Research advances in tumor budding of rectal cancer_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

ZHANG Xiaoyan ¹ , ZHANG Yiming ¹ , QIAO Miaomiao ¹ , LIU Nianjun ² ,  GUO Shunlin ²

1. The First Clinical Medical College of Lanzhou University, Lanzhou 730000, P. R. China;
2. Department of Radiology, The First Hospital of Lanzhou University, Lanzhou 730000, P. R. China;

Corresponding?author：

GUO Shunlin, Email: guoshunlin@msn.com

Keywords：

colorectal cancer; tumor budding; prognosis

DOI：

10.7507/1007-9424.202505109

Video：

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Objective To systematically summarize the assessment methods, pathological and molecular mechanisms of tumor budding (TB) in colorectal cancer (CRC), and to explore its potential value in personalized therapy and future research directions. Methods Through a systematic analysis of the literature, it focuses on elucidating the pathological processes and molecular mechanisms underlying TB formation, highlighting its complex interplay with the tumor microenvironment. The review also summarizes methodologies for TB counting and grading, spanning from conventional histopathological evaluation to innovative approaches leveraging radiomics and artificial intelligence. Results TB plays an essential role in clinical decision-making for CRC patients, demonstrating how TB grade influences surgical strategy selection and the planning of neoadjuvant and adjuvant therapies. Additionally, TB is also a key prognostic indicator of CRC, high-grade TB being consistently associated with increased risk of recurrence and reduced survival rate. Conclusions Future research should further unravel the molecular mechanisms of TB, refine TB assessment methodologies, and validate the clinical utility of TB in personalized treatment strategies through multicenter trials. These efforts are expected to improve therapeutic outcomes and prognosis for CRC patients.

Citation： ZHANG Xiaoyan, ZHANG Yiming, QIAO Miaomiao, LIU Nianjun, GUO Shunlin. Research advances in tumor budding of rectal cancer. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2025, 32(11): 1482-1486. doi: 10.7507/1007-9424.202505109 Copy

1.	Murphy CC, Zaki TA. Changing epidemiology of colorectal cancer-birth cohort effects and emerging risk factors. Nat Rev Gastroenterol Hepatol, 2024, 21(1): 25-34.
2.	Smith HG, Nilsson PJ, Shogan BD, et al. Neoadjuvant treatment of colorectal cancer: comprehensive review. BJS Open, 2024, 8(3): zrae038. doi: 10.1093/bjsopen/zrae038.
3.	Jiang SX, Zarrin A, Shahidi N. T1 colorectal cancer management in the era of minimally invasive endoscopic resection. World J Gastrointest Oncol, 2024, 16(6): 2284-2294.
4.	Le Tran N, Wang Y, Nie G. Podocalyxin in normal tissue and epithelial cancer. Cancers (Basel), 2021, 13(12): 2863. doi: 10.3390/cancers13122863.
5.	Lugli A, Zlobec I, Berger MD, et al. Tumour budding in solid cancers. Nat Rev Clin Oncol, 2021, 18(2): 101-115.
6.	Zheng S, Luo J, Xie S, et al. Tumor budding of cervical squamous cell carcinoma: epithelial-mesenchymal transition-like cancer stem cells? PeerJ, 2022, 10: e13745. doi: 10.7717/peerj.13745.
7.	Bakir B, Chiarella AM, Pitarresi JR, et al. EMT, MET, plasticity, and tumor metastasis. Trends Cell Biol, 2020, 30(10): 764-776.
8.	梁迪, 劉艷榮. 腫瘤出芽分子機制的研究進展. 濟寧醫學院學報, 2024, 47(1): 61-64.
9.	Buch A, Khan U, Rathod H, et al. Tumor budding in breast carcinoma: a systematic review and meta-analysis. J Cancer Res Ther, 2023, 19(7): 1697-1713.
10.	Omae T, Omori Y, Makihara Y, et al. Mechanism of tumor budding in patient-derived metachronous oral primary squamous cell carcinoma cell lines. Int J Mol Sci, 2025, 26(7): 3347. doi: 10.3390/ijms26073347.
11.	Zanoletti E, Daloiso A, Nicolè L, et al. Tumor budding to investigate local invasion, metastasis, and prognosis of head and neck carcinoma: a systematic review. Head Neck, 2024, 46(3): 651-671.
12.	Dawson H, Christe L, Eichmann M, et al. Tumour budding/T cell infiltrates in colorectal cancer: proposal of a novel combined score. Histopathology, 2020, 76(4): 572-580.
13.	Hatthakarnkul P, Quinn JA, Ammar A, et al. Molecular mechanisms of tumour budding and its association with microenvironment in colorectal cancer. Clin Sci (Lond), 2022, 136(8): 521-535.
14.	Tie Y, Tang F, Wei YQ, et al. Immunosuppressive cells in cancer: mechanisms and potential therapeutic targets. J Hematol Oncol, 2022, 15(1): 61. doi: 10.1186/s13045-022-01282-8.
15.	Miyazaki K, Hoshino D, Kasajima R, et al. Oncofetal morphogenesis similar to embryonic gut formation by a subpopulation of DLD-1 human colon cancer cells. Exp Cell Res, 2024, 442(2): 114188. doi: 10.1016/j.yexcr.2024.114188.
16.	Mohamed SY, Kaf RM, Ahmed MM, et al. The prognostic value of cancer stem cell markers (Notch1, ALDH1, and CD44) in primary colorectal carcinoma. J Gastrointest Cancer, 2019, 50(4): 824-837.
17.	Trinh A, L?drach C, Dawson HE, et al. Tumour budding is associated with the mesenchymal colon cancer subtype and RAS/RAF mutations: a study of 1 320 colorectal cancers with Consensus Molecular Subgroup (CMS) data. Br J Cancer, 2018, 119(10): 1244-1251.
18.	Lugli A, Kirsch R, Ajioka Y, et al. Recommendations for reporting tumor budding in colorectal cancer based on the International Tumor Budding Consensus Conference (ITBCC) 2016. Mod Pathol, 2017, 30(9): 1299-1311.
19.	Zlobec I, B?chli M, Galuppini F, et al. Refining the ITBCC tumor budding scoring system with a “zero-budding” category in colorectal cancer. Virchows Arch, 2021, 479(6): 1085-1090.
20.	李君, 馮梅寶, 來茂德, 等. 影響結直腸癌預后病理參數的診斷問題. 臨床與實驗病理學雜志, 2024, 40(12): 1241-1250.
21.	Studer L, Blank A, Bokhorst JM, et al. Taking tumour budding to the next frontier-a post International Tumour Budding Consensus Conference (ITBCC) 2016 review. Histopathology, 2021, 78(4): 476-484.
22.	Haddad TS, Lugli A, Aherne S, et al. Improving tumor budding reporting in colorectal cancer: a Delphi consensus study. Virchows Arch, 2021, 479(3): 459-469.
23.	Knebel M, Philipp Kühn J, K?rner S, et al. Optimizing prognostic assessment in high-risk head and neck squamous cell carcinomas: the impact of tumor budding and a novel histomorphological scoring system. Cancer Med, 2025, 14(4): e70685. doi: 10.1002/cam4.70685.
24.	McGenity C, Clarke EL, Jennings C, et al. Artificial intelligence in digital pathology: a systematic review and meta-analysis of diagnostic test accuracy. NPJ Digit Med, 2024, 7(1): 114. doi: 10.1038/s41746-024-01106-8.
25.	Haddad TS, Bokhorst JM, van den Dobbelsteen L, et al. Tumor budding and poorly differentiated clusters as a biological continuum in colorectal cancer invasion and prognosis. Sci Rep, 2025, 15(1): 16944. doi: 10.1038/s41598-025-00866-x.
26.	周振, 沈浮, 陸海迪, 等. 動態增強磁共振成像術前評估直腸癌腫瘤出芽等級的價值. 中國醫學計算機成像雜志, 2022, 28(4): 379-384.
27.	Peng L, Wang D, Zhuang Z, et al. Preoperative noninvasive evaluation of tumor budding in rectal cancer using multiparameter MRI radiomics. Acad Radiol, 2024, 31(6): 2334-2345.
28.	Li Z, Chen F, Zhang S, et al. The feasibility of MRI-based radiomics model in presurgical evaluation of tumor budding in locally advanced rectal cancer. Abdom Radiol (NY), 2022, 47(1): 56-65.
29.	Liu Z, Jia J, Bai F, et al. Predicting rectal cancer tumor budding grading based on MRI and CT with multimodal deep transfer learning: a dual-center study. Heliyon, 2024, 10(7): e28769. doi: 10.1016/j.heliyon.2024.e28769.
30.	Liu Z, Yang H, Nie L, et al. Prediction of tumor budding grading in rectal cancer using a multiparametric MRI radiomics combined with a 3D vision transformer deep learning approach. Acad Radiol, 2025, 32(8): 4512-4523.
31.	Tanaka H, Yamashita K, Urabe Y, et al. Management of T1 colorectal cancer. Digestion, 2025, 106(2): 122-130.
32.	Reis MT, Matsushita M, Santos W, et al. Independent prognostic significance of tumor budding and poorly differentiated clusters in Brazilian patients with stage Ⅱ colorectal cancer. Surg Exp Pathol, 2025, 8: 25. doi: 10.1186/s42047-025-00196-2.
33.	Yamadera M, Shinto E, Kajiwara Y, et al. Differential survival benefits of 5-fluorouracil-based adjuvant chemotherapy for patients with microsatellite-stable stage Ⅲ colorectal cancer according to the tumor budding status: a retrospective analysis. Dis Colon Rectum, 2019, 62(11): 1316-1325.
34.	Liang W, Jie H, Xie H, et al. High KRT17 expression in tumour budding indicates immunologically ‘hot’ tumour budding and predicts good survival in patients with colorectal cancer. Clin Transl Immunology, 2024, 13(3): e1495. doi: 10.1002/cti2.1495.
35.	Farchoukh L, Hartman DJ, Ma C, et al. Intratumoral budding and automated CD8-positive T-cell density in pretreatment biopsies can predict response to neoadjuvant therapy in rectal adenocarcinoma. Mod Pathol, 2021, 34(1): 171-183.
36.	Rogers AC, Gibbons D, Hanly AM, et al. Prognostic significance of tumor budding in rectal cancer biopsies before neoadjuvant therapy. Mod Pathol, 2014, 27(1): 156-162.
37.	Li J, Ma Y, Wen L, et al. Prognostic impact of tumor budding in rectal cancer after neoadjuvant therapy: a systematic review and meta-analysis. Syst Rev, 2024, 13(1): 22. doi: 10.1186/s13643-023-02441-9.
38.	Nagata K, Shinto E, Yamadera M, et al. Prognostic and predictive values of tumour budding in stage Ⅳ colorectal cancer. BJS Open, 2020, 4(4): 693-703.
39.	Luo YH, Yan ZC, Liu JY, et al. Association of tumor budding with clinicopathological features and prognostic value in stage Ⅲ-Ⅳ colorectal cancer. World J Gastroenterol, 2024, 30(2): 158-169.
40.	Akabane S, Shimizu W, Takakura Y, et al. Tumor budding as a predictive marker for 5-fluorouracil response in adjuvant-treated stage Ⅲ colorectal cancer. Int J Clin Oncol, 2021, 26(7): 1285-1292.
41.	Rogers AC, Winter DC, Heeney A, et al. Systematic review and meta-analysis of the impact of tumour budding in colorectal cancer. Br J Cancer, 2016, 115(7): 831-840.
42.	Kajiwara Y, Oka S, Tanaka S, et al. Nomogram as a novel predictive tool for lymph node metastasis in T1 colorectal cancer treated with endoscopic resection: a nationwide, multicenter study. Gastrointest Endosc, 2023, 97(6): 1119-1128.
43.	Santos EKAND, Triches BG, Silva GPD, et al. Peritumoral budding as a predictor for lymphnode metastases in colorectal carcinomas: what is the importance? Arq Bras Cir Dig, 2025, 38: e1875. doi: 10.1590/0102-6720202500006e1875.
44.	Kang G, Pyo JS, Kim NY, et al. Clinicopathological significances and prognostic role of intratumoral budding in colorectal cancers. J Clin Med, 2022, 11(19): 5540. doi: 10.3390/jcm11195540.
45.	Shi X, Wang X, Yao W, et al. Mechanism insights and therapeutic intervention of tumor metastasis: latest developments and perspectives. Signal Transduct Target Ther, 2024, 9(1): 192. doi: 10.1038/s41392-024-01885-2.

1. Murphy CC, Zaki TA. Changing epidemiology of colorectal cancer-birth cohort effects and emerging risk factors. Nat Rev Gastroenterol Hepatol, 2024, 21(1): 25-34.
2. Smith HG, Nilsson PJ, Shogan BD, et al. Neoadjuvant treatment of colorectal cancer: comprehensive review. BJS Open, 2024, 8(3): zrae038. doi: 10.1093/bjsopen/zrae038.
3. Jiang SX, Zarrin A, Shahidi N. T1 colorectal cancer management in the era of minimally invasive endoscopic resection. World J Gastrointest Oncol, 2024, 16(6): 2284-2294.
4. Le Tran N, Wang Y, Nie G. Podocalyxin in normal tissue and epithelial cancer. Cancers (Basel), 2021, 13(12): 2863. doi: 10.3390/cancers13122863.
5. Lugli A, Zlobec I, Berger MD, et al. Tumour budding in solid cancers. Nat Rev Clin Oncol, 2021, 18(2): 101-115.
6. Zheng S, Luo J, Xie S, et al. Tumor budding of cervical squamous cell carcinoma: epithelial-mesenchymal transition-like cancer stem cells? PeerJ, 2022, 10: e13745. doi: 10.7717/peerj.13745.
7. Bakir B, Chiarella AM, Pitarresi JR, et al. EMT, MET, plasticity, and tumor metastasis. Trends Cell Biol, 2020, 30(10): 764-776.
8. 梁迪, 劉艷榮. 腫瘤出芽分子機制的研究進展. 濟寧醫學院學報, 2024, 47(1): 61-64.
9. Buch A, Khan U, Rathod H, et al. Tumor budding in breast carcinoma: a systematic review and meta-analysis. J Cancer Res Ther, 2023, 19(7): 1697-1713.
10. Omae T, Omori Y, Makihara Y, et al. Mechanism of tumor budding in patient-derived metachronous oral primary squamous cell carcinoma cell lines. Int J Mol Sci, 2025, 26(7): 3347. doi: 10.3390/ijms26073347.
11. Zanoletti E, Daloiso A, Nicolè L, et al. Tumor budding to investigate local invasion, metastasis, and prognosis of head and neck carcinoma: a systematic review. Head Neck, 2024, 46(3): 651-671.
12. Dawson H, Christe L, Eichmann M, et al. Tumour budding/T cell infiltrates in colorectal cancer: proposal of a novel combined score. Histopathology, 2020, 76(4): 572-580.
13. Hatthakarnkul P, Quinn JA, Ammar A, et al. Molecular mechanisms of tumour budding and its association with microenvironment in colorectal cancer. Clin Sci (Lond), 2022, 136(8): 521-535.
14. Tie Y, Tang F, Wei YQ, et al. Immunosuppressive cells in cancer: mechanisms and potential therapeutic targets. J Hematol Oncol, 2022, 15(1): 61. doi: 10.1186/s13045-022-01282-8.
15. Miyazaki K, Hoshino D, Kasajima R, et al. Oncofetal morphogenesis similar to embryonic gut formation by a subpopulation of DLD-1 human colon cancer cells. Exp Cell Res, 2024, 442(2): 114188. doi: 10.1016/j.yexcr.2024.114188.
16. Mohamed SY, Kaf RM, Ahmed MM, et al. The prognostic value of cancer stem cell markers (Notch1, ALDH1, and CD44) in primary colorectal carcinoma. J Gastrointest Cancer, 2019, 50(4): 824-837.
17. Trinh A, L?drach C, Dawson HE, et al. Tumour budding is associated with the mesenchymal colon cancer subtype and RAS/RAF mutations: a study of 1 320 colorectal cancers with Consensus Molecular Subgroup (CMS) data. Br J Cancer, 2018, 119(10): 1244-1251.
18. Lugli A, Kirsch R, Ajioka Y, et al. Recommendations for reporting tumor budding in colorectal cancer based on the International Tumor Budding Consensus Conference (ITBCC) 2016. Mod Pathol, 2017, 30(9): 1299-1311.
19. Zlobec I, B?chli M, Galuppini F, et al. Refining the ITBCC tumor budding scoring system with a “zero-budding” category in colorectal cancer. Virchows Arch, 2021, 479(6): 1085-1090.
20. 李君, 馮梅寶, 來茂德, 等. 影響結直腸癌預后病理參數的診斷問題. 臨床與實驗病理學雜志, 2024, 40(12): 1241-1250.
21. Studer L, Blank A, Bokhorst JM, et al. Taking tumour budding to the next frontier-a post International Tumour Budding Consensus Conference (ITBCC) 2016 review. Histopathology, 2021, 78(4): 476-484.
22. Haddad TS, Lugli A, Aherne S, et al. Improving tumor budding reporting in colorectal cancer: a Delphi consensus study. Virchows Arch, 2021, 479(3): 459-469.
23. Knebel M, Philipp Kühn J, K?rner S, et al. Optimizing prognostic assessment in high-risk head and neck squamous cell carcinomas: the impact of tumor budding and a novel histomorphological scoring system. Cancer Med, 2025, 14(4): e70685. doi: 10.1002/cam4.70685.
24. McGenity C, Clarke EL, Jennings C, et al. Artificial intelligence in digital pathology: a systematic review and meta-analysis of diagnostic test accuracy. NPJ Digit Med, 2024, 7(1): 114. doi: 10.1038/s41746-024-01106-8.
25. Haddad TS, Bokhorst JM, van den Dobbelsteen L, et al. Tumor budding and poorly differentiated clusters as a biological continuum in colorectal cancer invasion and prognosis. Sci Rep, 2025, 15(1): 16944. doi: 10.1038/s41598-025-00866-x.
26. 周振, 沈浮, 陸海迪, 等. 動態增強磁共振成像術前評估直腸癌腫瘤出芽等級的價值. 中國醫學計算機成像雜志, 2022, 28(4): 379-384.
27. Peng L, Wang D, Zhuang Z, et al. Preoperative noninvasive evaluation of tumor budding in rectal cancer using multiparameter MRI radiomics. Acad Radiol, 2024, 31(6): 2334-2345.
28. Li Z, Chen F, Zhang S, et al. The feasibility of MRI-based radiomics model in presurgical evaluation of tumor budding in locally advanced rectal cancer. Abdom Radiol (NY), 2022, 47(1): 56-65.
29. Liu Z, Jia J, Bai F, et al. Predicting rectal cancer tumor budding grading based on MRI and CT with multimodal deep transfer learning: a dual-center study. Heliyon, 2024, 10(7): e28769. doi: 10.1016/j.heliyon.2024.e28769.
30. Liu Z, Yang H, Nie L, et al. Prediction of tumor budding grading in rectal cancer using a multiparametric MRI radiomics combined with a 3D vision transformer deep learning approach. Acad Radiol, 2025, 32(8): 4512-4523.
31. Tanaka H, Yamashita K, Urabe Y, et al. Management of T1 colorectal cancer. Digestion, 2025, 106(2): 122-130.
32. Reis MT, Matsushita M, Santos W, et al. Independent prognostic significance of tumor budding and poorly differentiated clusters in Brazilian patients with stage Ⅱ colorectal cancer. Surg Exp Pathol, 2025, 8: 25. doi: 10.1186/s42047-025-00196-2.
33. Yamadera M, Shinto E, Kajiwara Y, et al. Differential survival benefits of 5-fluorouracil-based adjuvant chemotherapy for patients with microsatellite-stable stage Ⅲ colorectal cancer according to the tumor budding status: a retrospective analysis. Dis Colon Rectum, 2019, 62(11): 1316-1325.
34. Liang W, Jie H, Xie H, et al. High KRT17 expression in tumour budding indicates immunologically ‘hot’ tumour budding and predicts good survival in patients with colorectal cancer. Clin Transl Immunology, 2024, 13(3): e1495. doi: 10.1002/cti2.1495.
35. Farchoukh L, Hartman DJ, Ma C, et al. Intratumoral budding and automated CD8-positive T-cell density in pretreatment biopsies can predict response to neoadjuvant therapy in rectal adenocarcinoma. Mod Pathol, 2021, 34(1): 171-183.
36. Rogers AC, Gibbons D, Hanly AM, et al. Prognostic significance of tumor budding in rectal cancer biopsies before neoadjuvant therapy. Mod Pathol, 2014, 27(1): 156-162.
37. Li J, Ma Y, Wen L, et al. Prognostic impact of tumor budding in rectal cancer after neoadjuvant therapy: a systematic review and meta-analysis. Syst Rev, 2024, 13(1): 22. doi: 10.1186/s13643-023-02441-9.
38. Nagata K, Shinto E, Yamadera M, et al. Prognostic and predictive values of tumour budding in stage Ⅳ colorectal cancer. BJS Open, 2020, 4(4): 693-703.
39. Luo YH, Yan ZC, Liu JY, et al. Association of tumor budding with clinicopathological features and prognostic value in stage Ⅲ-Ⅳ colorectal cancer. World J Gastroenterol, 2024, 30(2): 158-169.
40. Akabane S, Shimizu W, Takakura Y, et al. Tumor budding as a predictive marker for 5-fluorouracil response in adjuvant-treated stage Ⅲ colorectal cancer. Int J Clin Oncol, 2021, 26(7): 1285-1292.
41. Rogers AC, Winter DC, Heeney A, et al. Systematic review and meta-analysis of the impact of tumour budding in colorectal cancer. Br J Cancer, 2016, 115(7): 831-840.
42. Kajiwara Y, Oka S, Tanaka S, et al. Nomogram as a novel predictive tool for lymph node metastasis in T1 colorectal cancer treated with endoscopic resection: a nationwide, multicenter study. Gastrointest Endosc, 2023, 97(6): 1119-1128.
43. Santos EKAND, Triches BG, Silva GPD, et al. Peritumoral budding as a predictor for lymphnode metastases in colorectal carcinomas: what is the importance? Arq Bras Cir Dig, 2025, 38: e1875. doi: 10.1590/0102-6720202500006e1875.
44. Kang G, Pyo JS, Kim NY, et al. Clinicopathological significances and prognostic role of intratumoral budding in colorectal cancers. J Clin Med, 2022, 11(19): 5540. doi: 10.3390/jcm11195540.
45. Shi X, Wang X, Yao W, et al. Mechanism insights and therapeutic intervention of tumor metastasis: latest developments and perspectives. Signal Transduct Target Ther, 2024, 9(1): 192. doi: 10.1038/s41392-024-01885-2.

CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Research advances in tumor budding of rectal cancer

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