Pancreatic, Neuroendocrine GI, and Adrenal Cancers
Pancreatic, Neuroendocrine GI, and Adrenal Cancers
Pancreatic cancer is the fourth leading cause of cancer death in the United States. In 2016, an estimated 53,070 new cases will be diagnosed, with 41,780 deaths. It is estimated that by 2020, pancreas cancer will be the second leading cause of cancer deaths in the United States.
Incidence and Epidemiology
The incidence of pancreatic cancer is slightly higher in men than in women. These gender differences are most prominent among younger individuals.
The peak incidence of pancreatic carcinoma occurs in the seventh decade of life. Two-thirds of new cases occur in people > 65 years of age. Recently, several epidemiologic studies have demonstrated worrisome projections regarding pancreatic cancer: an analysis of the Surveillance, Epidemiology and End Results (SEER) database has projected a marked increase in the number of cancer cases in the next 20 years, which is attributed in part to the increasing number of adults over the age of 65. The authors estimated that there will be a 55% increase in the number of pancreatic cancer cases over the next 20 years.
The incidence of pancreatic cancer in the US is higher in the black population, with an excess risk of 40% to 50% over that of whites, and a higher incidence among black males compared with black females. Perhaps more importantly, black males probably have the highest risk of pancreatic cancer worldwide.
Cancer of the pancreas is a highly lethal disease, with ductal adenocarcinoma being the most common histologic type. The overall 5-year survival has not improved in the past 30 years and remains < 5%. Median survival is approximately 6 months for patients with metastatic disease and 10 months for patients with locally advanced disease. Approximately 50% of patients with pancreatic adenocarcinoma present with clinically apparent metastatic disease, and only a minority (10% to 20%) of patients are considered resectable. There have been some increases in 5-year survival following a curative resection (21% to 25%), potentially due to increased referral to higher-volume teaching institutions; however, 50% of patients die of recurrent tumor within 2 years.
In the past, surgical resection has been associated with high morbidity and mortality. In the last 20 years, however, there have been marked improvements in outcomes following resection. Several single-institution series have reported mortality rates of < 3% following resection. Factors that appear to be important in predicting long-term survival following resection include clear surgical margins, small tumor size (< 2 cm), negative lymph nodes, and reduced perioperative morbidity.
Etiology and Risk Factors
The specific risk factors for pancreatic cancer are not as striking as those for other gastrointestinal (GI) malignancies, such as esophageal and gastric carcinomas. There does, however, appear to be a significant relationship between pancreatic cancer and environmental carcinogens.
Cigarette smoke is one of the carcinogens directly linked to pancreatic malignancies. Heavy cigarette smokers have at least a twofold greater risk for pancreatic carcinoma than nonsmokers. In Japan, cigarette smoking carries an even greater risk, which can be as much as 10-fold in men smoking one to two packs of cigarettes daily.
These compounds, found particularly in processed meat products, reliably induce pancreatic cancer in a variety of laboratory animals. However, no study has directly linked dietary carcinogens to pancreatic cancers in humans. A recent report evaluated the association between dietary nitrate and nitrite intake and pancreatic cancer risk in the National Institute of Health (NIH)-AARP Diet and Health Study. This study showed modest evidence that processed meat sources of dietary nitrate and nitrite may be associated with pancreatic cancer among men only.
The contribution of caffeine consumption to the development of pancreatic carcinoma is controversial. One case-controlled study showed a correlation between caffeine consumption and pancreatic cancer. However, most other studies including a meta-analysis have been equivocal.
There has been no clear-cut relationship shown between alcohol use and pancreatic carcinoma.
Hyperglycemia does not seem to be a risk factor for pancreatic cancer. However, 10% of all patients are found to have new-onset diabetes mellitus with the diagnosis of pancreatic carcinoma.
A report by the American Institute for Cancer Research (AICR) and the World Cancer Research Fund (WCRF) estimated that 28% of pancreatic cancers can be attributable to obesity. As the obesity problem in the United States worsens, this percentage may continue to increase (as described in the WCRF/AICR report, Policy and Action for Cancer Prevention, 2009). Furthermore, recent data suggest that obesity may influence survival in pancreatic cancer, with obese patients having a reduced survival compared with non-obese patients.
More than 80% of resected pancreatic cancers have been found to harbor activating point mutations in the oncogene KRAS. In addition, the tumor-suppressor genes pl6, CDKN2A, TP53, SMAD4, and DPC4 are frequently inactivated in this cancer. Research is also focusing on aberrantly methylated genes in pancreatic cancer using methylation-specific polymerase chain reaction and the identification of microRNAs as targets for detection strategies.
It is estimated that hereditary factors, due to germline mutations, may account for 5% of pancreatic cases. Familial pancreatic carcinoma has been associated with the following genetic syndromes: hereditary pancreatitis, ataxia-telangiectasia, hereditary nonpolyposis colorectal cancer, familial atypical mole melanoma syndrome, Peutz-Jeghers syndrome, and familial breast cancer. Patients with BRCA 1 and BRCA 2 mutations are at increased risk for developing pancreatic cancer, and these individuals may respond to platinum-based chemotherapy and poly (ADP-ribose) polymerase (PARP) inhibitors. Families with CDKN2A germline mutations may be at higher risk of developing pancreatic cancer than those without these mutations.
In 2012, the International Cancer of the Pancreas Screening (CAPS) Consortium released consensus guidelines on screening for pancreatic cancer. This multidisciplinary panel of 49 experts recommended against routine screening in the general population, but did recommend screening with endoscopic ultrasound (EUS) and/or magnetic resonance imaging (MRI)/magnetic resonance cholangiopancreatography (MRCP) for the following high-risk groups: those with at least two blood relatives and at least one first-degree relative with pancreatic cancer; individuals who are carriers of p16, PALB2, or BRCA2 mutations plus a first-degree relative with pancreatic cancer; those with Peutz-Jeghers syndrome; and those with Lynch syndrome plus a first degree relative with pancreatic cancer.
Signs and Symptoms
The initial clinical features of pancreatic carcinoma include anorexia, weight loss, abdominal discomfort or pain, and new-onset diabetes mellitus or thrombophlebitis. The vague nature of these complaints may delay diagnosis for several months.
Specific symptoms usually relate to localized invasion of peripancreatic structures. The most common symptom is back pain, which stems from tumor invasion of the splanchnic plexus and retroperitoneum or pancreatitis. This pain is described as severe, gnawing, and radiating to the middle of the back. Pain can also be epigastric or in the right upper quadrant if bile duct obstruction is present.
In a majority of cases, when tumors involved the head of the pancreas, patients also present with jaundice. Painless or sometimes painful jaundice occurs when lesions involve the intrapancreatic bile duct.
Tumor invasion of the duodenum or gastric outlet may give rise to nausea or vomiting as a presenting symptom. This symptom is rare early in the course of the disease. Changes in bowel habits related to pancreatic insufficiency may also be present, along with associated steatorrhea.
Recent onset of glucose intolerance associated with GI symptoms in elderly patients should alert physicians to the possibility of pancreatic carcinoma.
When it occurs without cholecystitis or cholangitis, a palpable gallbladder suggests malignant obstruction of the common bile duct until proved otherwise. This so-called Courvoisier’s sign is present in about 25% of patients with pancreatic cancer.
Other physical findings. Other physical findings include Trousseau’s syndrome (migratory superficial phlebitis), ascites, Virchow’s node (left supraclavicular lymph node), or a periumbilical mass (Sister Mary Joseph’s node).