CHAPTER 40: PANCREATIC CANCER

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. 49. Infiltrating ductal adenocarcinomas, the subject of this chapter, account for the vast majority of cases and arise most frequently in the head of the 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. It was estimated that pancreatic cancer would 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 epidemiologic 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 multiorgan 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 multiorgan 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 syndrome, 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 >10-fold 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.

CLINICAL PRESENTATION

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.

PHYSICAL SIGNS

Patients can present with jaundice and cachexia, and scratch marks may be present. Of patients with operable tumors, 25% have a palpable gallbladder (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).

DIAGNOSTIC IMAGING

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. 40-1). 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 pancreatic lesions, identifying stricture or obstruction in pancreatic or common bile ducts, and facilitating stent placement (Fig. 40-2). Magnetic resonance cholangiopancreatography (MRCP) is a noninvasive method for accurately depicting the level and degree of bile and pancreatic duct dilatation. EUS is highly sensitive in detecting lesions smaller than 3 cm in size and is useful as a local staging tool for assessing vascular invasion and lymph node involvement. Positron-emission tomography with fluorodeoxyglucose positron emission tomography (FDG-PET) should be considered before surgery or radical chemoradiotherapy (CRT), as it is superior to conventional imaging in detecting distant metastases.

TISSUE DIAGNOSIS AND CYTOLOGY

Preoperative confirmation of malignancy is not always necessary in patients with radiologic appearances consistent with operable pancreatic cancer. However, EUS-guided fine-needle aspiration is the technique of choice when there is any doubt and for use in patients who require neoadjuvant treatment. It has an accuracy of approximately 90% and has a smaller risk of intraperitoneal dissemination compared with the percutaneous route. Percutaneous biopsy of the pancreatic primary or liver metastases is only acceptable in patients with inoperable or metastatic disease. ERCP is a useful method for obtaining ductal brushings, but the diagnostic value of pancreatic juice sampling is only in the order of 25–30%.

SERUM MARKERS

Tumor-associated carbohydrate antigen 19-9 (CA 19-9) is elevated in approximately 70–80% of patients with pancreatic carcinoma but is not recommended as a routine diagnostic or screening test as its sensitivity and specificity are inadequate for accurate diagnosis. Preoperative CA 19-9 levels correlate with tumor stage, and postresection CA 19-9 level has prognostic value. It is an indicator of asymptomatic recurrence in patients with completely resected tumors and is used as a biomarker of response in patients with advanced disease undergoing chemotherapy. A number of studies have established a high pretreatment CA 19-9 level as an independent prognostic factor.

The American Joint Committee on Cancer (AJCC) tumor, node, metastasis (TNM) staging of pancreatic cancer takes into account the location and size of the tumor, the involvement of lymph nodes, and distant metastasis. This information is then combined to assign a stage (Fig. 40-3). From a practical standpoint, patients are grouped according to whether the cancer is resectable, locally advanced (unresectable, but without distant spread), or metastatic.

The early detection and future treatment of pancreatic cancer rely on an improved understanding of molecular pathways involved in the development of this disease. This will ultimately lead to the discovery of novel agents and the identification of patient groups who are likely to benefit most from targeted therapy.