Pancreatic cancer is the fourth leading cause of cancer death in the United States and is associated with a poor prognosis. Endocrine tumors affecting the pancreas are discussed in Chap. 350. Infiltrating ductal adenocarcinomas, the subject of this chapter, account for the vast majority of cases and arise most frequently in the head of pancreas. At the time of diagnosis 85–90% of patients have inoperable or metastatic disease, which is reflected in the 5-year survival rate of only 5% for all stages combined. An improved 5-year survival of up to 20% may be achieved when the tumor is detected at an early stage and when complete surgical resection is accomplished.
Pancreatic cancer represents 3% of all newly diagnosed malignancies in the United States. The most common age group at diagnosis is 60–79 years for both sexes. Pancreatic cancer will be diagnosed in approximately 43,140 patients and account for 36,800 deaths in 2010. Over the past 30 years, 5-year survival rates have not improved substantially.
Cigarette smoking may be the cause of up to 20–25% of all pancreatic cancers and is the most common environmental risk factor for this disease. Other risk factors are not well established due to inconsistent results from epidemiological studies, but include chronic pancreatitis and diabetes. It is difficult to evaluate whether these conditions are causally related, or develop as a consequence of cancer. Alcohol does not appear to be a risk factor unless excess consumption gives rise to chronic pancreatitis.
Pancreatic cancer is associated with a number of well-defined molecular hallmarks. The most frequent genetic aberrations comprise KRAS mutations, mostly affecting codon 12, which are observed in 60–75% of pancreatic cancers. The tumor-suppressor genes p16, p53, and SMAD4 are frequently inactivated; the p16 gene locus on chromosome 9p21 is deleted in up to 95% of tumors, the p53 gene is inactivated by mutation or deleted in 50–70% of tumors, and the SMAD4 gene is deleted in 55% of pancreatic tumors. Furthermore, SMAD4 gene inactivation is associated with poorer survival in patients with surgically resected pancreatic adenocarcinoma. IGF-1R and focal adhesion kinase (FAK) interact to promote cell proliferation and survival, and their simultaneous inhibition synergistically inhibits pancreatic cell growth. Overexpression and/or aberrant activation of c-Src is frequently observed, which results in cell adhesion, enhanced migration, invasion, and cell proliferation. Survivin is overexpressed in more than 80% of pancreatic tumors, which results in resistance to apoptosis, and genomic sequencing has identified PALB2 as a susceptibility gene for pancreatic cancer.
Up to 16% of pancreatic cancers are thought to be inherited. This occurs in three separate clinical settings: (1) familial multi-organ cancer syndromes, (2) genetically driven chronic diseases, and (3) familial pancreatic cancer with as yet unidentified genetic abnormalities, which comprise the largest proportion of inherited pancreatic cancer. The familial multi-organ cancer syndromes consist of Peutz-Jeghers syndrome, familial atypical multiple mole melanoma (FAMMM), familial breast-ovarian cancer associated with germline mutations in BRCA1 and BRCA2, hereditary nonpolyposis colorectal cancer (HNPCC), familial adenomatous polyposis (FAP), and Li-Fraumeni syndrome. Peutz-Jeghers, associated with mutations in the STK11 gene, carries the highest lifetime risk of pancreatic cancer with a relative risk of approximately 132-fold above that of the general population. Genetically driven chronic causes of pancreatic cancer include hereditary pancreatitis, cystic fibrosis, and ataxia telangiectasia. The absolute number of affected first-degree relatives is also correlated with increased cancer risk, and patients with at least two first-degree relatives with pancreatic cancer should be considered to have familial pancreatic cancer until proven otherwise.
Screening is not routinely recommended as putative tumor markers such as Ca 19-9 and CEA have insufficient sensitivity, and computed tomography (CT) has inadequate resolution to detect pancreatic dysplasia. Endoscopic ultrasound (EUS) is a more promising screening tool, and preclinical efforts are focused on identifying biomarkers that may detect pancreatic cancer at an early stage. Consensus practice recommendations based largely on expert opinion have chosen a threshold of >tenfold increased risk for developing pancreatic cancer to select individuals who may benefit from screening. This includes family members with ≥3 first-degree relatives with pancreatic cancer, and patients with FAMMM, Peutz-Jeghers syndrome, or hereditary pancreatitis.
Obstructive jaundice occurs frequently when the cancer is located in the head of pancreas. This may be accompanied by symptoms of abdominal discomfort, pruritus, lethargy, and weight loss. Less common presenting features include epigastric pain, backache, new onset diabetes mellitus, and acute pancreatitis caused by pressure effects on the pancreatic duct. Nausea and vomiting, resulting from gastroduodenal obstruction, may also be a symptom of this disease.
Patients can present with jaundice and cachexia, and scratch marks may be present. Of patients with operable tumors 25% have a palpable gall bladder (Courvoisier's sign). Physical signs related to the development of distant metastases include hepatomegaly, ascites, left supraclavicular lymphadenopathy (Virchow's node), and periumbilical lymphadenopathy (Sister Mary Joseph's nodes).
Patients who present with clinical features suggestive of pancreatic cancer undergo imaging to confirm the presence of a tumor, and to establish whether the mass is likely to be inflammatory or malignant in nature. Other imaging objectives include the local and distant staging of the tumor, which will determine resectability and provide prognostic information. Dual phase, contrast-enhanced spiral CT is the imaging modality of choice (Fig. 93-1). It provides accurate visualization of surrounding viscera, vessels, and lymph nodes, thus determining tumor resectability. Intestinal infiltration, and liver and lung metastases are also reliably depicted on CT. There is no advantage of magnetic resonance imaging (MRI) over CT in predicting tumor resectability, but selected cases may benefit from MRI to characterize the nature of small indeterminate liver lesions and to evaluate the cause of biliary dilatation when no obvious mass is seen on CT. Endoscopic retrograde cholangiopancreatography (ERCP) is useful for revealing small ...