Swati Sonal1, Vikram Deshpande2, David T Ting3, James C Cusack1, Aparna R Parikh3, Azfar Neyaz2,4, Amaya Pankaj3, Martin S Taylor2, Anne M Dinaux1,5, Lieve G J Leijssen1,6, Chloe Boudreau1, Joseph J Locascio7, Hiroko Kunitake1, Robert N Goldstone1, Liliana G Bordeianou1, Christy E Cauley1, Rocco Ricciardi1, David L Berger8. 1. Department of General and Gastrointestinal Surgery, Massachusetts General Hospital & Harvard Medical School, Boston, MA, USA. 2. Department of Pathology, Massachusetts General Hospital & Harvard Medical School, Boston, MA, USA. 3. Massachusetts General Hospital Cancer Center & Harvard Medical School, Boston, MA, USA. 4. Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA. 5. Chirurgie, Albert Schweitzer Ziekenhuis, Dordrecht, The Netherlands. 6. Department of Gastroenterology and Hepatology, Amsterdams University Medical Centers, Amsterdam, The Netherlands. 7. Department of Neurology, Massachusetts General Hospital & Harvard Medical School, Boston, MA, USA. 8. Department of General and Gastrointestinal Surgery, Massachusetts General Hospital & Harvard Medical School, Boston, MA, USA. dberger@partners.org.
Abstract
BACKGROUND: Extramural vascular invasion (EMVI) is a known poor prognostic factor in colorectal carcinoma; however, its molecular basis has not been defined. This study aimed to assess the expression of molecular markers in EMVI positive colorectal carcinoma to understand their tumor microenvironment. METHODS: Immunohistochemistry was performed on tissue microarrays of surgically resected colorectal cancer specimens for immunological markers, and BRAFV600E mutation (and on the tissue blocks for mismatch repair proteins). Automated quantification was used for CD8, LAG3, FOXP3, PU1, and CD163, and manual quantification was used for PDL1, HLA I markers (beta-2 microglobulin, HC10), and HLA II. The Wilcoxon rank-sum test was used to compare EMVI positive and negative tumors. A logistic regression model was fitted to assess the predictive effect of biomarkers on EMVI. RESULTS: There were 340 EMVI positive and 678 EMVI negative chemo naïve tumors. PDL1 was barely expressed on tumor cells (median 0) in the entire cohort. We found a significantly lower expression of CD8, LAG3, FOXP3, PU1 cells, PDL1 positive macrophages, and beta-2 microglobulin on tumor cells in the EMVI positive subset (p ≤ 0.001). There was no association of BRAFV600E or deficient mismatch repair proteins (dMMR) with EMVI. PU1 (OR 0.8, 0.7-0.9) and low PDL1 (OR 1.6, 1.1-2.3) independently predicted EMVI on multivariate logistic regression among all biomarkers examined. CONCLUSION: There is a generalized blunting of immune response in EMVI positive colorectal carcinoma, which may contribute to a worse prognosis. Tumor-associated macrophages seem to play the most significant role in determining EMVI.
BACKGROUND: Extramural vascular invasion (EMVI) is a known poor prognostic factor in colorectal carcinoma; however, its molecular basis has not been defined. This study aimed to assess the expression of molecular markers in EMVI positive colorectal carcinoma to understand their tumor microenvironment. METHODS: Immunohistochemistry was performed on tissue microarrays of surgically resected colorectal cancer specimens for immunological markers, and BRAFV600E mutation (and on the tissue blocks for mismatch repair proteins). Automated quantification was used for CD8, LAG3, FOXP3, PU1, and CD163, and manual quantification was used for PDL1, HLA I markers (beta-2 microglobulin, HC10), and HLA II. The Wilcoxon rank-sum test was used to compare EMVI positive and negative tumors. A logistic regression model was fitted to assess the predictive effect of biomarkers on EMVI. RESULTS: There were 340 EMVI positive and 678 EMVI negative chemo naïve tumors. PDL1 was barely expressed on tumor cells (median 0) in the entire cohort. We found a significantly lower expression of CD8, LAG3, FOXP3, PU1 cells, PDL1 positive macrophages, and beta-2 microglobulin on tumor cells in the EMVI positive subset (p ≤ 0.001). There was no association of BRAFV600E or deficient mismatch repair proteins (dMMR) with EMVI. PU1 (OR 0.8, 0.7-0.9) and low PDL1 (OR 1.6, 1.1-2.3) independently predicted EMVI on multivariate logistic regression among all biomarkers examined. CONCLUSION: There is a generalized blunting of immune response in EMVI positive colorectal carcinoma, which may contribute to a worse prognosis. Tumor-associated macrophages seem to play the most significant role in determining EMVI.
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Authors: Muhammed R S Siddiqui; Constantinos Simillis; Chris Hunter; Manish Chand; Jemma Bhoday; Aurelie Garant; Te Vuong; Giovanni Artho; Shahnawaz Rasheed; Paris Tekkis; Al-Mutaz Abulafi; Gina Brown Journal: Br J Cancer Date: 2017-04-27 Impact factor: 7.640
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