PURPOSE: Adenocarcinoma in villous adenoma is a rare malignancy arising from adenomatous polyps with a high villous content. This study aims to identify the demographic, prognostic, and socioeconomic factors influencing overall survival using data sourced from the National Cancer Database (NCDB). METHODS: Patients diagnosed with adenocarcinoma in villous adenoma were identified from the NCDB between 2004 and 2020. Kaplan-Meier curves, multivariable Cox proportional hazards models, life tables, and log-rank tests were used to assess the impact of variables such as age, sex, NCDB tumor stage, Charlson-Deyo (CD) comorbidity score, primary therapies, adjuvant therapies, and socioeconomic factors on survival. RESULTS: This cohort of 19,120 patients with adenocarcinoma in villous adenoma revealed multiple statistically significant factors affecting survival. Demographically, males had an 18% higher risk of mortality compared to females (hazard ratio (HR): 0.82
95% confidence interval (CI): 0.79-0.86
p<
0.002), older age (76-100 age group, five years: 45.3%
10 years: 20.7%
p<
0.002) correlated with poorer outcomes, and Black patients had a 22% increased mortality risk relative to White patients (HR: 1.22
95% CI: 1.14-1.30
p<
0.002). Socioeconomically, patients in lower-income brackets (<
6,277 vs. ≥ 4,063, HR: 0.88
95% CI: 0.82-0.94
p<
0.002) and those with Medicare or Medicaid insurance faced increased mortality risks compared to those with private insurance (Medicare, HR: 1.26
95% CI: 1.19-1.33
p<
0.002
Medicaid, HR: 1.57
95% CI: 1.41-1.74
p<
0.002). Disease and comorbidity factors showed that higher CD comorbidity scores (10-year survival: 25.9% for CD 2
17.8% for CD 3
p<
0.002) and stage IV disease (HR: 9.23
95% CI: 8.32-10.24
p<
0.002) were associated with poorer outcomes. Regarding treatment, primary radiation increased mortality risk by 24% (HR: 1.24
95% CI: 1.15-1.33
p<
0.002), while neoadjuvant radiation and adjuvant chemotherapy decreased mortality risk by 39% (HR: 0.61
95% CI: 0.54-0.69
p<
0.002) and 26% (HR: 0.74
95% CI: 0.68-0.81
p<
0.002), respectively. CONCLUSION: Adenocarcinoma in villous adenoma outcomes is influenced by age, sex, race, NCDB cancer stage, comorbidities, and treatment type. Surgical intervention remains the primary treatment and confers improved survival outcomes, emphasizing the importance of early detection and treatment. Further research, including prospective studies, is needed to validate these findings, investigate the mechanisms underlying observed disparities, and optimize treatment strategies, particularly the role of adjuvant therapies.