Stromal scoring in advanced colon and rectal cancer: stroma-rich tumors and their association with aggressive phenotypes

Ricella Souza da Silva; Eduardo Queiroga; Cynthia Osório; Karin Cunha; Eliane Dias

doi:10.2298/AOO210403003S

Ricella M. Souza da Silva Pathological Anatomy Service, Lauro Wanderley University Hospital of Federal University of Paraíba, João Pessoa, Paraíba, 58050-585, Brazil; Postgraduate Program in Pathology, Fluminense Federal University, Niterói, Rio de Janeiro, 24033-900, Brazil
Eduardo M. Queiroga Laboratory of Pathological Anatomy, Alcides Carneiro University Hospital of the Federal University of Campina Grande, Campina Grande, Paraíba, 58400-398, Brazil
Cynthia A. B. de Toledo Osório Department of Pathology, A. C. Camargo Cancer Center, São Paulo, 01525-001, Brazil
Karin S. Cunha Postgraduate Program in Pathology, Fluminense Federal University, Niterói, Rio de Janeiro, 24033-900, Brazil
Eliane P. Dias Department of Pathology, Fluminense Federal University, Niterói, Rio de Janeiro, 24033-900, Brazil

DOI: https://doi.org/10.2298/AOO210403003S

Keywords: Tumor microenvironment, Tumor-stroma proportion, colorectal cancer, advanced disease, aggressive phenotypes

Abstract

Background: Our aim was to explore relevance of the proportion between neoplastic cell component and tumor-associated stroma in order to assess its association with confirmed aggressive phenotypes of right/left colon and rectum cancers in a large series of patients. Methods: The quantification of stroma component was performed in patients diagnosed with colorectal adenocarcinoma who underwent surgical resection. The analyzed variables were age, gender, anatomical/pathological features, and tumor-stroma proportion. Tumor-stroma proportion was estimated based on slides used in routine pathology for determination of T status and was described as low, with a stromal percentage ≤50% or high, with a stromal percentage >50%. The tumor-stroma proportion was estimated by two observers, and the inter-observer agreement was assessed. Results: The sample included 390 colorectal adenocarcinoma patients. Stroma-rich tumors were observed in 53.3% of cases. Well-differentiated tumors had the lowest stromal proportions (p = 0.028). Stroma-poor tumors showed less depth of invasion (p<0.001). High stromal content was observed in association with tumor budding, perineural, angiolymphatic, and lymph node involvement, and distant metastasis (p≤0.001). Colorectal adenocarcinoma without lymph node or distant metastasis involvement had lower stromal proportion, while metastatic ones exhibited high stromal content (p <0.001). The inter-rater reliability (concordance)
between the estimations of pathologists for tumor-stroma proportions was high (κ=0.746). Conclusion: The tumor stroma proportion in colorectal adenocarcinoma was associated with adverse prognostic factors, reflecting the stage of the disease. Stroma-rich tumors showed a significant correlation with advancement of the disease and its aggressiveness. Due to its availability tumor-stroma proportion evaluation has high application potential and can complement current staging system for colorectal adenocarcinoma.

Author Biography

Ricella M. Souza da Silva, Pathological Anatomy Service, Lauro Wanderley University Hospital of Federal University of Paraíba, João Pessoa, Paraíba, 58050-585, Brazil; Postgraduate Program in Pathology, Fluminense Federal University, Niterói, Rio de Janeiro, 24033-900, Brazil

References

Colangelo T, Polcaro G, Muccillo L, D’Agostino G, Rosato V, Ziccardi P, et al. Friend or foe? The tumour microenvironment dilemma in colorectal cancer. Biochim Biophys Acta Rev Cancer. 2017 Jan;1867(1):1–18.

Colvin H, Mori M. Colorectal cancer: Back to the stroma--the real villain in colorectal cancer? Nat Rev Gastroenterol Hepatol. 2015 May;12(5):256–8.

Huet E, Jaroz C, Nguyen HQ, Belkacemi Y, Taille A, Stavrinides V, et al. Stroma in normal and cancer wound healing. FEBS J. 2019 Aug;286(15):2909–20.

Jakubowska K, Kisielewski W, Kańczuga-Koda L, Koda M, Famulski W. Stromal and intraepithelial tumor-infiltrating lymphocytes in colorectal carcinoma. Oncol Lett. 2017 Dec;14(6):6421–32.

Scheer R, Baidoshvili A, Zoidze S, Elferink MAG, Berkel AEM, Klaase JM, et al. Tumor-stroma ratio as prognostic factor for survival in rectal adenocarcinoma: A retrospective cohort study. World J Gastrointest Oncol. 2017 Dec 15;9(12):466–74.

Mesker WE, Junggeburt JMC, Szuhai K, de Heer P, Morreau H, Tanke HJ, et al. The carcinoma-stromal ratio of colon carcinoma is an independent factor for survival compared to lymph node status and tumor stage. Cell Oncol. 2007;29(5):387–98.

West NP, Dattani M, McShane P, Hutchins G, Grabsch J, Mueller W, et al. The proportion of tumour cells is an independent predictor for survival in colorectal cancer patients. Br J Cancer. 2010 May 11;102(10):1519–23.

Park JH, Richards CH, McMillan DC, Horgan PG, Roxburgh CSD. The relationship between tumour stroma percentage, the tumour microenvironment and survival in patients with primary operable colorectal cancer. Ann Oncol. 2014 Mar;25(3):644–51.

De Wever O, Mareel M. Role of tissue stroma in cancer cell invasion. J Pathol. 2003 Jul;200(4):429–47.

Sandberg TP, Stuart MPME, Oosting J, Tollenaar RAEM, Sier CFM, Mesker WE. Increased expression of cancer-associated fibroblast markers at the invasive front and its association with tumor-stroma ratio in colorectal cancer. BMC Cancer. 2019 Mar 29;19(1):284.

Ribeiro Franco PI, Rodrigues AP, de Menezes LB, Pacheco Miguel M. Tumor microenvironment components: Allies of cancer progression. Pathol Res Pract. 2020 Jan;216(1):152729.

McCorry AM, Loughrey MB, Longley DB, Lawler M, Dunne PD. Epithelial‐to‐mesenchymal transition signature assessment in colorectal cancer quantifies tumour stromal content rather than true transition. J Pathol. 2018 Dec;246(4):422–6.

van Pelt GW, Hansen TF, Bastiaannet E, Frifeldt SK, van Krieken JHJ, AEM Tollenaar R, et al. Stroma-High Lymph Node Involvement Predicts Poor Survival More Accurately for Patients with Stage III Colon Cancer. J Med Surg Pathol [Internet]. 2016 [cited 2020 Oct 27];01(02). Available from: https://www.omicsonline.org/open-access/stromahigh-lymph-node-involvement-predicts-poor-survival-more-accuratelyfor-patients-with-stage-iii-colon-cancer-jmsp-1000116.php?aid=72496

Ao T, Kajiwara Y, Yonemura K, Shinto E, Mochizuki S, Okamoto K, et al. Morphological consistency of desmoplastic reactions between the primary colorectal cancer lesion and associated metastatic lesions. Virchows Arch. 2020 Jul;477(1):47–55.

Hansen TF, Kjær-Frifeldt S, Lindebjerg J, Rafaelsen SR, Jensen LH, Jakobsen A, et al. Tumor-stroma ratio predicts recurrence in patients with colon cancer treated with neoadjuvant chemotherapy. Acta Oncol. 2018 Apr;57(4):528–33.

Sandberg TP, Oosting J, van Pelt GW, Mesker WE, Tollenaar RAEM, Morreau H. Erratum: Molecular profiling of colorectal tumors stratified by the histological tumor-stroma ratio - Increased expression of galectin-1 in tumors with high stromal content. Oncotarget. 2019 22;10(24):2416.

van Wyk HC, Roseweir A, Alexander P, Park JH, Horgan PG, McMillan DC, et al. The Relationship Between Tumor Budding, Tumor Microenvironment, and Survival in Patients with Primary Operable Colorectal Cancer. Ann Surg Oncol. 2019 Dec;26(13):4397–404.

Abstracts: 31stEuropean Congress of Pathology. Virchows Arch. 2019 Sep 1;475(S1):1–436.

Huijbers A, Tollenaar R a. EM, v Pelt GW, Zeestraten ECM, Dutton S, McConkey CC, et al. The proportion of tumor-stroma as a strong prognosticator for stage II and III colon cancer patients: validation in the VICTOR trial. Ann Oncol. 2013 Jan;24(1):179–85.

Martin B, Banner BM, Schäfer E-M, Mayr P, Anthuber M, Schenkirsch G, et al. Tumor proportion in colon cancer: results from a semiautomatic image analysis approach. Virchows Arch. 2020 Aug;477(2):185–93.

Geessink OGF, Baidoshvili A, Klaase JM, Ehteshami Bejnordi B, Litjens GJS, van Pelt GW, et al. Computer aided quantification of intratumoral stroma yields an independent prognosticator in rectal cancer. Cell Oncol (Dordr). 2019 Jun;42(3):331–41.

Nagtegaal ID, Odze RD, Klimstra D, Paradis V, Rugge M, Schirmacher P, et al. The 2019 WHO classification of tumours of the digestive system. Histopathology. 2020;76(2):182–8.

Amin MB, American Joint Committee on Cancer, American Cancer Society, editors. AJCC cancer staging manual. Eight edition / editor-in-chief, Mahul B. Amin, MD, FCAP ; editors, Stephen B. Edge, MD, FACS [and 16 others] ; Donna M. Gress, RHIT, CTR-Technical editor ; Laura R. Meyer, CAPM-Managing editor. Chicago IL: American Joint Committee on Cancer, Springer; 2017. 1024 p.

Schmoll HJ, Van Cutsem E, Stein A, Valentini V, Glimelius B, Haustermans K, et al. ESMO Consensus Guidelines for management of patients with colon and rectal cancer. a personalized approach to clinical decision making. Ann Oncol. 2012 Oct;23(10):2479–516.

Zunder SM, Gelderblom H, Tollenaar RA, Mesker WE. The significance of stromal collagen organization in cancer tissue: An in-depth discussion of literature. Critical Reviews in Oncology/Hematology. 2020 Jul 1;151:102907.

Gasparini B, Valadão M, Miranda-Filho A, Silva CMFP da. [Analysis of the age-period-cohort effect on mortality from colorectal cancer in Rio de Janeiro State, Brazil, from 1980 to 2014]. Cad Saude Publica. 2018 12;34(3):e00038017.

van Pelt GW, Krol JA, Lips IM, Peters FP, van Klaveren D, Boonstra JJ, et al. The value of tumor-stroma ratio as predictor of pathologic response after neoadjuvant chemoradiotherapy in esophageal cancer. Clinical and Translational Radiation Oncology. 2020 Jan 1;20:39–44.

van Pelt GW, Kjær-Frifeldt S, van Krieken JHJM, Al Dieri R, Morreau H, Tollenaar R a. EM, et al. Scoring the tumor-stroma ratio in colon cancer: procedure and recommendations. Virchows Arch. 2018 Oct;473(4):405–12.

Landis JR, Koch GG. An application of hierarchical kappa-type statistics in the assessment of majority agreement among multiple observers. Biometrics. 1977 Jun;33(2):363–74.

Ahn S, Cho J, Sung J, Lee JE, Nam SJ, Kim K-M, et al. The prognostic significance of tumor-associated stroma in invasive breast carcinoma. Tumour Biol. 2012 Oct;33(5):1573–80.

de Kruijf EM, van Nes JGH, van de Velde CJH, Putter H, Smit VTHBM, Liefers GJ, et al. Tumor-stroma ratio in the primary tumor is a prognostic factor in early breast cancer patients, especially in triple-negative carcinoma patients. Breast Cancer Res Treat. 2011 Feb;125(3):687–96.

Dekker TJA, van de Velde CJH, van Pelt GW, Kroep JR, Julien J-P, Smit VTHBM, et al. Prognostic significance of the tumor-stroma ratio: validation study in node-negative premenopausal breast cancer patients from the EORTC perioperative chemotherapy (POP) trial (10854). Breast Cancer Res Treat. 2013 Jun;139(2):371–9.

Zhang T, Xu J, Shen H, Dong W, Ni Y, Du J. Tumor-stroma ratio is an independent predictor for survival in NSCLC. Int J Clin Exp Pathol. 2015;8(9):11348–55.

Liu J, Liu J, Li J, Chen Y, Guan X, Wu X, et al. Tumor-stroma ratio is an independent predictor for survival in early cervical carcinoma. Gynecol Oncol. 2014 Jan;132(1):81–6.

Courrech Staal EFW, Wouters MWJM, van Sandick JW, Takkenberg MM, Smit VTHBM, Junggeburt JMC, et al. The stromal part of adenocarcinomas of the oesophagus: does it conceal targets for therapy? Eur J Cancer. 2010 Mar;46(4):720–8.

Pietras K, Ostman A. Hallmarks of cancer: interactions with the tumor stroma. Exp Cell Res. 2010 May 1;316(8):1324–31.

Siegel RL, Miller KD, Sauer AG, Fedewa SA, Butterly LF, Anderson JC, et al. Colorectal cancer statistics, 2020. CA: A Cancer Journal for Clinicians. 2020;70(3):145–64.

Hynes SO, Coleman HG, Kelly PJ, Irwin S, O’Neill RF, Gray RT, et al. Back to the future: routine morphological assessment of the tumour microenvironment is prognostic in stage II/III colon cancer in a large population-based study. Histopathology. 2017 Jul;71(1):12–26.

Mesker WE, Liefers G-J, Junggeburt JMC, van Pelt GW, Alberici P, Kuppen PJK, et al. Presence of a high amount of stroma and downregulation of SMAD4 predict for worse survival for stage I-II colon cancer patients. Cell Oncol. 2009;31(3):169–78.

Devarasetty M, Dominijanni A, Herberg S, Shelkey E, Skardal A, Soker S. Simulating the human colorectal cancer microenvironment in 3D tumor-stroma co-cultures in vitro and in vivo. Sci Rep [Internet]. 2020 Jun 17 [cited 2021 Jun 8];10. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7300090/

Eriksen AC, Sørensen FB, Lindebjerg J, Hager H, dePont Christensen R, Kjær-Frifeldt S, et al. The prognostic value of tumour stroma ratio and tumour budding in stage II colon cancer. A nationwide population-based study. Int J Colorectal Dis. 2018;33(8):1115–24.

Ueno H, Jones AM, Wilkinson KH, Jass JR, Talbot IC. Histological categorisation of fibrotic cancer stroma in advanced rectal cancer. Gut. 2004 Apr;53(4):581–6.

Pereira Júnior T, Alves AJ da C, Nogueira AMMF. Câncer colorretal: análise anatomopatológica de 476 colectomias consecutivas em Belo Horizonte (MG). J Bras Patol Med Lab. 2005 Jun;41(3):175–84.

Volpato MG, Koch K de S. Fatores de mau prognóstico nas peças operatórias de pacientes submetidos ao tratamento cirúrgico do câncer colorretal. Rev bras colo-proctol. 2008 Dec;28(4):414–24.

Wu J, Liang C, Chen M, Su W. Association between tumor-stroma ratio and prognosis in solid tumor patients: a systematic review and meta-analysis. Oncotarget. 2016 Oct 18;7(42):68954–65.

Souza da Silva RM, Queiroga EM, Paz AR, Neves FFP, Cunha KS, Dias EP. Standardized Assessment of the Tumor-Stroma Ratio in Colorectal Cancer: Interobserver Validation and Reproducibility of a Potential Prognostic Factor. Clin MedInsightsPathol. 2021 Jan 1;14:2632010X21989686.

Micke P, Strell C, Mattsson J, Martín-Bernabé A, Brunnström H, Huvila J, et al. The prognostic impact of the tumour stroma fraction: A machine learning-based analysis in 16 human solid tumour types. EBioMedicine 2021 Mar 1; 65.