The early detection of pancreatic cancer: what will it take to diagnose and treat curable pancreatic neoplasia?

Abstract

Pancreatic cancer is the deadliest of all solid malignancies. Early detection offers the best hope for a cure, but characteristics of this disease, such as the lack of early clinical symptoms, make the early detection difficult. Recent genetic mapping of the molecular evolution of pancreatic cancer suggests that a large window of opportunity exists for the early detection of pancreatic neoplasia, and developments in cancer genetics offer new, potentially highly specific approaches for screening of curable pancreatic neoplasia. We review the challenges of screening for early pancreatic neoplasia, as well as opportunities presented by incorporating molecular genetics into these efforts.

Figure 1

A normal pancreatic duct (panel A), and multiple pancreatic intraepithelial neoplasia (PanIN) lesions from the pancreas of a single patient with a family history of pancreatic cancer (Panels B-F). These include PanIN-1 (panel B), PanIN with associated lobulocentric atrophy (Panels B and C), PanIN-2 (Panel E), and PanIN-3 (Panel F). (all hematoxylin and eosin). KRAS mutations and telomere shortening occur early in PanIN-1 lesions, p16/CDKN2A loss occurs slightly later in PanIN-2, and SMAD4 and TP53 inactivation are late events (PanIN-3 and invasive carcinoma).

Figure 2

Genetic changes shed by precursor lesions involving the pancreatic duct system can be detected in pancreatic secretions collected at the time of endoscopy. EUS=endoscopic ultrasound. (Illustration by Christian Rose, copyright Johns Hopkins University).

Figure 3

Fluid from pancreatic cysts can be aspirated at the time of endoscopic ultrasound (EUS), and the mutations present in the cyst fluid can suggest cyst type. (Illustration by Christian Rose, copyright Johns Hopkins University)

Figure 4

There are a series of steps which need to be overcome to diagnose and treat curable pancreatic cancer. (1) First, the curable lesions that give rise to advanced pancreatic cancers have to be characterized. (2) There has to be a reasonable window of opportunity to detect these potentially curable lesions. (3,4) A test has to be developed to detect the compendium of curable localized lesions, and lesions with a reasonable chance of progressing have to be distinguished from those with little or no risk of progressing. Not shown, the prevalence of the disease has to be reasonably high in the population to be screened, and an evidence base has to be developed which demonstrates that screening actually saves lives.