Tumor budding as a prognostic factor in head and neck cancer
Keywords:
head and neck cancer, prognosis, survival, tumor buddingAbstract
Introduction: Head and neck cancer is a global health problem. Recurrence or relapse increases mortality, leading to the identification of new prognostic factors, such as tumor relapse.
Objective: To describe the development and significance of tumor budding as a prognostic factor in head and neck cancer.
Methods: The EMBASE, Cochrane, and Scopus databases were consulted, as well as the PubMed platform. Medical Subject Headings (MeSH) terms were used, and articles published between January 2010 and December 2024, in both Spanish and English, were considered. A total of 193 articles were reviewed, and 63 were selected: review articles (8), original research articles (47), textbooks (3), websites (2), and diagnostic and treatment guidelines (3).
Development: Tumor budding, defined as clusters of tumor cells at the invasive front, may represent a marker of tumor aggressiveness in head and neck cancer. Tumor buds are graded and associated with features such as lymph node dissemination and vascular invasion. They are considered key prognostic and predictive factors, as they are linked to an increased risk of recurrence and metastasis, thus proving useful in prognosis assessment and therapeutic decision-making.
Conclusions: Survival in head and neck cancer depends on clinical and histopathological factors, such as the presence of tumor budding, which is associated with a poor prognosis.
Downloads
References
1. Mendenhall WM, Dziegielewski PT, Dunn LA. General Principles in the Management of Head and Neck Cancer. En: DeVita Jr VT, Lawrence TS, Rosemberg SA, editores. DeVita, Hellman, and Rosemberg´s Cancer Principles and Practice on Oncology. 12.a ed. Wolters Kluwer; 2023, 276-86.
2. Joshi N, Geiger J, Broughman JR, Burkey B. Head and Neck Cancer. En: Abraham J, Gulley JL, editores. The Bethesda Handbook of Clinical Oncology. 6.a ed. Wolters Kluwer; 2023, 18-48.
3. Sacks R, Boyce-Fappiano D, Moreno A, Mott F. Head and Neck Cancer. En: Kantarjian HM, Wolf RA, Rieber AG, editores. The MD Anderson Manual of Medical Oncology. 4a ed. McGraw Hill; 2022, 555-75.
4. World Health Organization. Globocan [Internet]. Francia: International Agency for Research on Cancer. 2022 [acceso: 03/04/2024]. Disponible en: http://globocan.iarc.fr
5. Ministerio de Salud Pública. Anuario Estadístico de Salud 2023. La Habana: Dirección de registros médicos y estadísticas de salud; 2024. [acceso: 03/04/2024]. Disponible en: https://www.paho.org/sites/default/files/2025-02/anuario-estadistico-salud-2023-ed-2024.pdf
6. Barsouk A, Aluru JS, Rawla P, Saginala K, Barsouk A. Epidemiology, Risk Factors, and Prevention of Head and Neck Squamous Cell Carcinoma [Internet]. Med Sci. 2023; 11(2): 42. DOI: 10.3390/medsci11020042
7. Gormley M, Creaney G, Schache A, Ingarfield K, Conway D. Reviewing the epidemiology of head and neck cancer: definitions, trends and risk factors [Internet]. British Dental Journal. 2022; 233(9):780-6. DOI: 10.1038/s41415-022-5166-x
8. Kansy B, Wehrs T, Bruderek K, Si Y, Ludwig S, Droege F, et al. HPV associated head and neck cancer is characterized by distinct profiles of CD8+ T cells and myeloid derived suppressor cells [Internet]. Cancer Immunol Immunother. 2023; 72:4367–83. DOI: 10.1007/s00262-023-03571-8
9. Caudell J, Gillison M, Maghami E, Spencer S, Pfister D, Adkins D, et al. NCCN Guidelines Insights: Head and Neck Cancer, version 1.2022 [Internet]. J Natl Compr Canc Netw. 2022; 20(3):224-34. DOI: 10.6004/jnccn.2022.0016
10. Johnson DE, Burtness B, Leemans CR, Wai V, Bauman JE, Grandis JR. Head and neck squamous cell carcinoma [Internet]. Nat Rev Dis Primers. 2021; 6(1):92. DOI: 10.1038/s41572-020-00224-3
11. Mei Z, Huang J, Qiao AK. Immune checkpoint pathways in immunotherapy for head and neck squamous cell carcinoma [Internet]. International Journal of Oral Science. 2020; 12:16. DOI: 10.1038/s41368-020-0084-8
12. Mesia R, Iglesias L, Lambea J, Martínez J, Soria A, Taberna M, et al. SEOM clinical guidelines for the treatment of head and neck cancer [Internet]. Clinical and Translational Oncology. 2021; 23:913–21. DOI: 10.1007/s12094-020-02533-1
13. Ghosh S, Shah PA, Johnson FM. Novel Systemic Treatment Modalities Including Immunotherapy and Molecular Targeted Therapy for Recurrent and Metastatic Head and Neck Squamous Cell Carcinoma [Internet]. Int J Mol Sci. 2022; 23:7889. DOI: 10.3390/ijms23147889
14. Cacchi C, Fischer HJ, Wermker K, Rashad A, Jonigk DD, Hölzle F, et al. New Tumor Budding Evaluation in Head and Neck Squamous Cell Carcinomas [Internet]. Cancers. 2024; 16(3):587. DOI: 10.3390/cancers16030587
15. Shi E, Wu Z, Karaoglan BS, Schwenk S, Kranz G, Razak NA, et al. 5ʹ-Ectonucleotidase CD73/NT5E supports EGFR-mediated invasion of HPV-negative head and neck carcinoma cells [Internet]. Journal of Biomedical Science. 2023; 30:72. DOI: 10.1186/s12929-023-00968-6
16. Zhang S, Zeng N, Yang J, He J, Zhu F, Liao W, et al. Advancements of radiotherapy for recurrent head and neck cancer in modern era [Internet]. Radiation Oncology. 2023;18:166. DOI: 10.1186/s13014-023-02342-0
17. Descamps G, Karaca Y, Lechien JR, Kindt N, Decaestecker C, Remmelink M, et al. Classical risk factors, but not HPV status, predict survival after chemoradiotherapy in advanced head and neck cancer Patients [Internet]. J Cancer Res Clin Oncol. 2016; 142:2185–96. DOI: 10.1007/s00432-016-2203-7
18. Smith EM, Pawlita M, Rubenstein LM, Haugen TH, Hamsikova E, Turek LP. Risk factors and survival by HPV-16 E6 and E7 antibody status in human papillomavirus positive head and neck cancer [Internet]. Int J Cancer. 2010; 127:111–7. DOI: 10.1002/ijc.25015
19. Riggauer J, Blaser D, Elicin O, Gahl B, Giger R, Mueller SA, et al. Risk Factors for Fear of Recurrence in Head and Neck Cancer Patients [Internet]. Laryngoscope. 2023; 133(7):1630-7. DOI: 10.1002/lary.30340
20. Grün A, Kuhnt T, Schlomm T, Olze H, Budach V, Stromberger C. Repeat Radiation for Local Recurrence of Head and Neck Tumors and in Prostate Cancer [Internet]. Dtsch Arztebl Int. 2020; 117:167–74. DOI: 10.3238/arztebl.2020.0167
21. Lee DY, Abraham J, Ross E, Ridge JA, Lango M, Liu JC, et al. Rapid Recurrence in Head and Neck Cancer: An Underappreciated Problem with Poor Outcome [Internet]. Head Neck. 2021; 43(1):212–22. DOI: 10.1002/hed.26479
22. Diez A, Ceulaer JD, Derpoorter C, Spaas C, Backer TD, Lamoral P, et al. Tracking the Molecular Fingerprint of Head and Neck Cancer for Recurrence Detection in Liquid Biopsies [Internet]. Int J Mol Sci. 2022; 23:2403. DOI: 10.3390/ijms23052403
23. Chen K, Collins G, Wang H, Tatt JW. Pathological Features and Prognostication in Colorectal Cancer [Internet]. Curr Oncol. 2021; 28:5356–83. DOI: 10.3390/curroncol28060447
24. Dawson H, Galuppini F, Träger P, Berger MD, Studer P, Brügger L, et al. Validation of the International Tumor Budding Consensus Conference 2016 recommendations on tumor budding in stage I-IV colorectal cancer [Internet]. Human Pathology. 2019; 85:145-51. DOI: 10.1016/j.humpath.2018.10.023
25. Luo L. High-grade tumor budding is a risk factor for survival in patients with laryngeal squamous cell carcinoma [Internet]. Brazilian Journal of Otorhinolaryngology. 2023; 89(5):101310. DOI: 10.1016/j.bjorl.2023.101310
26. Lugli A, Zlobec I, Berger MD, Kirsch R, Nagtegaal ID. Tumour budding in solid cancers [Internet]. Nat Rev Clin Oncol. 2021; 18:101–15. DOI: 10.1038/s41571-020-0422-y
27. Canguçu AL, Valério E, Pimenta RB, Cordeiro T, Lopes CA, Neotti T. The prognostic influence of tumour budding in Western patients with stage II colorectal cancer [Internet]. ecancer. 2020; 14:1130. DOI: 10.3332/ecancer.2020.1130
28. Stögbauer F, Beck S, Ourailidis L, Hess J, Poremba C, Lauterbach M, et al. Tumour budding-based grading as independent prognostic biomarker in HPV-positive and HPV-negative head and neck Cancer [Internet]. British Journal of Cancer. 2023; 128:2295–2306. DOI: 10.1038/s41416-023-02240-y
29. Zanoletti E, Daloiso A, Nicolè L, Cazzador D, Mondello T, Franz L, et al. Tumor budding to investigate local invasion, metastasis, and prognosis of head and neck carcinoma: A systematic Review [Internet]. Head & Neck.Wiley Periodicals LLC. 2024; 46:651–71. DOI: 10.1002/hed.27583
30. Xu B, Salama AM, Valero C, Yuan A, Khimraj A, Saliba M, et al. The prognostic role of histologic grade, worst pattern of invasion and tumor budding in early oral tongue squamous cell carcinoma: a comparative study [Internet]. Virchows Arch. 2021; 479(3):597–606. DOI: 10.1007/s00428-021-03063-z
31. BjerkliI IH, Laurvik H, Nginamau ES, Søland TM, Costea D, Hov H, et al. Tumor budding score predicts lymph node status in oral tongue squamous cell carcinoma and should be included in the pathology report [Internet]. PLoSONE. 2020; 15(9):e0239783. DOI: 10.1371/journal.pone.0239783
32. Ziai H, Warner A, Mundi N, Patel K, Chung EJ, Howlett CJ, et al. Does HPV Subtype Predict Outcomes in Head and Neck Cancers? [Internet]. International Journal of Otolaryngology. 2021; 6672373:11. DOI: 10.1155/2021/6672373
33. Heck JE, Berthiller J, Vaccarella S, Winn DM, Smith EM, Shan'gina O, et al. Sexual behaviours and the risk of head and neck cancers: a pooled analysis in the International Head and Neck Cancer Epidemiology (INHANCE) consortium [Internet]. Int J Epidemiol. 2010; 39(1):166-81. DOI: 10.1093/ije/dyp350
34. Machiels JP, Leemans CR, Golusinski W, Grau C, Licitra L, Gregoire V. Squamous cell carcinoma of the oral cavity, larynx, oropharynx and hypopharynx: EHNSESMOESTRO Clinical Practice Guidelines for diagnosis, treatment and follow-up [Internet]. Annals of Oncology. 2020; 31(11): 1462-75. DOI: 10.1016/j.annonc.2020.07.011
35. Mäkitie AA, Almangush A, Rodrigo JP, Ferlito A and Leivo I. Hallmarks of cancer: Tumor budding as a sign of invasion and metastasis in head and neck cancer [Internet]. Head Neck Wiley Periodicals LLC. 2019; 41(10):3712-8. DOI: 10.1002/hed.25872
36. Kai K, Aishima S, Aoki S, Takase Y, Uchihashi K, Masuda M, et al. Cytokeratin immunohistochemistry improves interobserver variability between unskilled pathologists in the evaluation of tumor budding in T1 colorectal cancer [Internet]. Pathol Int. 2016; 66(2):75-82. DOI: 10.1111/pin.12374
37. Seki M, Sano T, Yokoo S, Oyama T. Tumour budding evaluated in biopsy specimens is a useful predictor of prognosis in patients with cN0 early stage oral squamous cell carcinoma [Internet]. Histopathology. 2017; 70:869-79. DOI: 10.1111/his.13144
38. Acharya S, Raj M, Hallikeri K, Desai A. Histological assessment of budding and depth of invasion (BD) model in biopsies of oral squamous cell carcinoma [Internet]. J Oral Maxillofac Pathol. 2020; 24:581. DOI: 10.4103/jomfp.JOMFP_236_19
39. Almangush A, Leivo I, Siponen M, Sundquist E, Mroueh R, Mäkitie AA. Evaluation of the budding and depth of invasion (BD) model in oral tongue cancer biopsies [Internet]. Virchows Arch. 2018; 472:231-6. DOI: 10.1007/s00428-017-2212-1
40. Wen X, Zee SY, Shroyer KR, Bandovic J. Intratumoral Budding and Tumor Microenvironment in Pretreatment Rectal Cancer Biopsies Predict the Response to Neoadjuvant Chemoradiotherapy [Internet]. Appl Immunohistochem Mol Morphol. 2022; 30(1):1-7. DOI: 10.1097/PAI.0000000000000966
41. Farchoukh L, Hartman DJ, Ma C, Celebrezze J, Medich D, Bahary N, et al. Intratumoral budding and automated CD8-positive T-cell density in pretreatment biopsies can predict response to neoadjuvant therapy in rectal adenocarcinoma [Internet]. Mod Pathol. 2021; 34(1):171–83. DOI: 10.1038/s41379-020-0619-8
42. Li J, Ma Y, Wen L, Zhang G, Huang C, Wang J, et al. Prognostic impact of tumor budding in rectal cancer after neoadjuvant therapy: a systematic review and meta-analysis [Internet]. Syst Rev. 2024; 13:22. DOI: 10.1186/s13643-023-02441-9
43. Morodomi T, Isomoto H, Shirouzu K, Kakegawa K, Irie K, Morimatsu M. An index for estimating the probability of lymph node metastasis in rectal cancers. Lymph node metastasis and the histopathology of actively invasive regions of cancer [Internet]. Cancer. 1989; 63(3):539-43. DOI: 10.1002/1097-0142(19890201)63:3<539::aid-cncr2820630323>3.0.co;2-s
44. Ueno H, Murphy J, Jass JR, Mochizuki H, Talbot IC. Tumor 'budding' as an index to estimate the potential of aggressiveness in rectal cancer [Internet]. Histopathology. 2002; 40(2):127-32. DOI: 10.1046/j.1365-2559.2002.01324.x
45. Okuyama K, Suzuki K, Yanamoto S. Relationship between Tumor Budding and Partial Epithelial–Mesenchymal Transition in Head and Neck Cancer [Internet]. Cancers. 2023; 15(4):1111. DOI: 10.3390/cancers1504111
46. Zheng S, Luo J, Xie S, Lu S, Liu Q, Xiao H, et al. Tumor budding of cervical squamous cell carcinoma: epithelial-mesenchymal transition-like cancer stem cells? [Internet]. PeerJ. 2022; 10:e13745. DOI: 10.7717/peerj.13745
47. Assis EM, Rodríguez M, Campos J, Mantuani MI, Marangon H, Ribeiro G, et al. Microvascular density and tumor budding in oral squamous cell carcinoma [Internet]. Med Oral Patol Oral Cir Bucal. 2023; 28(2):e174-82. DOI: 10.4317/medoral.25640
48. Sharaf K, Lechner A, Haider SP, Wiebringhaus R, Walz C, Kranz G, et al. Discrimination of Cancer Stem Cell Markers ALDH1A1, BCL11B, BMI-1, and CD44 in Different Tissues of HNSCC Patients [Internet]. Curr Oncol. 2021; 28(4):2763-74. DOI: 10.3390/curroncol28040241
49. Jakob M, Sharaf K, Schirmer M, Leu M, Küfer S, Bertlich M, et al. Role of cancer stem cell markers ALDH1, BCL11B, BMI-1, and CD44 in the prognosis of advanced HNSCC [Internet]. Strahlenther Onkol. 2021; 197:231-45. DOI: 10.1007/s00066-020-01653-5
50. Wang W, Xie N, Yi C, Zhang M, Xiong G, Xu X, et al. Prognostic and clinicopathological significance of cytocapsular tubes in oral squamous cell carcinoma [Internet]. J Oral Pathol Med. 2022; 51(6):520-8. DOI: 10.1111/jop.13323
51. Ekmekci S, Kucuk U, Kokkoz S, Cakir E, Gumussoy M. Tumor budding in laryngeal carcinoma [Internet]. Indian J Pathol Microbiol. 2019; 62:7-10. DOI: 10.4103/IJPM.IJPM_428_17
52. Boxberg M, Kuhn PH, Reiser M, Erb A, Steiger K, Pickhard A, et al. Tumor Budding and Cell Nest Size Are Highly Prognostic in Laryngeal and Hypopharyngeal Squamous CellCarcinoma [Internet]. Am J Surg Pathol. 2019; 43:303–13. DOI: 10.1097/PAS.0000000000001178
53. ÖztürkÇ, Paşaoğlu HE, Emre F, Ege TS, Tetikkurt US. High tumor budding activity may predict poor prognosis in laryngeal squamous cell carcinomas [Internet]. Indian JPathol Microbiol. 2022; 65:280-7. DOI: 10.4103/IJPM.IJPM_1299_20
54. Gomes S, Oliveira RV, Marinho TM, Nobre F, Fernandes K, et al. Tumor Budding and Poor Prognosis in Oral Cancer: A Systematic Review and Meta-Analysis [Internet]. Asian Pac J Cancer Prev. 2023; 24(8):2565-73. DOI: 10.31557/APJCP.2023.24.8.2565
55. Deshpande NS, Munemane AB, Karle RR, Dongre SD. Relevance of tumor budding and pattern of invasion in oral squamous cell carcinoma [Internet]. Int J App Basic Med Res. 2024;14:29-34. DOI: 10.4103/ijabmr.ijabmr_391_23
56. Kligerman MP, Moon PK, Tusty M, Cloutier JM, Ma Y, Holsinger CF, et al. Impact of Histologic Risk Factors on Recurrence Rates for Oral Cavity Squamous Cell Carcinoma [Internet]. Annals of Otology, Rhinology & Laryngology. 2023; 132(7):731-7. DOI: 10.1177/00034894221111223
57. Dourado MR, Miwa KYM, Hamada GB, Paranaıba LM, Calone IS, Domingueti CB, et al. Prognostication for oral squamous cell carcinoma patients based on the tumour–stroma ratio and tumour budding [Internet]. Histopathology. 2020; 76(6):906-18. DOI: 10.1111/his.14070
58. Cacchi C, Fischer HJ, Wermker K, Rashad A, Jonigk DD, Hölzle F, et al. New Tumor Budding Evaluation in Head and Neck Squamous Cell Carcinomas [Internet]. Cancers. 2024; 16(3):587. DOI: 10.3390/cancers16030587
59. Stögbauer F, Wirth M, Lauterbach M, Wollenberg B, Schmidl B, Hoch CC, et al. Tumor budding and lymphovascular invasion as prognostic factors in p16-positive oropharyngeal squamous cell carcinomas [Internet]. Br J Cancer. 2024; 132(2):212-21. DOI: 10.1038/s41416-024-02912-3
60. MäkitieAA, Almangush A, Rodrigo JP, Ferlito A, Leivo I. Hallmarks of cancer: Tumor budding as a sign of invasion and metastasis in head and neck cancer [Internet]. Head & Neck. 2019; 41(10):3712-18. DOI: 10.1002/hed.25872
61. Luo WR, Gao F, Li SY, Yao KT. Tumour budding and the expression of cancer stem cell marker aldehyde dehydrogenase 1 in nasopharyngeal carcinoma [Internet]. Histopathology. 2012; 61(6):1072–81. DOI: 10.1111/j.1365-2559.2012.04350.x
62. Luo W. Nasopharyngeal carcinoma ecology theory: cancer asmultidimensional spatiotemporal “unity of ecology and evolution” pathological ecosystem [Internet]. Theranostics. 2023; 13(5):1607-1631. DOI: 10.7150/thno.82690
63. ImaiT, Ito S, Oikawa T, Asada Y, Matsumoto K, Miyazaki T, et al. Risk factors for cervical lymph node metastasis in endoscopically resected superficial hypopharyngeal cancers [Internet]. Auris Nasus Larynx. 2019; 46(3):424-30. DOI: 10.1016/j.anl.2018.09.005
64. Maffeis V, Cappellesso R, Galuppini F, Guzzardo V, Zanon A, Cazzador D, et al. Tumor budding is an adverse prognostic marker in intestinal-type sinonasal adenocarcinoma and seems to be unrelated to epithelial-mesenchymal transition [Internet]. Virchows Archiv. 2020; 477(2):241-248. DOI: 10.1007/s00428-020-02748-1
65. Meerwein CM, Brada MD, Soyka MB, Holzmann D, Rupp NJ. Reappraisal of Grading in Intestinal Type Sinonasal Adenocarcinoma: Tumor Budding as an Independent Prognostic Parameter [Internet]. Head and Neck Pathology. 2022; 16:670–678. DOI: 10.1007/s12105-022-01410-3
66. Puccio S, Azzarello G, Maffeis V, Laurino L, Mairani E, Conte F, et al. Tumor Budding, p53, and DNA Mismatch Repair Markers in Sinonasal Intestinal-Type Adenocarcinoma: A Retrospective Study Supports the Adverse Prognostic Impact of Tumor Budding [Internet]. Cancers. 2024; 16(10):1895. DOI: 10.3390/cancers16101895
Published
How to Cite
Issue
Section
License
Copyright (c) 2025 Alejandro Manuel Perez Fonteboa, Edelberto Gámez Pérez, Ricardo Valdés Durán, Rolando Dario Rosales Campos
This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License.
Authors who have publications with this Journal accept the following terms:
- The authors will retain their copyright and guarantee the Journal the right of first publication of their work, which will simultaneously be subject to the Creative Commons Attribution License. The content presented here can be shared, copied and redistributed in any medium or format; Can be adapted, remixed, transformed or created from the material, using the following terms: Attribution (giving appropriate credit to the work, providing a link to the license, and indicating if changes have been made); non-commercial (you cannot use the material for commercial purposes) and share-alike (if you remix, transform or create new material from this work, you can distribute your contribution as long as you use the same license as the original work).
- The authors may adopt other non-exclusive license agreements for the distribution of the published version of the work (for example: depositing it in an institutional electronic archive or publishing it in a monographic volume) as long as the initial publication in this Journal is indicated.
- Authors are allowed and recommended to disseminate their work through the Internet (e.g., in institutional electronic archives or on their website) before and during the submission process, which can produce interesting exchanges and increase citations. of the published work.
