Pancreatic Cancer

-Learning About Pancreatic Cancer-

Pancreatic Cancer Teaching Site: Content, Study Questions, Practice Exams

Information about Pancreatic Cancer

Pancreatic Cancer Education

Site developer:  Michael Gordon, Ph.D.

Comments/suggestions: email: Michael Gordon

→ Requires free Shockwave Flash Player  for viewing certain videos, download and install, if needed,  from: http://www.adobe.com/support/flashplayer/downloads.html ←

Search For Pancreatic Cancer Information

↓

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. 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 pancreaticoblastoma, 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, P. 53, 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  

      • "Malignant epithelial neoplasm mostly of children with acinar, endocrine and ductal differentiation and commonly showing squamoid corpuscles."20

•  Background²

  •  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.

•  Etiologic considerations:

  • 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, chronic pancreatitis, 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

•  Epidemiology:  pancreatic cancer is represents the fourth leading cancer cause of death in the United States.  In the 40 year period from 1930 to 1970 pancreatic cancer incidence has doubled to on average about nine cases per 100,000 individuals.  The lethality of pancreatic cancer is extremely high. 

  • Most (95%) pancreatic cancers are classified as exocrine pancreatic cancers and of those about two thirds are localized in the pancreatic head with the remaining third in the body and tail sections of the pancreas.  The remaining 5% of malignancies are classified as islet cell tumors.³ 

  • Historically, pancreatic adenocarcinoma was thought to occur with a slight increase likelihood in males; however, more recent analysis suggests that the risk in women is approaching that of the risk in men.  One possible explanation has been an increase in the use of tobacco among females in recent decades. 

  • Pancreatic cancer is more likely to occur in blacks than in whites with a ratio of relative risk of about 2:1.  By contrast, the risk in Asians is less than that observed in whites (0.7: 1).  Individuals living in industrialized countries by contrast to some African and Asian countries are at increased risk.  This finding has been interpreted to be consistent with environmental factors associated with the Western lifestyle.  Furthermore, elevated incidence rates noted in African Americans is in contrast to those lower rates observed in individuals living in African countries.  This observation is consistent for a role of environmental factors possibly in contrast to strong hereditary factors in the development of pancreatic carcinoma.⁴ 

  • Genetic predisposition has been implicated in pancreatic cancer.  For example, up to about 10% of patients indicate that a first-degree relative exhibited the same disease.  In first-degree relatives of familial pancreatic carcinoma kindreds, about a 20-fold increase in pancreatic cancer risk was determined based on data analysis from the National Familial Pancreatic Tumor Registry (http://pathology.jhu.edu/pancreas/BasicIntro.php?area=ba). Examples of familial syndromes associated with pancreatic cancer include³:

    • Familial pancreatic cancer with a frequency of <1% (gene unknown); For at least one pair of first-degree  relatives with pancreatic cancer  is associated with about a 20 fold increase in risk for pancreatic cancer.⁸

    • Familial breast/ovarian cancer with a frequency of 5-7% (gene BRCA2); the mode of inheritance here is autosomal dominant and is associated with an approximately tenfold increase in pancreatic cancer risk.⁸  BRCA2 mutation represents the most common germline mutations in patients thought to have hereditary pancreatic cancer.⁹

    • Hereditary nonpolyposis colorectal cancer (HNPCC) with a frequency of <3% (gene MMR)

      • MMR refers to DNA mismatch repair genes, responsible for genomic integrity in both mitotic and meiotic replication.  Abnormalities in MMR genes increase cancer likelihood.  The MMR gene family includes MLH1, MSH2, MSH6, PMS2 and MLH3.  Germline mutations in MMR genes appear responsible for the common cancer genetic syndrome hereditary nonpolyposis colon cancer.⁵ Pancreatic carcinoma that occur in this population exhibit a particular histologic appearance described as "medullary histology". Medullary histology is characterized by pushing borders, syncytial growth patterns and poor differentiation.¹¹

      • Family history is important in determining whether a patient might belong to an HNPCC family. The definition of an HNPCC family (referred to as the Amsterdam criteria) includes (1) three relatives with colorectal cancer [one first-degree relative to the other two], (2) two successive generations, and (3) one colorectal cancer occurring in someone 50 years old or less. Other considerations which may predispose to a conclusion of HNPCC familial association involve multiple relatives with colon cancer including those who have had more than one colorectal cancer or colon and endometrial cancer as well as clusters of colorectal and other cancers of the gastrointestinal, urinary or female reproductive system.¹²

      •  Example pedigree of an HNPCC Family¹² 

    • Peutz-Jeghers syndrome with a frequency of <1% (gene LKB1/STK11).

      • This syndrome is autosomal dominant and increases the likelihood of pancreatic cancer by about 140 times.⁸  The clinical manifestation includes mucocutaneous melanin macules and hamartomatous gastrointestinal tract polyps.   Hamartomatous polyps consist of normal gastrointestinal tract cellular elements but exhibit distorted architecture. These polyps are noted in a number of syndromes all of which exhibit PTEN germline mutations.  PTEN (phosphatase and tensin) gene is a tumor suppressor gene.

       

      • Peutz–Jeghers syndrome polyp exhibiting the arborizing pattern of smooth-muscle proliferation (figure abbreviation:  mm-muscularis mucosa)⁷

    • Familial atypical multiple mole melanoma with a frequency of <1% (gene p16); in addition to the increased risk of melanoma, carriers of  p16 germline mutations in the context of familial atypical multiple mole melanoma syndrome appear to have a 10-to 20-fold increased risk of developing pancreatic carcinoma.⁹

    • Hereditary pancreatitis with the frequency of <1% (gene PRSS1);in this type of hereditary pancreatitis, involving mutations in the cationic trypsinogen gene (PRSS1) pancreatitis  symptoms may be observed in children and adolescents and is associated with a 50-fold increased risk of developing pancreatic cancer.⁹ 

    • von Hippel-Lindau disease with a frequency of <1% (gene VHL);

    • Ataxia-telangiectasia is an autosomal recessive inherited disorder (rare) associated with (1) cerebellar ataxia, (2) oculocutaneous telangiectasias, and (3)  cellular and humoral immunodeficiency. The gene thought responsible (ATM), although occasionally associated with pancreatic cancer, confers increased risk of breast cancer, ovarian cancer, biliary tract cancer, and stomach cancer.

      • Oculocutaneous telangiectasia (Louis-Bar syndrome) is characterized by dilated blood vessels (permanently). As noted above, the disorder is associated with a diverse phenotypic expression and is likely due to mutation of the ATM gene (human chromosome 11 (11q23.3).¹⁰

      • Ataxia telangiectasia¹⁰

         

•  Screening for pancreatic cancer³:

  • Factors acting against population-based screening for pancreatic cancer include its low incidence, limited or no efficacy of possible screening tools and even more disappointing, limited possibility for effective management even with early detection of early tumors.

  • In a certain population of individuals who are known to have an elevated likelihood for development of pancreatic cancer, it might seem that screening would have particular value; however, screening efficacy even in this circumstance has not been validated.  Limiting our discussion to screening alone, a serum tumor marker, CA19-9, is not effective for screening because of three primary factors:³

    1. (1) Only 85%-90% of individuals even secrete CA19-9.

    2. (2) In early stages of the disease, CA19-9 levels may be within normal range.

    3. (3) Some benign conditions including acute cholangitis and pancreatitis (chronic) may cause elevation in CA19-9.³

  • In 90% of pancreatic cancers, K-ras mutations are present; however, again K-ras mutations may be associated with other disorders including pancreatitis and dysplastic lesions that may not progress to pancreatic cancer.  As a consequence, false positives are likely and therefore K-ras mutation assays would not provide the necessary specificity and sensitivity as pancreatic cancer markers.

    • Background: K-ras (official name: v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog) is a homolog from the mammalian ras gene family and codes for a protein which is a member of the small GTPase superfamily.  The activating mutation is a single amino acid substitution and the transformed protein appears involved in various malignancies including pancreatic cancer, lung adenocarcinoma, mucinous adenoma and colorectal carcinoma.  Two isoforms differing in the C-terminal region occurs consequent to alternative splicing.⁶

  • Some screening approaches have utilized radiological imaging approaches for assessment and high-risk patient categories. One technique that has been central in pancreatic cancer screening is endoscopic ultrasonography (EUS). This approach provides not only good initialization of the pancreas but also permits assessment of small changes in pancreatic morphology. Small abnormalities (<1 cm) may be appreciated using this approach; furthermore, fine-needle aspiration guided by EUS allows for cytologic diagnosis for lesions measuring from 2-5 mm.

    • Endoscopic ultrasonography is a procedure which utilizes both endoscopy and ultrasound visualization to provide images around the G.I. tract. Endoscopy is a reference to the procedure of inserting a long flexible tube via the mouth (or the rectum) and ultrasound is the imaging modality, based on high-frequency sound waves. In EUS the ultrasound transducer is localized on the tip of the endoscope, allowing the transducer to get very close to the site of interest. One of the advantages of EUS is the ability to discriminate between a pancreatic inflammatory mass or a cancerous mass. An inflammatory mass may occur subsequent to irritation by alcohol, other toxins or a stone. Furthermore, EUS may be helpful in assessing pancreatic cysts.¹³

      • EUS may be used to evaluate the following organs and pathologies: "anal sphincter and incontinence, Barrett's esophagus with high-grade dysplasia, neuroendocrine tumors, common bile duct stones, gastric cancer/MALT lymphoma, esophageal cancer, lung cancer, pancreatic cancer, pancreatitis, cystic neoplasms of the pancreas, rectal cancer, rectal fistulas, smooth muscle tumors, enlarged lymph nodes." ¹⁴

    • One important prospective trial conducted at Johns Hopkins Medical Institutions (JHMI) considered 78 patients with either a strong family history for pancreatic cancer or a known genetic predisposing syndrome, Peutz-Jeghers syndrome (see above).  In a study both EUS and CT were performed for the follow-up set of imaging studies a year later. The control group consisted of 149 patients thought to be at average risk for pancreatic cancer. In cases in which the US study was abnormal, EUS-guided fine needle aspiration along with endoscopic retrograde cholangiopancreatography (ERCP) including aspiration of pancreatic juice for molecular characterization was performed.⁹

      • 10% of the 78 high-risk patients (8 individuals) exhibited pancreatic neoplasia confirmed by surgery or fine-needle aspiration; 6 patients exhibited 8 benign intraductal papillary mucinous neoplasms (IPMNs);1 patient had an IPMN that had progressed to invasive ductal adenocarcinoma and an additional patient had pancreatic intraepithelial neoplasia. Endoscopic ultrasonography and CT scanning also identified 3 patients with 5 extrapancreatic neoplasms. The conclusions in this study indicated that screening using EUS and CT scanning diagnosed significant asymptomatic pancreatic as well as extrapancreatic neoplasm in the high-risk group; furthermore, abnormalities indicative of where suggestive of chronic pancreatitis were more commonly identified at EUS and ERCP in the high-risk individual group.^9.11,18

       

    • ERCP (Endoscopic Retrograde Cholangio-Pancreatography)^15,16,17

      Concerning ERCP (endoscopic retrograde cholangiopancreatography): this procedure allows evaluation of potential pathologies in the liver, gallbladder, bile ducts, and pancreas. The liver produces a liquid (bile) which helps digest fats. The gallbladder is a pear-shaped organ which stores the bile until needed. The bile ducts carry bile from the liver to the gallbladder and small intestine. Collectively these ducts are referred to as the "biliary tree." Referencing the figure again, the pancreas is a relatively larger gland compared to the gallbladder and produces substances which facilitate digestion as well as hormones; a prominent example of the latter is insulin. ERCP helps analyze and sometimes treat conditions of the bile ducts, including gallstone, inflammatory strictures or scars, leaks from trauma and surgery, and cancer. The ERCP utilizes an endoscope along with x-rays to visualize the inside of the stomach and duodenum. The endoscope is swallowed and guided into the duodenum and localized where the ducts of the biliary tree and pancreas open into the duodenum. (see above right)  The dye injection into the biliary tree and pancreas permits x-ray visualization. Complications of ERCP include pancreatitis (inflammation of the pancreas), infection, perforation of the duodenum, or bleeding. Of these possible complications pancreatitis is relatively more common than the others.15