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Category: Gastroenterology | Oncology

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Pancreatic cancer overview

Published: July 07, 2009. Updated: July 29, 2009

 

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Pancreatic cancer is a malignant neoplasm of the pancreas.

Incidence

Pancreatic cancer occurs at an incidence of approximately 10 per 100,000 per year. Due to the aggressiveness of this tumor and difficult early diagnosis the mortality rate is virtually equal to the incidence (10 per 100,000).

Pancreatic cancer is the fifth leading cause of cancer-related death for both men and women (following lung, colon, breast, and prostate cancers) and is responsible for 5% of all cancer-related deaths.

Estimated new cases and deaths from pancreatic cancer in the United States in 2005:

  • New cases: 32,180.
  • Deaths: 31,800.

Gender

Pancreatic cancer is slightly higher in males than in females especially in younger populations.

Age

The disease incidence peaks between the age of 67 and 79 and is rare below the age of 40.

Race and ethnicity

Blacks are more at risk than whites (50% excess risk). Black males have the highest incidence of pancreatic cancer worldwide.

Geography

Pancreatic cancer incidence and mortality statistics are similar throughout the world. The reasons for the slight regional and ethnic differences in the incidence of pancreatic cancer are unknown, but this may be due to a trend toward a decline in tobacco use in certain groups and regions. Incidence rates are highest in industrialized societies and western countries. 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.

  • In Europe, rates are highest in the Nordic countries.
  • In the United States, rates are particularly high in native Hawaiians, African Americans, and Korean Americans, with the highest rates in African Americans. The fact that the rates in African Americans are considerably higher than in native Africans suggests an environmental influence.

Causes and risk factors

Smoking

The risk is ascribed to tobacco-specific nitrosamines.

  • Current estimates suggest that approximately 30% of pancreatic cancer cases are due to cigarette smoking.
  • Heavy cigarette smokers have at least a twofold greater risk of developing pancreatic carcinoma than nonsmokers. The risk increases with increasing duration and amount of cigarette smoking.
  • The excess risk levels off 10 to 15 years after cessation of smoking.

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.

Genetic factors

Cancer of the pancreas is a genetic disease. Over 80% of resected pancreatic cancers have been found to harbor activating point mutations in K-ras. In addition, the tumor- suppressor genes p16, p53, and DPC4 are all frequently inactivated in this cancer.

Familial pancreatic carcinoma has been associated with the following genetic syndromes: hereditary pancreatitis, ataxia-telangiectasia, hereditary nonpolyposis colorectal cancer (HNPCC), familial atypical mole melanoma (FAMM) syndrome, Peutz-Jeghers syndrome, and familial breast cancer. Families with p16 germline mutations may be at higher risk of developing pancreatic cancer than those without these mutations.

Diet

Diet rich in fat and meat has been proposed as a risk factor. Diets high in salt, dehydrated foods, fried foods, refined sugars, or soybeans may also increase the risk of pancreatic cancer.

N-nitroso compounds, found particularly in processed meat products, reliably induce pancreatic cancer in a variety of laboratory animals. This has not been confirmed in humans.

One study found a correlation between barbecued meat and pancreatic cancer. Well-done, barbecued meat contains potential carcinogens such as heterocyclic amines and polycyclic aromatic hydrocarbons, compounds not found in meat prepared in other ways.

Decreased pancreatic cancer rates have been associated with the high consumption of vegetables, citrus fruits, fiber, and vitamin C. The recent observation that limonene, a natural product found in citrus fruits, is a potent inhibitor of the K-ras oncoprotein makes the association of diets high in citrus fruits with a reduced risk of pancreatic cancer particularly interesting.

The point to make here is that smoking and diet are estimated to be responsible for at least 40% of the cases making it a potentially preventable disease.

Controversial risk factors

The association of pancreatic cancer with alcohol, diabetes and caffeine as causative agents has not been established. Most cases of pancreatic cancers present with new onset diabetes mellitus which is a consequence of pancreatic cancer rather than a cause.

Alcohol

Caffeine

Diabetes

Most cases of pancreatic cancers present with new onset diabetes mellitus which is a consequence of pancreatic cancer rather than a cause. A meta-analysis of studies published between 1975 and 1994 showed that pancreatic cancer occurred with increased frequency in patients with long-standing diabetes. The mechanisms underlying the association between pancreatic cancer and diabetes are obscure; however, the diabetic state seems to enhance the growth of pancreatic cancer in animal models.

Previous surgical interference

  • Previous cholicystectomy: Cholecystokinin is the primary hormone that causes growth of exocrine pancreatic cells; others include epidermal growth factor and insulin-like growth factors. Pancreatic cancer has been induced experimentally by long-term duodenogastric reflux, which is associated with increased cholecystokinin levels. Some clinical evidence suggests that cholecystectomy, which also increases the circulating cholecystokinin, may increase the risk for pancreatic cancer.
  • Previous partial gastrectomy: Partial gastrectomy appears to correlate with a two to five times higher than expected incidence of pancreatic cancer 15 to 20 years later. The increased formation of N-nitroso compounds by bacteria that produce nitrate reductase and proliferate in the hypoacidic stomach has been proposed to account for the increased occurrence of gastric and pancreatic cancer after partial gastrectomy.

Chronic pancreatitis

Chronic pancreatitis and hereditary pancreatitis are not established risk factors for pancreatic cancer. Some reports have indicated that chronic pancreatitis is associated with a 15-fold increase in the risk for pancreatic cancer.

Symptoms and signs

1. Abdominal pain (80%)

Abdominal pain is the presenting symptom in almost 80% of cases and usually carries a bad prognosis. Pain usually occurs as a result of invasion of the tumor into the neighboring celiac plexus which is a sign that surgery will not be possible. Abdominal pain is usually chronic, dull aching and referred to the upper back.

2. Anorexia (65%)

3. Weight loss (60%)

4. Early satiety (60%)

5. Xerostomia and sleep problems (55%)

6. Jaundice (50%)

Jaundice, on the other hand, is the first symptom in 50% of the cases; and in contrast to pain, usually carries a good prognosis. This is because jaundice occurring early in the course of the disease directs the investigation to the possible diagnosis of cancer of the pancreas, in contrast to abdominal pain which is a vague symptom. Which is why periampullary neoplasms and those within the intrapancreatic portion of the common bile duct which cause biliary obstruction early in the disease have a better prognosis. In contrast, adenocarcinomas arising in the pancreas that do not obstruct the intrapancreatic portion of the bile duct are often not diagnosed until they are locally advanced or metastatic. In the absence of extrahepatic biliary obstruction, few pancreatic cancer patients present with potentially resectable disease.

7. GIT complaints (30%)

Other GIT symptoms include nausea, vomiting, constipation. Pancreatic exocrine insufficiency due to obstruction of the pancreatic duct commonly results in malabsorption, steatorrhea, and mild changes in stool frequency.

8. Cachexia

Signs

Important signs include those that indicate that resection by surgery will not be possible. These include:

  • Performance status
  • Cardiopulmonary function
  • Left supraclavicular adenopathy
  • Ascites

Other important signs include deep venous thrombosis.

Diagnosis

CT scan

CT scan is the most important diagnostic and staging tool.

  • It can detect tumors as small as 2cm and can determine if the tumor is surgically resectable or not. It has a sensitivity of 95% in this setting.
  • Liver metastases
  • Lymph node enlargement
  • Perivascular invasion (SMA, and superior mesenteric-portal vein (SMPV)). Sensitivity: 88% to 97%.
  • Relationship of the tumor to the celiac axis
  • Dilatation of the pancreatic duct and obstruction site

Ultrasonography

More accurate than CT in distinguishing obstructive from nonobstructive jaundice. In contrast to CT its efficacy decreases with obesity and excessive bowel gas.

ERCP

Although endoscopic retrograde cholangiopancreatography and fine-needle aspiration biopsy are invasive procedures, they do offer certain advantages. Endoscopic retrograde cholangiopancreatography (ERCP) has high sensitivity in diagnosing pancreatic carcinoma (94%) [28]. It can localize the tumor and detect the site of ductal obstruction. Furthermore, endoscopic retrograde cholangiopancreatography permits the aspiration of pancreatic secretions for cytologic examination. Access to bile also allows measurement of other cancer-derived factors such as the K-ras oncogene. As reported in one series [29], the false-negative rate for ERCP is only 3%. Although the radiographic diagnosis of pancreatic cancer can generally be made using a combination of CT, ultrasonography, and endoscopic retrograde cholangiopancreatography, fine-needle aspiration biopsy, which has a sensitivity of 86% [30], can provide a histologic diagnosis

  • Sensitivity: 94%
  • Delineates the site of obstruction
  • Cytological examination

Fine Needle Aspiration Biopsy

  • Sensitivity: 86%
  • Histological diagnosis

Tumor markers

CEA

  • Sensitivity: 40%
  • Elevated in pancreatitis, other benign and malignant tumors.

CA 19-9

  • Sensitivity: 70%
  • Levels increase with more advanced stage
  • Lower sensitivity in early detection
  • Elevated in chronic pancreatitis, GIT cancers

Tumor markers such as CEA and CA 19-9 have a lower specificity but can help in suggesting the diagnosis when the presentation is obscure.

A diagnosis of pancreatic cancer is not possible without pathological evidence. This must be taken prior to surgery. With advances in diagnosis such as endoscopic ultrasound and CT guided biopsies, it is not justified to undergo a diagnostic laparoscopy except in very rare cases. Endoscopy (ERCP) also allows for cytological examination (as most cancers are of ductal origin).

Pathology

  • Adenocarcinoma of the pancreas: originates from the ductal cells and comprises most of the cases. This diagnosis rests on the presence of nuclear, and cellular pleomorphism within the ductal cells, discontinuity of the ductal epithelium and vascular and lymphatic invasion.
  • Other rare types include: acinar cell and cystadenocarcinoma.

It should be clearly differentiated from islet cell tumors which carry a good prognosis. They have a different histological appearance and stain positive for chromogranin.

Staging and prognostic factors

Staging of adrenal cancer

  • The TNM staging system for pancreatic cancer

It should be noted that TNM classification is not of clinical value beyond the classification of resectable and irresectable disease. Resectable disease is defined as T1N0M0 and T2N0M0 in terms of the TNM system.

Prognostic factors (Risk factors for recurrence)

The two main prognostic factors for adrenal cancer are:

  • Completeness of resection
  • Stage of disease

Treatment

Treatment with curative intent is only possible with surgery in patients with resectable disease. This is defined as tumors of the head that do not invade adjacent structures (such as the celiac plexus or the superior mesenteric artery). Adjuvant chemoradiation is not standard but employed by many centers. For locally advanced disease combined chemo-radiotherapy may be beneficial.

1. Resectable cases

Staging and determination of resectability is of great prognostic value. Tools for evaluation of resectability include CT, MRI, angiography and laparoscopy 'operative determination'. Operative determination of resectability includes careful examination of the liver, porta hepatis, and portal and superior mesenteric vessels. The head of the pancreas and uncinate process are mobilized by an extensive Kocher maneuver to evaluate the head of the pancreas. The SMA is palpated, and its relationship to the tumor is assessed. The hepatic artery and celiac trunk are examined to make certain there is no vascular encasement.

Resectable cases do not show any of the following:

  • No local extension of the tumor into the adjacent organs.
  • No lymph node enlargement
  • No invasion of the mesenteric vessels
  • No invasion of the celiac plexus

Whipple's operation

Pancreaticoduodenectomy (Whipple's operation and its variants) is the treatment of choice. Variants of Whipple's operation include pylorus preserving procedure to reduce postgastrectomy syndrome and an extended Whipple's procedure which is commonly used in Japan.

Benefit

Overall 5-year survival for tumors resected for cure and that are <2cm in size is approximately 18%.

Surgical mortality

Surgical mortality ranges from 5% in the best hands to 20%. Major complications occur in 30% of cases and range from sepsis, abscess formation, hemorrhage and fistula formation.

Adjuvant therapy

A small Gastrointestinal Tumor Study Group (GITSG) trial demonstrated a significant prolongation of survival (median survival increase, from 11 to 20 months) among patients with pancreatic adenocarcinoma who received irradiation plus bolus 5-FU chemotherapy after curative resection, as compared with those given no adjuvant treatment. An improvement in the long-term cure rate was also observed among those given chemoradiation therapy.

2. Locally advanced cases

Combined chemo-radiotherapy

Several single-institution studies have evaluated the role of preoperative irradiation in conjunction with fluorouracil (5-FU)- and gemcitabine (Gemzar)-based chemotherapy. In these studies, 60%- 80% of the lesions were completely resected 1.0-1.5 months after the completion of chemoradiotherapy. Median survival has ranged from 16 to 25 months.

Intraoperative electron-beam radiotherapy

Intraoperative electron-beam radiotherapy has been associated with excellent local control.

3. Metastatic cases

Chemotherapy

For cases that have spread outside the pancreas to the lymph nodes or the liver, chemotherapy may offer palliation.

Benefit

Survival for patients with stage IV tumors is less than 2% at 5 years with a median survival at usually less than 6 months.


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