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  • Review Article
  • Published:

Tumour budding in solid cancers

Nature Reviews Clinical Oncology volume 18, pages 101–115 (2021)Cite this article

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Abstract

Tumour budding is an emerging prognostic biomarker in colorectal cancer (CRC) and other solid cancers. Tumour buds are usually defined as isolated single cancer cells or clusters of up to four cancer cells located at the invasive tumour front. The prognostic value of tumour budding is now supported by a large body of evidence, whereas the utility of this phenotype as a predictive biomarker remains under investigation. The application of tumour budding indices in clinical practice requires a standardized scoring system that can be tailored to specific tumour types and clinical scenarios. In the context of CRC, tumour budding can be assessed according to the method agreed at the International Tumour Budding Consensus Conference (ITBCC) in 2016. Using the ITBCC scoring system, tumour budding is an independent predictor of lymph node metastasis in patients with pT1 CRC and of unfavourable survival in patients with stage II colon cancer. Regardless of the clinical scenario or tumour type, the assertion that ‘the more tumour buds, the worse the clinical outcome’ applies. In this Review, we provide an overview of tumour budding in solid cancers, highlighting the molecular and biological aspects of this phenomenon, including its associations with epithelial–mesenchymal transition and features of the tumour microenvironment. We also describe the available evidence demonstrating the value of tumour budding as a biomarker across various solid cancers.

Key points

  • Tumour budding is an independent prognostic factor across a variety of solid cancers.

  • In general, the higher the tumour bud count, the worse the clinical outcome.

  • Tumour budding is included as a prognostic factor in published cancer classification guidelines of the Union for International Cancer Control (UICC), the American Joint Committee on Cancer (AJCC) and the World Health Organization (WHO).

  • Grading systems for tumour budding vary between different types of solid cancers.

  • Tumour budding is strongly associated with epithelial–mesenchymal transition and various factors in the tumour microenvironment, where individual tumour buds interact with diverse components of the tumour stroma and immune system.

  • The development of international, evidence-based, standardized scoring systems for tumour budding is essential for future multicentre retrospective clinical studies and prospective randomized clinical trials in order to better define the different prognostic groups.

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Fig. 1: Visualization of tumour budding by immunohistochemistry.
Fig. 2: Key processes involved in the tumour budding phenotype.
Fig. 3: An overview of the prognostic associations of tumour budding in cancers arising at various anatomical sites.

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References

  1. Brierley, J. D., Gospodarowicz, M. K. & Wittekind, C. TNM Classification of Malignant Tumours. 8th edn (Wiley Blackwell, 2017).

  2. Amin, M. B. et al. (eds). AJCC Cancer Staging Manual. 8th edn (Springer, 2017).

  3. WHO Classification of Tumours Editorial Board. in Digestive System Tumours. 5th edn (IARC, 2019).

  4. Koelzer, V. H., Langer, R., Zlobec, I. & Lugli, A. Tumor budding in upper gastrointestinal carcinomas. Front. Oncol. 4, 216 (2014).

    PubMed  PubMed Central  Google Scholar 

  5. Kadota, K. et al. Tumor budding correlates with the protumor immune microenvironment and is an independent prognostic factor for recurrence of stage I lung adenocarcinoma. Chest 148, 711–721 (2015).

    PubMed  PubMed Central  Google Scholar 

  6. Mitrovic, B., Schaeffer, D. F., Riddell, R. H. & Kirsch, R. Tumor budding in colorectal carcinoma: time to take notice. Mod. Pathol. 25, 1315–1325 (2012).

    CAS  PubMed  Google Scholar 

  7. Imai, T. Growth patterns in human carcinoma. Their classification and relation to prognosis. Obstet. Gynecol. 16, 296–308 (1960).

    CAS  PubMed  Google Scholar 

  8. Berg, K. B. & Schaeffer, D. F. Tumor budding as a standardized parameter in gastrointestinal carcinomas: more than just the colon. Mod. Pathol. 31, 862–872 (2018).

    PubMed  Google Scholar 

  9. Almangush, A., Salo, T., Hagstrom, J. & Leivo, I. Tumour budding in head and neck squamous cell carcinoma - a systematic review. Histopathology 65, 587–594 (2014).

    PubMed  Google Scholar 

  10. Zlobec, I. & Lugli, A. Tumour budding in colorectal cancer: molecular rationale for clinical translation. Nat. Rev. Cancer 18, 203–204 (2018).

    CAS  PubMed  Google Scholar 

  11. Lugli, A. et al. Intratumoral budding as a potential parameter of tumor progression in mismatch repair-proficient and mismatch repair-deficient colorectal cancer patients. Hum. Pathol. 42, 1833–1840 (2011).

    PubMed  Google Scholar 

  12. Lugli, A. et al. Recommendations for reporting tumor budding in colorectal cancer based on the international tumor budding consensus conference (ITBCC) 2016. Mod. Pathol. 30, 1299–1311 (2017).

    PubMed  Google Scholar 

  13. Loughrey, M. et al. Colorectal Cancer Histopathology Reporting Guide. (International Collaboration on Cancer Reporting, 2020).

  14. Burgart, L. et al. Protocol for the examination of excisional biopsy specimens from patients with primary carcinoma of the colon and rectum. Version 4.1.0.0. College of American Pathologists https://documents.cap.org/protocols/cp-gilower-colonrectum-resection-20-4100.pdf (2020).

  15. Hanahan, D. & Weinberg, R. A. Hallmarks of cancer: the next generation. Cell 144, 646–674 (2011).

    CAS  PubMed  Google Scholar 

  16. Klymkowsky, M. W. & Savagner, P. Epithelial-mesenchymal transition: a cancer researcher’s conceptual friend and foe. Am. J. Pathol. 174, 1588–1593 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Polyak, K. & Weinberg, R. A. Transitions between epithelial and mesenchymal states: acquisition of malignant and stem cell traits. Nat. Rev. Cancer 9, 265–273 (2009).

    CAS  PubMed  Google Scholar 

  18. Yilmaz, M. & Christofori, G. EMT, the cytoskeleton, and cancer cell invasion. Cancer Metastasis Rev. 28, 15–33 (2009).

    PubMed  Google Scholar 

  19. Attramadal, C. G. et al. Tumor budding, EMT and cancer stem cells in T1-2/N0 oral squamous cell carcinomas. Anticancer Res. 35, 6111–6120 (2015).

    CAS  PubMed  Google Scholar 

  20. Kohler, I. et al. Detailed analysis of epithelial-mesenchymal transition and tumor budding identifies predictors of long-term survival in pancreatic ductal adenocarcinoma. J. Gastroenterol. Hepatol. 30, 78–84 (2015).

    CAS  PubMed  Google Scholar 

  21. Nakagawa, Y. et al. Tumor budding and E-cadherin expression are useful predictors of nodal involvement in T1 esophageal squamous cell carcinoma. Anticancer Res. 33, 5023–5029 (2013).

    PubMed  Google Scholar 

  22. Lee, S. J. et al. Combined aberrant expression of E-cadherin and S100A4, but not beta-catenin is associated with disease-free survival and overall survival in colorectal cancer patients. Diagn. Pathol. 8, 99 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Zlobec, I. et al. Role of APAF-1, E-cadherin and peritumoral lymphocytic infiltration in tumour budding in colorectal cancer. J. Pathol. 212, 260–268 (2007).

    CAS  PubMed  Google Scholar 

  24. Koyuncuoglu, M. et al. Tumor budding and E-Cadherin expression in endometrial carcinoma: are they prognostic factors in endometrial cancer? Gynecol. Oncol. 125, 208–213 (2012).

    CAS  PubMed  Google Scholar 

  25. Jensen, D. H. et al. Molecular profiling of tumour budding implicates TGFβ-mediated epithelial-mesenchymal transition as a therapeutic target in oral squamous cell carcinoma. J. Pathol. 236, 505–516 (2015).

    CAS  PubMed  Google Scholar 

  26. Galvan, J. A. et al. Expression of E-cadherin repressors SNAIL, ZEB1 and ZEB2 by tumour and stromal cells influences tumour-budding phenotype and suggests heterogeneity of stromal cells in pancreatic cancer. Br. J. Cancer 112, 1944–1950 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Hong, K. O. et al. Tumor budding is associated with poor prognosis of oral squamous cell carcinoma and histologically represents an epithelial-mesenchymal transition process. Hum. Pathol. 80, 123–129 (2018).

    CAS  PubMed  Google Scholar 

  28. Dardare, J., Witz, A., Merlin, J. L., Gilson, P. & Harle, A. SMAD4 and the TGFβ pathway in patients with pancreatic ductal adenocarcinoma. Int. J. Mol. Sci. 21, 3534 (2020).

    CAS  PubMed Central  Google Scholar 

  29. Oyanagi, H. et al. SMAD4 alteration associates with invasive-front pathological markers and poor prognosis in colorectal cancer. Histopathology 74, 873–882 (2019).

    PubMed  PubMed Central  Google Scholar 

  30. Gosens, M. J., van Kempen, L. C., van de Velde, C. J., van Krieken, J. H. & Nagtegaal, I. D. Loss of membranous Ep-CAM in budding colorectal carcinoma cells. Mod. Pathol. 20, 221–232 (2007).

    CAS  PubMed  Google Scholar 

  31. Lugli, A. et al. Prognostic impact of the expression of putative cancer stem cell markers CD133, CD166, CD44s, EpCAM, and ALDH1 in colorectal cancer. Br. J. Cancer 103, 382–390 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Lawlor, R. T. et al. Prognostic role of high-grade tumor budding in pancreatic ductal adenocarcinoma: a systematic review and meta-analysis with a focus on epithelial to mesenchymal transition. Cancers 11, 113 (2019).

    PubMed Central  Google Scholar 

  33. Maffeis, V. et al. Tumor budding is an adverse prognostic marker in intestinal-type sinonasal adenocarcinoma and seems to be unrelated to epithelial-mesenchymal transition. Virchows Arch. 477, 241–248 (2020).

    CAS  PubMed  Google Scholar 

  34. Galvan, J. A. et al. TWIST1 and TWIST2 promoter methylation and protein expression in tumor stroma influence the epithelial-mesenchymal transition-like tumor budding phenotype in colorectal cancer. Oncotarget 6, 874–885 (2015).

    PubMed  Google Scholar 

  35. Yamada, N. et al. Tumor budding at the invasive front of colorectal cancer may not be associated with the epithelial-mesenchymal transition. Hum. Pathol. 60, 151–159 (2017).

    CAS  PubMed  Google Scholar 

  36. Derynck, R. & Weinberg, R. A. EMT and cancer: more than meets the eye. Dev. Cell 49, 313–316 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Zhou, B. et al. Interaction between laminin-5gamma2 and integrin beta1 promotes the tumor budding of colorectal cancer via the activation of Yes-associated proteins. Oncogene 39, 1527–1542 (2020).

    CAS  PubMed  Google Scholar 

  38. Katayama, M. & Sekiguchi, K. Laminin-5 in epithelial tumour invasion. J. Mol. Histol. 35, 277–286 (2004).

    CAS  PubMed  Google Scholar 

  39. Shinto, E., Mochizuki, H., Ueno, H., Matsubara, O. & Jass, J. R. A novel classification of tumour budding in colorectal cancer based on the presence of cytoplasmic pseudo-fragments around budding foci. Histopathology 47, 25–31 (2005).

    CAS  PubMed  Google Scholar 

  40. Shinto, E. et al. Tumor buds show reduced expression of laminin-5 gamma 2 chain in DNA mismatch repair deficient colorectal cancer. Dis. Colon. Rectum 49, 1193–1202 (2006).

    PubMed  Google Scholar 

  41. Okado, Y. et al. Tumor budding and laminin5-gamma2 in squamous cell carcinoma of the external auditory canal are associated with shorter survival. Springerplus 4, 814 (2015).

    PubMed  PubMed Central  Google Scholar 

  42. Marangon Junior, H. et al. Laminin-5 gamma 2 chain expression is associated with intensity of tumor budding and density of stromal myofibroblasts in oral squamous cell carcinoma. J. Oral Pathol. Med. 43, 199–204 (2014).

    PubMed  Google Scholar 

  43. Masuda, R. et al. Laminin-5gamma2 chain expression is associated with tumor cell invasiveness and prognosis of lung squamous cell carcinoma. Biomed. Res. 33, 309–317 (2012).

    CAS  PubMed  Google Scholar 

  44. Taira, T. et al. Characterization of the immunophenotype of the tumor budding and its prognostic implications in squamous cell carcinoma of the lung. Lung Cancer 76, 423–430 (2012).

    PubMed  Google Scholar 

  45. Kevans, D. et al. Epithelial-mesenchymal transition (EMT) protein expression in a cohort of stage II colorectal cancer patients with characterized tumor budding and mismatch repair protein status. Int. J. Surg. Pathol. 19, 751–760 (2011).

    CAS  PubMed  Google Scholar 

  46. Masaki, T. et al. Laminin-5 gamma 2 chain and matrix metalloproteinase-2 may trigger colorectal carcinoma invasiveness through formation of budding tumor cells. Anticancer Res. 23, 4113–4119 (2003).

    CAS  PubMed  Google Scholar 

  47. Sordat, I. et al. Tumor cell budding and laminin-5 expression in colorectal carcinoma can be modulated by the tissue micro-environment. Int. J. Cancer 88, 708–717 (2000).

    CAS  PubMed  Google Scholar 

  48. Hlubek, F., Spaderna, S., Jung, A., Kirchner, T. & Brabletz, T. -catenin activates a coordinated expression of the proinvasive factors laminin-5 γ2 chain and MT1-MMP in colorectal carcinomas. Int. J. Cancer 108, 321–326 (2004).

    CAS  PubMed  Google Scholar 

  49. Prall, F. & Ostwald, C. High-degree tumor budding and podia-formation in sporadic colorectal carcinomas with K-ras gene mutations. Hum. Pathol. 38, 1696–1702 (2007).

    CAS  PubMed  Google Scholar 

  50. Shinto, E. et al. Differential prognostic significance of morphologic invasive markers in colorectal cancer: tumor budding and cytoplasmic podia. Dis. Colon. Rectum 49, 1422–1430 (2006).

    PubMed  Google Scholar 

  51. Rizzi, C. et al. The expression of the high-mobility group A2 protein in colorectal cancer and surrounding fibroblasts is linked to tumor invasiveness. Hum. Pathol. 44, 122–132 (2013).

    CAS  PubMed  Google Scholar 

  52. Sugai, T. et al. Vascular invasion and stromal S100A4 expression at the invasive front of colorectal cancer are novel determinants and tumor prognostic markers. J. Cancer 8, 1552–1561 (2017).

    PubMed  PubMed Central  Google Scholar 

  53. Markl, B. et al. Tumour budding, uPA and PAI-1 are associated with aggressive behaviour in colon cancer. J. Surg. Oncol. 102, 235–241 (2010).

    CAS  PubMed  Google Scholar 

  54. Guzinska-Ustymowicz, K. MMP-9 and cathepsin B expression in tumor budding as an indicator of a more aggressive phenotype of colorectal cancer (CRC). Anticancer Res. 26, 1589–1594 (2006).

    CAS  PubMed  Google Scholar 

  55. Karamitopoulou, E. et al. Loss of Raf-1 kinase inhibitor protein (RKIP) is strongly associated with high-grade tumor budding and correlates with an aggressive phenotype in pancreatic ductal adenocarcinoma (PDAC). J. Transl Med. 11, 311 (2013).

    PubMed  PubMed Central  Google Scholar 

  56. Banias, L. et al. Nuclear maspin expression: A biomarker for budding assessment in colorectal cancer specimens. Pathol. Res. Pract. 213, 1227–1230 (2017).

    CAS  PubMed  Google Scholar 

  57. Dawson, H. et al. Tyrosine kinase receptor B (TrkB) expression in colorectal cancers highlights anoikis resistance as a survival mechanism of tumour budding cells. Histopathology 66, 715–725 (2015).

    PubMed  Google Scholar 

  58. Tanaka, K. et al. Tropomyosin-related receptor kinase B at the invasive front and tumour cell dedifferentiation in gastric cancer. Br. J. Cancer 110, 2923–2934 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Righi, A. et al. Tumour budding is associated with hypoxia at the advancing front of colorectal cancer. Histopathology 66, 982–990 (2015).

    PubMed  Google Scholar 

  60. Hatzikirou, H., Basanta, D., Simon, M., Schaller, K. & Deutsch, A. ‘Go or grow’: the key to the emergence of invasion in tumour progression? Math. Med. Biol. 29, 49–65 (2012).

    CAS  PubMed  Google Scholar 

  61. Dawson, H. et al. The apoptotic and proliferation rate of tumour budding cells in colorectal cancer outlines a heterogeneous population of cells with various impacts on clinical outcome. Histopathology 64, 577–584 (2014).

    PubMed  Google Scholar 

  62. Rubio, C. A. Arrest of cell proliferation in budding tumor cells ahead of the invading edge of colonic carcinomas. A preliminary report. Anticancer Res. 28, 2417–2420 (2008).

    PubMed  Google Scholar 

  63. Marangon Junior, H. et al. Cell proliferation is associated with intensity of tumor budding in oral squamous cell carcinoma. J. Oral Pathol. Med. 47, 128–135 (2018).

    PubMed  Google Scholar 

  64. Hacking, S. et al. Tumor budding in colorectal carcinoma showing a paradoxical mitotic index (Via PHH3) with possible association to the tumor stromal microenvironment. Appl. Immunohistochem. Mol. Morphol. https://doi.org/10.1097/PAI.0000000000000805 (2019).

    Article  Google Scholar 

  65. Boxberg, M. et al. Immunohistochemical expression of CD44 in oral squamous cell carcinoma in relation to histomorphological parameters and clinicopathological factors. Histopathology 73, 559–572 (2018).

    PubMed  Google Scholar 

  66. Zheng, Z. et al. Heterogeneous expression of Lgr5 as a risk factor for focal invasion and distant metastasis of colorectal carcinoma. Oncotarget 9, 30025–30033 (2018).

    PubMed  PubMed Central  Google Scholar 

  67. Zhou, Y. et al. Cancer stem cells in progression of colorectal cancer. Oncotarget 9, 33403–33415 (2018).

    PubMed  Google Scholar 

  68. Hostettler, L., Zlobec, I., Terracciano, L. & Lugli, A. ABCG5-positivity in tumor buds is an indicator of poor prognosis in node-negative colorectal cancer patients. World J. Gastroenterol. 16, 732–739 (2010).

    PubMed  PubMed Central  Google Scholar 

  69. Meyer, S. N. et al. Co-expression of cytokeratin and vimentin in colorectal cancer highlights a subset of tumor buds and an atypical cancer-associated stroma. Hum. Pathol. 87, 18–27 (2019).

    CAS  PubMed  Google Scholar 

  70. Chouat, E. et al. Tumor budding is a prognostic factor linked to epithelial mesenchymal transition in pancreatic ductal adenocarcinoma. Study report and literature review. Pancreatology 18, 79–84 (2018).

    PubMed  Google Scholar 

  71. Wang, C. et al. Tumor budding correlates with poor prognosis and epithelial-mesenchymal transition in tongue squamous cell carcinoma. J. Oral Pathol. Med. 40, 545–551 (2011).

    PubMed  PubMed Central  Google Scholar 

  72. Carr, I., Levy, M. & Watson, P. The invasive edge: invasion in colorectal cancer. Clin. Exp. Metastasis 4, 129–139 (1986).

    CAS  PubMed  Google Scholar 

  73. Jass, J. R., Love, S. B. & Northover, J. M. A new prognostic classification of rectal cancer. Lancet 1, 1303–1306 (1987).

    CAS  PubMed  Google Scholar 

  74. Bronsert, P. et al. Cancer cell invasion and EMT marker expression: a three-dimensional study of the human cancer-host interface. J. Pathol. 234, 410–422 (2014).

    CAS  PubMed  Google Scholar 

  75. Prall, F., Ostwald, C. & Linnebacher, M. Tubular invasion and the morphogenesis of tumor budding in colorectal carcinoma. Hum. Pathol. 40, 1510–1512 (2009).

    CAS  PubMed  Google Scholar 

  76. Guinney, J. et al. The consensus molecular subtypes of colorectal cancer. Nat. Med. 21, 1350–1356 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Trinh, A. et al. Tumour budding is associated with the mesenchymal colon cancer subtype and RAS/RAF mutations: a study of 1320 colorectal cancers with Consensus Molecular Subgroup (CMS) data. Br. J. Cancer 119, 1244–1251 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. De Smedt, L. et al. Expression profiling of budding cells in colorectal cancer reveals an EMT-like phenotype and molecular subtype switching. Br. J. Cancer 116, 58–65 (2017).

    PubMed  Google Scholar 

  79. Bakhoum, S. F. et al. Chromosomal instability drives metastasis through a cytosolic DNA response. Nature 553, 467–472 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Arner, E. N., Du, W. & Brekken, R. A. Behind the wheel of epithelial plasticity in KRAS-Driven Cancers. Front. Oncol. 9, 1049 (2019).

    PubMed  PubMed Central  Google Scholar 

  81. Steinestel, K., Lennerz, J. K., Eder, S., Kraft, K. & Arndt, A. Invasion pattern and histologic features of tumor aggressiveness correlate with MMR protein expression, but are independent of activating KRAS and BRAF mutations in CRC. Virchows Arch. 465, 155–163 (2014).

    CAS  PubMed  Google Scholar 

  82. Barresi, V., Bonetti, L. R. & Bettelli, S. KRAS, NRAS, BRAF mutations and high counts of poorly differentiated clusters of neoplastic cells in colorectal cancer: observational analysis of 175 cases. Pathology 47, 551–556 (2015).

    CAS  PubMed  Google Scholar 

  83. Jang, S. et al. KRAS and PIK3CA mutations in colorectal adenocarcinomas correlate with aggressive histological features and behavior. Hum. Pathol. 65, 21–30 (2017).

    CAS  PubMed  Google Scholar 

  84. Jass, J. R. et al. APC mutation and tumour budding in colorectal cancer. J. Clin. Pathol. 56, 69–73 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Xie, N. et al. Decreased miR-320a promotes invasion and metastasis of tumor budding cells in tongue squamous cell carcinoma. Oncotarget 7, 65744–65757 (2016).

    PubMed  PubMed Central  Google Scholar 

  86. Karamitopoulou, E. et al. MicroRNA dysregulation in the tumor microenvironment influences the phenotype of pancreatic cancer. Mod. Pathol. 30, 1116–1125 (2017).

    CAS  PubMed  Google Scholar 

  87. Moller, T. et al. Co-detection of miR-21 and TNF-α mRNA in budding cancer cells in colorectal cancer. Int. J. Mol. Sci. 20, 1907 (2019).

    CAS  PubMed Central  Google Scholar 

  88. Knudsen, K. N. et al. miR-21 expression analysis in budding colon cancer cells by confocal slide scanning microscopy. Clin. Exp. Metastasis 35, 819–830 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Mongroo, P. S. & Rustgi, A. K. The role of the miR-200 family in epithelial-mesenchymal transition. Cancer Biol. Ther. 10, 219–222 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Martinez-Ciarpaglini, C. et al. Low miR200c expression in tumor budding of invasive front predicts worse survival in patients with localized colon cancer and is related to PD-L1 overexpression. Mod. Pathol. 32, 306–313 (2019).

    CAS  PubMed  Google Scholar 

  91. Boland, C. R. & Goel, A. Microsatellite instability in colorectal cancer. Gastroenterology 138, 2073–2087.e3 (2010).

    CAS  PubMed  Google Scholar 

  92. Koelzer, V. H. et al. Active immunosurveillance in the tumor microenvironment of colorectal cancer is associated with low frequency tumor budding and improved outcome. Transl Res. 166, 207–217 (2015).

    CAS  PubMed  Google Scholar 

  93. Koelzer, V. H. et al. Phenotyping of tumor-associated macrophages in colorectal cancer: impact on single cell invasion (tumor budding) and clinicopathological outcome. Oncoimmunology 5, e1106677 (2016).

    PubMed  Google Scholar 

  94. Zlobec, I., Minoo, P., Terracciano, L., Baker, K. & Lugli, A. Characterization of the immunological microenvironment of tumour buds and its impact on prognosis in mismatch repair-proficient and -deficient colorectal cancers. Histopathology 59, 482–495 (2011).

    PubMed  Google Scholar 

  95. Orhan, A. et al. The prognostic value of tumour-infiltrating lymphocytes in pancreatic cancer: a systematic review and meta-analysis. Eur. J. Cancer 132, 71–84 (2020).

    CAS  PubMed  Google Scholar 

  96. Zhao, Y. et al. Prognostic value and clinicopathological roles of phenotypes of tumour-associated macrophages in colorectal cancer. J. Cancer Res. Clin. Oncol. 145, 3005–3019 (2019).

    CAS  PubMed  Google Scholar 

  97. Galon, J. et al. Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science 313, 1960–1964 (2006).

    CAS  PubMed  Google Scholar 

  98. Idos, G. E. et al. The prognostic implications of tumor infiltrating lymphocytes in colorectal cancer: a systematic review and meta-analysis. Sci. Rep. 10, 3360 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Kuwahara, T. et al. Intratumoural-infiltrating CD4+ and FOXP3+ T cells as strong positive predictive markers for the prognosis of resectable colorectal cancer. Br. J. Cancer 121, 659–665 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Pages, F. et al. International validation of the consensus Immunoscore for the classification of colon cancer: a prognostic and accuracy study. Lancet 391, 2128–2139 (2018).

    PubMed  Google Scholar 

  101. Lugli, A. et al. CD8+lymphocytes/ tumour-budding index: an independent prognostic factor representing a ‘pro-/anti-tumour’ approach to tumour host interaction in colorectal cancer. Br. J. Cancer 101, 1382–1392 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Karamitopoulou, E. Tumour microenvironment of pancreatic cancer: immune landscape is dictated by molecular and histopathological features. Br. J. Cancer 121, 5–14 (2019).

    PubMed  PubMed Central  Google Scholar 

  103. Dawson, H. et al. Tumour budding/T cell infiltrates in colorectal cancer: proposal of a novel combined score. Histopathology 76, 572–580 (2019).

    Google Scholar 

  104. Nearchou, I. P. et al. Automated analysis of lymphocytic infiltration, tumor budding, and their spatial relationship improves prognostic accuracy in colorectal cancer. Cancer Immunol. Res. 7, 609–620 (2019).

    CAS  PubMed  Google Scholar 

  105. Wartenberg, M. et al. Integrated genomic and immunophenotypic classification of pancreatic cancer reveals three distinct subtypes with prognostic/predictive significance. Clin. Cancer Res. 24, 4444–4454 (2018).

    CAS  PubMed  Google Scholar 

  106. Ueno, H. et al. Histologic categorization of desmoplastic reaction: its relevance to the colorectal cancer microenvironment and prognosis. Ann. Surg. Oncol. 22, 1504–1512 (2015).

    PubMed  Google Scholar 

  107. Rogers, A. C. et al. Systematic review and meta-analysis of the impact of tumour budding in colorectal cancer. Br. J. Cancer 115, 831–840 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Bosch, S. L., Teerenstra, S., de Wilt, J. H., Cunningham, C. & Nagtegaal, I. D. Predicting lymph node metastasis in pT1 colorectal cancer: a systematic review of risk factors providing rationale for therapy decisions. Endoscopy 45, 827–834 (2013).

    PubMed  Google Scholar 

  109. Ueno, H. et al. Risk factors for an adverse outcome in early invasive colorectal carcinoma. Gastroenterology 127, 385–394 (2004).

    PubMed  Google Scholar 

  110. Cappellesso, R. et al. Tumor budding as a risk factor for nodal metastasis in pT1 colorectal cancers: a meta-analysis. Hum. Pathol. 65, 62–70 (2017).

    CAS  PubMed  Google Scholar 

  111. Betge, J. et al. Tumor budding is an independent predictor of outcome in AJCC/UICC stage II colorectal cancer. Ann. Surg. Oncol. 19, 3706–3712 (2012).

    PubMed  Google Scholar 

  112. Zlobec, I. et al. Intratumoural budding (ITB) in preoperative biopsies predicts the presence of lymph node and distant metastases in colon and rectal cancer patients. Br. J. Cancer 110, 1008–1013 (2014).

    CAS  PubMed  Google Scholar 

  113. Giger, O. T., Comtesse, S. C., Lugli, A., Zlobec, I. & Kurrer, M. O. Intra-tumoral budding in preoperative biopsy specimens predicts lymph node and distant metastasis in patients with colorectal cancer. Mod. Pathol. 25, 1048–1053 (2012).

    PubMed  Google Scholar 

  114. Rogers, A. C. et al. Prognostic significance of tumor budding in rectal cancer biopsies before neoadjuvant therapy. Mod. Pathol. 27, 156–162 (2014).

    PubMed  Google Scholar 

  115. Almangush, A. et al. Evaluation of the budding and depth of invasion (BD) model in oral tongue cancer biopsies. Virchows Arch. 472, 231–236 (2018).

    PubMed  Google Scholar 

  116. Almangush, A. et al. Does evaluation of tumour budding in diagnostic biopsies have a clinical relevance? A systematic review. Histopathology 74, 536–544 (2019).

    PubMed  Google Scholar 

  117. Jesinghaus, M. et al. Pre-operative cellular dissociation grading in biopsies is highly predictive of post-operative tumour stage and patient outcome in head and neck squamous cell carcinoma. Br. J. Cancer 122, 835–846 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  118. Lino-Silva, L. S. et al. Mismatch repair protein expression and intratumoral budding in rectal cancer are associated with an increased pathological complete response to preoperative chemoradiotherapy: a case-control study. World J. Clin. Oncol. 9, 133–139 (2018).

    PubMed  PubMed Central  Google Scholar 

  119. Seki, M., Sano, T., Yokoo, S. & Oyama, T. Histologic assessment of tumor budding in preoperative biopsies to predict nodal metastasis in squamous cell carcinoma of the tongue and floor of the mouth. Head Neck 38, E1582–E1590 (2016).

    PubMed  Google Scholar 

  120. Backes, Y. et al. Histologic factors associated with need for surgery in patients with pedunculated T1 colorectal carcinomas. Gastroenterology 154, 1647–1659 (2018).

    PubMed  Google Scholar 

  121. Barel, F. et al. Histopathological factors help to predict lymph node metastases more efficiently than extra-nodal recurrences in submucosa invading pT1 colorectal cancer. Sci. Rep. 9, 8342 (2019).

    PubMed  PubMed Central  Google Scholar 

  122. Slik, K. et al. Combined epithelial marker analysis of tumour budding in stage II colorectal cancer. J. Pathol. Clin. Res. 5, 63–78 (2019).

    CAS  PubMed  Google Scholar 

  123. Nearchou, I. P. et al. Novel internationally verified method reports desmoplastic reaction as the most significant prognostic feature for disease-specific survival in stage II colorectal cancer. Am. J. Surg. Pathol. 43, 1239–1248 (2019).

    PubMed  Google Scholar 

  124. Romiti, A. et al. Study of histopathologic parameters to define the prognosis of stage II colon cancer. Int. J. Colorectal Dis. 34, 905–913 (2019).

    PubMed  Google Scholar 

  125. Lee, V. W. K. & Chan, K. F. Tumor budding and poorly-differentiated cluster in prognostication in Stage II colon cancer. Pathol. Res. Pract. 214, 402–407 (2018).

    PubMed  Google Scholar 

  126. Ueno, H. et al. Prospective multicenter study on the prognostic and predictive impact of tumor budding in stage II colon cancer: results from the SACURA trial. J. Clin. Oncol. 37, 1886–1894 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  127. van Wyk, H. C. et al. The relationship between tumor budding, tumor microenvironment, and survival in patients with primary operable colorectal cancer. Ann. Surg. Oncol. 26, 4397–4404 (2019).

    PubMed  PubMed Central  Google Scholar 

  128. Almangush, A., Karhunen, M., Hautaniemi, S., Salo, T. & Leivo, I. Prognostic value of tumour budding in oesophageal cancer: a meta-analysis. Histopathology 68, 173–182 (2016).

    PubMed  Google Scholar 

  129. Roh, M. S., Lee, J. I. & Choi, P. J. Tumor budding as a useful prognostic marker in esophageal squamous cell carcinoma. Dis. Esophagus 17, 333–337 (2004).

    CAS  PubMed  Google Scholar 

  130. Koike, M. et al. Multivariate analysis of the pathologic features of esophageal squamous cell cancer: tumor budding is a significant independent prognostic factor. Ann. Surg. Oncol. 15, 1977–1982 (2008).

    PubMed  Google Scholar 

  131. Miyata, H. et al. Tumor budding in tumor invasive front predicts prognosis and survival of patients with esophageal squamous cell carcinomas receiving neoadjuvant chemotherapy. Cancer 115, 3324–3334 (2009).

    PubMed  Google Scholar 

  132. Brown, M. et al. Tumour budding and a low host inflammatory response are associated with a poor prognosis in oesophageal and gastro-oesophageal junction cancers. Histopathology 56, 893–899 (2010).

    PubMed  Google Scholar 

  133. Nakanishi, Y. et al. Correlation between tumor budding and post-resection prognosis in patients with invasive squamous cell carcinoma of the thoracic esophagus. World J. Surg. 35, 349–356 (2011).

    PubMed  Google Scholar 

  134. Ito, E. et al. New invasive patterns as a prognostic factor for superficial esophageal cancer. J. Gastroenterol. 47, 1279–1289 (2012).

    PubMed  Google Scholar 

  135. Teramoto, H. et al. Tumor budding as a useful prognostic marker in T1-stage squamous cell carcinoma of the esophagus. J. Surg. Oncol. 108, 42–46 (2013).

    PubMed  PubMed Central  Google Scholar 

  136. Niwa, Y. et al. Epithelial to mesenchymal transition correlates with tumor budding and predicts prognosis in esophageal squamous cell carcinoma. J. Surg. Oncol. 110, 764–769 (2014).

    CAS  PubMed  Google Scholar 

  137. Jesinghaus, M. et al. A novel grading system based on tumor budding and cell nest size is a strong predictor of patient outcome in esophageal squamous cell carcinoma. Am. J. Surg. Pathol. 41, 1112–1120 (2017).

    PubMed  Google Scholar 

  138. Jesinghaus, M. et al. Cellular dissociation grading based on the parameters tumor budding and cell nest size in pretherapeutic biopsy specimens allows for prognostic patient stratification in esophageal squamous cell carcinoma independent from clinical staging. Am. J. Surg. Pathol. 43, 618–627 (2019).

    PubMed  Google Scholar 

  139. Min, B. H. et al. Nomogram for prediction of lymph node metastasis in patients with superficial esophageal squamous cell carcinoma. J. Gastroenterol. Hepatol. 3, 1009–1015 (2020).

    Google Scholar 

  140. Mitobe, J. et al. Clinicopathological investigation of lymph node metastasis predictors in superficial esophageal squamous cell carcinoma with a focus on evaluation of lympho-vascular invasion. Scand. J. Gastroenterol. 48, 1173–1182 (2013).

    PubMed  Google Scholar 

  141. Fuchinoue, K. et al. Immunohistochemical analysis of tumor budding as predictor of lymph node metastasis from superficial esophageal squamous cell carcinoma. Esophagus 17, 168–174 (2020).

    PubMed  Google Scholar 

  142. Landau, M. S. et al. Tumor budding is associated with an increased risk of lymph node metastasis and poor prognosis in superficial esophageal adenocarcinoma. Mod. Pathol. 27, 1578–1589 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  143. Thies, S. et al. Impact of peritumoral and intratumoral budding in esophageal adenocarcinomas. Hum. Pathol. 52, 1–8 (2016).

    PubMed  Google Scholar 

  144. Gabbert, H. E., Meier, S., Gerharz, C. D. & Hommel, G. Tumor-cell dissociation at the invasion front: a new prognostic parameter in gastric cancer patients. Int. J. Cancer 50, 202–207 (1992).

    CAS  PubMed  Google Scholar 

  145. Kemi, N., Eskuri, M., Ikalainen, J., Karttunen, T. J. & Kauppila, J. H. Tumor budding and prognosis in gastric adenocarcinoma. Am. J. Surg. Pathol. 43, 229–234 (2019).

    PubMed  Google Scholar 

  146. Olsen, S., Jin, L., Fields, R. C., Yan, Y. & Nalbantoglu, I. Tumor budding in intestinal-type gastric adenocarcinoma is associated with nodal metastasis and recurrence. Hum. Pathol. 68, 26–33 (2017).

    CAS  PubMed  Google Scholar 

  147. Ulase, D., Heckl, S., Behrens, H. M., Kruger, S. & Rocken, C. Prognostic significance of tumour budding assessed in gastric carcinoma according to the criteria of the International Tumour Budding Consensus Conference. Histopathology 76, 433–446 (2020).

    PubMed  Google Scholar 

  148. Guo, Y. X., Zhang, Z. Z., Zhao, G. & Zhao, E. H. Prognostic and pathological impact of tumor budding in gastric cancer: A systematic review and meta-analysis. World J. Gastrointest. Oncol. 11, 898–908 (2019).

    PubMed  PubMed Central  Google Scholar 

  149. Che, K. et al. Prognostic significance of tumor budding and single cell invasion in gastric adenocarcinoma. Onco. Targets Ther. 10, 1039–1047 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  150. Du, M. et al. Tumor budding and other risk factors of lymph node metastasis in submucosal early gastric carcinoma: a multicenter clinicopathologic study in 621 radical gastrectomies of chinese patients. Am. J. Surg. Pathol. 43, 1074–1082 (2019).

    PubMed  Google Scholar 

  151. Gulluoglu, M. et al. Tumor budding is independently predictive for lymph node involvement in early gastric cancer. Int. J. Surg. Pathol. 23, 349–358 (2015).

    CAS  PubMed  Google Scholar 

  152. Bailey, P. et al. Genomic analyses identify molecular subtypes of pancreatic cancer. Nature 531, 47–52 (2016).

    CAS  PubMed  Google Scholar 

  153. Puleo, F. et al. Stratification of pancreatic ductal adenocarcinomas based on tumor and microenvironment features. Gastroenterology 155, 1999–2013.e3 (2018).

    PubMed  Google Scholar 

  154. Lang-Schwarz, C. et al. Budding and tumor-infiltrating lymphocytes - combination of both parameters predicts survival in colorectal cancer and leads to new prognostic subgroups. Hum. Pathol. 79, 160–167 (2018).

    PubMed  Google Scholar 

  155. Ogino, M. et al. Impact of tumour budding grade in 310 patients who underwent surgical resection for extrahepatic cholangiocarcinoma. Histopathology 74, 861–872 (2019).

    PubMed  Google Scholar 

  156. Ohike, N. et al. Tumor budding as a strong prognostic indicator in invasive ampullary adenocarcinomas. Am. J. Surg. Pathol. 34, 1417–1424 (2010).

    PubMed  PubMed Central  Google Scholar 

  157. Okubo, S. et al. The prognostic impact of differentiation at the invasive front of biliary tract cancer. J. Surg. Oncol. 117, 1278–1287 (2018).

    PubMed  Google Scholar 

  158. Tanaka, M. et al. Tumor budding in intrahepatic cholangiocarcinoma: a predictor of postsurgery outcomes. Am. J. Surg. Pathol. 43, 1180–1190 (2019).

    PubMed  Google Scholar 

  159. Ueno, H., Murphy, J., Jass, J. R., Mochizuki, H. & Talbot, I. C. Tumour ‘budding’ as an index to estimate the potential of aggressiveness in rectal cancer. Histopathology 40, 127–132 (2002).

    CAS  PubMed  Google Scholar 

  160. Kai, K. et al. Tumor budding and dedifferentiation in gallbladder carcinoma: potential for the prognostic factors in T2 lesions. Virchows Arch. 459, 449–456 (2011).

    CAS  PubMed  Google Scholar 

  161. Almangush, A. et al. Tumour budding in oral squamous cell carcinoma: a meta-analysis. Br. J. Cancer 118, 577–586 (2018).

    PubMed  Google Scholar 

  162. Yu, P. et al. A novel prognostic model for tongue squamous cell carcinoma based on the characteristics of tumour and its microenvironment: iBD score. Histopathology 74, 766–779 (2019).

    PubMed  Google Scholar 

  163. Ho, Y. Y., Wu, T. Y., Cheng, H. C., Yang, C. C. & Wu, C. H. The significance of tumor budding in oral cancer survival and its relevance to the eighth edition of the American Joint committee on cancer staging system. Head Neck 41, 2991–3001 (2019).

    PubMed  Google Scholar 

  164. Xie, N. et al. Validation of the International Tumor Budding Consensus Conference (2016) recommendations in oral tongue squamous cell carcinoma. J. Oral Pathol. Med. 48, 451–458 (2019).

    PubMed  Google Scholar 

  165. Elseragy, A. et al. A proposal to revise the histopathologic grading system of early oral tongue cancer incorporating tumor budding. Am. J. Surg. Pathol. 43, 703–709 (2019).

    PubMed  Google Scholar 

  166. Luo, W. R., Gao, F., Li, S. Y. & Yao, K. T. Tumour budding and the expression of cancer stem cell marker aldehyde dehydrogenase 1 in nasopharyngeal carcinoma. Histopathology 61, 1072–1081 (2012).

    PubMed  Google Scholar 

  167. Marangon Junior, H. et al. Immunolocalization of cancer stem cells marker ALDH1 and its association with tumor budding in oral squamous cell carcinoma. Head. Neck Pathol. 13, 535–542 (2019).

    PubMed  Google Scholar 

  168. Makitie, A. A., Almangush, A., Rodrigo, J. P., Ferlito, A. & Leivo, I. Hallmarks of cancer: tumor budding as a sign of invasion and metastasis in head and neck cancer. Head Neck 41, 3712–3718 (2019).

    PubMed  Google Scholar 

  169. Neppl, C., Zlobec, I., Schmid, R. A. & Berezowska, S. Validation of the International Tumor Budding Consensus Conference (ITBCC) 2016 recommendation in squamous cell carcinoma of the lung-a single-center analysis of 354 cases. Mod. Pathol. 33, 802–811 (2020).

    CAS  PubMed  Google Scholar 

  170. Yamaguchi, Y. et al. Histopathologic features of the tumor budding in adenocarcinoma of the lung: tumor budding as an index to predict the potential aggressiveness. J. Thorac. Oncol. 5, 1361–1368 (2010).

    PubMed  Google Scholar 

  171. Masuda, R. et al. Tumor budding is a significant indicator of a poor prognosis in lung squamous cell carcinoma patients. Mol. Med. Rep. 6, 937–943 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  172. Kadota, K. et al. Comprehensive pathological analyses in lung squamous cell carcinoma: single cell invasion, nuclear diameter, and tumor budding are independent prognostic factors for worse outcomes. J. Thorac. Oncol. 9, 1126–1139 (2014).

    PubMed  PubMed Central  Google Scholar 

  173. Gujam, F. J., McMillan, D. C., Mohammed, Z. M., Edwards, J. & Going, J. J. The relationship between tumour budding, the tumour microenvironment and survival in patients with invasive ductal breast cancer. Br. J. Cancer 113, 1066–1074 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  174. Sun, Y. et al. Prognostic value of poorly differentiated clusters in invasive breast cancer. World J. Surg. Oncol. 12, 310 (2014).

    PubMed  PubMed Central  Google Scholar 

  175. Liang, F. et al. The prognostic value of tumor budding in invasive breast cancer. Pathol. Res. Pract. 209, 269–275 (2013).

    PubMed  Google Scholar 

  176. Salhia, B. et al. High tumor budding stratifies breast cancer with metastatic properties. Breast Cancer Res. Treat. 150, 363–371 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  177. Laedrach, C., Salhia, B., Cihoric, N., Zlobec, I. & Tapia, C. Immunophenotypic profile of tumor buds in breast cancer. Pathol. Res. Pract. 214, 25–29 (2018).

    CAS  PubMed  Google Scholar 

  178. Park, J. Y., Hong, D. G., Chong, G. O. & Park, J. Y. Tumor budding is a valuable diagnostic parameter in prediction of disease progression of endometrial endometrioid carcinoma. Pathol. Oncol. Res. 25, 723–730 (2019).

    CAS  PubMed  Google Scholar 

  179. Huang, B., Cai, J., Xu, X., Guo, S. & Wang, Z. High-grade tumor budding stratifies early-stage cervical cancer with recurrence risk. PLoS ONE 11, e0166311 (2016).

    PubMed  PubMed Central  Google Scholar 

  180. Satabongkoch, N. et al. Prognostic value of tumor budding in early-stage cervical adenocarcinomas. Asian Pac. J. Cancer Prev. 18, 1717–1722 (2017).

    PubMed  PubMed Central  Google Scholar 

  181. Jesinghaus, M. et al. Introducing a novel highly prognostic grading scheme based on tumour budding and cell nest size for squamous cell carcinoma of the uterine cervix. J. Pathol. Clin. Res. 4, 93–102 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  182. Kucuk, U. et al. Prognostic significance of tumor budding in muscle invasive urothelial carcinomas of the bladder. Turk. J. Urol. 45, 273–278 (2018).

    PubMed  PubMed Central  Google Scholar 

  183. Koelzer, V. H. et al. Tumor budding in colorectal cancer revisited: results of a multicenter interobserver study. Virchows Arch. 466, 485–493 (2015).

    CAS  PubMed  Google Scholar 

  184. Hase, K., Shatney, C., Johnson, D., Trollope, M. & Vierra, M. Prognostic value of tumor “budding” in patients with colorectal cancer. Dis. Colon Rectum 36, 627–635 (1993).

    CAS  PubMed  Google Scholar 

  185. Ueno, H. et al. A new prognostic staging system for rectal cancer. Ann. Surg. 240, 832–839 (2004).

    PubMed  PubMed Central  Google Scholar 

  186. Nakamura, T., Mitomi, H., Kikuchi, S., Ohtani, Y. & Sato, K. Evaluation of the usefulness of tumor budding on the prediction of metastasis to the lung and liver after curative excision of colorectal cancer. Hepatogastroenterology 52, 1432–1435 (2005).

    PubMed  Google Scholar 

  187. Lugli, A., Karamitopoulou, E. & Zlobec, I. Tumour budding: a promising parameter in colorectal cancer. Br. J. Cancer 106, 1713–1717 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  188. Rieger, G. et al. Comprehensive assessment of tumour budding by cytokeratin staining in colorectal cancer. Histopathology 70, 1044–1051 (2017).

    PubMed  Google Scholar 

  189. Bokhorst, J. M. et al. Assessment of individual tumor buds using keratin immunohistochemistry: moderate interobserver agreement suggests a role for machine learning. Mod. Pathol. 33, 825–833 (2020).

    CAS  PubMed  Google Scholar 

  190. Fauzi, M. F. A. et al. Tumor budding detection system in whole slide pathology images. J. Med. Syst. 44, 38 (2019).

    PubMed  Google Scholar 

  191. Takamatsu, M. et al. Immunohistochemical evaluation of tumor budding for stratifying T1 colorectal cancer: optimal cut-off value and a novel computer-assisted semiautomatic method. Mod. Pathol. 32, 675–683 (2019).

    PubMed  Google Scholar 

  192. Weis, C. A. et al. Automatic evaluation of tumor budding in immunohistochemically stained colorectal carcinomas and correlation to clinical outcome. Diagn. Pathol. 13, 64 (2018).

    PubMed  PubMed Central  Google Scholar 

  193. Jepsen, R. K. et al. Digital image analysis of pan-cytokeratin stained tumor slides for evaluation of tumor budding in pT1/pT2 colorectal cancer: results of a feasibility study. Pathol. Res. Pract. 214, 1273–1281 (2018).

    CAS  PubMed  Google Scholar 

  194. Brieu, N. et al. Automated tumour budding quantification by machine learning augments TNM staging in muscle-invasive bladder cancer prognosis. Sci. Rep. 9, 5174 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  195. Pedersen, N. J. et al. Construction of a pathological risk model of occult lymph node metastases for prognostication by semi-automated image analysis of tumor budding in early-stage oral squamous cell carcinoma. Oncotarget 8, 18227–18237 (2017).

    PubMed  PubMed Central  Google Scholar 

  196. Karamitopoulou, E. et al. Tumour budding is a strong and independent prognostic factor in pancreatic cancer. Eur. J. Cancer 49, 1032–1039 (2013).

    CAS  PubMed  Google Scholar 

  197. Liu, D. N. et al. Superior mesenteric artery margin in pancreaticoduodenectomy for pancreatic adenocarcinoma. Oncotarget 8, 7766–7776 (2017).

    PubMed  Google Scholar 

  198. Lohneis, P. et al. Tumour buds determine prognosis in resected pancreatic ductal adenocarcinoma. Br. J. Cancer 118, 1485–1491 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  199. O’Connor, K. et al. Tumor budding is an independent adverse prognostic factor in pancreatic ductal adenocarcinoma. Am. J. Surg. Pathol. 39, 472–478 (2015).

    PubMed  Google Scholar 

  200. Zhang, L., Guo, L., Tao, M., Fu, W. & Xiu, D. Parasympathetic neurogenesis is strongly associated with tumor budding and correlates with an adverse prognosis in pancreatic ductal adenocarcinoma. Chin. J. Cancer Res. 28, 180–186 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  201. Zhao, Y. et al. Invasion types are associated with poor prognosis in lung squamous carcinoma patients. Medicine 94, e1634 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  202. Weichert, W. et al. Proposal of a prognostically relevant grading scheme for pulmonary squamous cell carcinoma. Eur. Respir. J. 47, 938–946 (2016).

    CAS  PubMed  Google Scholar 

  203. Kadota, K. et al. Tumor spread through air spaces is an independent predictor of recurrence-free survival in patients with resected lung squamous cell carcinoma. Am. J. Surg. Pathol. 41, 1077–1086 (2017).

    PubMed  Google Scholar 

  204. Kadota, K. et al. A grading system combining tumor budding and nuclear diameter predicts prognosis in resected lung squamous cell carcinoma. Am. J. Surg. Pathol. 41, 750–760 (2017).

    PubMed  Google Scholar 

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Acknowledgements

The authors acknowledge research funding from the KWF Kankerbestrijding (Dutch Cancer Society; grant 10602 to A.L., I.Z., R.K. and I.D.N.).

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  1. Institute of Pathology, University of Bern, Bern, Switzerland

    Alessandro Lugli & Inti Zlobec

  2. Department of Medical Oncology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland

    Martin D. Berger

  3. Pathology and Laboratory Medicine, Mount Sinai Hospital, University of Toronto, Ontario, Canada

    Richard Kirsch

  4. Department of Pathology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Centre, Nijmegen, The Netherlands

    Iris D. Nagtegaal

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Lugli, A., Zlobec, I., Berger, M.D. et al. Tumour budding in solid cancers. Nat Rev Clin Oncol 18, 101–115 (2021). https://doi.org/10.1038/s41571-020-0422-y

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