Background: Ampullary Adenocarcinomas (AACs) are an heterogeneous group of tumors and there are different methods of categorization of histological subtypes. Histology phenotype based on immunohistochemistry (IHC) of caudal-type homeodomain transcription factor 2 (CDX2) and Cytokeratins (CK7 and CK20) staining has been tested in order to identify three most important sub-classes: Intestinal (INT), Pancreato-Biliary (PB) and Mixed-Type (MT). The identification of MT tumor is often difficult with conventional histology and its clinical outcome is unclear. This study aims to identify only two subtype in AACs samples, using an IHC score based-on CDX2, CK7 and CK20 evaluation. Method: We arranged on TMA platform tissue samples from 20 patients with resected AAC and obtained their classification by histology and IHC expression of CDX2, CK7 and CK 20. We obtain IHC score for each marker summing the number of positive cells (0=no stained cells; 1< 25%; 2<50% and 3>50% and their intensity (1=weak; 2=middle and 3=strong). A global score (GS) for each tumor was obtained by the contribution of each marker. The MT tumor were located into INT or PB group on the basis of predominant immune-molecular phenotype. The overall survival values of INT and PB patients were obtained by Kaplan-Meyer methods. Results: Histological parameters defined AAC subtype samples as follows: 15% INT, 45%PB and 40% MT. Using the IHC expression and the GS,75% and 25% of MT samples were assigned to INT and PB, respectively. The mean value of GS was 9.5 (range 4-16). All INT samples had a GS over the mean, while all PB sample had a global score under the mean (p=0.0011). In particular, the INT samples are identified by high expression of CDX2 and CK20, while PB samples showed high expression of CK7 and negative expression of CK20 (p=0.0008). The Overall Survival (OS) of molecular intestinal histomolecular phenotype (INT) vs PB phenotype showed significant differences (85.7 vs 20.3 months, HR, 8.39; 95% CI, 1.38 to 18.90; p=0.0152). Conclusion: Histopathologic and molecular criteria combination define clinically relevant histomolecular phenotypes of AACs which could potentially represent distinct diseases with significant implications for current therapeutic strategies.
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