Earlier Diagnosis of Pancreatic Cancer: Is It Possible?

Abstract

Pancreatic ductal adenocarcinoma has a very high mortality rate which has been only minimally improved in the last 30 years. This high mortality is closely related to late diagnosis, which is usually made when the tumor is large and has extensively infiltrated neighboring tissues or distant metastases are already present. This is a paradoxical situation for a tumor that requires nearly 15 years to develop since the first founding mutation. Response to chemotherapy under such late circumstances is poor, resistance is frequent, and prolongation of survival is almost negligible. Early surgery has been, and still is, the only approach with a slightly better outcome. Unfortunately, the relapse percentage after surgery is still very high. In fact, early surgery clearly requires early diagnosis. Despite all the advances in diagnostic methods, the available tools for improving these results are scarce. Serum tumor markers permit a late diagnosis, but their contribution to an improved therapeutic result is very limited. On the other hand, effective screening methods for high-risk populations have not been fully developed as yet. This paper discusses the difficulties of early diagnosis, evaluates whether the available diagnostic tools are adequate, and proposes some simple and not-so-simple measures to improve it.

Keywords: early diagnosis; endoscopic ultrasound; intraductal neoplasia; natural history of pancreatic cancer; pancreatic cancer; screening; tumor markers.

Figure 1

The development of pancreatic cancer is a slow process that takes around 15 years to become symptomatic. The pace of progression seems to accelerate concomitantly with the presentation of the first symptoms. In order to be therapeutically effective, early diagnosis needs to occur immediately before symptoms develop or very shortly afterwards. This therapeutic window may be as short as weeks or a few months at best. Lower panels show frequently found mutations according to the progression of the tumor [39].

Figure 2

Left panel: structure of the protein glypican-1 linked to the cell membrane by glycosylphosphatidylinositol (GPI) (modified from Fico et al. [279]). Right panel: shows a possible mechanism of production of glypican-1-rich exosomes, although not experimentally confirmed. Hypoxia is one of the main factors in stimulating this production [280]. Pancreatic cancers have very high levels of hypoxia [281].

Figure 3

The diagram shows the correlation between tumor progression and diagnostic means. It is quite evident that tumor markers are not useful for early diagnosis, while EUS is the main contributor to achieving diagnosis in a period where the disease is still within the range of a possible surgical solution.

Figure 4

A proposed screening scheme for early diagnosis of pancreatic cancer based on the findings in the literature and personal experience.