Tumor infiltrating lymphocyte grade in Merkel cell carcinoma: relationships with clinical factors and independent prognostic value

Surrogate markers of the host immune response are not currently included in AJCC staging for Merkel cell carcinoma (MCC), and have not been consistently associated with clinical outcomes. We performed an analysis of a large national database to investigate tumor infiltrating lymphocyte (TIL) grade as an independent predictor of overall survival (OS) for patients with MCC and to characterize the relationship between TIL grade and other clinical prognostic factors.
The NCDB was queried for patients with resected, non-metastatic MCC with known TIL grade (absent, non-brisk and brisk). Multivariable Cox regression modeling was performed to define TIL grade as a predictor of OS adjusting for other relevant clinical factors. Multinomial, multivariable logistic regression was performed to characterize the relationship between TIL grade and other clinical prognostic factors. Multiple imputation was performed to account for missing data bias.
Both brisk (HR 0.55, CI 0.36–0.83) and non-brisk (HR 0.77, CI 0.60–0.98) were associated with decreased adjusted hazard of death relative to absent TIL grade. Adverse clinical factors such as 1–3 positive lymph nodes, lymphovascular invasion (LVI) and immunosuppression were associated with increased likelihood of non-brisk TIL relative to absent TIL grade (p values <.05). Extracapsular extension (ECS) was associated with decreased likelihood of brisk TIL relative to absent TIL grade (p<.05).
Histopathologic TIL grade was independently predictive for OS in this large national cohort. Significant differences in the likelihood of non-brisk or brisk TIL relative to absent grade were present with regards to LVI, ECS and immune status. TIL grade may be a useful prognostic factor to consider in addition to more granular characterization of TIL morphology and immunophenotype.

目前默克尔细胞癌（Merkel cell carcinoma, MCC）的美国癌症联合委员会（American Joint Committee on Cancer, AJCC）分期尚未纳入宿主免疫应答的替代标志物，且此类标志物与临床结局的关联尚未得到一致证实。本研究针对大型国家级数据库开展分析，旨在探究肿瘤浸润淋巴细胞（tumor infiltrating lymphocyte, TIL）分级作为MCC患者总生存期（overall survival, OS）的独立预测因子，并明确TIL分级与其他临床预后因素之间的关联关系。
本研究从国家癌症数据库（National Cancer Database, NCDB）中检索接受手术切除、无远处转移且TIL分级已知（缺失、非活跃及活跃）的MCC患者。采用多变量Cox回归模型，在校正其他相关临床混杂因素的前提下，明确TIL分级作为OS预测因子的价值；同时运用多分类多变量logistic回归模型，刻画TIL分级与其他临床预后因素的关联。为控制缺失数据带来的偏倚，本研究实施了多重插补处理。
相较于TIL分级缺失的患者，活跃组（风险比HR=0.55，95%置信区间CI：0.36~0.83）与非活跃组（HR=0.77，CI：0.60~0.98）的校正后死亡风险均显著降低。与TIL分级缺失的患者相比，存在1~3枚阳性淋巴结、淋巴血管侵犯（lymphovascular invasion, LVI）及免疫抑制等不良临床特征的患者，其非活跃TIL分级的发生风险显著升高（p值<0.05）。而包膜外侵犯（extracapsular extension, ECS）则与活跃TIL分级的发生风险降低显著相关（p<0.05）。
本研究纳入的大型国家级队列数据显示，组织病理学TIL分级可作为OS的独立预测因子。相较于TIL分级缺失的患者，非活跃或活跃TIL分级的发生风险与LVI、ECS及免疫状态显著相关。除了对TIL形态学与免疫表型进行更精细的表征外，TIL分级或可作为一项具有应用价值的预后参考因素。