1. Adjuvant treatment: I would first request expert GI pathology review if available, to confirm the mixed histology and assess tumour stage, nodal status, differentiation, lymphovascular/perineural invasion and margins. IHC with CK7, CK20, CDX2, MUC1 and MUC2 can help characterize the intestinal versus pancreatobiliary phenotype, although the overall morphology remains important. Treatment should be guided by subtype and recurrence risk. For a fit patient with high-risk mixed disease, I would favour adjuvant chemotherapy rather than observation. Current guidance supports mFOLFIRINOX for pancreatobiliary/mixed tumours, while FOLFOX/CAPOX may be more appropriate for intestinal tumours.
2. Pancreatobiliary subtype: For a fit patient with resected, high-risk pancreatobiliary ampullary adenocarcinoma, I would favour six months of modified FOLFIRINOX (oxaliplatin, irinotecan, leucovorin and 5-FU). This reflects the biological similarity to pancreatic cancer, although ampullary-specific prospective evidence remains limited. For a frail patient or one unable to tolerate intensive therapy, gemcitabine-based or fluoropyrimidine-based treatment would be reasonable alternatives.
3. Molecular biomarkers: I would perform MMR/MSI testing and broad molecular profiling. Important biomarkers include HER2, BRAF V600E, NTRK, RET, KRAS, BRCA1/2, PALB2 and TMB. The most important routine biomarker is MMR/MSI; an MSI-H/dMMR tumour may be particularly sensitive to immunotherapy, especially in advanced disease. Actionable NTRK or RET alterations may allow tissue-agnostic targeted therapy, while BRCA/PALB2 alterations may influence platinum or PARP-based strategies. However, most of these tumour markers are not readily available in Nigeria. I would explain that targeted oral therapy does not automatically replace adjuvant chemotherapy. For this patient, the approach would be: confirm subtype, then assess recurrence risk then perform molecular testing then give appropriate adjuvant chemotherapy if fit then reserve targeted/immunotherapy for an actionable biomarker, particularly if disease recurs or becomes advanced