General Considerations

Pancreatic cancer is a challenging disease associated with an overall 5-year survival of 4–6%. It is the second most common gastrointestinal malignancy, and the fourth leading cause of cancer-related deaths in the United States. In 2012, the incidence was estimated as 43,920 new cases in the United States, while in 1996 there were 26,300 new cases.

The disease is more common in men than in women (1.3:1) and in certain ethnic and racial groups (eg, Blacks, Polynesians, and native New Zealanders). It is rare before the age of 40, but the incidence increases sharply after the seventh decade.

Pathogenesis & Risk Factors

Most pancreatic neoplasms arise from the three different types of the epithelial cells found in the pancreas. Acinar cells account for 80% of the volume of the gland but constitute 1% of exocrine tumors. Ductal cells constitute 10–15% of the volume but give rise to 90% of all tumors. Other malignant pancreatic tumors from the exocrine pancreas include intraductal papillary mucinous neoplasms with invasive carcinoma (2–3%), mucinous cystic neoplasms with invasive carcinoma (1%), solid pseudopapillary neoplasms (<1%), acinar cell carcinoma (<1%), and serous cystadenocarcinoma (<1%). Endocrine cells are 1–2% of volume and account for 1–2% of the tumors. These tumors are known as pancreatic neuroendocrine tumors (PNET) or islet cell tumors. Nonepithelial tumors are very rare.

Approximately 70% of ductal tumors are localized to the head of the pancreas, 5–10% to the body, and 10–15% to the tail. These tumors appear as scirrhous whitish irregular tumor with a desmoplastic reaction that can mimic chronic pancreatitis particularly at the time of surgical resection. The desmoplastic reaction can make it impossible to evaluate radiologically the response to preoperative treatment.

These tumors are often associated with pancreatic intraepithelial neoplasia (PanIN), which is metaplasia and proliferation of the ductal epithelium. PanIN is associated with varying degrees of dysplasia ranging from mild (PanIN-1), moderate (PanIN-2), to severe (PanIN-3), which was previously known as carcinoma in situ. In general, a surgeon will resect to remove invasive carcinoma and PanIN-3, but not PanIN-1 or PanIN-2.

A. Molecular Pathogenesis

It has been proposed that pancreatic cancer develops from PanIN following an evolution similar to the adenoma–carcinoma sequence seen in colorectal tumors with accumulating genetic alterations with progression of low to high grade in PanIN-1 to -3. Although the precise mechanism and sequence of genetic mutations responsible for the development of pancreatic cancer remains unclear, genetic alterations found in these tumors can be classified into three categories: (1) activation of oncogenes; (2) inactivation of tumor suppressor genes; and (3) defect in DNA mismatch repair genes. The sonic hedgehog signaling pathway also appears to play a role. The sonic hedgehog gene, which is involved with embryonic development, appears to be unregulated in early and late stages of pancreatic carcinogenesis.

1. Activation of oncogenes

Mutations of the K-ras oncogene are seen in more than 90% of tumors and are the hallmark of pancreatic adenocarcinoma. Although this mutation may be seen in nonmalignant conditions such as chronic pancreatitis, it appears to be an early genetic alteration in pancreatic carcinogenesis.

2. Inactivation of tumor suppressor genes

Inactivation and loss of function of tumor suppressor genes results in critical disruption of the cell cycle involving cellular differentiation, growth inhibition, regulation of transcription, DNA repair, and apoptosis. The genes most frequently involved are CDKN2A (95%), P53 (60%), DPC4 (50%), BRCA2, and STK11. About 10% of patients with hereditary pancreatic cancer harbor germline mutations of the BRCA2 gene.

3. Defect of DNA mismatch repair gene

Mutations of mismatch repair genes, such as MLH1 and MSH2, have been found in 4% of pancreatic tumors.

B. Hereditary Risk Factors

1. Family history of pancreatic cancer

Genetic predisposition is the greatest risk factor for the development of pancreatic cancer. About 5–10% of patients with pancreatic cancer have a first-degree relative with the disease. The risk of pancreatic cancer increases according to the number of family members with the disease; the risk of developing cancer is twofold for a patient with one family member compared to the general population, and the risk increases to 6- and 30-folds with two and three family members, respectively. These patients present at an earlier age, and smoking appears to contribute to the development of the cancer.

2. Hereditary pancreatitis

This autosomal-dominant condition caused by a PRSS1 gene mutation is strongly associated with pancreatic cancer although it accounts for only a small fraction of the total number of cases. Patients presents with recurrent attacks of acute pancreatitis early in life that may progress to chronic pancreatitis. The risk of an affected family member developing cancer is as high as 40% by age 70 and is highest among those who smoke.

3. Other conditions

Several hereditary syndromes are associated with an increased risk of developing endocrine or exocrine pancreatic cancer. These include familial atypical multiple-mole melanoma (FAMMM) syndrome, multiple endocrine neoplasia type I syndrome, Lynch syndrome II, von Hippel Lindau syndrome, and ataxia–telangiectasia.

Diabetes mellitus is associated with pancreatic cancer, especially with new-onset diabetes after the age of 50 and in most cases there is no family history. In most patients the diagnosis of pancreatic cancer is made within 2 years of the onset of diabetes mellitus. Obesity is associated with increased risk of pancreatic cancer and decreased survival after diagnosis.

C. Environmental Risk Factors

The best-established environmental risk factor associated with pancreatic cancer is cigarette smoking. It is estimated that 30% of pancreatic cancer is due to cigarette smoking. The relative risk of pancreatic cancer among current smokers is two- to threefold compared to the general population. The risk increases with the number of cigarettes consumed and returns to baseline 10–15 years after the patient stops smoking.

Diet appears to be another important environmental factor. Diets high in fat, meat, total energy, and carbohydrates appear to be linked to the development of pancreatic cancer, while consumption of citrus fruits, vegetables, fiber, and vitamin C seem to have a protective effect. Low levels of selenium and lycopene have been associated with the development of pancreatic cancer.

Data on coffee and alcohol consumption, use of aspirin and other nonsteroidal anti-inflammatory drugs, and the development of pancreatic cancer have been conflicting, and recent studies show no definite relationship. Some studies have shown an association between Helicobacter pylori infection and pancreatic cancer, as well as Hepatitis B virus, although the exact mechanism is still unclear.

D. Nonhereditary Risk Factors

The cumulative 20-year risk of pancreatic adenocarcinoma is 4% in patients with nonhereditary chronic pancreatitis. Gastrectomy for peptic ulcer disease increases the risk of pancreatic cancer; the mechanism is unknown but might be related to the relative achlorhydria. In a recent study, obesity significantly increased the risk of pancreatic cancer.

Clinical Findings

A. Symptoms and Signs

Owing to the lack of characteristic signs and symptoms, most patients with pancreatic tumors present late in the course of the disease. As a result, fewer than 20% of tumors are resectable at the time of diagnosis. Patients may present with vague, low-intensity, dull abdominal discomfort or pain that radiates to the back and may be associated with weight loss, anorexia, weakness, diarrhea, and vomiting (Table 29–1). The pain is primarily due to the invasion of the celiac and superior mesenteric plexus, but may rarely be due to acute pancreatitis due to occlusion of the main pancreatic duct by tumor.

Location of the tumor also defines the symptoms and the prognosis. Tumors of the head of the pancreas produce symptoms early, and painless jaundice is seen in more than 50% of cases due to obstruction of the extrahepatic bile duct. In fewer than one-third of patients, obstruction of the bile duct by pancreatic neoplasm is accompanied by a palpable, nontender gallbladder referred to as Courvoisier sign. This finding also may be seen in bile duct obstruction by cholangiocarcinoma, duodenal carcinoma, and carcinoma of the ampulla of Vater.

Tumors of the body and tail are either “asymptomatic” or manifest with nonspecific symptoms, such as abdominal discomfort, and the diagnosis is mostly made after metastatic disease has developed. They can also present with jaundice, caused by liver metastasis.

Obstruction of the pancreatic duct may lead to pancreatic exocrine insufficiency in the form of steatorrhea and malabsorption. New-onset diabetes mellitus after the age of 50 has been associated with the development of pancreatic cancer, especially in the absence of a family history of diabetes. Other uncommon manifestations of pancreatic neoplasm includes thrombophlebitis, specifically migratory superficial thrombophlebitis first described as Trousseau syndrome, psychiatric disturbances, pruritus due to cholestasis, signs and symptoms of gastrointestinal bleeding, and obstruction due to erosion and growth of the pancreatic neoplasm into the duodenal lumen. In patients older than age 50, pancreatic cancer can present with features of irritable bowel syndrome. Paraneoplastic syndrome includes cicatricial and bullous pemphigoid and pancreatic panniculitis presenting as erythematous subcutaneous nodular fat necrosis classically located in the lower extremities.

PNETs are rare, occurring in four of 1 million patients. Over 70% are functional. Gastrinomas and nonfunctional PNETs are the most frequent malignant PNET; insulinomas are the most frequent benign PNET. Nonfunctional PNETs present with symptoms related to the mass. Functional PNETs present with symptoms related to the active secreted hormone.

With the widespread use of abdominal CT imaging, incidental asymptomatic small pancreatic lesions are being detected in increasing frequency. Usually, these lesions are cysts. One study examined 321 patients diagnosed with pancreatic cancer over 8 years and found that 24 (7%) were found incidentally, half were adenocarcinomas, and half were PNETs.

B. Laboratory Findings

Malignant obstruction of the distal bile duct by a neoplasm of the pancreatic head characteristically produces cholestatic liver enzyme elevations with elevated alkaline phosphatase level and direct bilirubin (see Table 29–1). The rise in transaminases is usually mild. Despite biliary stasis, cholangitis is uncommon. Lipase and amylase are elevated in tumors that cause pancreatic duct obstruction and present as acute pancreatitis.

1. Tumor markers

CA 19-9 is a sialylated Lewis antigen that has been found in the biliary cells. It can be elevated with pancreatic cancer but also biliary obstruction of other etiology. It has a poor sensitivity for early-stage pancreatic cancer and is not recommended for screening purposes. When elevated, it can be useful to monitor treatment response. A level above 1000 is considered more specific for pancreatic cancer, although any level may be seen with benign conditions.

C. Imaging and Other Diagnostic Studies

Pancreatic adenocarcinoma is staged using a TNM classification (Table 29–2). It consists of evaluating the characteristics of the primary tumor, namely tumor size and infiltration into major vessels (T stage), regional lymph node involvement (N stage), and the presence and absence of distant metastasis (M stage). Various modalities are available for the diagnosis and staging of pancreatic tumors (see Chapter 9), including those described in the following text.

1. Computed tomography scan

The best initial imaging study is a high-quality three-phase helical CT scan of the abdomen and pelvis. This study will assess possible metastases to the liver, lung bases, regional lymph nodes, and peritoneal cavity (carcinomatosis). If there is no evidence of metastases, the study will assess resectability from the standpoint of vascular invasion. A high-quality CT scan is quite accurate in assessing vascular invasion. One meta-analysis showed that studies since 2004 had a sensitivity of 85% and specificity of 82% in detecting vascular invasion. A chest CT adds little to the abdominal CT as usually when the chest CT shows possible metastases, the abdominal CT has shown evidence of unresectability.

2. Endoscopic ultrasound

EUS has a diagnostic sensitivity similar to helical CT scan but may be superior in diagnosing small pancreatic tumors. EUS-guided fine-needle aspiration (EUS–FNA) has a diagnostic sensitivity of about 85–90% with a false-negative rate of 10–15%. It is safe procedure with minimal risk of tumor seeding. EUS is less accurate in predicting superior mesenteric vein and superior mesenteric artery involvement by the tumor.

3. Endoscopic retrograde cholangiopancreatography

Pancreatic tumors appear as strictures of the pancreatic duct or the bile duct on ERCP. This stricturing of both the bile duct and the pancreatic duct is referred to as the “double duct sign.” Advances in pancreatic imaging such as helical CT have made ERCP unnecessary as an initial test. Major limitations of ERCP are the limited ability to obtain a tissue diagnosis in malignant bile duct obstruction (positive in <50% of cases); limited utility for pancreatic tumor staging, as it provides no information about tumor extent, vascular invasion, or involvement of the lymph nodes; and risk of complications such as pancreatitis and perforation.

4. Magnetic resonance imaging