新辅助抗 PD-1 治疗后切除的非小细胞肺癌的反应的病理特征：提出了定量免疫相关病理反应标准（irPRC）。
Pathologic features of response to neoadjuvant anti-PD-1 in resected non-small-cell lung carcinoma: a proposal for quantitative immune-related pathologic response criteria (irPRC).
机构信息
Department of Pathology, Johns Hopkins University SOM, Baltimore, USA.
Department of Pathology, Johns Hopkins University SOM, Baltimore, USA; Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University SOM, Baltimore, USA; The Johns Hopkins Bloomberg-Kimmel Institute for Cancer Immunotherapy, Baltimore, USA.
出版信息
Ann Oncol. 2018 Aug 1;29(8):1853-1860. doi: 10.1093/annonc/mdy218.
BACKGROUND
Neoadjuvant anti-PD-1 may improve outcomes for patients with resectable NSCLC and provides a critical window for examining pathologic features associated with response. Resections showing major pathologic response to neoadjuvant therapy, defined as ≤10% residual viable tumor (RVT), may predict improved long-term patient outcome. However, %RVT calculations were developed in the context of chemotherapy (%cRVT). An immune-related %RVT (%irRVT) has yet to be developed.
PATIENTS AND METHODS
The first trial of neoadjuvant anti-PD-1 (nivolumab, NCT02259621) was just reported. We analyzed hematoxylin and eosin-stained slides from the post-treatment resection specimens of the 20 patients with non-small-cell lung carcinoma who underwent definitive surgery. Pretreatment tumor biopsies and preresection radiographic 'tumor' measurements were also assessed.
RESULTS
We found that the regression bed (the area of immune-mediated tumor clearance) accounts for the previously noted discrepancy between CT imaging and pathologic assessment of residual tumor. The regression bed is characterized by (i) immune activation-dense tumor infiltrating lymphocytes with macrophages and tertiary lymphoid structures; (ii) massive tumor cell death-cholesterol clefts; and (iii) tissue repair-neovascularization and proliferative fibrosis (each feature enriched in major pathologic responders versus nonresponders, P < 0.05). This distinct constellation of histologic findings was not identified in any pretreatment specimens. Histopathologic features of the regression bed were used to develop 'Immune-Related Pathologic Response Criteria' (irPRC), and these criteria were shown to be reproducible amongst pathologists. Specifically, %irRVT had improved interobserver consistency compared with %cRVT [median per-case %RVT variability 5% (0%-29%) versus 10% (0%-58%), P = 0.007] and a twofold decrease in median standard deviation across pathologists within a sample (4.6 versus 2.2, P = 0.002).
CONCLUSIONS
irPRC may be used to standardize pathologic assessment of immunotherapeutic efficacy. Long-term follow-up is needed to determine irPRC reliability as a surrogate for recurrence-free and overall survival.
背景
新辅助抗 PD-1 可能改善可切除 NSCLC 患者的预后，并为检查与反应相关的病理特征提供关键窗口。新辅助治疗后显示主要病理反应的切除术，定义为≤10%的残留活肿瘤（RVT），可能预测患者的长期预后改善。然而，%RVT 的计算是在化疗的背景下提出的（%cRVT）。尚未开发出与免疫相关的%RVT（%irRVT）。
患者和方法
首例新辅助抗 PD-1（nivolumab，NCT02259621）试验刚刚报告。我们分析了接受确定性手术的 20 例非小细胞肺癌患者的术后切除标本的苏木精和伊红染色切片。还评估了预处理肿瘤活检和术前放射性“肿瘤”测量。
结果
我们发现，消退床（免疫介导的肿瘤清除区域）解释了之前 CT 成像和病理评估残留肿瘤之间的差异。消退床的特点是（i）免疫激活-密集的肿瘤浸润淋巴细胞伴巨噬细胞和三级淋巴结构；（ii）大量肿瘤细胞死亡-胆固醇裂隙；和（iii）组织修复-新生血管形成和增殖性纤维化（每种特征在主要病理反应者与非反应者中均更为丰富，P<0.05）。在任何预处理标本中均未发现这种独特的组织学发现模式。消退床的组织病理学特征用于制定“免疫相关病理反应标准”（irPRC），并且在病理学家中显示出可重复性。具体而言，与%cRVT 相比，%irRVT 具有更好的观察者间一致性[每例病例的%RVT 变异性中位数为 5%（0%-29%）与 10%（0%-58%），P=0.007]，并且在样本中病理学家之间的%RVT 中位数标准差降低了两倍（4.6 与 2.2，P=0.002）。
结论
irPRC 可用于标准化免疫治疗疗效的病理评估。需要进行长期随访以确定 irPRC 作为无复发生存和总生存的替代指标的可靠性。
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