Abstract
Purpose
Tumour budding is defined as the presence of isolated or small clusters of malignant cells at the invasive edge of the tumour. It is considered a negative prognostic factor in colorectal cancer (CRC) and is associated with a poor outcome and adverse pathological features. Here, we report a meta-analysis of the association of tumour budding and survival in stage II CRC patients.
Methods
PubMed, EMBASE, Web of Science and SCOPUS were searched for studies that assessed the relationship between tumour budding and 5-year overall survival (OS) in stage II CRC patients. Published data were extracted and used to compute odds ratios (ORs) for death at 5 years and hazard ratios (HRs) for survival amongst patients with respect to the extent of tumour budding, using multivariate analysis. Data were pooled using the Mantel–Haenszel random effect model.
Results
We analysed 12 studies that included a total of 1652 patients. High-grade budding was associated with worse OS at 5 years (OR for death, 6.25; 95 % confidence interval [CI], 4.04–9.67; P < 0.00001). The absolute difference in 5-year OS was −25 % (95 % CI, −18– − 33 %, P < 0.00001). It was particularly noteworthy that the presence of high-grade budding was associated with an increased risk of death (HR for death, 3.68; 95 % CI, 2.16–6.28, P < 0.00001).
Conclusions
Tumour budding is associated with worse survival in stage II CRC, in particular in pT3N0M0 patients. It could therefore potentially be used when deciding whether to administer adjuvant chemotherapy in high-risk node negative CRC patients.
Similar content being viewed by others
References
Quasar Collaborative Group, Gray R, Barnwell J, McConkey C, Hills RK, Williams NS, et al. Adjuvant chemotherapy versus observation in patients with colorectal cancer: a randomised study. Lancet. 2007;370:2020–9.
Wu X, Zhang J, He X, et al. Postoperative adjuvant chemotherapy for stage II colorectal cancer: a systematic review of 12 randomized controlled trials. J Gastrointest Surg. 2012;16:646–55.
http://www.nccn.org/professionals/physician_gls/pdf/colon.pdf. Accessed 31 May 2014.
Sargent DJ, Marsoni S, Monges G, et al. Defective mismatch repair as a predictive marker for lack of efficacy of fluorouracil-based adjuvant therapy in colon cancer. J Clin Oncol. 2010;28(20):3219–26. Erratum in: J Clin Oncol. 2010 Oct 20;28(30):4664.
Okuyama T, Oya M, Ishikawa H. Budding as a useful prognostic marker in pT3 well- or moderately-differentiated rectal adenocarcinoma. J Surg Oncol. 2003;83:42–7.
Okuyama T, Nakamura T, Yamaguchi M. Budding is useful to select high-risk patients in stage II welldifferentiated or moderately differentiated colon adenocarcinoma. Dis Colon Rectum. 2003;46:1400–6.
Nakamura T, Mitomi H, Kanazawa H, et al. Tumor budding as an index to identify high-risk patients with stage II colon cancer. Dis Colon Rectum. 2008;51:568–72.
Yasuda K, Inomata M, Shiromizu A, et al. Risk factors for occult lymph node metastasis of colorectal cancer invading the submucosa and indications for endoscopic mucosal resection. Dis Colon Rectum. 2007;50:1370–6.
Prall F, Nizze H, Barten M. Tumour budding as prognostic factor in stage I/II colorectal carcinoma. Histopathology. 2005;47:17–24.
Zlobec I, Lugli A. Epithelial mesenchymal transition and tumor budding in aggressive colorectal cancer: tumor budding as oncotarget. Oncotarget. 2010;1:651–61.
Morodomi T, Isomoto H, Shirouzu K, et al. 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. Cancer. 1989;63:539–43.
Shinto E, Jass JR, Tsuda H, et al. Differential prognostic significance of morphologic invasive markers in colorectal cancer: tumor budding and cytoplasmic podia. Dis Colon Rectum. 2006;49:1422–30.
Liberati A, Altman D, Tetzlaff J. The PRISMA statement for reportingsystematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. PLoS Med. 2009;6(7):e1000100.
Lai YH, Wu LC, Li PS, et al. Tumour budding is a reproducible index for risk stratification of patients with Stage II colon cancer. Color Dis. 2014;16(4):259–64.
Betge J, Kornprat P, Pollheimer MJ, et al. Tumor budding is an independent predictor of outcome in AJCC/UICC stage II colorectal cancer. Ann Surg Oncol. 2012;19(12):3706–12.
Canney AL, Kevans D, Wang LM, et al. Stage II colonic adenocarcinoma: a detailed study of pT4N0 with emphasis on peritoneal involvement and the role of tumour budding. Histopathology. 2012;61(3):488–96.
Kevans D, Wang LM, Sheahan K, 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. 2011;19(6):751–60.
Tanaka M, Hashiguchi Y, Ueno H, Hase K, Mochizuki H. Tumor budding at the invasive margin can predict patients at high risk of recurrence after curative surgery for stage II, T3 colon cancer. Dis Colon Rectum. 2003;46(8):1054–9.
Wang LM, Kevans D, Mulcahy H, et al. Tumor budding is a strong and reproducible prognostic marker in T3N0 colorectal cancer. Am J Surg Pathol. 2009;33(1):134–41.
Yoshida K, Yoshimatsu K, Otani T, Yokomizo H, Ogawa K. The depth of tumor invasion beyond the outer border of the muscularis propria as a prognostic factor for T3 rectal/rectosigmoid cancer. Anticancer Res. 2008;28(3B):1773–8.
Park KJ, Choi HJ, Roh MS, Kwon HC, Kim C. Intensity of tumor budding and its prognostic implications in invasive colon carcinoma. Dis Colon Rectum. 2005;48(8):1597–602.
Choi HJ, Park KJ, Shin JS, et al. Tumor budding as a prognostic marker in stage-III rectal carcinoma. Int J Color Dis. 2007;22:863–8.
Guzinska-Ustymowicz K. The role of tumour budding at the front of invasion and recurrence of rectal carcinoma. Anticancer Res. 2005;25:1269–72.
Ha SS, Choi HJ, Park KJ, et al. Intensity of tumor budding as an index for the malignant potential in invasive rectal carcinoma. Cancer Res Treat. 2005;37:177–82.
Hase K, Shatney C, Johnson D, et al. Prognostic value of tumor ‘budding’ in patients with colorectal cancer. Dis Colon Rectum. 1993;36:627–35.
Homma Y, Hamano T, Otsuki Y, et al. Severe tumor budding is a risk factor for lateral lymph node metastasis in early rectal cancers. J Surg Oncol. 2010;102:230–4.
Kajiwara Y, Ueno H, Hashiguchi Y, et al. Risk factors of nodal involvement in T2 colorectal cancer. Dis Colon Rectum. 2010;53:1393–9.
Kanazawa H, Mitomi H, Nishiyama Y, et al. Tumour budding at invasive margins and outcome in colorectal cancer. Color Dis. 2008;10:41–7.
Kazama S, Watanabe T, Ajioka Y, et al. Tumour budding at the deepest invasive margin correlates with lymph node metastasis in submucosal colorectal cancer detected by anticytokeratin antibody CAM5.2. Br J Cancer. 2006;94:293–8.
Lugli A, Karamitopoulou E, Panayiotides I, 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. 2009;101:1382–92.
Masaki T, Matsuoka H, Sugiyama M, et al. Tumor budding and evidence-based treatment of T2 rectal carcinomas. J Surg Oncol. 2005;92:59–63.
Sohn DK, Chang HJ, Park JW, et al. Histopathological risk factors for lymph node metastasis in submucosal invasive colorectal carcinoma of pedunculated or semipedunculated type. J Clin Pathol. 2007;60:912–5.
Ueno H, Mochizuki H, Hashiguchi Y, et al. Risk factors for an adverse outcome in early invasive colorectal carcinoma. Gastroenterology. 2004;127:385–94.
Ueno H, Murphy J, Jass JR, et al. Tumour ‘budding’ as an index to estimate the potential of aggressiveness in rectal cancer. Histopathology. 2002;40:127–32.
Ueno H, Price AB, Wilkinson KH, et al. A new prognostic staging system for rectal cancer. Ann Surg. 2004;240:832–9.
Yamauchi H, Togashi K, Kawamura YJ, et al. Pathological predictors for lymph node metastasis in T1 colorectal cancer. Surg Today. 2008;38:905–10.
Wang HS, Liang WY, Lin TC, et al. Curative resection of T1 colorectal carcinoma: risk of lymph node metastasis and long-term prognosis. Dis Colon Rectum. 2005;48:1182–92.
Ohtsuki K, Koyama F, Tamura T, et al. Prognostic value of immunohistochemical analysis of tumor budding in colorectal carcinoma. Anticancer Res. 2008;28:1831–6.
Suzuki A, Togashi K, Nokubi M, et al. Evaluation of venous invasion by Elastica van Gieson stain an tumor budding predicts local and distant metastases in patients with T1 stage colorectal cancer. Am J Surg Pathol. 2009;33:1601–7.
Syk E, Lenander C, Nilsson PJ, et al. Tumour budding correlates with local recurrence of rectal cancer. Color Dis. 2011;13:255–62.
Bartley AN, Hamilton SR, Alsabeh R, et al. Template for reporting results of biomarker testing of specimens from patients with carcinoma of the colon and rectum. Arch Pathol Lab Med. 2014;138(2):166–70.
Mitrovic B, Schaeffer DF, Riddell RH, Kirsch R. Tumor budding in colorectal carcinoma: time to take notice. Mod Pathol. 2012;25(10):1315–25.
Koelzer VH, Zlobec I, Berger MD, et al. Tumor budding in colorectal cancer revisited: results of a multicenter interobserver study. Virchows Arch. 2015;21.
Horcic M, Koelzer VH, Karamitopoulou E, et al. Tumor budding score based on 10 high-power fields is a promising basis for a standardized prognostic scoring system in stage II colorectal cancer. Hum Pathol. 2013;44(5):697–705.
Conflict of Interest
None.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Petrelli, F., Pezzica, E., Cabiddu, M. et al. Tumour Budding and Survival in Stage II Colorectal Cancer: a Systematic Review and Pooled Analysis. J Gastrointest Canc 46, 212–218 (2015). https://doi.org/10.1007/s12029-015-9716-1
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12029-015-9716-1