Pancreatic cancer overview
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor-In-Chief: Cafer Zorkun, M.D., Ph.D. [2]
Overview
Pancreatic cancer is a malignant tumour within the pancreatic gland.
About 95 percent of pancreatic tumors are adenocarcinomas. The remaining 5 percent include other tumors of the exocrine pancreas (e.g. serous cystadenomas), acinar cell cancers, and pancreatic neuroendocrine tumors (such as insulinomas). These tumors have a completely different diagnostic and therapeutic profile, and generally a more favorable prognosis.[1]
Historical prospective
Pancreatic cancer was first discovered in the 18th-century by Italian scientist Giovanni Battista Morgagni.
Classification
Pancreatic cancers can be classified based on the production of hormones into exocrine and endocrine cancers. Pancreatic exocrine tumors include different types such as Adenocarcinoma, Acinar cell carcinoma, Adenosquamous carcinoma and Pancreatoblastomas. Pancreatic endocrine tumors include Insulinomas, Glucagonomas, VIPomas, Somatostatinomas and Ppomas.
Pathophysiology
Pancreatic cancer is the result of activation or inactivation of multiple gene subsets. The progression and development of pancreatic cancer is influenced by complex interactions and crosstalk between several cellular signaling pathways that include inactivation of tumor suppressor genes, activation of oncogenes and deregulation of molecules in various signaling pathways. EGFR, Akt, NF-kB and Hedgehog pathways are most commonly involved in the pathogenesis of pancreatic cancer. Majority of ductal adenocarcinomas have varying degrees of mucin production and duct-like structures and present as moderate-poorly differentiated masses. The ductal adenocarcinomas are referred to as “desmoplastic” or "scirrhous" carcinomas due to their characteristic dense stromal fibrosis occurring due to alterations in transforming growth factor-beta (TGF-beta) signaling. Local extension of tumor cells may occur into adjacent structures such as superior mesenteric vessels, perineural invasion both inside and outside the pancreas (eg, the retroperitoneum), duodenum, portal vein and stomach. Lymph node spread can occur to the regional peripancreatic, mesenteric, perigastric, portahepatic and omental lymph nodes.
Differentiating Pancreatic Cancer from other Diseases
Pancreatic cancer must be differentiated from other pancreatic pathologies such as chronic pancreatitis, autoimmune pancreatitis, pancreatic pseudocyst, choledocholithiasis, and neuroendocrine tumors of the pancreas. Pathologies of the bile duct and duodenum such as Choledocholithiasis, gallstones (Cholelithiasis), Choledochal Cysts, Cholangiocarcinoma, Bile duct strictures and ampullary cancer should be differentiated from pancreatic cancer based on imaging and biopsy findings. Metastasis from different sites and vascular causes such as abdominal aortic aneurysms may also mimic pancreatic cancer.
Epidemiology and Demographics
In the United States, the age-adjusted prevalence of invasive pancreatic cancer is 11.7 per 100,000 in 2011.[2] Pancreatic cancer is more prevalent in males than females.
Risk Factors
Pancreatic cancer is associated with number of predisposing risk factors such as age, gender, ethnicity, and environmental exposures. The most potent risk factors for Pancreatic cancer include smoking, alcoholism, increased BMI, diabetes mellitus, chronic pancreatitis and a family history of pancreatic cancer. Individuals with hereditary pancreatitis, familial pancreatic cancer, Peutz-Jeghers disease, familial atypical multiple mole melanoma syndrome (FAMMM), von Hippel-Lindau syndrome, multiple endocrine neoplasia type 1, cystic fibrosis of the pancreas and familial cancer syndromes such as lynch syndrome, familial adenomatous polyposis (FAP) and hereditary breast and ovarian cancer-BRCA1 and BRCA2 mutations are also at an increased risk of pancreatic cancer. Other medical conditions which pose as a risk factor for Pancreatic cancer are inflammatory bowel disease, periodontal disease and peptic ulcer disease.
Screening
In asymptomatic adults who are at average risk, the U.S.P.S.T.F recommends against routine screening for pancreatic cancer due to the lack of mortality benefit. In high-risk individuals, with familial pancreatic cancer or in those with genetic syndromes predisposing to pancreatic cancer, screening is suggested. In high- risk groups, screening by endoscopic ultrasound (EUS), magnetic resonance imaging (MRI) and magnetic resonance cholangiopancreatography (MRCP) are recommended.
Natural History, Complications and Prognosis
The symptoms of pancreatic cancer usually develop in the sixth decade of life, and start with symptoms such as jaundice, light-colored stools, dark urine, pain in the upper or middle abdomen and back, unexplained weight loss, anorexia and fatigue.Symptoms typically develop about 20-30 years after exposure to risk factors such as smoking and alcohol. Genetic factors such as alterations in tumor suppressor genes, oncogenes and different signaling pathways are responsible. If left untreated, patients with pancreatic cancer may progress to develop exocrine pancreatic insufficiency arising from pancreatic duct obstruction leading to malabsorption, malnutrition and cachexia. Dudodenal obstruction and biliary obstruction may cause symptoms of bowel obstruction and jaundice. Common complications of pancreatic cancer may arise as a result of the disease or therapy (surgical or medical). Depending on the extent of the tumor at the time of diagnosis, the prognosis is generally regarded as poor, with complete remission extremely rare.
Diagnosis
Staging
The exocrine and endocrine tumors of the pancreas are staged with the help of a single pancreatic staging system. Staging of Pancreatic cancer aids in determining the extent of the disease and helps in arriving at the diagnosis. Staging plays a major role in planning effective treatment and assessing the prognosis. Staging of pancreatic adenocarcinoma is done with the TNM staging system based on the results of imaging modalities such as CT, MRI, PET, TUS, endoscopic studies such as EUS and biopsy with ERCP. The American Joint Committee on Cancer (AJCC) TNM system is most often used to stage cancers of the pancreas based on the information from three variables, namley the T, N, and M. T - Indicates the size of the primary tumor and the extent of it's growth outside the pancreas and into nearby organs. N - Indicates the spread to the regional lymph nodes, where the cancers usually first spread. M - Indicates the metastasis (spread) of cancer to other parts (organs) of the body. The most common sites for the spread of pancreatic cancer are the liver, lungs, and the peritoneum.
History and Symptoms
Symptoms of pancreatic cancer include jaundice, light-colored stools or dark urine, pain in the upper/middle abdomen and back, weight loss, loss of appetite and fatigue.
Physical Examination
Physical examination of patients with pancreatic cancer is usually remarkable for tenderness, weight loss, and jaundice.
Laboratory Findings
Laboratory findings consistent with the diagnosis of pancreatic cancer include abnormal liver function tests and elevated CA 19-9 and CEA levels.
Chest X-ray
There are no chest X-ray findings associated with Pancreatic cancer
Ultrasound
On ultrasound metastasis to liver and fluid in the peritoneal cavity can be identified.
Other imaging findings
ERCP and PTC are other imaging techniques that can be used to diagnose pancreatic cancer.
Treatment
Medical Therapy
The therapy for pancreatic cancer depends largely on the disease progression and the stage of cancer. There are five different types of treatment for patients with pancreatic cancer: surgery, radiation therapy, chemotherapy, chemoradiation therapy and targeted therapy. In patients with pancreatic cancer, surgery is the primary modality of treatment. Extrapancreatic disease, in contrast, requires palliative therapy and curative resection is not performed in such patients. Patients with unresectable disease may be treated with chemotherapy and/or radiation therapy as a part of adjuvant or neoadjuvant therapy. Chemotherapy may be administered when surgical intervention is not deemed appropriate. The National Comprehensive Cancer Network (NCCN) has recommended guidelines for treatment in patients based on their performance status, which is a major prognostic factor. Performance status assesses extent of metastatic disease, size of the tumor and degree of weight loss. In patients with locally advanced unresectable or metastatic disease with good performance status, a combination of Leucovorin,5-fuorouracil, Oxaliplatin and Irinotecan (FOLFIRINOX) is preferred. Radiotherapy may form part of neoadjuvant therapy to attempt to shrink a tumor to a resectable state, but its use on unresectable tumors remains controversial. Neoadjuvant therapy may be used as the toxic effects of chemotherapy can be tolerated more easily before surgery as compared to after resection. Moreover, shrinkage of the tumor with neoadjuvant therapy makes resection easier and improves patient prognosis.
Surgery
The mainstay of therapy for pancreatic cancer is surgery. Various methods of surgical resection may be employed and each of these has its own sets of risks and perioperative complications. The method of surgical resection depends on the locally invasive characteristics and size of the neoplasm. The different surgical techniques that may be used for resectable pancreatic cancer include pancreaticoduodenectomy (Whipple Procedure), pylorus sparing Whipple procedure, distal pancreatectomy and total pancreatectomy. The National Comprehensive Cancer Network (NCCN) has recommended certain guidelines on resectability of pancreatic neoplasms based on resection margins, probability of cure, age and comorbidities. Curative resection is not contraindicated in all patients with vascular invasion, especially in cases with venous invasion. Extrapancreatic disease requires palliative therapy and curative resection is not performed in such patients. CA19-9 levels are not used to dictate the initial strategy for treatment of pancreatic cancer. However, elevated levels of CA19-9 can help predict the likelihood of complete resection, the prognosis of patients with resectable disease and the presence of occult metastasis.
Primary Prevention
Primary prevention of pancreatic cancer involves the cessation of cigarette smoking, regular exercise and a healthy diet as per the American Cancer Society (ACS) guidelines. Cigarette smoking is considered to be the most significant modifiable risk factor for the development of pancreatic cancer. The risk of developing pancreatic cancer becomes almost equivalent to that of a nonsmoker after five years of smoking cessation. The American Cancer Society (ACS) has issued guidelines for diet and physical activity at both individual and community levels and advocates the intake of plenty of vegetables and fruits, protein from fowl and plant sources like whole grains and consumption of tuna, mackerel or salmon that are major sources of protein and long-chain omega-3 fatty acids.
Secondary Prevention
Secondary prevention of pancreatic cancer involves proper diet based on American Cancer Society (ACS) guidelines and palliative therapy for patients. Malabsorption may arise when pancreatic duct obstruction leads to exocrine pancreatic insufficiency. The diet proposed for pancreatic cancer patients is based on ACS guidelines and advocates administration of pancreatic enzyme replacement therapy, avoidance of high-protein/high-fat diets, individualized dietary prescriptions from a registered dietitian and dietary supplementation with omega-3 fatty acids. Palliative therapy is considered as an important part of secondary prevention and includes adequate analgesia, treatment of jaundice and duodenal obstruction, arising as complications of surgery.
References
- ↑ Ghaneh P, Costello E, Neoptolemos JP (2007). "Biology and management of pancreatic cancer". Gut. 56 (8): 1134–52. doi:10.1136/gut.2006.103333. PMID 17625148.
- ↑ Howlader N, Noone AM, Krapcho M, Garshell J, Miller D, Altekruse SF, Kosary CL, Yu M, Ruhl J, Tatalovich Z,Mariotto A, Lewis DR, Chen HS, Feuer EJ, Cronin KA (eds). SEER Cancer Statistics Review, 1975-2011, National Cancer Institute. Bethesda, MD, http://seer.cancer.gov/csr/1975_2011/, based on November 2013 SEER data submission, posted to the SEER web site, April 2014.