Pancreatic adenocarcinoma

Introduction

Pancreatic adenocarcinoma accounts for over 90% of tumours arising from exocrine pancreas. Due to its late presentation at an advanced stage, it has a poor prognosis in the majority of patients. In the United States in 2020 there was estimated to be in excess of 47 000 deaths due to pancreatic cancer. The disease represents 3% of all new cancer cases and accounts for 8% of all cancer deaths in the United States. The majority of cases are unresectable at the time of diagnosis and for the 15–20% who undergo resection, the 5-year survival is less than 20%.

Risk Factors ( Box 17.1 )

Diet and alcohol consumption

Dietary factors are implicated in the development of many cancers including pancreatic cancer through several biological mechanisms. A diet high in calories and fat over time leads to obesity, therefore having a negative impact on the pancreatic cancer risk, while meta-analyses have implicated red meat consumption as a factor in the development of pancreatic cancer. Conversely, consumption of certain nutrients found in a diet rich in fruit, vegetables and grains may be protective. Particular dietary nutrients associated with one carbon metabolism such as vitamin B6, B12, folate and methionine are thought to protect against cancer. Alcohol consumption has also been associated with an increased risk of cancer. A pooled analysis of 14 cohort studies showed an increased risk of pancreatic cancer with an alcohol intake of more than 30 g/day. A recent meta-analysis suggested that it is dose dependent, with high intake being more associated with an increased risk of pancreatic cancer in comparison to low to moderate intake. Chronic alcohol intake causes structural and functional impairment in the pancreas and alcohol is a causative factor in the development of chronic pancreatitis, which is characterised by fibrosis. Pancreatic stellate cells are activated by alcohol and appear responsible for this fibrosis.

Hereditary pancreatic cancer

Epidemiological evidence suggests that first-degree relatives with pancreatic cancer have at least a twofold increased risk of developing the disease. ^, Familial pancreatic cancer shows a trend towards younger onset of age and ethnic deviation as compared to sporadic pancreatic cancer. A meta-analysis of 6568 pancreatic cancer cases showed a significant increase in pancreatic cancer risk associated with having an affected relative, with an overall summary relative risk (RR) of 1.8 (95% CI, 1.48–2.12). Patients with familial pancreatic cancer make up 8–10% of all cases of pancreatic cancer. ^,

Although novel genes that predispose to familial pancreatic cancer remain to be fully elucidated, it is now well established that an increased risk is associated with familial conditions such as Peutz–Jeghers’ syndrome and germ-line mutations in BRCA1/BRCA2 (hereditary breast–ovarian cancer syndrome), CDKN2A (familial atypical mole and melanoma syndrome), PALB2 (familial breast cancer syndrome), ATM (familial breast cancer syndrome), mismatch repair genes (hereditary non polyposis colorectal cancer or Lynch syndrome) and PRSS1 and SPINK1 of hereditary pancreatitis. Patient with hereditary breast and ovarian cancer syndrome are reported to have a 3.5–10-fold increased risk of developing pancreatic adenocarcinoma. Mutations in the CFTR gene have been implicated in pancreatic cancer development. Guidelines for family members at risk of hereditary pancreatic cancer are currently being developed, albeit based on expert opinion.

Precursor lesions

Histologically, there are a number of distinct precursor lesions in regard to pancreatic carcinogenesis. Pre-neoplastic lesions are typically asymptomatic and small in size (<5 mm), therefore they are radiographically occult hence more commonly discovered at the time of resection. These lesions seem to follow a multi-step progression to invasive carcinoma, similar to that in colorectal carcinoma. The precursor lesions include pancreatic intra-epithelial neoplasia (Pan-IN), intraductal papillary mucinous neoplasm (IPMN) and mucinous cystic neoplasm (MCN). Pan-IN is the commonest of these, observed in approximately 82% of patients with pancreatic malignancy. In terms of classification, following the Baltimore Consensus Meeting in 2015 for Neoplastic Pancreatic Precursor Lesions, a revised two-tier system was suggested. Therefore all precursor lesions are classified as either low-grade or high-grade dysplastic lesions.

At the time of resection, these lesions are observed adjacent to adenocarcinoma and exhibit highly similar genetic alterations to their invasive companions. Notably, the frequency of p16 and K- ras mutations correlates directly with the severity of Pan-IN. This observation led primarily to the development of a pancreatic tumourigenesis model, which details a stepwise progression from Pan-IN to invasive carcinoma and is characterised by diverse molecular changes ( Fig. 17.1 ).

Pancreatic adenocarcinoma exhibits approximately 63 genetic alterations, the majority of which are point mutations, which include genes such as K-ras , p16/CDKN2A,TP53 and SMAD4 . K-ras is the most commonly observed mutation and is seen in >90% of pancreatic adenocarcinoma, in addition to about 45% of low-grade Pan-IN lesions. ^, K-ras is involved in a number of downstream signalling pathways hence mutations result in constitutive activation.

P16/CDKN2A (cyclin-dependent kinase inhibitor 2A gene) is a tumour suppressor gene, which is inactivated in up to 90% of pancreatic adenocarcinoma. The primary function is to regulate the cell cycle. In addition, TP53 and SMAD4 are tumour suppressor genes, which are inactivated in 75% and 55% of pancreatic cancer, respectively. ^, These changes are traditionally seen in late-stage precursor lesions, notably high-grade Pan-IN. Wadell et al. performed whole-genome analysis of 100 pancreatic adenocarcinomas thereby implicating several other genes, including KDM6A , PREX2 , ERBB , MET etc. In addition, whole-genome sequencing of 456 pancreatic ductal adenocarcinomas identified 32 significantly mutated genes, which aggregated into 10 distinct molecular pathways. Furthermore, work performed by the same group distinctly defined four pancreatic cancer subtypes; squamous, pancreatic progenitor, immunogenic and aberrantly differentiated endocrine exocrine. Each of these subtypes are characterised by different transcriptional networks, histopathological features and survival rates.

The development of this data offers important insight into the core mechanisms underlining pancreatic carcinogenesis and illuminating novel opportunities to target these molecular pathways.