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Q1. Which one of the followings is WRONG regarding Hodgkin Lymphoma (HL)?

  • (A) HL is a tumor of the germinal center B cells.
  • (B) HL is characterized by the presence of Reed-Sternberg cells.
  • (C) EBV positivity is most frequent in lymphocyte-predominant HL.
  • (D) EBV is clonal in any given tumor in HL.
  • (E) EBV-positive and EBV-negative HL arise through different mechanisms.
點此顯示正解

(C) EBV positivity is most frequent in lymphocyte-predominant HL.

詳解

Analysis

The stem asks for the WRONG statement, and the correct answer is (C).

Why (C) is the WRONG statement:

EBV positivity is extremely rare in lymphocyte-predominant HL (nodular lymphocyte-predominant Hodgkin lymphoma, NLPHL), not most frequent. NLPHL is characteristically EBV-negative in the vast majority of cases. Studies show that only 2.5-4.5% of NLPHL cases are EBV-positive123, whereas 25-70% of classical Hodgkin lymphoma (cHL) cases are EBV-positive14. The statement in option C is therefore factually incorrect—it reverses the actual relationship between EBV and HL subtypes6.

Why the other options are TRUE:

(A) HL is a tumor of the germinal center B cells — TRUE. Both classical HL and NLPHL derive from germinal center B cells, as demonstrated by immunoglobulin gene hypermutation patterns and gene expression profiles7[^11]. In classical HL, the Hodgkin and Reed-Sternberg (HRS) cells originate from "pre-apoptotic germinal center B cells"7, while NLPHL tumor cells (lymphocyte-predominant cells) have "largely retained their typical GC B-cell expression program"7.

(B) HL is characterized by the presence of Reed-Sternberg cells — TRUE. Reed-Sternberg cells are the pathognomonic neoplastic cells of classical Hodgkin lymphoma, first described by Dorothy Reed-Mendenhall and Carl Sternberg in the early 1900s4. These bi- or multinucleated cells are generated by incomplete cytokinesis and refusion of mononuclear Hodgkin cells7.

(D) EBV is clonal in any given tumor in HL — TRUE. When EBV is present in Hodgkin lymphoma, it is monoclonal, meaning all tumor cells carry the same EBV genome, indicating that the virus was present in the original transformed cell before clonal expansion[9][11]. This clonality supports EBV's role in early lymphomagenesis rather than as a secondary passenger infection.

(E) EBV-positive and EBV-negative HL arise through different mechanisms — TRUE. Genome-wide association studies provide strong evidence that EBV status represents distinct etiologic pathways in classical HL4. In EBV-positive cases, viral oncoproteins (particularly LMP-1 and LMP-2) rescue crippled germinal center B cells from apoptosis and drive constitutive NF-κB and JAK/STAT pathway activation78[^10]. EBV-negative cases must acquire these survival signals through alternative genetic lesions without viral assistance7.

詳解 · 中文翻譯

分析

題幹要求錯誤的敘述，正確答案是 (C)。

為什麼 (C) 是錯誤的敘述：

EBV 陽性在淋巴細胞優勢 HL（結節性淋巴細胞優勢何杰金淋巴瘤，NLPHL）中極為罕見，而不是最頻繁。 NLPHL 的特徵是在絕大多數病例中 EBV 陰性。研究顯示只有 2.5-4.5% 的 NLPHL 病例 EBV 陽性123，而 25-70% 的經典何杰金淋巴瘤（cHL）病例 EBV 陽性14。因此選項 C 中的敘述在事實上是不正確的—它反轉了 EBV 與 HL 亞型之間的實際關係6。

為什麼其他選項是正確的：

(A) HL 是生發中心 B 細胞的腫瘤 — 正確。經典 HL 和 NLPHL 都源自生發中心 B 細胞，如免疫球蛋白基因超突變型態和基因表達譜所證明7[^11]。在經典 HL 中，何杰金和 Reed-Sternberg (HRS) 細胞源自「前凋亡生發中心 B 細胞」7，而 NLPHL 腫瘤細胞（淋巴細胞優勢細胞）「主要保留其典型 GC B 細胞表達程序」7。

(B) HL 的特徵是存在 Reed-Sternberg 細胞 — 正確。Reed-Sternberg 細胞是經典何杰金淋巴瘤的病理特徵性腫瘤細胞，於 1900 年代初由 Dorothy Reed-Mendenhall 和 Carl Sternberg 首次描述4。這些雙核或多核細胞由不完全的細胞質分裂和單核何杰金細胞的重新融合產生7。

(D) EBV 在任何何杰金淋巴瘤腫瘤中是克隆性的 — 正確。當 EBV 存在於何杰金淋巴瘤時，它是單克隆的，意味著所有腫瘤細胞攜帶相同的 EBV 基因組，表明病毒在克隆擴增之前存在於原始轉化細胞中[9][11]。此克隆性支持 EBV 在早期淋巴瘤發生中的作用，而不是作為次要乘客感染。

(E) EBV 陽性和 EBV 陰性 HL 通過不同機制產生 — 正確。全基因組關聯研究提供強有力的證據表明 EBV 狀態在經典 HL 中代表不同的病因通路4。在 EBV 陽性病例中，病毒癌蛋白（特別是 LMP-1 和 LMP-2）從凋亡中拯救受損的生發中心 B 細胞，並驅動組成型 NF-κB 和 JAK/STAT 通路激活78[^10]。EBV 陰性病例必須通過沒有病毒幫助的替代遺傳缺陷獲得這些存活信號7。

參考文獻 (AMA)

  1. Huppmann AR, Nicolae A, Slack GW, et al. EBV May Be Expressed in the LP Cells of Nodular Lymphocyte-Predominant Hodgkin Lymphoma (NLPHL) in Both Children and Adults. The American Journal of Surgical Pathology. 2014;38(3):316-24. doi:10.1097/PAS.0000000000000107. PMID:24525501. ↩↩↩↩

  2. Gerhard-Hartmann E, Jöhrens K, Schinagl LM, et al. Epstein-Barr Virus Infection Patterns in Nodular Lymphocyte-Predominant Hodgkin Lymphoma. Histopathology. 2022;80(7):1071-1080. doi:10.1111/his.14652. PMID:35322462. ↩↩

  3. Brice P, de Kerviler E, Friedberg JW. Classical Hodgkin Lymphoma. Lancet (London, England). 2021;398(10310):1518-1527. doi:10.1016/S0140-6736(20)32207-8. PMID:33493434. ↩↩

  4. Englund A, Molin D, Enblad G, et al. The Role of Tumour-Infiltrating Eosinophils, Mast Cells and Macrophages in Classical and Nodular Lymphocyte Predominant Hodgkin Lymphoma in Children. European Journal of Haematology. 2016;97(5):430-438. doi:10.1111/ejh.12747. PMID:26872637. ↩↩↩↩↩↩

  5. Weniger MA, Küppers R. Molecular Biology of Hodgkin Lymphoma. Leukemia. 2021;35(4):968-981. doi:10.1038/s41375-021-01204-6. PMID:33686198. ↩

  6. Thorley-Lawson DA, Gross A. Persistence of the Epstein-Barr Virus and the Origins of Associated Lymphomas. The New England Journal of Medicine. 2004;350(13):1328-37. doi:10.1056/NEJMra032015. PMID:15044644. ↩↩

  7. Carbone A, Gloghini A, Caruso A, De Paoli P, Dolcetti R. The Impact of EBV and HIV Infection on the Microenvironmental Niche Underlying Hodgkin Lymphoma Pathogenesis. International Journal of Cancer. 2017;140(6):1233-1245. doi:10.1002/ijc.30473. PMID:27750386. ↩↩↩↩↩↩↩↩↩↩↩↩

  8. Oliveira LOD, Costa IB, Quaresma JAS. Association Between Epstein-Barr Virus LMP-1 and Hodgkin Lymphoma LMP-1 Mechanisms in Hodgkin Lymphoma Development. Reviews in Medical Virology. 2024;34(4):e2561. doi:10.1002/rmv.2561. PMID:38877989. ↩↩

Slide annotations

EBV infection is associated with 40–60% of Hodgkin's disease cases and most often with the mixed cellularity subtype.

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