Background
The pancreas is the tenth most common site of new cancers, but pancreatic cancer is the fourth leading cause of cancer deaths among men and women, being responsible for 6% of all cancer-related deaths. (See Epidemiology.)
Pancreatic cancer is notoriously difficult to diagnose in its early stages. At the time of diagnosis, 52% of all patients have distant disease and 26% have regional spread. The relative 1-year survival rate for pancreatic cancer is only 24%, and the overall 5-year survival is 5%.[1] (See Prognosis and Workup.)
Types of pancreatic cancer
Of all pancreatic cancers, 80% are adenocarcinomas of the ductal epithelium. Only 2% of tumors of the exocrine pancreas are benign. (See Etiology and Histologic Findings.)
Less common histologic appearances of exocrine pancreatic cancers include giant cell carcinoma, adenosquamous carcinoma, microglandular adenocarcinoma, mucinous carcinoma, cystadenocarcinoma, papillary cystic carcinoma, acinar cystadenocarcinoma, and acinar cell cystadenocarcinoma. Very rarely, primary connective tissue cancers of the pancreas can occur. The most common of these is primary pancreatic lymphoma.
An adenocarcinoma of the pancreas is seen below. (See Histologic Findings.)
Pancreatic cancer. Gross section of an adenocarcinoma of the pancreas measuring 5 X 6 cm resected from the pancreatic body and tail. Although the tumor was considered to have been fully resected and had not spread to any nodes, the patient died of recurrent cancer within 1 year. Pathophysiology
Typically, pancreatic cancer first metastasizes to regional lymph nodes, then to the liver and, less commonly, to the lungs. It can also directly invade surrounding visceral organs such as the duodenum, stomach, and colon, or it can metastasize to any surface in the abdominal cavity via peritoneal spread. Ascites may result, and this has an ominous prognosis. Pancreatic cancer may spread to the skin as painful nodular metastases. Metastasis to bone is uncommon.
Pancreatic cancer rarely spreads to the brain, but it can produce meningeal carcinomatosis.
Etiology
Pancreatic cancers can arise from the exocrine and endocrine portions of the pancreas, but 95% of them develop from the exocrine portion, including the ductal epithelium, acinar cells, connective tissue, and lymphatic tissue. Approximately 75% of all pancreatic carcinomas occur within the head or neck of the pancreas, 15-20% occur in the body of the pancreas, and 5-10% occur in the tail.
Estimates indicate that 40% of pancreatic cancer cases are sporadic in nature. Another 30% are related to smoking, and 20% may be associated with dietary factors. Only 5-10% are hereditary in nature.[2]
Diabetes mellitus may be associated with a 2-fold increase in the risk of developing pancreatic cancer. Less than 5% of all pancreatic cancers are related to underlying chronic pancreatitis.
Alcohol consumption does not appear to be an independent risk factor for pancreatic cancer unless it is associated with chronic pancreatitis.
The risk factors for pancreatic cancer are discussed in more detail below.
Smoking
Smoking is the most common environmental risk factor for pancreatic carcinoma. Estimates indicate that smoking accounts for up to 30% of cases of pancreatic cancer.
People who smoke have at least a 2-fold greater risk for pancreatic cancer than do nonsmokers. Current smokers with over a 40 pack-year history of smoking may have up to a 5-fold risk greater risk for the disease. Smokeless tobacco also increases the risk of pancreatic cancer.
It takes 5-10 years of discontinued smoking to reduce the increased risk of smoking to approximately that of nonsmokers.
Obesity and dietary factors
In a number of studies, obesity, especially central, has been associated with a higher incidence of pancreatic cancer. For example, Li et al found that being overweight or obese during early adulthood was associated with a greater risk of pancreatic cancer and a younger age of disease onset, while obesity at an older age was associated with lower overall survival.[3]
The incidence of pancreatic cancer is lower in persons with a diet rich in fresh fruits and vegetables. Fruits and vegetables rich in folate and lycopenes (such as tomatoes) may be especially good at reducing the risk of pancreatic cancer.[4, 5]
Consumption of red meat, especially of the processed kinds, is associated with a higher risk of pancreatic cancer. Poultry and dairy product consumption does not increase the risk of this disease.[6]
Despite early reports to the contrary, coffee consumption is not associated with an increased risk of pancreatic cancer.[7]
Diabetes mellitus
Numerous studies have examined the relative risk of pancreatic cancer in persons with diabetes mellitus.
Meta-analysis of 30 studies concluded that patients with diabetes mellitus of at least 5-years' duration have a 2-fold increased risk of developing pancreatic carcinoma. Pancreatic cancer may follow 18-36 months after a diagnosis of diabetes mellitus in elderly patients with no family history of diabetes mellitus.
The National Comprehensive Cancer Network (NCCN) guideline for pancreatic adenocarcinoma (2.2011 version) acknowledges long-standing diabetes mellitus as a risk factor for pancreatic cancer. The guideline also notes an association between sudden onset of type II diabetes mellitus in an adult older than 50 years and a new diagnosis of pancreatic cancer.[8]
Chronic pancreatitis
Long-standing, chronic pancreatitis is a substantial risk factor for the development of pancreatic cancer. A multicenter study of more than 2000 patients with chronic pancreatitis showed a 26-fold increase in the risk of developing pancreatic cancer. This risk increased linearly with time, with 4% of patients who had chronic pancreatitis for 20 years' duration developing pancreatic cancer.[9]
The risk of pancreatic cancer is even higher in patients with hereditary pancreatitis. The mean age of development of pancreatic cancer in these patients is approximately 57 years. The relative risk of pancreatic cancer in hereditary pancreatitis is increased more than 50-fold, and the cumulative risk rate of pancreatic cancer by age 70 years is 40%.
This cumulative risk increases to 75% in persons whose family has a paternal inheritance pattern.[10]
Chronic pancreatitis from alcohol consumption is also associated a much higher incidence and an earlier age of onset of pancreatic carcinoma.[11]
Genetic factors
Approximately 5-10% of patients with pancreatic carcinoma have some genetic predisposition to developing the disease.[12]
The molecular genetics of pancreatic adenocarcinoma have been well studied.[13, 14, 15] Of these tumors, 80-95% have mutations in the KRAS2 gene; 85-98% have mutations, deletions, or hypermethylation in the CDKN2 gene; 50% have mutations in p53; and about 55% have homozygous deletions or mutations in Smad4. Some of these mutations can also be found in high-risk precursors of pancreatic cancer. For example, in chronic pancreatitis, 30% of patients have detectable mutations in p16 and 10% have K-ras mutations.
Families with BRCA-2 mutations, which are associated with a high risk of breast cancer, also have an excess of pancreatic cancer.[16]
Assaying pancreatic juice for the genetic mutations associated with pancreatic adenocarcinoma is invasive, but it may be useful for the early diagnosis of the disease.[17] However, this approach is problematic, because genetic mutations in the pancreatic juice may be found in patients with inflammatory pancreatic disease.
Certain precursor lesions have been associated with pancreatic tumors arising from the ductal epithelium of the pancreas. The main morphologic form associated with ductal adenocarcinoma of the pancreas is pancreatic intraepithelial neoplasia (PIN). These lesions arise from specific genetic mutations and cellular alterations that contribute to the development of invasive ductal adenocarcinoma.[18]
The initial alterations appear to be related to KRAS2 gene mutations and telomere shortening. Thereafter, p16/CDKN2A is inactivated. Finally, the inactivation of TP53 and MAD4/DPC4 occur. These mutations have been correlated with increasing development of dysplasia and thus with the development of ductal carcinoma of the exocrine pancreas.
Based on more recent data from sequencing of human tumors, pancreatic cancer is a genetically complex and heterogeneous disease.[19] This is confounded by considerable variability in terms of the genetic malformations and pathways involved between individual tumors. In addition, the long time from early to clinically manifested disease (21.2 y on average) allows for an accumulation of complex genetic changes, which probably explains the fact that it is often resistant to chemotherapy and radiation therapy.[20, 21]
The inherited disorders that increase the risk of pancreatic cancer include hereditary pancreatitis, multiple endocrine neoplasia (MEN), hereditary nonpolyposis rectal cancer (HNPCC), familial adenomatous polyposis (FAP) and Gardner syndrome, familial atypical multiple mole melanoma (FAMMM) syndrome, von Hippel-Lindau syndrome (VHL), and germline mutations in the BRCA1 and BRCA2 genes.
Hereditary pancreatitis has been associated with a 40% cumulative risk of developing pancreatic cancer at 40%.[10] MEN-1 and VHL are other genetic syndromes associated with pancreatic endocrine tumor development.
Patients with MEN-1 develop symptomatic pancreatic endocrine tumors about 50% of the time, and these pancreatic tumors are noted to be the leading cause of disease-specific mortality.[22] Von Hippel-Lindau syndrome has been associated with malignancy in 17% of masses found in the pancreas in people with this syndrome.[23]
Syndromes associated with an increased risk of the development of colon cancer, such as HNPCC and FAP (and Gardner syndrome), have also shown an increased correlation with existence of pancreatic cancer, but the statistics have not been impressive.
In a cohort study of 1391 patients with FAP, only 4 developed pancreatic adenocarcinoma. No statistics are available to show the incidence of pancreatic cancer in patients with HNPCC.[24]
FAMMM has been shown to increase relative risk of developing pancreatic cancer by 13- to 22-fold and the incidence in sporadic cases to be 98%.[25]
The above disorders have specific genetic abnormalities associated with the noted increased risk of pancreatic cancer. Pancreatic cancer in hereditary pancreatitis is associated with a mutation in the PRSS1 gene. Pancreatic cancer appearing in FAP and HNPCC has been associated with a mutation in the APC gene and MSH2 and MLH1 genes respectively. FAMMM and pancreatic cancer has been associated with a mutation in CDKN2A. Endocrine tumors of the pancreas associated with VHL are thought to develop by way of the inactivation of the VHL tumor suppressor gene.[12]
Germline mutations in BRCA1 and BRCA2 have been shown to moderately increase the risk of developing pancreatic cancer by 2.3- to 3.6-fold, but BRCA2 has been associated more commonly with pancreatic cancer, at an incidence of 7%.[12]
Race-related factors
Black males in the United States have the highest incidence rate of pancreatic cancer.[26] (See Epidemiology, below.) The reasons for the higher incidence of pancreatic cancer in African Americans are unclear. Certainly, differences in risk factors for pancreatic cancer, such as dietary habits, obesity, and the frequency of cigarette smoking, are recognized among different population groups and may contribute to the higher incidence of this disease among blacks.
However, Arnold et al found that excess pancreatic cancer in blacks cannot be attributed to currently known risk factors, suggesting that as-yet undetermined factors play a role in the disease process.[27] One possibility is a difference in the underlying frequency of predisposing genetic mutations for pancreatic cancer.
Epidemiology
Incidence in the United States
The American Cancer Society estimated that in the United States in 2010, about 43,140 new cases of pancreatic cancer (21,370 in men and 21,770 in women) would be diagnosed and about 36,800 people (18,770 men and 18,030 women) will die of pancreatic cancer.[28]
Even so, the overall incidence of pancreatic cancer has been relatively stable for decades, with the rate in men having been stable since 1993. In women, however, the incidence has been increasing by 0.6% per year since 1994.[1] . These trends probably represent the effect of changing smoking rates for men and women.
International incidence
Worldwide, pancreatic cancer ranks 13th in incidence but 8th as a cause of cancer death.[29]
Most other countries have incidence rates of 8-12 cases per 100,000 persons per year. In some areas of the world, pancreatic cancer is quite infrequent; for example, the incidence in India is less than 2 cases per 100,000 persons per year.
Race predilection
The highest incidence rate of pancreatic cancer is 16.2 cases per 100,000 persons per year, in black males in the United States.[26] The incidence for black females in the United States was 12.4 cases per 100,000 persons per year from 2001 to 2005.
For white males in the United States from 2001 to 2005, the incidence was 12.1 cases per 100,000 persons per year, and for white females, the incidence was 9.1 cases per 100,000 persons per year.[26]
Native Hawaiian males and men of Korean, Czech, Latvian, and New Zealand Maori ancestry also have high incidence rates: 11 cases per 100,000 persons per year.
Age predilection
In the absence of predisposing conditions, such as familial pancreatic cancer and chronic pancreatitis, pancreatic cancer is unusual in persons younger than 45 years. After age 50 years, the frequency of pancreatic cancer increases linearly.
The median age at diagnosis is 69 years in whites and 65 years in blacks; some single-institution data reported from large cancer centers suggest that the median age at diagnosis in both sexes has fallen to 63 years of age.
Mortality
As previously stated, pancreatic cancer is the fourth leading cause of cancer deaths among men and women, being responsible for 6% of all cancer-related deaths. The death rate from the disease has risen from 5 per 100,000 population in 1930 to more than 10 per 100,000 in 2003.
The American Cancer Society estimated that in the United States in 2009, 35,240 persons (18,030 men and 17,210 women) would die of pancreatic cancer.[1]
Prognosis
Pancreatic carcinoma is unfortunately usually a fatal disease. The collective median survival time for all patients is 4-6 months.
The relative 1-year survival rate for patients with pancreatic cancer is only 24%, and the overall 5-year survival rate is 5%, having increased from 3% rate as calculated between 1975 and 1977.[1] (However, patients with neuroendocrine and cystic neoplasms of the pancreas, such as mucinous cystadenocarcinomas or intraductal papillary mucinous neoplasms [IPMN], have much better survival rates than do patients with pancreatic adenocarcinoma.)
A 5-year survival in pancreatic cancer is no guarantee of cure; patients who survive for 5 years after successful surgery may still die of recurrent disease years after the 5-year survival point. The occasional patient with metastatic disease or locally advanced disease who survives beyond 2-3 years may die of complications of local spread, such as bleeding esophageal varices.
In patients able to undergo a successful curative resection (about 20% of patients), median survival time ranges from 12-19 months, and the 5-year survival rate is 15-20%. The best predictors of long-term survival after surgery are a tumor diameter of less than 3 cm, no nodal involvement, negative resection margins, and diploid tumor deoxyribonucleic acid (DNA) content.
The median survival for patients who undergo successful resection (only 20% of patients) is approximately 12-19 months, with a 5-year survival rate of 15-20%.
Patient Education
Smoking is the most significant reversible risk factor for pancreatic cancer.
Alcohol consumption does not increase the risk of pancreatic cancer unless it leads to chronic pancreatitis. A multicenter study of more than 2000 patients with chronic pancreatitis showed a 26-fold increase in the risk of developing pancreatic cancer.[9]
For patient education information, see the Liver, Gallbladder, and Pancreas Center and Cancer and Tumors Center, as well as Pancreatitis and Pancreatic Cancer.
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