computed tomography]] scans where tumor burden and invasion of the central nervous system have been found to indicate a poor prognosis.<ref name=":2" /><ref name=":0" />
```

## 流行病学

As a non-Hodgkin lymphoma (NHL), Burkitt lymphoma makes up 1-5% of cases, and it is more common in males than females with a 3–4 to 1 ratio. The endemic variant mainly impacts areas with an increased prevalence of malaria and EBV in Africa and Papua New Guinea. For children less than 18 years of age from equatorial Africa, the annual incidence of Burkitt lymphoma is 4–5/100,000. Additionally, in equatorial Africa, 50% of tumors that are diagnosed during childhood as well as 90% of lymphoma cases can be attributed to Burkitt lymphoma. The peak incidence for endemic Burkitt lymphoma is from ages 4 to 7 with an average age of 6 years. The sporadic variant with an annual incidence 2-3/million is more commonly found in North America and Europe comprising 1-2% of adult lymphomas and 30–40% of NHL cases. This variant is 3.5 times more commonly found in males compared to females and it is more frequent in younger individuals. The sporadic variant has a peak incidence at 11 years of age in children, and diagnosis typically occurs from 3–12 years of age on average. For adults, 45 years was the median age that the sporadic Burkitt lymphoma was diagnosed. The immunodeficiency-associated variant predominantly impacts the HIV-infected population. For those in the United States and with AIDS, the incidence of this variant was found to be 22/100,000 person-years. There is also an increased risk of developing this variant of Burkitt lymphoma for individuals that have received an organ transplant after 4–5 years.

人类疱疹病毒第四型感染与伯基特淋巴瘤有关。几乎所有地方性伯基特淋巴瘤病例中都发现了人类疱疹病毒第四型（EBV）。而伯基特淋巴瘤的散发性变异仅在10-20%病例中与EBV相关。

## 研究

### 基因目标

独特的基因改变促进了伯基特淋巴瘤的细胞存活，这与其他类型的淋巴瘤不同。TCF3 and ID3 (基因)基因突变对应于可能被发现适靶向治疗的细胞存活途径。