Tumour budding at the deepest invasive margin correlates with lymph node metastasis in submucosal colorectal cancer detected by anticytokeratin antibody CAM5.2

Abstract

In the past few years, tumour budding at the invasive margin has been reported as a new risk factor for lymph node metastasis in advanced colorectal cancers, but it is sometimes difficult to detect tumour budding in submucosal colorectal cancer by haematoxylin and eosin staining. We immunohistochemically examined tumour budding at the deepest invasive margin of 56 surgically resected submucosal colorectal carcinomas using anticytokeratin antibody CAM5.2, furthermore checked by AE1/AE3, and determined the relation between tumour budding and clinicopathological factors. Moreover, we used the monoclonal antibody D2-40 for immunohistochemistry to detect lymphatic involvement. Tumour budding was detected in 42 cases (75.0%), and the buddingpositive group showed a significantly higher rate of lymph node metastasis (including isolated tumour cells) (16/42 vs 0/14; P ¼ 0.004) than the budding-negative group. The sensitivity and negative predictive value of tumour budding alone for lymph node metastasis were superior to those of lymphatic invasion alone. Furthermore, the specificity and positive predictive value of the combination of either lymphatic invasion or tumour budding were superior to those of lymphatic invasion alone. Tumour budding detected immunohistochemically by using CAM5.2 is a newly found risk factor for lymph node metastasis and may help to avoid oversurgery in the future.

Tumor budding in colorectal carcinoma: time to take notice

“…There is a strong association between budding and the presence of lymph node metastases and lymphovascular invasion, 11,12,[15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32] defined by the presence of tumor cells within an endothelium-lined space, and it has been suggested that buds represent the part of the tumor that has gained the ability to invade lymphatics and vascular channels. 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. 11,12,32 The tumor-host interaction at the invasive front may be of prognostic importance in the setting of tumor budding.…”

“…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.…”

“…16,19,22,25,26,29,30,37,43,44 In the largest of these studies, Ueno et al 26 demonstrated that, in submucosally invasive colorectal carcinoma, high tumor grade, lymphovascular invasion, and tumor budding are the three factors independently associated with lymph node metastases. Patients without any of these three features showed exceptionally low rates of lymph node metastases (1%, 1/138); in the presence of one risk factor, the rate of nodal metastases increased substantially to 21% (12/58), and when two or three factors were present, the risk was 36% (20/55), suggesting that in the absence of these factors, polypectomy alone is sufficient treatment for early colorectal carcinoma provided the resection margins are clear.…”

“…12,13,22,23,31,32,38,40,43,44,48,51,54,55 The use of immunohistochemistry in the assessment of budding is somewhat controversial: some authors argue that the evaluation of budding should be limited to H&E-stained slides because of the cost and impracticality of performing immunohistochemistry in routine cases, while others argue that immunohistochemistry should be used routinely to improve the accuracy and reproducibility of bud counts. In addition to cost considerations, the use of immunohistochemistry may also require the establishment of a separate cutoff for defining positive budding.…”