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Q10. Which one is wrong about cytogenetic/molecular patterns in lymphoid malignancy?

  • (A) MYD88 p.L265P mutation test is recommended in patients with lymphoplasmacytic Lymphoma / Waldenström Macroglobulinemia
  • (B) BRAF p.V600E mutation occurs in 98% to 100% of patients with classical hairy cell leukemia
  • (C) MYC and BCL2 or BCL6 translocations for identification of “double-hit” or “triple-hit” lymphoma and Burkitt lymphoma
  • (D) The t(11;18) and t(1;14) are most common in gastric, intestinal, and lung MALT lymphomas.
  • (E) MYD88 mutation is characteristic of splenic marginal zone lymphoma
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(E) MYD88 mutation is characteristic of splenic marginal zone lymphoma

詳解

Why Option (E) is the INCORRECT Statement

MYD88 mutation is NOT characteristic of splenic marginal zone lymphoma (SMZL). MYD88 L265P is found in only 5-6% of SMZL cases, making it rare rather than characteristic2[^12]. In contrast, SMZL is characterized by mutations in NOTCH2, KLF2, TNFAIP3, and 7q31-32 deletions24. The genetic landscape of SMZL consists of two main clusters: the NNK cluster (58% of cases) with NF-κB, NOTCH, and KLF2 mutations, and the DMT cluster (32% of cases) with TP53, MAPK, and TLR pathway mutations4. MYD88 L265P is instead the hallmark mutation of lymphoplasmacytic lymphoma/Waldenström macroglobulinemia (>90-95% of cases)[8][11], making option (E) fundamentally incorrect.

Why the Other Options Are CORRECT

(A) MYD88 p.L265P mutation test is recommended in patients with lymphoplasmacytic lymphoma/Waldenström macroglobulinemia — This is correct. The MYD88 L265P mutation occurs in >90-95% of Waldenström macroglobulinemia cases and is considered the hallmark of this disease[8][11]. It serves as a valuable diagnostic biomarker to differentiate lymphoplasmacytic lymphoma from morphological mimics and has therapeutic implications, as it predicts response to BTK inhibitors[8][10].

(B) BRAF p.V600E mutation occurs in 98% to 100% of patients with classical hairy cell leukemia — This is correct. BRAF V600E is the defining molecular feature of classical hairy cell leukemia, occurring in nearly all cases. While the search results note that a minor proportion (≤5%) of SMZL may carry BRAF V600E5, the statement specifically refers to classical hairy cell leukemia where the mutation frequency is indeed 98-100%.

(C) MYC and BCL2 or BCL6 translocations for identification of "double-hit" or "triple-hit" lymphoma and Burkitt lymphoma — This is correct. MYC translocations combined with BCL2 and/or BCL6 rearrangements define double-hit and triple-hit lymphomas, which are high-grade B-cell lymphomas with aggressive behavior. MYC translocations are also characteristic of Burkitt lymphoma, making this testing clinically important for classification and prognostication.

(D) The t(11;18) and t(1;14) are most common in gastric, intestinal, and lung MALT lymphomas — This is correct. The t(11;18)(q21;q21) translocation generates a BIRC3/MALT1 fusion protein, while t(1;14)(p22;q32) leads to BCL10 upregulation3. These translocations involving the immunoglobulin heavy-chain locus are characteristic of extranodal marginal zone lymphomas (MALT lymphomas) at these anatomical sites and activate the NF-κB pathway36.

詳解 · 中文翻譯

為什麼選項 (E) 是不正確的敘述

MYD88 突變不是脾邊緣帶淋巴瘤 (SMZL) 的特徵。 MYD88 L265P 僅在 5-6% 的 SMZL 病例中發現，使其罕見而不是特徵2[^12]。相比之下，SMZL 的特徵是 NOTCH2、KLF2、TNFAIP3 的突變和 7q31-32 缺失24。SMZL 的遺傳景觀包括兩個主要群集：NNK 群集（58% 的病例），具有 NF-κB、NOTCH 和 KLF2 突變，以及 DMT 群集（32% 的病例），具有 TP53、MAPK 和 TLR 通路突變4。MYD88 L265P 相反是淋巴漿細胞淋巴瘤/Waldenström 巨球蛋白血症（>90-95% 的病例）的標誌突變[8][11]，使選項 (E) 從根本上不正確。

為什麼其他選項是正確的

(A) 推薦在淋巴漿細胞淋巴瘤/Waldenström 巨球蛋白血症患者中進行 MYD88 p.L265P 突變測試 — 這是正確的。MYD88 L265P 突變發生在 >90-95% 的 Waldenström 巨球蛋白血症病例中，被認為是此疾病的標誌[8][11]。它作為有價值的診斷生物標誌物區分淋巴漿細胞淋巴瘤與形態學模仿物，並具有治療含義，因為它預測 BTK 抑制劑的反應[8][10]。

(B) BRAF p.V600E 突變發生在 98% 至 100% 的經典毛細胞白血病患者中 — 這是正確的。BRAF V600E 是經典毛細胞白血病的定義分子特徵，發生在幾乎所有病例中。雖然搜索結果指出一小部分（≤5%）SMZL 可能攜帶 BRAF V600E5，敘述特別指經典毛細胞白血病，其中突變頻率確實是 98-100%。

(C) MYC 和 BCL2 或 BCL6 易位用於識別「雙擊」或「三擊」淋巴瘤和 Burkitt 淋巴瘤 — 這是正確的。MYC 易位與 BCL2 和/或 BCL6 重排組合定義雙擊和三擊淋巴瘤，這些是具有侵襲性行為的高級 B 細胞淋巴瘤。MYC 易位也是 Burkitt 淋巴瘤的特徵，使此測試在分類和預後評估中在臨床上很重要。

(D) t(11;18) 和 t(1;14) 在胃、腸和肺 MALT 淋巴瘤中最常見 — 這是正確的。t(11;18)(q21;q21) 易位產生 BIRC3/MALT1 融合蛋白，而 t(1;14)(p22;q32) 導致 BCL10 上調3。這些涉及免疫球蛋白重鏈位點的易位是這些解剖位置節外邊緣帶淋巴瘤 (MALT 淋巴瘤) 的特徵，激活 NF-κB 通路36。

參考文獻 (AMA)

  1. Rossi D, Bertoni F, Zucca E. Marginal-Zone Lymphomas. The New England Journal of Medicine. 2022;386(6):568-581. doi:10.1056/NEJMra2102568. PMID:35139275. ↩

  2. Varettoni M, Arcaini L, Zibellini S, et al. Prevalence and Clinical Significance of the MYD88 (L265P) Somatic Mutation in Waldenstrom's Macroglobulinemia and Related Lymphoid Neoplasms. Blood. 2013;121(13):2522-8. doi:10.1182/blood-2012-09-457101. PMID:23355535. ↩↩↩↩

  3. Bonfiglio F, Bruscaggin A, Guidetti F, et al. Genetic and Phenotypic Attributes of Splenic Marginal Zone Lymphoma. Blood. 2022;139(5):732-747. doi:10.1182/blood.2021012386. PMID:34653238. ↩↩↩↩

  4. Banerjee Nair S, Hyun TS, Naresh KN. MYD88 Gene and Protein: Molecular Architecture, Signalling Mechanisms and Clinical Implications in Lymphoid Malignancies. Journal of Clinical Pathology. 2026;79(6):363-369. doi:10.1136/jcp-2026-210690. PMID:41922162. ↩↩↩↩

  5. Silkenstedt E, Salles G, Campo E, Dreyling M. B-Cell Non-Hodgkin Lymphomas. Lancet (London, England). 2024;403(10438):1791-1807. doi:10.1016/S0140-6736(23)02705-8. PMID:38614113. ↩↩

  6. Yu X, Li W, Deng Q, et al. L265P Mutation in Lymphoid Malignancies. Cancer Research. 2018;78(10):2457-2462. doi:10.1158/0008-5472.CAN-18-0215. PMID:29703722. ↩↩

  7. Blombery P, de Jong D, Ferry JA, et al. Closing the Gap Between Biology and Classification in Splenic B-Cell Lymphomas. Histopathology. 2025;86(1):69-78. doi:10.1111/his.15323. PMID:39403047. ↩

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