Q44. Correlations between acquired molecular abnormalities and specific lymphoma entities are a central part of the WHO classification and the understanding of lymphomagenesis. Immunophenotyping further identifies protein expression patterns that correlate with specific cytogenetic abnormalities and with prognosis. Which description is wrong about prognostic biomarkers by immunohistochemistry in aggressive lymphoma?

• (A) Anaplastic lymphoma kinase (ALK) expression has been associated with an improved outcome in anaplastic large cell lymphoma
• (B) BCL-6 expression has been associated with an improved outcome in diffuse large cell lymphoma (DLBCL), but its absence may be less deleterious in the rituximab era.
• (C) ABC-like (activated B cell) lymphoma expressing BCL-2 had inferior survival than those who without BCL-2 expression
• (D) DLBCL with MYC plus BCL-2 expression was classified as double expressor DLBCL had poor prognosis, but better than double hit DLBCL.
• (E) DLBCL with CD10+; or CD10-/BCL-6+/MUM1- are markers for non-GCB subtypes who has inferior survival than GCB subtype DLBCL.

點此顯示正解

(E) DLBCL with CD10+; or CD10-/BCL-6+/MUM1- are markers for non-GCB subtypes who has inferior survival than GCB subtype DLBCL.

詳解

Why Option (E) is the INCORRECT statement:

Option (E) states that CD10+ or CD10-/BCL-6+/MUM1- are markers for non-GCB subtypes with inferior survival. This is wrong because these immunophenotypic patterns actually define the GCB (germinal center B-cell) subtype, not the non-GCB subtype, according to the Hans algorithm¹²⁶.

The Hans algorithm specifically classifies DLBCL as follows: - GCB subtype: CD10+ OR (CD10-/BCL-6+/MUM1-) - Non-GCB subtype: CD10-/BCL-6-/MUM1+ OR CD10-/BCL-6+/MUM1+ OR CD10-/BCL-6-/MUM1-⁶

Furthermore, the GCB subtype has superior survival compared to non-GCB/ABC subtypes, not inferior survival. The ABC/non-GCB subtype is associated with poor prognosis, with 3-year progression-free survival of approximately 40-50% versus 75% for GCB subtype²⁵. Option (E) reverses both the immunophenotypic classification and the prognostic implications.

Table 2⁶

Why the other options are CORRECT statements:

(A) ALK expression and improved outcome in ALCL: TRUE. ALK-positive anaplastic large cell lymphoma is well-established to have a significantly better prognosis than ALK-negative ALCL. ALK expression is a favorable prognostic marker in this entity.

(B) BCL-6 expression and improved outcome in DLBCL: TRUE. BCL-6 expression has been associated with improved outcomes in DLBCL, particularly as it is a marker of GCB-type DLBCL²⁴. The statement correctly notes that its absence may be less deleterious in the rituximab era, reflecting the evolving prognostic landscape with modern immunochemotherapy.

(C) ABC-like DLBCL with BCL-2 expression and inferior survival: TRUE. BCL-2 overexpression is associated with worse prognosis in DLBCL⁵[^10][12]. The combination of ABC phenotype (already poor prognosis) with BCL-2 expression confers particularly inferior survival. Studies demonstrate that BCL-2 overexpression is associated with inferior disease-free survival and disease-specific survival[^12].

(D) Double expressor DLBCL has poor prognosis but better than double hit: TRUE. Double expressor lymphoma (DEL), defined by MYC and BCL-2 protein co-expression by IHC (typically ≥40% MYC and ≥50% BCL-2), has worse prognosis than standard DLBCL⁵[^10][11][^13]. However, double-hit lymphoma (DHL), defined by concurrent MYC and BCL2/BCL6 genetic rearrangements detected by FISH, has an even worse prognosis than double expressor lymphoma[^13][14]. DHL is now classified as high-grade B-cell lymphoma with MYC and BCL2/BCL6 rearrangements in WHO classification and represents the most aggressive category⁵[^10].

詳解 · 中文翻譯

為什麼選項 (E) 是不正確的敘述：

選項 (E) 陳述 CD10+ 或 CD10-/BCL-6+/MUM1- 是非-GCB 亞型的標誌，預後較差。這是錯誤的，因為根據 Hans 演算法，這些免疫表型型態實際上定義了 GCB（生發中心 B 細胞）亞型，而不是非-GCB 亞型¹²⁶。

Hans 演算法特別將 DLBCL 分類如下： - GCB 亞型：CD10+ 或 (CD10-/BCL-6+/MUM1-) - 非-GCB 亞型：CD10-/BCL-6-/MUM1+ 或 CD10-/BCL-6+/MUM1+ 或 CD10-/BCL-6-/MUM1-⁶

此外，GCB 亞型與非-GCB/ABC 亞型相比具有優越的存活率，而不是較差的存活率。ABC/非-GCB 亞型與差的預後相關，3 年無進展生存期約為 40-50%，而 GCB 亞型為 75%²⁵。選項 (E) 同時反轉了免疫表型分類和預後含義。

Table 2⁶

為什麼其他選項是正確的敘述：

(A) ALK 表達和 ALCL 中的改善預後：正確。ALK 陽性間變性大細胞淋巴瘤很好地確立了比 ALK 陰性 ALCL 的預後顯著更好。ALK 表達在此實體中是有利的預後標誌物。

(B) BCL-6 表達和 DLBCL 中的改善預後：正確。BCL-6 表達已與 DLBCL 中的改善預後相關，特別是因為它是 GCB 型 DLBCL 的標誌物²⁴。敘述正確地指出其缺失在利妥昔單抗時代可能損害較小，反映了現代免疫化療的預後演變。

(C) ABC 型 DLBCL 伴 BCL-2 表達和較差存活率：正確。BCL-2 過度表達與 DLBCL 的較差預後相關⁵[^10][12]。ABC 表型（已經預後差）與 BCL-2 表達的組合賦予特別較差的存活率。研究證明 BCL-2 過度表達與較差的無病生存期和疾病特異性存活率相關[^12]。

(D) 雙表達 DLBCL 有差的預後但比雙擊更好：正確。雙表達淋巴瘤（DEL），由 IHC 定義為 MYC 和 BCL-2 蛋白共表達（通常 ≥40% MYC 和 ≥50% BCL-2），比標準 DLBCL 有更差的預後⁵[^10][11][^13]。然而，雙擊淋巴瘤（DHL），由 FISH 檢測的並發 MYC 和 BCL2/BCL6 遺傳重排定義，比雙表達淋巴瘤有更差的預後[^13][14]。DHL 現在在 WHO 分類中被分類為伴 MYC 和 BCL2/BCL6 重排的高級 B 細胞淋巴瘤，代表最侵襲性的類別⁵[^10]。

參考文獻 (AMA)

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1. 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. ↩↩

2. Sehn LH, Salles G. Diffuse Large B-Cell Lymphoma. The New England Journal of Medicine. 2021;384(9):842-858. doi:10.1056/NEJMra2027612. PMID:33657296. ↩↩↩↩↩↩

3. Pasqualucci L. Molecular Pathogenesis of Germinal Center-Derived B Cell Lymphomas. Immunological Reviews. 2019;288(1):240-261. doi:10.1111/imr.12745. PMID:30874347. ↩

4. Peroja P, Pedersen M, Mantere T, et al. Mutation of TP53, Translocation Analysis and Immunohistochemical Expression of MYC, BCL-2 and BCL-6 in Patients With DLBCL Treated With R-Chop. Scientific Reports. 2018;8(1):14814. doi:10.1038/s41598-018-33230-3. PMID:30287880. ↩↩

5. Yan LX, Liu YH, Luo DL, et al. MYC Expression in Concert With BCL2 and BCL6 Expression Predicts Outcome in Chinese Patients With Diffuse Large B-Cell Lymphoma, Not Otherwise Specified. PloS One. 2014;9(8):e104068. doi:10.1371/journal.pone.0104068. PMID:25090026. ↩↩↩↩↩↩↩↩

6. Ma Z, Niu J, Cao Y, et al. Clinical Significance of 'Double-Hit' and 'Double-Expression' Lymphomas. Journal of Clinical Pathology. 2020;73(3):126-138. doi:10.1136/jclinpath-2019-206199. PMID:31615842. ↩↩↩↩↩↩

7. Xu J, Liu JL, Medeiros LJ, et al. MYC Rearrangement and MYC/BCL2 Double Expression but Not Cell-of-Origin Predict Prognosis in R-CHOP treated Diffuse Large B-Cell Lymphoma. European Journal of Haematology. 2020;104(4):336-343. doi:10.1111/ejh.13384. PMID:31944390. ↩

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