A Novel Combined Tumor Budding-Poorly Differentiated Clusters Grading System Predicts Recurrence and Survival in Stage I-III Colorectal Cancer

Abstract

Tumor budding (TB) and poorly differentiated clusters (PDCs) are powerful prognostic factors in colorectal cancer (CRC). Despite their morphologic and biological overlap, TB and PDC are assessed separately and are distinguished by an arbitrary cutoff for cell cluster size. This cutoff can be challenging to apply in practice and its biological significance remains unclear. We developed a novel scoring system that incorporates TB and PDC into a single parameter ("Combined Score"; CS), eliminating the need for such cutoffs and allowing the prognostic value of PDC to be captured alongside TB. In a cohort of 481 stage I-III CRC resections, CS was significantly associated with American Joint Committee on Cancer (AJCC) stage, T-stage, N-stage, histologic grade, tumor deposits, lymphovascular invasion, and perineural invasion (P < 0.0001). In addition, CS was significantly associated with decreased 5-year recurrence-free survival, overall survival, and disease-specific survival (P < 0.0001). TB and PDC showed similar associations with oncologic outcomes, with hazard ratios consistently lower than for CS. The association between CS and oncologic outcomes remained significant in subgroup analyses stratified by AJCC stage, anatomic location (rectum/colon) and neoadjuvant therapy status. On multivariable analysis, CS retained its significant association with oncologic outcomes (P = 0.0002, 0.005, and 0.009) for recurrence-free survival, disease-specific survival, and overall survival, respectively. In conclusion, CS provides powerful risk stratification in CRC which is at least equivalent to that of TB and PDC assessed individually. If validated elsewhere, CS has practical advantages and a biological rationale that may make it an attractive alternative to assessing these features separately.

Tumor Budding Assessment in Colorectal Carcinoma

“…This study adds to the growing body of evidence validating high-grade tumor budding (ITBCC Bd3) as an independent prognostic factor in surgically resected CRC 6–8,13,23–31 . In a large cohort of patients undergoing resection of stage I-III CRC with curative intent, high-grade TB (Bd3) was strongly associated with other adverse histologic features, cancer-related mortality and recurrence.…”

“…This study adds to the growing body of evidence validating high-grade tumor budding (ITBCC Bd3) as an independent prognostic factor in surgically resected CRC. [6][7][8]13,[23][24][25][26][27][28][29][30][31] In a large cohort of patients undergoing resection of stage I-III CRC with curative intent, highgrade TB (Bd3) was strongly associated with other adverse histologic features, cancer-related mortality and recurrence. The prognostic significance of TB was independent of other adverse histologic factors in multivariable Cox proportional hazards analyses and was also present in resections performed after neoadjuvant therapy.…”

“…5 Numerous studies and meta-analyses have shown TB to be a powerful predictor of recurrence and mortality in CRC. [6][7][8][9][10][11][12] Although the prognostic significance of TB appears to retain validity across a number of different scoring systems, the presence of a single international standard is essential for both diagnostic practice and clinical trials; indeed, the absence of such a standard was previously a major barrier to the reporting of TB in routine pathology practice. 13 This barrier was removed when members of the International Tumor Budding Consensus Conference (ITBCC, Bern, Switzerland, 2016) agreed on a standardized method for TB assessment and reporting.…”

“…One such prognostic factor is tumor budding (TB), defined as the presence of single cells or groups of 4 or fewer cells at the tumor invasive front 5 . Numerous studies and meta-analyses have shown TB to be a powerful predictor of recurrence and mortality in CRC 6–12 . Although the prognostic significance of TB appears to retain validity across a number of different scoring systems, the presence of a single international standard is essential for both diagnostic practice and clinical trials; indeed, the absence of such a standard was previously a major barrier to the reporting of TB in routine pathology practice 13 .…”

Prognostic impact of tumor budding in rectal cancer after neoadjuvant therapy: a systematic review and meta-analysis

“…TB is an independent poor prognostic factor in colorectal cancer, and studies and meta-analyses have further validated that high-grade TB is significantly associated with lymph node metastasis in colorectal cancer ( P < 0.05) [ 15 , 30 ]. In addition, it was found that TB was significantly associated with poorer 5-year DFS, OS, and CSS in colorectal cancer ( P < 0.001), and TB showed the same correlation with 5-year DFS, OS, and CSS in the neoadjuvant subgroup [ 16 , 31 ]. However, the findings showed significant differences in the 5-year OS between rectal and colon cancers ( P ≤ 0.001) [ 32 , 33 ], and distinct differences in pathological manifestations, tumor immune microenvironments, and gene mutation profiles were found between tumor sites [ 21 , 34 ].…”