Purpose: Individuals with adenocarcinoma of the ampulla of Vater demonstrate a broad range of outcomes, presumably because these cancers may arise from any one of the three epithelia that converge at that location. This variability poses challenges for clinical decision-making and the development of novel therapeutic strategies.
Patients and Methods: We assessed the potential clinical utility of molecular pathological phenotypes defined using a combination of histopathology and protein expression (CDX2 and MUC1) in 208 patients from three independent cohorts who underwent operative resection for adenocarcinoma of the ampulla of Vater.
Results: Histological subtype, CDX2 and MUC1 expression were significant prognostic variables.Patients with a pancreaticobiliary phenotype (CDX2 negative, MUC1 positive) compared to a non-pancreaticobiliary phenotype carcinoma segregated into a poor prognostic group in the training (HR = 3.34, 95% CI: 1.69 – 6.62, P = 0.0005), and both validation cohorts (HR = 5.65, 95% CI: 2.77 – 11.5, P < 0.0001 and HR = 2.78, 95% CI: 1.25 – 7.17, P = 0.0119 respectively). Further stratification by lymph node (LN) status defined 3 clinically relevant phenotypes: 1. those with a non-pancreaticobiliary (intestinal) phenotype without LN metastases who had an excellent outcome; 2. those that had a pancreaticobiliary phenotype and lymph node metastases which had a poor outcome and 3. the remainder (non-pancreaticobiliary/LN positive or pancreaticobiliary/LN negative) who had an intermediate outcome.
Conclusion: Histopathological and molecular criteria define two clinically relevant phenotypes of adenocarcinoma of the ampulla of Vater and potentially represent distinct diseases with significant implications for current therapeutic strategies, the ability to interpret past clinical trials, and future trial design.