Pancreatic Adenocarcinoma

Posted by • September 12th, 2014

Cancer of the pancreas is predominantly adenocarcinoma and involves activating KRAS mutations in the large majority of cases. Surgical resection can be effective in localized disease; combination chemotherapy offers some palliation in advanced disease. A new review article on this topic comes from Massachusetts General Hospital’s David Ryan, Theodore Hong, and Nabeel Bardeesy.

Pancreatic ductal adenocarcinoma is the most lethal common cancer because it is usually diagnosed at an advanced stage and is resistant to therapy.

Clinical Pearls

•Describe the epidemiology of pancreatic adenocarcinoma.

Pancreatic adenocarcinoma is rarely diagnosed in persons younger than 40 years of age, and the median age at diagnosis is 71 years. Worldwide, the incidence of all types of pancreatic cancer (85% of which are adenocarcinomas) ranges from 1 to 10 cases per 100,000 people, is generally higher in developed countries and among men, and has remained stable for the past 30 years relative to the incidence of other common solid tumors. It is the eighth leading cause of death from cancer in men and the ninth leading cause of death from cancer in women throughout the world. In the United States this year, pancreatic cancer is expected to develop in 46,000 people, and 40,000 people are expected to die from it. Although it is estimated that 5 to 10% of pancreatic cancers have an inherited component, the genetic basis for familial aggregation has not been identified in most cases.

Table 1. Risk Factors and Inherited Syndromes Associated with Pancreatic Cancer.

What is the most common oncogenic mutation in pancreatic adenocarcinoma?

One of the defining features of pancreatic adenocarcinoma includes a very high rate of activating mutations in KRAS (>90%). As the most common oncogenic mutation in pancreatic adenocarcinoma, KRAS activation has been investigated in depth for its contributions to the tumorigenic growth of established cancers. Several studies have shown that the KRAS mutation is a marker of a poor prognosis in both patients with resectable tumors and those with unresectable tumors. Functional studies have shown that KRAS is critical for the sustained growth of advanced pancreatic adenocarcinoma.

Morning Report Questions

Q: What clinical features are associated with pancreatic cancer, and what initial diagnostic tests are most important?

A: Approximately 60 to 70% of pancreatic cancers are located in the head of the pancreas, and 20 to 25% are located in the body and tail of the pancreas. The presenting signs and symptoms are related to the location. Patients with pancreatic cancer most commonly present with abdominal pain, weight loss, asthenia, and anorexia. Jaundice is a common manifestation of tumors in the head of the pancreas. Diabetes is present in at least 50% of patients with pancreatic cancer. Once a pancreatic mass is detected, abdominal computed tomography with both arterial and venous phases is usually sufficient to determine the initial stage and treatment. Pancreatic cancer metastasizes primarily to the liver, abdomen, and lungs. A biopsy of the pancreatic mass is most often accomplished by means of endoscopic ultrasonography. Although the tumor markers carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9) have neither sensitivity nor specificity for use in screening to detect pancreatic cancer, if   elevated, they are useful in following patients with known disease.

Q: What is the prognosis of pancreatic cancer, and what treatment options are available for early stage disease?

A: More than 90% of patients who have received a diagnosis of pancreatic cancer die from the disease. Approximately 70% of these patients die from extensive metastatic disease; the other 30% have limited metastatic disease at the time of death, but many of them have bulky primary tumors. Surgical resection is the only potentially curative therapy for pancreatic cancer. A pancreaticoduodenectomy (the Whipple procedure) is required to remove tumors in the head and neck of the pancreas. Only 15 to 20% of patients are considered to be candidates for surgical resection, and many of these patients are found to have microscopically positive margins at the time of surgery. Adjuvant therapy includes systemic therapy to reduce the risk of distant metastases and chemoradiotherapy to reduce the risk of locoregional failure. A series of studies has established that 6 months of chemotherapy with either gemcitabine or fluorouracil, as compared with observation, improves overall survival. Although there is a clear consensus regarding the value of adjuvant chemotherapy, the role of adjuvant radiation therapy is controversial. Two European studies showed no benefit of adjuvant radiation therapy.

Figure 3. Anatomy and Surgical Resectability of Pancreatic Cancer. 

Table 2. Adjuvant Therapy for Pancreatic Cancer.

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