CD8+ lymphocytes/ tumour-budding index: an independent prognostic factor representing a ‘pro-/anti-tumour’ approach to tumour host interaction in colorectal cancer

Abstract

Background:The tumour-host interaction at the invasive front of colorectal cancer, including the epithelial–mesenchymal transition and its hallmark ‘tumour budding', is an important area of investigation in terms of prognosis. The aim of this study was to determine the prognostic impact of a ‘pro-/anti-tumour' approach defined by an established ‘pro-tumour' (tumour budding) and host-related ‘anti-tumour' factor of the adaptive immunological microenvironment (CD8+ lymphocytes).Methods:Double immunostaining for CK22/CD8 on whole tissue sections (n=279; Cohort 1) and immunohistochemistry for CD8+ using tissue microarrays (n=191; Cohort 2) was carried out. Tumour buds, CD8+ and CD8+ T-lymphocytes : tumour buds indices were evaluated per high-power field.Results:In Cohort 1, a low-CD8+/ buds index was associated with lymph node metastasis (P<0.001), vascular invasion (P=0.009), worse survival in univariate (P<0.001) and multivariable (P<0.001) analysis, and furthermore in lymph node-negative patients (P=0.002). In Cohort 2, the CD8+/ buds index was associated with T stage (P<0.001), N stage (P=0.041), vascular invasion (P=0.005) and survival in patients with TNM stage II (P=0.019), stage III (P=0.004), and adjuvantly untreated (P=0.009) and treated patients (P<0.001).Conclusion:The CD8+ lymphocyte : tumour-budding index is an independent prognostic factor in colorectal cancer and a promising approach for a future prognostic score for patients with this disease.

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.…”

“…Lugli et al 23 have demonstrated that a peritumoral lymphocytic reaction is associated with improved prognosis in the setting of tumor budding, suggesting that the immune response might target the tumor buds. The nature of the stroma at the invasive margin may provide further prognostic information, with myxoid stroma being associated with worse prognosis, 20,39 but further studies are needed to confirm the reproducibility and prognostic importance of these findings.…”

“…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.…”

“…23,49,50 It has been postulated that the relative infrequency of budding in microsatellite unstable tumors may, at least in part, explain the relatively better prognosis of these tumors. 49 Interestingly, compared with mismatch repair-proficient tumors, mismatch repair-deficient tumors have been shown to display less cytoplasmic pseudofragmentation in the context of high-grade budding, 51 and to be associated with less intratumoral budding, 14 both of which are associated with a worse prognosis.…”

“…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.…”