Tumor Budding as an Index to Identify High-Risk Patients with Stage II Colon Cancer

Abstract

Tumor budding is useful for prognosis and identifying patients with Stage II colon cancer who have a high risk of disease recurrence after curative surgery.

Tumor budding in colorectal carcinoma: time to take notice

“…In one of the earlier studies of tumor budding, Hase et al 18 demonstrated that 5-year survival rates of Dukes B (stage II, T3-4 N0) patients with high-grade budding are significantly worse than those of Dukes C (N þ ) patients without budding (29 percent vs 66 percent; Po0.001). A number of more recent studies have confirmed that patients with Stage II colorectal carcinoma do significantly worse when high-grade budding is present, [34][35][36]38,41,45 and several studies have shown that survival rates of patients with Stage II colorectal carcinoma with high-grade budding are equivalent to survival rates of patients with Stage III colorectal carcinoma. [34][35][36] In their studies of Stage II and III pT3 tumors, Okuyama et al 34,35 found that tumor budding was the only factor on multivariate analysis to be associated with decreased survival and was more prognostically significant than lymph node metastases.…”

“…This idea is supported by two intriguing morphological studies: Morodomi et al 33 examined serial sections of high-budding areas to demonstrate that budding nests are often found adjacent to areas of lymphovascular space invasion, and, in a more recent study, Ohtsuki et al 31 performed double staining for anti-cytokeratin antibodies and anti-lymphatic antibodies, finding that a number of 'buds' at the invasive edge of a tumor are in fact located in small lymphatic spaces. Similarly, the presence of budding has been associated with increased risk of distant metastases, [34][35][36] suggesting that budding may also be associated with vascular invasion. A few tumor-budding studies have used vascular markers and/or elastic stains to assess vascular invasion, 11,12,19,22,26,32,37,38 but only four have analyzed the relationship between budding and vascular invasion: Kazama et al 22 found no relationship between budding and vascular invasion, whereas three other studies have reported a statistically significant correlation between budding and venous invasion, though the association was not as pronounced as the relationship with lymphatic invasion and lymph node metastases.…”

“…11,12,[15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32] On multivariate analysis, budding has consistently emerged as an independent adverse prognostic factor, associated with local tumor recurrence and distant metastases, and significantly worse overall and disease-free survival. 12,15,16,21,27,28,31,32,[34][35][36]38,40,41 The adverse prognostic impact of high-grade tumor budding is seen in both early and advanced colorectal carcinoma, and there are several scenarios in which this feature might influence clinical decision making, particularly in early colorectal carcinoma.…”

“…The QUASAR trial demonstrated that chemotherapy does result in increased survival in Stage II patients, but the improvement was small and may not justify the costs and side effects of chemotherapy in all patients. 46 The significantly worse outcome experienced by Stage II patients with tumor budding has prompted some authors to suggest that adjuvant chemotherapy should be considered in these patients, 18,[34][35][36]41 but there are no published data assessing the effectiveness of chemotherapy in Stage II colorectal carcinoma with tumor budding.…”

“…Furthermore, while the majority of studies have evaluated only areas with the greatest amount of budding, others have proposed calculating an average bud count, 11 counting the number of buds along the entire invasive front 19,24,52,53 or calculating the proportion of invasive front with tumor budding. 21,36,40 Such methodological heterogeneity is illustrated in Table 1, which summarizes the bud counting methods used in a sample of tumor-budding studies.…”