Pancreatic Cancer: Pathogenesis, Screening, Diagnosis, and Treatment

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a clinically challenging cancer, due to both its late stage at diagnosis and its resistance to chemotherapy. However, recent advances in our understanding of the biology of PDAC have revealed new opportunities for early detection and targeted therapy of PDAC. In this review, we discuss the pathogenesis of PDAC, including molecular alterations in tumor cells, cellular alterations in the tumor microenvironment, and population-level risk factors. We review the current status of surveillance and early detection of PDAC, including populations at high risk and screening approaches. We outline the diagnostic approach to PDAC and highlight key treatment considerations, including how therapeutic approaches change with disease stage and targetable subtypes of PDAC. Recent years have seen significant improvements in our approaches to detect and treat PDAC, but large-scale, coordinated efforts will be needed to maximize the clinical impact for patients and improve overall survival.

Keywords: Cancer Screening; Pancreatic Cancer; Pancreatic Ductal Adenocarcinoma.

Figure 1.

Precancerous neoplasia in the pancreas. (A) Low-grade PanINs involve the pancreatic ducts. They have apical mucin and mild cytologic atypia, with the nuclei still retaining their polarity. (B) High-grade PanIN shows increase architectural and cytologic atypia, which architectural complexity, nuclear pleomorphism, and loss of nuclear polarity. (C) Invasive PDAC shows severe architectural and cytologic atypia with a striking desmoplastic response in the stroma.

Figure 2.

Mechanisms of pancreatic cancer pathogenesis. Molecular contributions to pathogenesis include somatic mutations in driver genes, chromosomal alterations, epigenetic alterations, and transcriptional reprogramming, all occurring in tumor cells. Cellular contributions from the non-neoplastic tumor microenvironment include alterations in cancer-associated fibroblasts and the immune microenvironment. Population-level contributions include inherited DNA mutations, diabetes, obesity, smoking, and chronic pancreatitis.

Figure 3.

A refined model of multistep tumorigenesis in premalignant pancreatic tumorigenesis. Low-grade IPMNs are characterized by multiple mutations in the initiating oncogene KRAS, suggesting polyclonal evolution of multiple genetically independent precancers. Selection of a clone leads to the development of a high-grade IPMN, which then undergoes ongoing evolution, at times with distinct alterations in the same gene arising in distinct subclones. Selection of an advanced clone that invades the basement membrane leads to the development of invasive PDAC. While this model has been validated in human IPMN samples, its applicability to microscopic human PanINs requires further investigation.

Figure 4.

Incident indeterminate solid nodule: low-grade PanIN lesion. EUS and microscopic images from a familial pancreatic cancer relative who developed a 5-mm hypoechoic nodule in the tail (A). EUS-fine needle aspiration performed at 2 separate visits showed atypical cells. EUS-guided tattooing was performed to localize the lesion for surgical resection and histologic evaluation. Distal pancreatectomy with pathology examination of the specimen revealed a focal cluster of multiple low-grade PanIN with adjacent fibrosis (B), corresponding to the location of the preoperative tattoo.

Figure 5.

Incident screen-detected PDAC arising in a low-risk BD-IPMN. A familial pancreatic cancer patient with 3 affected FDR, who at baseline screening had subcentimeter cysts in the head (7 mm, yellow arrow) by MRI (A) and EUS (B). Surveillance continued with annual MRI alternating with EUS. Seven years from baseline, EUS showed a mildly dilated main pancreatic duct (4 mm) in the neck of the gland without a mass and 5 low-risk subcentimeter cystic lesions in the head, body, and tail. These changes did not meet international consensus guideline criteria for resection of IPMN. Repeat EUS at the next scheduled visit 1 year later showed the IPMN in the head (C, yellow arrow) associated with an asymptomatic PDAC (orange arrow, D), not visible on CT. Pancreaticoduodenectomy revealed a moderately differentiated T2N1 PDAC (hematoxylin-eosin stained pathology, image E) arising in an IPMN (F), low-grade IPMN, and extensive low-grade PanIN and associated lobulocentric atrophy (G). The patient is alive and well 4 years later.