Michael E. Kelly and Kevin C. Conlon

Introduction

Adenocarcinoma of the pancreas accounts for 3% of new cancer cases per annum,¹ yet it is the fourth leading cause of cancer-related death in Western countries. The insidious nature of the disease and its vagueness of presentation contribute to late diagnosis. Eighty per cent of patients have unresectable tumours at initial diagnosis. The overall survival at 5 years still remains at 6%, unchanged over the last four decades.¹ However, in recent years improvements in preoperative imaging and staging modalities, coupled with advancements in adjuvant therapies with the use of immunomodulators and monoclonal antibodies, have resulted in some degrees of optimism. Progress has been made as the molecular basis of the disease is better understood. With such poor survival rates and recent high-profile media attention, a renewed interest in tackling this elusive cancer has arisen.

Around 95% of pancreatic tumours are adenocarcinoma, originating from the exocrine part of the pancreas. Nearly all of these are ductal adenocarcinomas, which is the focus of this chapter.

Epidemiology

An estimated 44  000 new cases of adenocarcinoma of the pancreas occurred in the USA in 2011, and almost 38  000 died in the same year.² In the UK, 8085 people were diagnosed with pancreatic cancer and 8020 people died during 2009.³ The incidence of pancreatic cancer varies with age, sex and ethnicity. In 2008, the standardised incidence rate of pancreatic cancer was 3.9 per 100 000 population, while the standardised mortality rate was slightly lower at 3.7 per 100 000 population. Pancreatic cancer is the eleventh commonest cancer in males and eighth commonest cancer in females.⁴ The peak incidence for the disease occurs between the seventh and eighth decades of life, and is rare under the age of 30. In the American population, African and Hawaiian ethnicities confer a higher incidence than Caucasian, whereas Asian and Hispanic ethnic groups have a lower risk of developing the disease. The incidence of pancreatic cancer is rising, particularly in Europe, although this observation is subject to reporting bias related to improved diagnostics. However, pancreatic neoplasm must be detected at an early stage to enable the potential for curative treatment.

Risk factors (see Box 15.1)

Precursor lesions

Histologically distinct precursor lesions have been attributed to pancreatic carcinogenesis. Preneoplastic lesions are usually asymptomatic and can be incidentally discovered at the time of resection. They appear to follow a multi-step progression to invasive carcinoma.¹⁵ These precursor lesions include pancreatic intraepithelial neoplasia (PanIN), intraductal papillary mucinous neoplasm (IPMN) and mucinous cystic neoplasm (MCN).¹⁶ Because of their small size (usually < 5 mm), they are difficult to detect, making them elusive to computerised tomography (CT) or magnetic resonance imaging (MRI).¹⁵

Pan-INs are the most frequent preneoplastic lesions, observed in approximately 82% of pancreas with neoplasm.¹⁷ They are subclassified into PanIN-1, PanIN-2 and PanIN-3 depending upon the degree of cytological and architectural atypia.¹⁷ Each of these precursor lesions harbours a unique repertoire of clinicopathological and genetic characteristics that has an impact on the natural history and prognosis of these lesions.

Workers in Johns Hopkins University proposed pancreatic intraepithelial neoplasms (PanIN; 1A → 1B → 2 → 3) as the precursor lesions to invasive carcinoma.¹⁸ The model is analogous to that of ductal carcinoma in situ (DCIS) of the breast or adenomatous polyps in colorectal cancer. The lesions display atypical mucinous epithelium replacing the physiological cuboidal epithelium. The evidence for PanIN being a true premalignant state is largely circumstantial. These lesions were first described adjacent to resected adenocarcinoma. The more atypical PanIN-2 and -3 were seen exclusively in neoplastic pancreas. These lesions also display similar genetic aberrations to the frankly invasive samples. In particular, the percentage of p16 and K-ras mutations increases with the more atypical PanIN. These data have heralded development of a tumour genesis model involving sequential progression from PanIN-1a to invasive adenocarcinoma.¹⁹

Classically, evolution from precursor lesions to pancreatic neoplasm (ductal adenocarcinoma) involves diverse molecular changes (Fig. 15.1). Recent studies indentified at least 119 independent loci that may potentially play a role in tumour progression, including K-ras, TP53, p16/CDKN2A, MYC and AKT2.²⁰ The K-ras gene product mediates signal transduction in a number of growth factor receptors. K-ras single point mutation is observed in 90–95% of pancreatic ductal adenocarcinoma, representing the most common mutation in this disease.²¹ K-ras is currently the focus of multiple ongoing studies to see if it can be utilised as a diagnostic tool.¹³ Altered epidermal growth factor receptor expression (EGFR) causing overexpression is thought to be an early event in pancreatic carcinogenesis.²²

Inactivation of numerous tumour suppressor genes, including p16/CDKN2A and TP53, plays a pivotal role in the development of pancreatic cancer. Loss of tumour suppression is noted in 70–95% of pancreatic neoplasm.¹⁷ Other targets including transforming growth factor-β (TGF-β) receptor genes, BRCA2, HER-2/NEU, DPC4, MKK4 and EBER-1 are currently under investigation. The discussion about these genes is outside the scope of this chapter. However, the best chance for cure in the treatment of pancreatic cancer lies with detecting these non-invasive lesions before progression to invasive carcinoma.

Presentation

The majority of patients present with vague and non-specific symptoms (Box 15.2). As a result, the disease is commonly widespread at diagnosis, and approximately 80% of patients present with unresectable disease.

Tumours in the body and tail of the pancreas usually present late. Pain is the most consistent symptom. Painless jaundice is seen in 13% of patients while 34% present with only pain and 46% present with both pain and jaundice. Weight loss and anorexia are observed in 7% of patients. Rarely, tumour invasion into stomach or duodenum can present as haematemesis and malaena. Patients may also present with late-onset diabetes mellitus and acute pancreatitis.²³ Limited series have examined the screening of asymptomatic cohorts, with little evidence to support the introduction of population screening for pancreatic cancer.¹⁴ However, there may be a place for targeted screening of high-risk groups in the near future.

The classical Courvoisier sign (palpable gallbladder in the presence of painless jaundice) occurs in less than 25% of patients. Jaundice may represent either primary disease causing biliary obstruction or external compression of the biliary system by metastatic nodal disease. Pain is a more common symptom than physicians usually appreciate, occurring due to the involvement of the visceral afferent nerves or relating to an induced local pancreatitis. Pain on initial presentation is synonymous with a higher incidence of unresectability. Weight loss is common, often associated with early satiety, nausea or vomiting. The latter symptom may be due to gastric outlet obstruction.

Virchow’s node (left supraclavicular node associated with upper gastrointestinal (GI) malignancy), thrombophlebitis migrans (non-specific paraneoplastic sign named after Trousseau) and Sister Mary Joseph nodule (umbilical metastatic lesion via the falciform ligament) are well-described features of advanced disease. Hepatomegaly is seen in 65% of patients and may indicate liver metastases. Blumer’s shelf (rectally palpable rectovesical or rectovaginal mass) rarely occurs and is not usually sought as part of routine examination.

The most useful aid in disease diagnosis is a high index of suspicion. Vague epigastric symptoms and weight loss in the presence of normal endoscopy and preliminary radiology should initiate further detailed investigation.

Investigation