Chapter 42: 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. 51. 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 6% for all stages combined. An improved 5-year survival of up to 24% 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 65–84 years for both sexes. Pancreatic cancer was estimated to have been diagnosed in approximately 45,220 patients and accounted for approximately 38,460 deaths in 2013. Although survival rates have almost doubled over the past 35 years for this disease, overall survival remains low.

An estimated 278,684 cases of pancreatic cancer occur annually worldwide (the thirteenth most common cancer globally), with up to 60% of these cases diagnosed in more developed countries. It remains the eighth most common cause of cancer death in men and the ninth most common in women. The incidence is highest in the United States and western Europe and lowest in parts of Africa and South Central Asia. However, increasing rates of obesity, diabetes, and tobacco use in addition to access to diagnostic radiology in the developing world are likely to increase incidence rates in these countries. In this situation, consideration of the cost implications of adoption of current treatment paradigms in resource-constrained environments will be necessary. Primary prevention such as limiting tobacco use and avoiding obesity may be more cost effective than improvements in treatment of preexisting disease.

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. A longstanding history of type 1 or type 2 diabetes also appears to be a risk factor; however, diabetes may also occur in association with pancreatic cancer, possibly confounding this interpretation. Other risk factors may include obesity, chronic pancreatitis, and ABO blood group status. 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 four genes most commonly mutated or inactivated in pancreatic cancer are KRAS (predominantly codon 12, in 60–75% of pancreatic cancers), the tumor-suppressor genes p16 (deleted in 95% of tumors), p53 (inactivated or mutated in 50–70% of tumors), and SMAD4 (deleted in 55% of tumors). The pancreatic cancer precursor lesion pancreatic intraepithelial neoplasia (PanIN) acquires these genetic abnormalities in a progressive manner associated with increasing dysplasia; initial KRAS mutations are followed by p16 loss and finally p53 and SMAD4 alterations. SMAD4 gene inactivation is associated with a pattern of widespread metastatic disease in advanced-stage patients and poorer survival in patients with surgically resected pancreatic adenocarcinoma.

Up to 16% of pancreatic cancers may be inherited. Germline mutations in the following genes are associated with a significantly increased risk of pancreatic cancer and other cancers: (1) STK11 gene (Peutz-Jeghers syndrome), which carries a 132-fold increased lifetime risk of pancreatic cancer above the general population; (2) BRCA2 (increased risk of breast, ovarian, and pancreatic cancer); (3) p16/CDKN2A (familial atypical multiple mole melanoma), which carries an increased risk of melanoma and pancreatic cancer; (4) PALB2, which confers an increased risk of breast and pancreatic cancer; (5) hMLH1 and MSH2 (Lynch syndrome), which carries an increased risk of colon and pancreatic cancer; and (6) ATM (ataxia-telangiectasia), which carries an increased risk of breast cancer, lymphoma, and pancreatic cancer. Familial pancreatitis and an increased risk of pancreatic cancer are associated with mutations of the PRSS1 (serine protease 1) gene. However, for most familial pancreatic syndromes, the underlying genetic cause remains unexplained. 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.

The desmoplastic stroma surrounding pancreatic adenocarcinoma functions as a mechanical barrier to chemotherapy and secretes compounds essential for tumor progression and metastasis. Key mediators of these functions include the activated pancreatic stellate cell and the glycoprotein SPARC (secreted protein acidic and rich in cysteine), which is expressed in 80% of pancreatic ductal adenocarcinomas. Targeting this extracellular environment has become increasingly important in the treatment of advanced disease.

Screening is not routinely recommended because the incidence of pancreatic cancer in the general population is low (lifetime risk 1.3%), putative tumor markers such as carbohydrate antigen 19-9 (CA19-9) and carcinoembryonic antigen (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 greater than fivefold increased risk for developing pancreatic cancer to select individuals who may benefit from screening. This includes people with two or more first-degree relatives with pancreatic cancer, patients with Peutz-Jeghers syndrome, and BRCA 2, p16, and hereditary nonpolyposis colorectal cancer (HNPCC) mutation carriers with one or more affected first-degree relatives.

PanIN represents a spectrum of small (<5 mm) neoplastic but noninvasive precursor lesions of the pancreatic ductal epithelium demonstrating mild, moderate, or severe dysplasia (PanIN 1–3, respectively); however, not all PanIN lesions will progress to frank invasive malignancy. Cystic pancreatic tumors such as intraductal mucinous papillary neoplasms (IPMNs) and mucinous cystic neoplasms (MCNs) are increasingly detected radiologically and are frequently asymptomatic. Main duct IPMNs are more likely to occur in older persons and have higher malignant potential than branched duct IPMNs (invasive cancer in 45% vs 18% of resected lesions, respectively). In contrast, MCNs are solitary lesions of the distal pancreas that do not communicate with the duct system. MCNs have an almost exclusive female distribution (95%). The rate of invasive cancer in resected MCNs is lower (<18%) with increased rates associated with larger tumors or the presence of nodules.

Clinical presentation

Obstructive jaundice occurs frequently when the cancer is located in the head of the 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 nodules (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. 42-1). 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; however, it is associated with a risk of pancreatitis (Fig. 42-2). 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 less than 3 cm in size (more sensitive than CT for lesions <2 cm) and is useful as a local staging tool for assessing vascular invasion and lymph node involvement. Fluorodeoxyglucose positron emission tomography (FDG-PET) should be considered before surgery or radical chemoradiotherapy (CRT), because 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 also 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 sensitivity of ERCP for diagnosis ranges from 35 to 70%.

Serum markers

Tumor-associated CA19-9 is elevated in approximately 70–80% of patients with pancreatic carcinoma but is not recommended as a routine diagnostic or screening test because its sensitivity and specificity are inadequate for accurate diagnosis. Preoperative CA19-9 levels correlate with tumor stage, and postresection CA19-9 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 CA19-9 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. 42-3). 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 relies 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.

Acknowledgment

Dr. Irene Chong is acknowledged for her work on this chapter in the HPIM 18th edition of Harrison’s Principles of Internal Medicine.