Histological Tumor Budding Associated with Obesity in Nonmetastatic Colorectal Cancer

Investigators analyzed the relationship between tumor budding and obesity in patients with colorectal cancer.

Results from a study published in JAMA Network Open identified a novel association between obesity and tumor budding (TB) in patients with colorectal cancer (CRC). In a large cohort of patients with nonmetastatic CRC, higher TB grade was significantly associated with obesity. Higher TB grade was also independently correlated with increased infiltrative tumor border, higher cancer stage, and worse overall prognosis.

Investigators conducted a histological review of colon cancer specimens collected between 2008 and 2015 at a medical center in Kentucky. The study population consisted of adults with a clinical diagnosis of CRC. Samples from patients with stage 0 cancer or stage IV cancer were excluded. Clinical and demographic data were extracted from patient medical records, including age, race, sex, and body mass index (BMI).

TB was defined as 1 to 4 malignant cells at the invasive edge of the tumor, determined by independent assessment from 2 pathologists.

The primary outcome was the association between TB and obesity, evaluated using a multivariable partial proportional odds logistic regression. Obesity was defined as a BMI of 30 kg/m2 or greater.

Secondary analyses evaluated the association between TB and other clinical factors, histological factors, and survival time. Odds ratios (ORs) were reported for each potential correlate of TB. Survival time was modeled using the Kaplan-Meier method and evaluated as a function of TB using Cox proportional hazards regression. Regression models were adjusted for relevant covariates, including age, sex, race, cancer stage, tumor location, and Appalachian status.

A total of 200 specimens were reviewed. Median patient age was 62 (interquartile range [IQR] 55-75) years. Mean BMI was 28.5 ± 8.4 kg/m2. Just over half (51.0%) of patients were women. The distribution of specimens by cancer stage was as follows: 28.5% stage I tumors, 37.0% stage II tumors, and 34.5% stage III tumors. 

Overall, 48.5% of specimens had low-grade TB (<5 buds), 18.0% had intermediate-grade TB (5-9 buds), and 33.5% had high-grade TB (≥10 buds). A greater proportion of patients with high-grade TB had a BMI ≥30 kg/m2 when compared against patients with low-grade TB (44.8% vs 27.8%; P =.02).

In multivariable regression models, patients with obesity were significantly more likely to have intermediate- or high-grade TB compared with patients without obesity (OR, 4.25; 95% confidence interval [CI], 1.95-9.26; P <.001). Higher TB grade was also associated with greater tumor node metastasis (TNM) stage. Patients with stage III cancer were significantly more likely than patients with stage I cancer to present with high-grade TB over intermediate- or low-grade TB (OR, 3.32; 95% CI, 1.06-10.41; P =.04).

Other correlates of high TB grade included cecal vs non-cecal tumor location (OR, 2.55; 95% CI, 1.09-5.97; P =.03), greater poorly differentiated tumor clusters (PDCs) grade (grade 2 vs 1: OR, 9.14; 95% CI, 3.49-23.93; grade 3 vs 1: OR, 5.10; 95% CI, 2.30-11.27), and increased infiltrative tumor border (OR, 1.03; 95% CI, 1.01-1.04; P <.001).

In survival models, greater TB grade was associated with worse overall survival. Compared to low-grade TB, patients with high-grade TB had substantially increased risk of death over follow-up (hazard ratio [HR], 2.67; 95% CI, 1.45-4.90). Patients with intermediate-grade TB also had increased risk vs low-grade TB (HR, 2.20; 95% CI, 1.11-4.35). Greater tumor budding grade and patient age were also associated with worse survival. BMI did not independently predict overall survival in multivariable models.

In a study which assessed CRC outcomes in patients with TB, obesity was substantially associated with increased TB grade. Further, TB grade was associated with other prognostic indicators, including infiltrative tumor border configuration and overall cancer stage. Study limitations include the relatively small study cohort. Further population-based analyses are necessary to expound on these findings.

“These findings suggest that TB grade may have important implications for the prognosis of patients with colon cancer,” investigators wrote. “The novel finding of the association between obesity and high TB grade may contribute to the etiology behind the trend of early-onset colon cancer. Further mechanistic evaluations are needed to identify the direct link between TB and obesity at the molecular level.”


Gan T, Schaberg KB, He D, et al. Association between obesity and histological tumor budding in patients with nonmetastatic colon cancer. JAMA Netw Open. Published online April 1, 2021. doi: 10.1001/jamanetworkopen.2021.3897