Tumor–stroma ratio in colitis-associated colorectal cancer
Keywords:
Tumor microenvironment, oncogenesis, colorectal cancer, colitis-associated colorectal cancer, inflammatory bowel disease, tumor biology
Abstract
High stroma content, as measured by tumor-stroma ratio (TSR), is generally a negative prognostic parameter for epithelial cancers, including sporadic colorectal cancer (sCRC). Inflammatory bowel disease patients have higher risk for colorectal cancer than the background population. Evidence suggests that this colitis-associated colorectal cancer (CAC) is more aggressive and occurs at younger age than sCRC. CAC also differs from sCRC in oncogenesis and prognosis. This study tests the hypothesis that TSR in CAC tumors correlates with survival. Age at CAC diagnosis relative to TSR was also explored. TSR was quantified in 36 CAC cases. In routine hematoxylin–eosin staining, the amount of stroma was estimated in categorical steps of 10% increments per image field. The area with highest amount of stroma and tumor tissue at all quadrants of the visual field boundary was scored for TSR. For statistical analysis, tumors were divided into stroma-high (> 50%) or stroma-low (≤ 50%). Of all cases, 22 were stroma-high and 14 were stroma-low. Five-year survival in the stroma-high group was 32% (n = 22), compared to 71% (n = 14) in the stroma-low group (p = 0.049). High stroma content was more frequent if cancer diagnosis was before 60 years of age (17/23) compared to after 60 years of age (5/13). Despite differences in oncogenesis and tumor biology in CAC compared to sCRC, high stroma content also predicts worse outcome in CAC and is particularly common in younger patients.
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References
1. Ekbom A, Helmick C, Zack M, Adami H-O. Ulcerative colitis and colorectal cancer. N Engl J Med. 1990;323:1228–33. doi: https://doi.org/10.1056/NEJM199011013231802
2. Eaden JA, Abrams KR, Mayberry JF. The risk of colorectal cancer in ulcerative colitis: a meta-analysis. Gut. 2001;48:526–35. doi: https://doi.org/10.1136/gut.48.4.526
3. Gillen CD, Andrews HA, Prior P, Allan RN. Crohn’s disease and colorectal cancer. Gut. 1994;35:651–5. doi: https://doi.org/10.1136/gut.35.5.651
4. Olén O, Erichsen R, Sachs MC, Pedersen L, Halfvarson J, Askling J, et al. Colorectal cancer in ulcerative colitis: a Scandinavian population-based cohort study. Lancet. 2020;395:123–31. doi: https://doi.org/10.1016/S0140-6736(19)32545-0
5. Nieminen U, Jussila A, Nordling S, Mustonen H, Färkkilä MA. Inflammation and disease duration have a cumulative effect on the risk of dysplasia and carcinoma in IBD: a case-control observational study based on registry data. Int J Cancer J Int Cancer. 2014;134:189–96. doi: https://doi.org/10.1002/ijc.28346
6. Gupta RB, Harpaz N, Itzkowitz S, Hossain S, Matula S, Kornbluth A, et al. Histologic inflammation is a risk factor for progression to colorectal neoplasia in ulcerative colitis: a cohort study. Gastroenterology. 2007;133:1099–105; quiz 1340–1. doi: https://doi.org/10.1053/j.gastro.2007.08.001
7. Jess T, Loftus EV, Jr, Velayos FS, Winther KV, Tremaine WJ, Zinsmeister AR, et al. Risk factors for colorectal neoplasia in inflammatory bowel disease: a nested case-control study from Copenhagen County, Denmark and Olmsted County, Minnesota. Am J Gastroenterol. 2007;102:829–36. doi: https://doi.org/10.1111/j.1572-0241.2007.01070.x
8. Bonovas S, Fiorino G, Lytras T, Nikolopoulos G, Peyrin-Biroulet L, Danese S. Systematic review with meta-analysis: use of 5-aminosalicylates and risk of colorectal neoplasia in patients with inflammatory bowel disease. Aliment Pharmacol Ther. 2017;45:1179–92. doi: https://doi.org/10.1111/apt.14023
9. Li H, Fan X, Houghton J. Tumor microenvironment: the role of the tumor stroma in cancer. J Cell Biochem. 2007;101:805–15. doi: https://doi.org/10.1002/jcb.21159
10. D’Arcangelo E, Wu NC, Cadavid JL, McGuigan AP. The life cycle of cancer-associated fibroblasts within the tumour stroma and its importance in disease outcome. Br J Cancer. 2020;122:931–42. doi: https://doi.org/10.1038/s41416-019-0705-1
11. Fan S, Zhou L, Zhang W, Wang D, Tang D. Role of imbalanced gut microbiota in promoting CRC metastasis: from theory to clinical application. Cell Commun Signal. 2024;22:232. doi: https://doi.org/10.1186/s12964-024-01615-9
12. Lu W, Kang Y. Epithelial-mesenchymal plasticity in cancer progression and metastasis. Dev Cell. 2019;49:361–74. doi: https://doi.org/10.1016/j.devcel.2019.04.010
13. QUASAR Collaborative Group. Adjuvant chemotherapy versus observation in patients with colorectal cancer: a randomised study. Lancet. 2007;370:2020–9. doi: https://doi.org/10.1016/S0140-6736(07)61866-2
14. AJCC cancer staging manual. Available from: https://link-springer-com.ezproxy.its.uu.se/book/9783319406176 [cited 10 January 2024].
15. Xu M, Li Y, Liu Y, Chang J, Zhou C, Weng W, et al. The development and implementation of pathological parameters and molecular testing impact prognosis of colorectal adenocarcinoma. J Natl Cancer Cent. 2024;4:74–85. doi: https://doi.org/10.1016/j.jncc.2024.02.001
16. Yang L, Yang J, Kleppe A, Danielsen HE, Kerr DJ. Personalizing adjuvant therapy for patients with colorectal cancer. Nat Rev Clin Oncol. 2024;21:67–79. doi: https://doi.org/10.1038/s41571-023-00834-2
17. Strous MTA, van der Linden RLA, Gubbels ALHM, Faes TKE, Bosscha K, Bronkhorst CM, et al. Node-negative colon cancer: histological, molecular, and stromal features predicting disease recurrence. Mol Med. 2023;29:77. doi: https://doi.org/10.1186/s10020-023-00677-8
18. Lea D, Håland S, Hagland HR, Søreide K. Accuracy of TNM staging in colorectal cancer: a review of current culprits, the modern role of morphology and stepping-stones for improvements in the molecular era. Scand J Gastroenterol. 2014;49:1153–63. doi: https://doi.org/10.3109/00365521.2014.950692
19. 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 Off J Int Soc Cell Oncol. 2007;29:387–98. doi: https://doi.org/10.1155/2007/175276
20. 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;57:528–33. doi: https://doi.org/10.1080/0284186X.2017.1385841
21. 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;25:644–51. doi: https://doi.org/10.1093/annonc/mdt593
22. van Pelt GW, Sandberg TP, Morreau H, Gelderblom H, van Krieken JHJM, Tollenaar RAEM, et al. The tumour–stroma ratio in colon cancer: the biological role and its prognostic impact. Histopathology. 2018;73:197–206. doi: https://doi.org/10.1111/his.13489
23. Polack M, Smit MA, van Pelt GW, Roodvoets AGH, Meershoek-Klein Kranenbarg E, Putter H, et al. Results from the UNITED study: a multicenter study validating the prognostic effect of the tumor–stroma ratio in colon cancer. ESMO Open. 2024;9:102988. doi: https://doi.org/10.1016/j.esmoop.2024.102988
24. 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 Pathol. 2021;14:2632010X21989686. doi: https://doi.org/10.1177/2632010X21989686
25. Rutter M, Saunders B, Wilkinson K, Rumbles S, Schofield G, Kamm M, et al. Severity of inflammation is a risk factor for colorectal neoplasia in ulcerative colitis. Gastroenterology. 2004;126:451–9. doi: https://doi.org/10.1053/j.gastro.2003.11.010
26. Saraggi D, Fassan M, Mescoli C, Scarpa M, Valeri N, Michielan A, et al. The molecular landscape of colitis-associated carcinogenesis. Dig Liver Dis. 2017;49:326–30. doi: https://doi.org/10.1016/j.dld.2016.12.011
27. Guinney J, Dienstmann R, Wang X, de Reyniès A, Schlicker A, Soneson C, et al. The consensus molecular subtypes of colorectal cancer. Nat Med. 2015;21:1350–6. doi: https://doi.org/10.1038/nm.3967
28. Rajamäki K, Taira A, Katainen R, Välimäki N, Kuosmanen A, Plaketti R-M, et al. Genetic and epigenetic characteristics of inflammatory bowel disease-associated colorectal cancer. Gastroenterology. 2021;161:592–607. doi: https://doi.org/10.1053/j.gastro.2021.04.042
29. Lutgens MWMD, van Oijen MGH, van der Heijden GJMG, Vleggaar FP, Siersema PD, Oldenburg B. Declining risk of colorectal cancer in inflammatory bowel disease: an updated meta-analysis of population-based cohort studies. Inflamm Bowel Dis. 2013;19:789–99. doi: https://doi.org/10.1097/MIB.0b013e31828029c0
30. Olén O, Erichsen R, Sachs MC, Pedersen L, Halfvarson J, Askling J, et al. Colorectal cancer in Crohn’s disease: a Scandinavian population-based cohort study. Lancet Gastroenterol Hepatol. 2020;5:475–84. doi: https://doi.org/10.1016/S2468-1253(20)30005-4
31. Everhov ÅH, Erichsen R, Järås J, Pedersen L, Halfvarson J, Askling J, et al. Colorectal cancer in elderly-onset inflammatory bowel disease: a 1969–2017 Scandinavian register-based cohort study. Aliment Pharmacol Ther. 2022;56:1168–82. doi: https://doi.org/10.1111/apt.17175
32. Sebastian S, Hernández V, Myrelid P, Kariv R, Tsianos E, Toruner M, et al. Colorectal cancer in inflammatory bowel disease: results of the 3rd ECCO pathogenesis scientific workshop (I). J Crohns Colitis. 2014;8:5–18. doi: https://doi.org/10.1016/j.crohns.2013.04.008
33. Herrinton LJ, Liu L, Levin TR, Allison JE, Lewis JD, Velayos F. Incidence and mortality of colorectal adenocarcinoma in persons with inflammatory bowel disease from 1998 to 2010. Gastroenterology. 2012;143:382–9. doi: https://doi.org/10.1053/j.gastro.2012.04.054
34. Lundqvist E, Westberg K, Boman SE, Myrberg IH, Everhov ÅH, Myrelid P, et al. Outcome after surgery for colon cancer in a national cohort of patients with and without inflammatory bowel disease. Aliment Pharmacol Ther. 2025;n/a:n/a. doi: https://doi.org/10.1111/apt.70296
35. Lundqvist E, Westberg K, Dietrich CE, Everhov ÅH, Myrelid P, Glimelius B, et al. Treatment and survival of non-metastatic rectal cancer in patients with inflammatory bowel disease: nationwide cohort study. BJS Open. 2025;9:zraf014. doi: https://doi.org/10.1093/bjsopen/zraf014
36. Bogach J, Pond G, Eskicioglu C, Seow H. Age-related survival differences in patients with inflammatory bowel disease – associated colorectal cancer: a population-based cohort study. Inflamm Bowel Dis. 2019;25:1957–65. doi: https://doi.org/10.1093/ibd/izz088
37. Klimeck L, Heisser T, Hoffmeister M, Brenner H. Colorectal cancer: a health and economic problem. Best Pract Res Clin Gastroenterol. 2023;66:101839. doi: https://doi.org/10.1016/j.bpg.2023.101839
38. Siegel RL, Wagle NS, Cercek A, Smith RA, Jemal A. Colorectal cancer statistics, 2023. CA Cancer J Clin. 2023;73:233–54. doi: https://doi.org/10.3322/caac.21772
39. van Pelt GW, Kjær-Frifeldt S, van Krieken JHJM, Al Dieri R, Morreau H, Tollenaar RAEM, et al. Scoring the tumor-stroma ratio in colon cancer: procedure and recommendations. Virchows Arch. 2018;473:405–12. doi: https://doi.org/10.1007/s00428-018-2408-z
40. Therneau TM. A package for survival analysis in R. 2024. Available from: https://CRAN.R-project.org/package=survival [cited 28 October 2025].
41. R Core Team. R: a language and environment for statistical computing. Vienna: R Foundation for Statistical Computing; 2024. Available from: https://www.R-project.org/ [cited 28 October 2025].
42. Therneau TM, Grambsch PM. Modeling survival data: extending the cox model. New York, NY: Springer; 2000.
43. Ishii G. New insights into cancer pathology learned from the dynamics of cancer-associated fibroblasts. Pathol Int. 2024;74:493–507. doi: https://doi.org/10.1111/pin.13461
44. Feliu J, Gámez-Pozo A, Martínez-Pérez D, Pérez-Wert P, Matamala-Luengo D, Viñal D, et al. Functional proteomics of colon cancer consensus molecular subtypes. Br J Cancer. 2024;130:1670–8. doi: https://doi.org/10.1038/s41416-024-02650-6
45. Strous MTA, Faes TKE, Gubbels ALHM, van der Linden RLA, Mesker WE, Bosscha K, et al. A high tumour-stroma ratio (TSR) in colon tumours and its metastatic lymph nodes predicts poor cancer-free survival and chemo resistance. Clin Transl Oncol. 2022;24:1047–58. doi: https://doi.org/10.1007/s12094-021-02746-y
46. Huijbers A, van Pelt GW, Kerr RS, Johnstone EC, Tollenaar RAEM, Kerr DJ, et al. The value of additional bevacizumab in patients with high-risk stroma-high colon cancer. A study within the QUASAR2 trial, an open-label randomized phase 3 trial. J Surg Oncol. 2018;117:1043–8. doi: https://doi.org/10.1002/jso.24998
47. Cheddani H, Dauchet L, Fumery M, Charpentier C, Bouvier AM, Dupas J-L, et al. Cancer in elderly onset inflammatory bowel disease: a population-based study. Off J Am Coll Gastroenterol ACG. 2016;111:1428. doi: https://doi.org/10.1038/ajg.2016.304
48. Zhu Y, Zhu M, Lance P. IL1β-mediated stromal COX-2 signaling mediates proliferation and invasiveness of colonic epithelial cancer cells. Exp Cell Res. 2012;318:2520–30. doi: https://doi.org/10.1016/j.yexcr.2012.07.021
49. Zhu Y, Zhu M, Lance P. iNOS signaling interacts with COX-2 pathway in colonic fibroblasts. Exp Cell Res. 2012;318:2116–27. doi: https://doi.org/10.1016/j.yexcr.2012.05.027
50. Björner K, Chen W-N, Gannavarapu VR, Axling F, Gulyas M, Halim MA, et al. High iNOS and IL-1β immunoreactivity are features of colitis-associated colorectal cancer tumors, but fail to predict 5-year survival. Ups J Med Sci. 2024;28:10241. doi: https://doi.org/10.48101/ujms.v128.10241
51. Li Y, Wang L, Pappan L, Galliher-Beckley A, Shi J. IL-1β promotes stemness and invasiveness of colon cancer cells through Zeb1 activation. Mol Cancer. 2012;11:87. doi: https://doi.org/10.1186/1476-4598-11-87
52. Sahoo K, Sundararajan V. IL-1β and associated molecules as prognostic biomarkers linked with immune cell infiltration in colorectal cancer: an integrated statistical and machine learning approach. Discov Oncol. 2025;16:252. doi: https://doi.org/10.1007/s12672-025-01989-3
2. Eaden JA, Abrams KR, Mayberry JF. The risk of colorectal cancer in ulcerative colitis: a meta-analysis. Gut. 2001;48:526–35. doi: https://doi.org/10.1136/gut.48.4.526
3. Gillen CD, Andrews HA, Prior P, Allan RN. Crohn’s disease and colorectal cancer. Gut. 1994;35:651–5. doi: https://doi.org/10.1136/gut.35.5.651
4. Olén O, Erichsen R, Sachs MC, Pedersen L, Halfvarson J, Askling J, et al. Colorectal cancer in ulcerative colitis: a Scandinavian population-based cohort study. Lancet. 2020;395:123–31. doi: https://doi.org/10.1016/S0140-6736(19)32545-0
5. Nieminen U, Jussila A, Nordling S, Mustonen H, Färkkilä MA. Inflammation and disease duration have a cumulative effect on the risk of dysplasia and carcinoma in IBD: a case-control observational study based on registry data. Int J Cancer J Int Cancer. 2014;134:189–96. doi: https://doi.org/10.1002/ijc.28346
6. Gupta RB, Harpaz N, Itzkowitz S, Hossain S, Matula S, Kornbluth A, et al. Histologic inflammation is a risk factor for progression to colorectal neoplasia in ulcerative colitis: a cohort study. Gastroenterology. 2007;133:1099–105; quiz 1340–1. doi: https://doi.org/10.1053/j.gastro.2007.08.001
7. Jess T, Loftus EV, Jr, Velayos FS, Winther KV, Tremaine WJ, Zinsmeister AR, et al. Risk factors for colorectal neoplasia in inflammatory bowel disease: a nested case-control study from Copenhagen County, Denmark and Olmsted County, Minnesota. Am J Gastroenterol. 2007;102:829–36. doi: https://doi.org/10.1111/j.1572-0241.2007.01070.x
8. Bonovas S, Fiorino G, Lytras T, Nikolopoulos G, Peyrin-Biroulet L, Danese S. Systematic review with meta-analysis: use of 5-aminosalicylates and risk of colorectal neoplasia in patients with inflammatory bowel disease. Aliment Pharmacol Ther. 2017;45:1179–92. doi: https://doi.org/10.1111/apt.14023
9. Li H, Fan X, Houghton J. Tumor microenvironment: the role of the tumor stroma in cancer. J Cell Biochem. 2007;101:805–15. doi: https://doi.org/10.1002/jcb.21159
10. D’Arcangelo E, Wu NC, Cadavid JL, McGuigan AP. The life cycle of cancer-associated fibroblasts within the tumour stroma and its importance in disease outcome. Br J Cancer. 2020;122:931–42. doi: https://doi.org/10.1038/s41416-019-0705-1
11. Fan S, Zhou L, Zhang W, Wang D, Tang D. Role of imbalanced gut microbiota in promoting CRC metastasis: from theory to clinical application. Cell Commun Signal. 2024;22:232. doi: https://doi.org/10.1186/s12964-024-01615-9
12. Lu W, Kang Y. Epithelial-mesenchymal plasticity in cancer progression and metastasis. Dev Cell. 2019;49:361–74. doi: https://doi.org/10.1016/j.devcel.2019.04.010
13. QUASAR Collaborative Group. Adjuvant chemotherapy versus observation in patients with colorectal cancer: a randomised study. Lancet. 2007;370:2020–9. doi: https://doi.org/10.1016/S0140-6736(07)61866-2
14. AJCC cancer staging manual. Available from: https://link-springer-com.ezproxy.its.uu.se/book/9783319406176 [cited 10 January 2024].
15. Xu M, Li Y, Liu Y, Chang J, Zhou C, Weng W, et al. The development and implementation of pathological parameters and molecular testing impact prognosis of colorectal adenocarcinoma. J Natl Cancer Cent. 2024;4:74–85. doi: https://doi.org/10.1016/j.jncc.2024.02.001
16. Yang L, Yang J, Kleppe A, Danielsen HE, Kerr DJ. Personalizing adjuvant therapy for patients with colorectal cancer. Nat Rev Clin Oncol. 2024;21:67–79. doi: https://doi.org/10.1038/s41571-023-00834-2
17. Strous MTA, van der Linden RLA, Gubbels ALHM, Faes TKE, Bosscha K, Bronkhorst CM, et al. Node-negative colon cancer: histological, molecular, and stromal features predicting disease recurrence. Mol Med. 2023;29:77. doi: https://doi.org/10.1186/s10020-023-00677-8
18. Lea D, Håland S, Hagland HR, Søreide K. Accuracy of TNM staging in colorectal cancer: a review of current culprits, the modern role of morphology and stepping-stones for improvements in the molecular era. Scand J Gastroenterol. 2014;49:1153–63. doi: https://doi.org/10.3109/00365521.2014.950692
19. 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 Off J Int Soc Cell Oncol. 2007;29:387–98. doi: https://doi.org/10.1155/2007/175276
20. 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;57:528–33. doi: https://doi.org/10.1080/0284186X.2017.1385841
21. 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;25:644–51. doi: https://doi.org/10.1093/annonc/mdt593
22. van Pelt GW, Sandberg TP, Morreau H, Gelderblom H, van Krieken JHJM, Tollenaar RAEM, et al. The tumour–stroma ratio in colon cancer: the biological role and its prognostic impact. Histopathology. 2018;73:197–206. doi: https://doi.org/10.1111/his.13489
23. Polack M, Smit MA, van Pelt GW, Roodvoets AGH, Meershoek-Klein Kranenbarg E, Putter H, et al. Results from the UNITED study: a multicenter study validating the prognostic effect of the tumor–stroma ratio in colon cancer. ESMO Open. 2024;9:102988. doi: https://doi.org/10.1016/j.esmoop.2024.102988
24. 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 Pathol. 2021;14:2632010X21989686. doi: https://doi.org/10.1177/2632010X21989686
25. Rutter M, Saunders B, Wilkinson K, Rumbles S, Schofield G, Kamm M, et al. Severity of inflammation is a risk factor for colorectal neoplasia in ulcerative colitis. Gastroenterology. 2004;126:451–9. doi: https://doi.org/10.1053/j.gastro.2003.11.010
26. Saraggi D, Fassan M, Mescoli C, Scarpa M, Valeri N, Michielan A, et al. The molecular landscape of colitis-associated carcinogenesis. Dig Liver Dis. 2017;49:326–30. doi: https://doi.org/10.1016/j.dld.2016.12.011
27. Guinney J, Dienstmann R, Wang X, de Reyniès A, Schlicker A, Soneson C, et al. The consensus molecular subtypes of colorectal cancer. Nat Med. 2015;21:1350–6. doi: https://doi.org/10.1038/nm.3967
28. Rajamäki K, Taira A, Katainen R, Välimäki N, Kuosmanen A, Plaketti R-M, et al. Genetic and epigenetic characteristics of inflammatory bowel disease-associated colorectal cancer. Gastroenterology. 2021;161:592–607. doi: https://doi.org/10.1053/j.gastro.2021.04.042
29. Lutgens MWMD, van Oijen MGH, van der Heijden GJMG, Vleggaar FP, Siersema PD, Oldenburg B. Declining risk of colorectal cancer in inflammatory bowel disease: an updated meta-analysis of population-based cohort studies. Inflamm Bowel Dis. 2013;19:789–99. doi: https://doi.org/10.1097/MIB.0b013e31828029c0
30. Olén O, Erichsen R, Sachs MC, Pedersen L, Halfvarson J, Askling J, et al. Colorectal cancer in Crohn’s disease: a Scandinavian population-based cohort study. Lancet Gastroenterol Hepatol. 2020;5:475–84. doi: https://doi.org/10.1016/S2468-1253(20)30005-4
31. Everhov ÅH, Erichsen R, Järås J, Pedersen L, Halfvarson J, Askling J, et al. Colorectal cancer in elderly-onset inflammatory bowel disease: a 1969–2017 Scandinavian register-based cohort study. Aliment Pharmacol Ther. 2022;56:1168–82. doi: https://doi.org/10.1111/apt.17175
32. Sebastian S, Hernández V, Myrelid P, Kariv R, Tsianos E, Toruner M, et al. Colorectal cancer in inflammatory bowel disease: results of the 3rd ECCO pathogenesis scientific workshop (I). J Crohns Colitis. 2014;8:5–18. doi: https://doi.org/10.1016/j.crohns.2013.04.008
33. Herrinton LJ, Liu L, Levin TR, Allison JE, Lewis JD, Velayos F. Incidence and mortality of colorectal adenocarcinoma in persons with inflammatory bowel disease from 1998 to 2010. Gastroenterology. 2012;143:382–9. doi: https://doi.org/10.1053/j.gastro.2012.04.054
34. Lundqvist E, Westberg K, Boman SE, Myrberg IH, Everhov ÅH, Myrelid P, et al. Outcome after surgery for colon cancer in a national cohort of patients with and without inflammatory bowel disease. Aliment Pharmacol Ther. 2025;n/a:n/a. doi: https://doi.org/10.1111/apt.70296
35. Lundqvist E, Westberg K, Dietrich CE, Everhov ÅH, Myrelid P, Glimelius B, et al. Treatment and survival of non-metastatic rectal cancer in patients with inflammatory bowel disease: nationwide cohort study. BJS Open. 2025;9:zraf014. doi: https://doi.org/10.1093/bjsopen/zraf014
36. Bogach J, Pond G, Eskicioglu C, Seow H. Age-related survival differences in patients with inflammatory bowel disease – associated colorectal cancer: a population-based cohort study. Inflamm Bowel Dis. 2019;25:1957–65. doi: https://doi.org/10.1093/ibd/izz088
37. Klimeck L, Heisser T, Hoffmeister M, Brenner H. Colorectal cancer: a health and economic problem. Best Pract Res Clin Gastroenterol. 2023;66:101839. doi: https://doi.org/10.1016/j.bpg.2023.101839
38. Siegel RL, Wagle NS, Cercek A, Smith RA, Jemal A. Colorectal cancer statistics, 2023. CA Cancer J Clin. 2023;73:233–54. doi: https://doi.org/10.3322/caac.21772
39. van Pelt GW, Kjær-Frifeldt S, van Krieken JHJM, Al Dieri R, Morreau H, Tollenaar RAEM, et al. Scoring the tumor-stroma ratio in colon cancer: procedure and recommendations. Virchows Arch. 2018;473:405–12. doi: https://doi.org/10.1007/s00428-018-2408-z
40. Therneau TM. A package for survival analysis in R. 2024. Available from: https://CRAN.R-project.org/package=survival [cited 28 October 2025].
41. R Core Team. R: a language and environment for statistical computing. Vienna: R Foundation for Statistical Computing; 2024. Available from: https://www.R-project.org/ [cited 28 October 2025].
42. Therneau TM, Grambsch PM. Modeling survival data: extending the cox model. New York, NY: Springer; 2000.
43. Ishii G. New insights into cancer pathology learned from the dynamics of cancer-associated fibroblasts. Pathol Int. 2024;74:493–507. doi: https://doi.org/10.1111/pin.13461
44. Feliu J, Gámez-Pozo A, Martínez-Pérez D, Pérez-Wert P, Matamala-Luengo D, Viñal D, et al. Functional proteomics of colon cancer consensus molecular subtypes. Br J Cancer. 2024;130:1670–8. doi: https://doi.org/10.1038/s41416-024-02650-6
45. Strous MTA, Faes TKE, Gubbels ALHM, van der Linden RLA, Mesker WE, Bosscha K, et al. A high tumour-stroma ratio (TSR) in colon tumours and its metastatic lymph nodes predicts poor cancer-free survival and chemo resistance. Clin Transl Oncol. 2022;24:1047–58. doi: https://doi.org/10.1007/s12094-021-02746-y
46. Huijbers A, van Pelt GW, Kerr RS, Johnstone EC, Tollenaar RAEM, Kerr DJ, et al. The value of additional bevacizumab in patients with high-risk stroma-high colon cancer. A study within the QUASAR2 trial, an open-label randomized phase 3 trial. J Surg Oncol. 2018;117:1043–8. doi: https://doi.org/10.1002/jso.24998
47. Cheddani H, Dauchet L, Fumery M, Charpentier C, Bouvier AM, Dupas J-L, et al. Cancer in elderly onset inflammatory bowel disease: a population-based study. Off J Am Coll Gastroenterol ACG. 2016;111:1428. doi: https://doi.org/10.1038/ajg.2016.304
48. Zhu Y, Zhu M, Lance P. IL1β-mediated stromal COX-2 signaling mediates proliferation and invasiveness of colonic epithelial cancer cells. Exp Cell Res. 2012;318:2520–30. doi: https://doi.org/10.1016/j.yexcr.2012.07.021
49. Zhu Y, Zhu M, Lance P. iNOS signaling interacts with COX-2 pathway in colonic fibroblasts. Exp Cell Res. 2012;318:2116–27. doi: https://doi.org/10.1016/j.yexcr.2012.05.027
50. Björner K, Chen W-N, Gannavarapu VR, Axling F, Gulyas M, Halim MA, et al. High iNOS and IL-1β immunoreactivity are features of colitis-associated colorectal cancer tumors, but fail to predict 5-year survival. Ups J Med Sci. 2024;28:10241. doi: https://doi.org/10.48101/ujms.v128.10241
51. Li Y, Wang L, Pappan L, Galliher-Beckley A, Shi J. IL-1β promotes stemness and invasiveness of colon cancer cells through Zeb1 activation. Mol Cancer. 2012;11:87. doi: https://doi.org/10.1186/1476-4598-11-87
52. Sahoo K, Sundararajan V. IL-1β and associated molecules as prognostic biomarkers linked with immune cell infiltration in colorectal cancer: an integrated statistical and machine learning approach. Discov Oncol. 2025;16:252. doi: https://doi.org/10.1007/s12672-025-01989-3
Published
2026-01-02
How to Cite
Björner , K., Gulyas , M., Hellström , P. M., & Webb , D.-L. (2026). Tumor–stroma ratio in colitis-associated colorectal cancer. Upsala Journal of Medical Sciences, 130, e13250. https://doi.org/10.48101/ujms.v130.13250
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Original Articles
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