Table of Contents
As noted above (left), the pancreas is a tapered, elongated gland located behind the stomach.
Its location in close proximity to the liver, stomach, and small intestine contributes to early metastatic spread of disease to nearby critical organs.
Introduction to Pancreatic Adenocarcinoma4
Pancreatic adenocarcinoma is one of the most lethal cancers, exhibiting an extremely low <3% five-year disease-free survival rate.
One aspect of this observation is that pancreatic carcinoma is often not detected before the disease is regionally advanced.
Localized metastatic findings preclude possibility of curative surgical resection in most cases.
Furthermore, compared to many other cancers, pancreatic adenocarcinoma appears relatively resistant to chemotherapeutic intervention and radiotherapy.
As a result of these factors, typical survival is about six months; however, in certain cases amenable to surgical intervention and in which the tumor is relatively susceptible to chemotherapy longer survival times are possible.4
Even in those cases in which the lesion may appear to be resectable based on imaging studies, 20%-40% of the time unresectable lesions will in fact be identified during exploratory surgery.
One indication of possibly successful cancer surgery, in general, is the presence of tumor cell-negative margins.
Unfortunately, even in patients with margin-negative resection, the five-year disease-free survival likelihood is less than one third.
In those patients who are fortunate to survive the initial five-year timeframe, about 50% of those patients will experience a recurrence between years 6-10.4
Nonetheless, improvements in preoperative pancreatic cancer staging have reduced the number of patients undergoing exploratory surgery only to find that their tumors are non-resectable.
Also, non-curative resection appears to extend survival in many cases as well as serving palliative ends.
Following surgery, chemotherapeutic approaches, recently identified, appear helpful in extending the survival time.4 These interventions will be discussed in subsequent sections.
Although there are various types of "pancreatic cancer", most malignant pancreatic neoplasms are ductal adenocarcinomas.
The lethality of ductal adenocarcinomas is reflected in that in spite of the fact the disorder accounts for less than 2% of new cancer cases in the United States, ductal adenocarcinomas represent the fifth leading cause of cancer-related mortality.
4th for men and 4th for women but 5th overall since when gender is combined both the incidence of breast and prostate cancers have the effect of reducing the rank for pancreatic cancer, K.J. Stelzer, M.D., personal communication.
As suggested above, one of the reasons for this lethality is that ductal adenocarcinoma of the pancreas tends to be detected relatively late in disease progression.
Accordingly, there is a major interest in effective screening for early identification of disease and for evaluation of new approaches utilizing biomarkers to accomplish this end.
Infiltrating ductal adenocarcinoma is responsible for about 75% of all malignant pancreatic cancer.
Variations of infiltrating ductal adenocarcinomas include mucinous, non-cystic adenocarcinoma or colloid carcinoma, displaying significant extracellular mucin production.
This histological finding is more likely in infiltrating duct adenocarcinomas evolving in association with either intraductal papillary mucinous neoplasms (IPMNs) or mucinous cystic neoplasms (MCNs).
Medullary carcinoma is another example of infiltrating ductal adenocarcinoma.11
Other pancreatic neoplasms include:
acinar cell sarcoma (ACCs), and
solid-pseudopapillary neoplasms (SPNs).11
Pancreaticoblastoma occurs in children, typically in those less than 15 years of age.
Following surgical resection, the survival rate is considered relatively good.
Pancreaticoblastoma exhibits genetic differences compared to other pancreatic neoplasms.
For instance, most pancreaticoblastomas exhibit allelic loss on chromosome 11p as well as changes in the APC/β-catenin pathway.
APC refers to the adenomatous polyposis gene, which is a tumor suppressor gene inactivated in colorectal cancers.
Mutations in this gene results in accumulation of β-catenin which upon binding to T cell factor-4 (Tcf-4) increases transcriptional activation of other genes; one of these other genes is the oncogene c-MYC.
Other genetic changes which are typically associated with ductal adenocarcinomas (K-ras, P53, and DPC4) are not observed in pancreaticoblastoma.
One possible conclusion is that pancreaticoblastomas might be more likely related to hepatoblastomas then to pancreatic ductal adenocarcinomas.11,19
The pancreas produces insulin in addition to digestive enzymes which flow into the duodenum by means of the pancreatic duct.
Approximately 1.5 L of pancreatic juice is secreted per day and consists of water, a variety of proteins, and ions HCO3-, Cl-, Na+, and K+. HCO3- is notable and at maximum flow rates can contribute 150 mEq/L with the pH reaching about 8.3.
Pancreatic juice alkalinity is important in neutralizing gastric acid entering the duodenum from the stomach.
Pancreatic enzymes facilitate digestion and absorption of fat, proteins, and carbohydrates.
Other pancreatic proteins are classified as plasma proteins, trypsin inhibitors, and mucoproteins.
Acinar cells secrete some enzymes in their enzymatic "active" configurations.
These enzymes include amylase, ribonuclease, deoxyribonucleases, and lipase.
Other enzymes are secreted as pro-enzymes, needing to be activated subsequently.
These pro-enzymes include chymotrypsinogen, trypsinogen, procarboxypeptidase, and phospholipase A2.
These pro-enzymes which are inactive and called zymogens are activated in the proximal intestinal lumen.
Premature activation of zymogens predisposes to pancreatic autodigestion; however, upon entering the duodenum, trypsinogen can be converted to the active form, trypsin, by enteropeptidase (enterokinase).
Trypsin exhibits an ability to activate its precursor trypsinogen, by an "autocatalytic" process. Pancreatic juice normally contains an inhibitor of trypsin which prevents autocatalytic activity.
Tobacco smoke is an important environmental factor that predisposes to pancreatic cancer development.
The increased risk associated with smoking is about 200%-300% and may contribute to the development of about 30% of pancreatic cancers.
Pancreatic cancer risk is attenuated by smoking cessation.11
Other factors that appear associated with the risk of pancreatic cancer development include:
a high-fat, high cholesterol diet
diabetes mellitus, and cirrhosis.
Further, analysis of the association between pancreatitis, diabetes and pancreatic cancer development is made difficult because pancreatic carcinoma itself, as it destroys pancreatic parenchyma, can cause pancreatitis and diabetes.
Nonetheless, meta-analysis of 20 epidemiological studies indicates a pooled relative risk for pancreatic cancer in patients with diabetes mellitus over a period of five years is about 100% greater (2X) compared to the risk of individuals without diabetes mellitus.9,11
A partial list of risk factors correlated with pancreatic cancer include:
Life-style factors including cigarette smoking (a dose-response relationship is noted in this case) and a lack of exercise.
Race/ethnic factors -- increased incidence in black man, native female Hawaiians, individuals of Ashkenazi Jewish heritage.
Inherited predispositions as described below.
Medical conditions such as cirrhosis, diabetes mellitus, chronic pancreatitis.
Dietary factors such as obesity, nitrosamines in food, and a high fat/cholesterol diet.
Occupational exposure to certain carcinogens such as: 2-naphthylamine, benzidine, gasoline products, polychlorinated biphenyls, DDT (dichlorodiphenyl-trichloroethane), and dry cleaning agents.
Certain high-risk occupations such as dry cleaning, working in sawmills, chemical plant occupation, electrical equipment manufacturing, working in mines and metal working.11