Stromal or intraepithelial tumor-infiltrating lymphocytes: which one has more prognostic significance in cervical cancer?

Purpose To investigate the effect of tumor-infiltrating lymphocytes (TILs) and tumor associated macrophages (TAMs) on treatment results in patients with cervical squamous cell carcinoma who underwent definitive or adjuvant radiotherapy (RT) or chemoradiotherapy (CRT). Methods Pathological specimens were evaluated from 96 cervical cancer patients who were treated with definitive or adjuvant RT/CRT between April 2001 and January 2020. The percentage of intraepithelial TILs (iTILs) and stromal TILs (sTILs) were calculated, and immunohistochemistry was used for identifying lymphocyte lineage with CD4, CD8, and CD20 antibodies and macrophages with CD68 antibody. Prognostic values of TILs/TAMs on oncological outcomes were evaluated. Results Thirty patients had early-stage disease and 66 patients had advanced-stage disease. Sixty-three and 33 patients received adjuvant RT and definitive CRT, respectively. Low number of sCD20 positive cells was associated with large tumor size and parametrial invasion. In multivariate analysis, low percentage of sTILs and advanced-stage disease were independent poor prognostic factors for overall survival, disease-free survival (DFS), and distant metastasis-free survival; low number of sCD4 positive cells was also an independent poor prognostic factor for DFS. Low percentage of sTILs and low number of sCD8 positive cells was correlated with high rates of distant metastasis ( p = 0.038 and p = 0.025, respectively). Conclusion sTILs have superior predictive value than iTILs in terms of prognosis. Stromal compartment should be investigated as a routine practice in TIL studies in cervical cancer. Intensifying the treatment in cervical cancer patients with low number of sTILs should be studied in further investigations.