Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London, United Kingdom.
J Clin Oncol. 2013 Jan 10;31(2):256-62. doi: 10.1200/JCO.2011.39.9881. Epub 2012 Oct 8.
The immune microenvironment is key to the pathophysiology of classical Hodgkin lymphoma (CHL). Twenty percent of patients experience failure of their initial treatment, and others receive excessively toxic treatment. Prognostic scores and biomarkers have yet to influence outcomes significantly. Previous biomarker studies have been limited by the extent of tissue analyzed, statistical inconsistencies, and failure to validate findings. We aimed to overcome these limitations by validating recently identified microenvironment biomarkers (CD68, FOXP3, and CD20) in a new patient cohort with a greater extent of tissue and by using rigorous statistical methodology.
Diagnostic tissue from 122 patients with CHL was microarrayed and stained, and positive cells were counted across 10 to 20 high-powered fields per patient by using an automated system. Two statistical analyses were performed: a categorical analysis with test/validation set-defined cut points and Kaplan-Meier estimated outcome measures of 5-year overall survival (OS), disease-specific survival (DSS), and freedom from first-line treatment failure (FFTF) and an independent multivariate analysis of absolute uncategorized counts.
Increased CD20 expression confers superior OS. Increased FOXP3 expression confers superior OS, and increased CD68 confers inferior FFTF and OS. FOXP3 varies independently of CD68 expression and retains significance when analyzed as a continuous variable in multivariate analysis. A simple score combining FOXP3 and CD68 discriminates three groups: FFTF 93%, 62%, and 47% (P < .001), DSS 93%, 82%, and 63% (P = .03), and OS 93%, 82%, and 59% (P = .002).
We have independently validated CD68, FOXP3, and CD20 as prognostic biomarkers in CHL, and we demonstrate, to the best of our knowledge for the first time, that combining FOXP3 and CD68 may further improve prognostic stratification.
免疫微环境是经典霍奇金淋巴瘤（CHL）病理生理学的关键。20%的患者在初始治疗后失败，还有其他患者接受了过度毒性的治疗。预后评分和生物标志物尚未显著影响结果。先前的生物标志物研究受到分析组织的范围、统计不一致性以及未能验证发现的限制。我们旨在通过在具有更大组织范围的新患者队列中验证最近确定的微环境生物标志物（CD68、FOXP3 和 CD20）并使用严格的统计方法来克服这些限制。
122 例 CHL 患者的诊断组织进行了微阵列和染色，并使用自动化系统对每个患者的 10 到 20 个高倍视野中的阳性细胞进行计数。进行了两种统计分析：使用测试/验证集定义的截止值的分类分析和Kaplan-Meier 估计的 5 年总生存率（OS）、疾病特异性生存率（DSS）和一线治疗失败无进展生存率（FFTF）的预后测量值，以及对绝对未分类计数的独立多变量分析。
增加 CD20 表达可改善 OS。增加 FOXP3 表达可改善 OS，增加 CD68 表达可降低 FFTF 和 OS。FOXP3 与 CD68 表达独立变化，在多变量分析中作为连续变量分析时仍具有统计学意义。结合 FOXP3 和 CD68 的简单评分可将患者分为三组：FFTF 为 93%、62%和 47%（P<0.001），DSS 为 93%、82%和 63%（P=0.03），OS 为 93%、82%和 59%（P=0.002）。
我们独立验证了 CD68、FOXP3 和 CD20 作为 CHL 的预后生物标志物，并且我们首次证明，结合 FOXP3 和 CD68 可能进一步改善预后分层。
