Necrosis Is Not the Main Part of Immune-Related Pathologic Response to Neoadjuvant Immunotherapy in Squamous Cell Lung Cancer

Recently, recommendations for pathologic assessment of lung cancer resection specimens after neoadjuvant therapy have been outlined by the International Association for the Study of Lung Cancer,1Travis W.D. Dacic S. Wistuba I. et al.IASLC multidisciplinary recommendations for pathologic assessment of lung cancer resection specimens following neoadjuvant therapy.J Thorac Oncol. 2020; 15: 709-740Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar and are intended as guidelines for clinical trials and routine clinical practice to improve consistency in the pathologic assessment of neoadjuvant treatment response. A standardized approach was also recommended to assess the percentages of the following: (1) viable tumor, (2) necrosis, and (3) stroma, with a total adding up to 100% for all systemic neoadjuvant therapies. Here, we report that necrosis is not the main part of the response to neoadjuvant anti–programmed cell death protein 1 (anti–PD-1) immunotherapy in squamous cell lung cancer. Necrosis is a common pathologic change in treatment-naive squamous cell lung cancer, especially in high-grade, fast-growing large tumors and is always located at the center of a tumor bed or a tumor cell nest (Fig. 1A) mainly because of insufficient blood supply. Unlike neoadjuvant chemotherapy, in which drugs kill tumor cells directly and may cause necrosis, the mechanisms underlying immunotherapy involve enhancing the systemic T-cell response to tumor antigens, therefore, needing a sufficient amount of immune cells and more time to kill tumor cells. As shown in Figure 1B, a large number of immune cells infiltrated into tumor cell nests after anti–PD-1 treatment and began to gradually clear tumor cells in an “out-in” way. Therefore, immune-related necrosis is not common during this slow process of tumor cell clearance. Histologic features of immune-related pathologic response to neoadjuvant immunotherapy mainly include lymphoid infiltrates or aggregates, tertiary lymphoid structures, dense plasma cells, interstitial foamy macrophages, proliferative fibrosis, and neovascularization (Fig. 1C).2Cottrell T.R. Thompson E.D. Forde P.M. et al.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).Ann Oncol. 2018; 29: 1853-1860Abstract Full Text Full Text PDF PubMed Scopus (123) Google Scholar,3Stein J.E. Lipson E.J. Cottrell T.R. et al.Pan-tumor pathologic scoring of response to PD-(L)1 blockade.Clin Cancer Res. 2020; 26: 545-551Crossref PubMed Scopus (32) Google Scholar This is in line with our finding that necrosis was not common in resected specimens with complete pathologic response after neoadjuvant anti–PD-1 treatment in our cohort (Fig. 1C).4Gao S. Li N. Gao S. et al.Neoadjuvant PD-1 inhibitor (sintilimab) in non-small cell lung cancer.J Thorac Oncol. 2020; 15: 816-826Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar In contrast, massive necrosis was found in cases with partial response or nonresponse (Fig. 1D–G), in which necrosis was located in the center of the tumor bed or tumor cell nests, preferring pre-existing necrosis instead of immunotherapy-related necrosis. However, in some situations, immunotherapy-related necrosis was found and mainly manifested as the sudden death of the entire cell nest caused by the destruction of stroma that provides nutrition for tumor cells. Tumor cell fragments were quickly phagocytized by macrophages to form granuloma (Fig. 1H). Together, we conclude that necrosis is not the main part of immune-related pathologic response to anti–PD-1 immunotherapy in squamous cell lung cancer. Although it is difficult to distinguish between necrosis caused by neoadjuvant chemotherapy and other causes (which is consistent with the finding that necrosis is not associated with prognosis in squamous cell lung cancer5Takahashi Y. Ishii G. Taira T. et al.Fibrous stroma is associated with poorer prognosis in lung squamous cell carcinoma patients.J Thorac Oncol. 2011; 6: 1460-1467Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar), immunotherapy-related necrosis is relatively easy to identify. Therefore, this suggests that the proposed establishment of a standardized approach for assessing pathologic response to neoadjuvant therapy for a pan-cancer purpose should also reflect the characteristics of the adjuvant treatment regimen. Assessment of necrosis is not recommended for the calculation of the proportion of residual viable tumor in the overall assessment of pathologic response to immunotherapy. Otherwise, neoadjuvant anti–PD-1 treatment efficacy will be overlooked, leading to mislead postsurgical treatment decisions for individual patients. Pathologic Assessment of Lung Squamous Cell Carcinoma After Neoadjuvant ImmunotherapyJournal of Thoracic OncologyVol. 16Issue 1PreviewLi et al.1 wrote a letter stating that necrosis is not the main part of the response to neoadjuvant anti–programmed cell death protein-1 immunotherapy in squamous lung cancer. However, neither in the original article published by Gao et al.2 nor in the letter to the editor of Li et al.1 do they provide any data to support their claim regarding necrosis in neoadjuvant anti–programmed cell death protein-1 immunotherapy-treated squamous cell carcinomas other than the photomicrographs. We encourage the authors to present any data on this point with clinical correlations including patient outcome. Full-Text PDF