Pathology of pancreatic ductal adenocarcinoma: facts, challenges and future developments

Abstract

Despite major improvements concerning its diagnosis and treatment, pancreatic ductal adenocarcinoma (PDAC) remains an aggressive disease with an extremely poor prognosis. Pathology, as interface discipline between basic and clinical medicine, has substantially contributed to the recent developments and has laid the basis for further progress. The definition and classification of precursor lesions of PDAC and their molecular characterization is a fundamental step for the potential identification of biomarkers and the development of imaging methods for early detection. In addition, by integrating findings in humans with the knowledge acquired through the investigation of transgenic mouse models for PDAC, a new model for pancreatic carcinogenesis has been proposed and partially validated in individuals with genetic predisposition for PDAC. The introduction and validation of a standardized system for pathology reporting based on the axial slicing technique has shown that most pancreatic cancer resections are R1 resections and that this is due to inherent anatomical and biological properties of PDAC. This standardized assessment of prognostic relevant parameters represents the basis for the successful conduction of multicentric studies and for the interpretation of their results. Finally, recent studies have shown that distinct molecular subtypes of PDAC exist and are associated with different prognosis and therapy response. The prospective validation of these results and the integration of molecular analyses in a comprehensive pathology report in the context of individualised cancer therapy represent a major challenge for the future.

Keywords: Atypical flat lesion; Molecular subtypes; Pancreatic cancer; Pancreatic ductal adenocarcinoma; Precursor lesions; R1.

Figure 1

Precursor lesions of pancreatic ductal adenocarcinoma in familial pancreatic cancer-patients. A: Low-grade pancreatic intraepithelial neoplasia; B: Gastric-type intraductal papillary mucinous neoplasm showing a ductal phenotype; C: Acinar-ductal metaplasia in areas of lobulocentric atrophy. Arrows indicate an atypical flat lesion; D: Atypical flat lesion with cellular atypia and typical stromal reaction.

Figure 2

Dual model of pancreatic carcinogenesis. The well-known precursor lesions (PanIN, IPMN and MCN) show a ductal phenotype. However, it seems now plausible that pancreatic ductal adenocarcinoma can directly originate from the centroacinar-acinar compartment through atypical flat lesions without the intermediate step of pancreatic intraepithelial neoplasia (PanIN) (acinar-ductal carcinogenesis). MCN: Mucinous cystic neoplasm; IPMN: Intraductal papillary mucinous neoplasm; ADM: Acinar ductal metaplasia; TC: Tubular complexes; MTC: Mucinous tubular complexes; AFL: Atypical flat lesion.

Figure 3

Dispersed growth of pancreatic ductal adenocarcinoma. Tumor deposits (star) of pancreatic ductal adenocarcinoma are found many mm away from the main tumor bulk. The curved line highlights the tumor front.

Figure 4

Milestones in pancreatic cancer biology. Mutations of KRAS, CDKN2A/p16, SMAD4 and TP53 represent the molecular fingerprint of pancreatic ductal adenocarcinoma (PDAC)[53]. Global genomic analysis of PDAC defined a set of 12 core signalling pathways commonly altered in the great majority of investigated tumors[17]. Three distinct molecular PDAC subtypes [“classical”, “quasi-mesenchymal” (QM) and “exocrine-like”] with prognostic relevance and distinct drug response were defined based on combined analysis of transcriptional profiles of primary tumor samples and human and mouse PDAC cell lines[54].