Pancreatic Ductal Adenocarcinoma: Molecular Pathology and Predictive Biomarkers

Abstract

Pancreatic ductal adenocarcinoma (PDAC) has an extremely poor prognosis due to the lack of methods or biomarkers for early diagnosis and its resistance to conventional treatment modalities, targeted therapies, and immunotherapies. PDACs are a heterogenous group of malignant epithelial neoplasms with various histomorphological patterns and complex, heterogenous genetic/molecular landscapes. The newly proposed molecular classifications of PDAC based on extensive genomic, transcriptomic, proteomic and epigenetic data have provided significant insights into the molecular heterogeneity and aggressive biology of this deadly disease. Recent studies characterizing the tumor microenvironment (TME) have shed light on the dynamic interplays between the tumor cells and the immunosuppressive TME of PDAC, which is essential to disease progression, as well as its resistance to chemotherapy, newly developed targeted therapy and immunotherapy. There is a critical need for the development of predictive markers that can be clinically utilized to select effective personalized therapies for PDAC patients. In this review, we provide an overview of the histological and molecular heterogeneity and subtypes of PDAC, as well as its precursor lesions, immunosuppressive TME, and currently available predictive molecular markers for patients.

Keywords: molecular pathology; pancreatic ductal adenocarcinoma; predictive marker; targeted therapy and immunotherapy; tumor microenvironment.

Figure 1

Pancreatic ductal adenocarcinomas (PDACs) with various histomorphological patterns (hematoxylin and eosin stain). (A) Moderately differentiated PDAC with extensive desmoplastic stroma; (B) moderately differentiated PDAC with interconnecting complex glands embedded in desmoplastic stroma; (C) large duct variant of PDAC; (D) poorly differentiated PDAC; (E) poorly differentiated PDAC intermixed with moderately differentiated areas; (F) clear cell variant of PDAC; (G) moderately differentiated PDAC showing extensive, complex intra-luminal micropapillary formation; (H) cribriform histology with foamy cells; (I) pagetoid involvement of pancreatic duct by PDAC (intra-ductal carcinoma).

Figure 2

The common histological features associated with aggressive clinical outcomes for pancreatic cancer patients (hematoxylin and eosin stain). (A) Tumor invasion into muscular vessels; (B) perineural invasion; (C) tumor invasion into the wall of superior mesenteric vein; (D) PDAC invasion through the muscularis propria of the duodenum and involves the mucosal surface; (E) PDAC invades into the peripancreatic and retroperitoneal soft tissue and involves the uncinate margin (marked by black ink); (F) metastatic PDAC in a regional lymph node.

Figure 3

Histological subtypes of pancreatic ductal adenocarcinoma (hematoxylin and eosin stain): (A) Adenosquamous carcinoma; (B) colloid carcinoma; (C) hepatoid carcinoma with bile lakes; (D) signet-ring cell carcinoma; (E) undifferentiated carcinoma; (F) undifferentiated carcinoma with osteoclast-like giant cells; (G) undifferentiated carcinoma with rhabdoid cells (rhabdoid carcinoma); (H) micropapillary carcinoma; (I) medullary carcinoma.

Figure 4

Heterogeneous response of PDAC to neoadjuvant therapy (hematoxylin and eosin stain). (A,B) Representative micrographs showing a PDAC with an area of minimal response (A) and near complete response in other areas (B); (C,D) representative micrographs showing a PDAC with complete response in primary tumor (C) but minimal response in the metastatic PDAC in the regional lymph node (D).

Figure 5

The precursor lesions of pancreatic ductal adenocarcinoma and the common molecular alterations. Abbreviations: PanIN, pancreatic intraepithelial neoplasia; IPMN, intraductal papillary mucinous neoplasm; IOPN, intraductal oncocytic papillary neoplasm; ITPN, intraductal tubulopapillary neoplasm; MCN, mucinous cystic neoplasm.