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Tumor-Infiltrating Lymphocytes and Macrophages in Intrahepatic Cholangiocellular Carcinoma. Impact on Prognosis after Complete Surgery

  • Original Article
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Journal of Gastrointestinal Surgery Aims and scope

Abstract

Background

Immune infiltrate impacts prognosis of several tumors. To assess the prognostic impact of tumor-infiltrating lymphocytes and macrophages in patients undergoing resection for intrahepatic cholangiocellular carcinoma (ICC).

Methods

All consecutive patients undergoing surgery for ICC between 2008 and 2016 were considered. Inclusion criteria were complete resection and follow-up > 12 months. Tissue sections were immunostained for CD3+, CD4+, CD8+, Foxp3+, and CD68+. The number of positive cells was quantified using a computer-aided image analysis system. Different cut-off values were tested as predictors of overall survival (OS).

Results

Fifty-three patients were analyzed. ICC were T1 in 28 patients, multifocal in 11, and N+ in 13. After a median follow-up of 42 months, 5-year OS was 52.1%. The following immune infiltrate values were associated with better OS: CD3+ > 0.10% (5-year OS 63.3% vs. 13.6% if ≤ 0.10%, p = 0.001); CD8+ > 0.10% (56.2% vs. 28.6% if ≤ 0.10%, p = 0.051); Foxp3+ absent (59.4% vs. 16.0% if present, p = 0.049). CD4+ and CD68+ infiltrates were not associated with OS. Three-year OS rates in patients with 0, 1, and ≥ 2 negative prognostic factors were 73.6%, 47.3%, and 14.3%, respectively (p < 0.001). CD3+ infiltrate stratified prognosis in T1 tumors (3-year OS 71.7% if CD3+ > 0.10% vs. 14.3% if ≤ 0.10%, p < 0.001).

Conclusions

Tumor-infiltrating lymphocytes are associated with prognosis of ICC patients after complete surgery. CD3+ and CD8+ infiltrate is associated with higher survival and lower recurrence risk, while Foxp3+ infiltrate is associated with worse prognosis. CD3+ infiltrate allows refining prediction of prognosis in early tumors.

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Authors and Affiliations

  1. Department of Surgery, Division of Hepatobiliary & General Surgery, Humanitas Clinical and Research Center, IRCCS, Via Manzoni 56, Rozzano - Milan, 20089, Italy

    Luca Vigano, Cristiana Soldani, Barbara Franceschini, Matteo Cimino, Matteo Donadon & Guido Torzilli

  2. Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Italy

    Luca Vigano, Ana Lleo, Matteo Donadon, Massimo Roncalli, Alessio Aghemo, Luca Di Tommaso & Guido Torzilli

  3. Division of Internal Medicine and Hepatology, Department of Internal Medicine, Humanitas Clinical and Research Center, IRCCS, Rozzano, Italy

    Ana Lleo & Alessio Aghemo

  4. Pathology Unit, Humanitas Clinical and Research Center, IRCCS, Rozzano, Italy

    Massimo Roncalli & Luca Di Tommaso

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  1. Luca Vigano
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Contributions

Substantial contributions to the conception or design of the work: Viganò, Roncalli, Aghemo, Torzilli

Acquisition, analysis, or interpretation of data for the work: Viganò, Soldani, Franceschini, Cimino, Lleo, Donadon, Di Tommaso

Drafting the work: Viganò, Soldani, Franceschini, Cimino, Lleo, Donadon, Di Tommaso

Revising it critically for important intellectual content: Viganò, Roncalli, Aghemo, Torzilli

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Correspondence to Guido Torzilli.

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ESM 1

P values of different cut-offs values of CD3+ and CD8+ infiltrates (every 0.05% increase) when tested as predictors of overall survival. The lowest p value (white arrow) was used for the analyses. Dotted green line: p = 0.05 (DOCX 153 kb)

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Vigano, L., Soldani, C., Franceschini, B. et al. Tumor-Infiltrating Lymphocytes and Macrophages in Intrahepatic Cholangiocellular Carcinoma. Impact on Prognosis after Complete Surgery. J Gastrointest Surg 23, 2216–2224 (2019). https://doi.org/10.1007/s11605-019-04111-5

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