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Q1. Which of the following statements is INCORRECT about post-transplantation lymphoproliferative disorders (PTLD)?

  • (A) Tumor must be positive for EBV
  • (B) Preemptive monitoring of peripheral blood EBV viral load does not have diagnostic value.
  • (C) Most of PTLD after hematopoietic stem cell transplantation are derived from donor lymphocytes.
  • (D) PTLD after organ transplantation are derived from recipient cells.
  • (E) The cornerstone of the initial management of PTLD is to reduce immunosuppression.
點此顯示正解

(A) Tumor must be positive for EBV

詳解

Analysis of Board Question

1. Why Option (A) is FALSE (INCORRECT)

Option (A) states "Tumor must be positive for EBV" — this is false. PTLD does not require EBV positivity. While EBV is associated with the majority of PTLD cases, particularly those occurring early after transplantation, up to 50% of PTLD cases after solid-organ transplantation are EBV-negative1. The proportion of EBV-negative PTLD has been increasing, particularly in late-onset cases occurring 5-15 years or more after transplantation2. EBV-negative PTLD is recognized as a distinct entity with different molecular-genomic features compared to EBV-positive cases[^4]. The pathogenesis of EBV-negative PTLD is less clear and may involve mechanisms such as persistent antigen stimulation, long-term immunosuppression, or infection with other viruses1.

2. Why the Other Options are TRUE

(B) Preemptive monitoring of peripheral blood EBV viral load does not have diagnostic value — TRUE

While EBV viral load monitoring can be used for risk stratification and preemptive therapy decisions, peripheral blood EBV viral load does not have diagnostic value for PTLD itself. The diagnosis of PTLD requires tissue biopsy and histopathologic examination. EBV viremia may be present without PTLD, and conversely, PTLD (particularly EBV-negative cases) can occur without detectable EBV viremia. The AST guidelines emphasize that PTLD diagnosis is based on tissue pathology, not viral load monitoring[3][7].

(C) Most PTLD after hematopoietic stem cell transplantation are derived from donor lymphocytes — TRUE

After allogeneic hematopoietic stem-cell transplantation, most cases of PTLD are derived from donor (EBV-infected) lymphocytes, with almost 100% association with EBV2. These cases typically occur in the first year after transplantation, and T-cell depletion strategies and donor type are considered the strongest risk factors2. This contrasts with solid organ transplantation, where PTLD arises from recipient cells.

(D) PTLD after organ transplantation are derived from recipient cells — TRUE

In solid organ transplantation, PTLD develops primarily from the recipient's lymphocytes2. This is particularly relevant in EBV-seronegative recipients who undergo primary EBV infection after transplantation, which increases PTLD risk by a factor of 10 to 75 compared to seropositive recipients2. The allograft itself is not the source of the malignant lymphocytes in solid organ transplant PTLD.

(E) The cornerstone of the initial management of PTLD is to reduce immunosuppression — TRUE

Reduction of immunosuppression (RIS) is the cornerstone of initial PTLD management[^8]. This approach aims to partially restore EBV-specific cellular immunity without inducing graft rejection. RIS leads to regression of PTLD in 20-80% of cases[^8]. The typical approach includes reducing calcineurin inhibitors by at least 50% and discontinuing antimetabolic agents[7][8]. Response to RIS is expected within 2-4 weeks, after which additional interventions should be considered if there is inadequate response[7][8]. This applies across the spectrum of PTLD histologies, though EBV-negative disease, bulky disease, advanced stage, and older age are associated with lower response rates to RIS alone[^8].

詳解 · 中文翻譯

板考分析

1. 為什麼選項 (A) 是虛假的（不正確的）

選項 (A) 陳述「腫瘤必須是 EBV 陽性的」— 這是虛假的。PTLD 不需要 EBV 陽性。雖然 EBV 與大多數 PTLD 病例相關，特別是移植後早期發生的病例，多達 50% 的固體器官移植後 PTLD 病例是 EBV 陰性的1。EBV 陰性 PTLD 的比例一直在增加，特別是在移植後 5-15 年或更長時間後發生的晚期病例中2。EBV 陰性 PTLD 被認為是不同實體，具有與 EBV 陽性病例相比不同的分子-基因組特徵[^4]。EBV 陰性 PTLD 的病因不太清楚，可能涉及持續抗原刺激、長期免疫抑制或其他病毒感染等機制1。

2. 為什麼其他選項是正確的

(B) 周邊血 EBV 病毒負荷的前瞻性監測沒有診斷價值 — 正確

雖然 EBV 病毒負荷監測可用於風險分層和前瞻性治療決策，周邊血 EBV 病毒負荷沒有 PTLD 本身的診斷價值。PTLD 的診斷需要組織活檢和組織病理學檢查。EBV 病毒血症可能在沒有 PTLD 的情況下存在，相反，PTLD（特別是 EBV 陰性病例）可在沒有可檢測 EBV 病毒血症的情況下發生。AST 指南強調 PTLD 診斷基於組織病理學，而不是病毒負荷監測[3][7]。

(C) 造血幹細胞移植後大多數 PTLD 源自供體淋巴細胞 — 正確

在異體造血幹細胞移植後，大多數 PTLD 病例源自供體（EBV 感染的）淋巴細胞，與 EBV 的關聯幾乎 100%2。這些病例通常發生在移植後第一年，T 細胞耗盡策略和供體類型被認為是最強的風險因素2。這與固體器官移植形成對比，其中 PTLD 源自受體細胞。

(D) 器官移植後 PTLD 源自受體細胞 — 正確

在固體器官移植中，PTLD 主要由受體淋巴細胞發展2。這在 EBV 血清陰性受者中特別相關，這些受者在移植後經歷初級 EBV 感染，相比血清陽性受者增加 PTLD 風險 10 至 75 倍2。同種異體移植本身不是固體器官移植 PTLD 中惡性淋巴細胞的來源。

(E) PTLD 初始管理的基礎是減少免疫抑制 — 正確

減少免疫抑制 (RIS) 是 PTLD 初始管理的基礎[^8]。此方法旨在部分恢復 EBV 特異性細胞免疫，而不誘導移植物排斥。RIS 導致 PTLD 在 20-80% 的病例中回歸[^8]。典型的方法包括將鈣調神經磷酸酶抑制劑減少至少 50% 並停用抗代謝藥劑[7][8]。對 RIS 的反應預期在 2-4 週內發生，之後如果反應不足應考慮進行其他干預[7][8]。這適用於 PTLD 組織學的整個譜系，儘管 EBV 陰性疾病、大體疾病、進展期疾病和年齡較大與對 RIS 單獨的較低反應率相關[^8]。

參考文獻 (AMA)

  1. Dierickx D, Habermann TM. Post-Transplantation Lymphoproliferative Disorders in Adults. The New England Journal of Medicine. 2018;378(6):549-562. doi:10.1056/NEJMra1702693. PMID:29414277. ↩↩↩↩

  2. Allen UD, Preiksaitis JK, AST Infectious Diseases Community of Practice. Post-Transplant Lymphoproliferative Disorders, Epstein-Barr Virus Infection, and Disease in Solid Organ Transplantation: Guidelines From the American Society of Transplantation Infectious Diseases Community of Practice. Clinical Transplantation. 2019;33(9):e13652. doi:10.1111/ctr.13652. PMID:31230381. ↩↩↩↩↩↩↩↩↩↩

Slide annotations

EBV-negative PTLD has been documented in up to 30 percent of PTLD in some series (other virus: HHV-8 in PEL-PTLD). While an increased EBV viral load is suggestive of PTLD, the diagnosis of PTLD is based on the histologic evaluation of a tissue biopsy.

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