PANCREAS

The pancreas is a combined endocrine and exocrine organ situated in the retroperitoneum and lying slightly obliquely transversely across the upper abdomen, draped over the aorta and vertebral bodies. The large bulk of the organ comprises exocrine glands that produce digestive enzymes, which are secreted into the pancreatic ducts, which drain into the duodenum via the major and minor papillae. The common bile duct also drains into the duodenum via the major papilla and the common bile duct and main pancreatic duct join to form the ampulla of Vater, immediately proximal to the papilla, which is controlled by the sphincter of Oddi. The endocrine glands of the pancreas are located in microscopic structures known as the Islets of Langerhans and they produce several hormones, including insulin, glucagon, somatostatin, gastrin, pancreatic polypeptide and bombesin among others

Pancreatic ductal adenocarcinoma (PDAC) is a particularly lethal form of cancer as indicated by its being the fourth ranked cause of death by cancer in Western countries, while representing only 3% of the new cancer cases each year.

Tobacco, diabetes, obesity and chronic pancreatitis are described as risk factors for PDAC, but, with the exception of familial PDAC, no high risk population is defined.

Due to the absence of specific symptoms PDAC is usually diagnosed late and up to 60% of patients have advanced PDAC at the time of diagnosis, when median survival is only 3 to 6 months.

Resection is the only potentially curative treatment but is only appropriate for patients whose general condition is still good and whose tumour does not show any evidence of local invasion or metastatic spread. Because of its poor prognosis, improvement of PDAC prognosis requires detecting and managing this cancer before regional invasion and metastasis.

Three types of neoplastic precursor lesions to PDAC have been described and characterized. Such lesions are, most of the time, asymptomatic, and they may occur together with unresectable carcinoma.

Pancreatic Intraepithelial Neoplasia (PanIN)

• microscopic ductal lesions usually measuring less than 1 cm, generally located in the head of the pancreas; illusive to detection by MRI (Magnetic Resonance Imagery) or CT (Computed Tomography); usually found concomitantly with tumour resection.
• classified into 3 grades: PanIN-1 (which are subdivided into PanIN-1A and PanIN-1B), PanIN-2 and PanIN-3/ in situ carcinoma, depending on the degree of architectural and cytological atypia with increasing papillary architecture to cellular atypia and frequent mitosis, preceding invasive carcinoma
• the most frequent preneoplastic lesions of the pancreas, observed in 82% of pancreas with pancreatic cancer
• low grade PanINs appear to be found in 16-80% of normal pancreas in the absence of neoplasia, while high grade PanINs are nearly exclusively associated with adenocarcinoma. It is suggested that only 1% of PanINs evolve into PDAC, so it is tempting to consider low grade PanINs as benign lesions in absence of key point mutations. Key genetic events enhance PanIN-1 to PanIN-2 transition, leading to a “no turning back” development into PDAC.
• a mouse model expressing the constitutively activated K-RAS G12D proto-oncogene recapitulates PanIN lesions and is the common in vivo model for PanINs study

Intraductal Papillary Mucinous Neoplasms (IPMN)

• far less common than PanIN lesions, accounting for 3-5% of pancreatic tumours
• divided into adenoma, borderline and intraductal papillary mucinous carcinoma (IPMC) according to the highest degree of dysplasia detected
• comprise large lesions with long finger-like papillary architecture, larger than 1 cm and delimited by a columnar, mucin-secreting epithelium
• communicate with pancreatic main duct
• invasive carcinoma occurs in 20-50% of IPMNs and are located on the main pancreatic duct or in the secondary branches of the main duct
• further anatomical criteria depending on the extension of the disease in the organ are taken into consideration, with IPMNs being classified into three groups: main pancreatic duct IPMN (MPD-IPMN), branch duct IPMN (BD-IPMN), and mixed IPMN
• current knowledge indicates that approximately 70% of MPD-IPMNs may progress into invasive cancer
• resection represents the only curative treatment for IPMNs, with long-term follow-up of resected patients showing 5-year survival rates of 88% for benign and non-invasive lesions and between 36 and 60% for IPMC

PanINs and IPMNs exhibit similar histological and molecular features and the distinction between those two types of lesions is based on their size and location. Depending on the lesion origin (main duct or peripheral ductules), PanINs and IPMNs can be considered as similar lesions with different clinical outcome. A transgenic mouse model which develops PanIN lesions in addition to cystic lesions of the pancreas resembling human IPMNs following TGF-α overexpression in mutant K-RAS favours of a common origin of both types of lesions.

Mucinous Cystic Neoplasms (MCN)

• rare and large (1 to 3 cm) mucin secreting neoplasms, lined by a columnar, mucin-filled epithelium and with a characteristic ovarian-type stroma beneath the epithelial layer, separating the lesion from the pancreatic main duct
• higher incidence in women as compared to men (ratio 20 to 1)-  for unknown reasons.
• are classified according to their degree of epithelial dysplasia: mucinous cystadenoma, borderline mucinous cystic neoplasms and mucinous cystic neoplasms with in situ carcinoma
• by virtue of their size and location, they are often associated with non-specific symptoms (abdominal discomfort and abdominal mass due to compression of pancreatic duct).
  = about 20% are associated with PDAC
• all MCNs may progress to mucinous cystadenocarcinoma, which has a very low resectability and a very poor prognosis
• The 5 year-survival rate for patient with a surgically resected MCNs in the absence of PDAC is close to 100%, but survival rate falls to 60% when an adjacent neoplasia is diagnosed
• mice expressing activated K-RAS(G12D) and deleted for Smad4/Dpc4 develop pancreatic cystic neoplasms in the body and the tail of the pancreas in addition to low-grade PanINs
• according to the size of these lesions, IPMNs and MCNs can be detected using CT and MRI and have a better prognosis compared to microscopic PanIN.