Pancreatic cancer

Pancreatic cancer is a relatively common form of human cancer and is associated with a poor prognosis. The risk of pancreatic cancer increases with age and the tumor is more common in women in Northern America, Western and Northern Europe, Australia, and New Zealand. The overall survival varies very little between developed and developing countries and five-year survival rates range from 2% to 9%. The extensive spread of pancreatic cancer at the time for diagnosis is a major reason for the dismal prognosis. The cause of pancreatic cancer is unknown. However, pancreatic cancer is more common in persons with diabetes and chronic pancreatitis, as well as in tobacco smokers. Inherited genetic syndromes and mutations in several genes (BRCA, PALPB2, CDKN2A, PRSS1, STK11, MLH1, and MSH1) cause up to 10% of pancreatic cancer.

Symptoms of pancreatic cancer usually do not become apparent before cancer has reached an advanced stage. Two-thirds of tumors arise in the head of the pancreas causing biliary obstruction and jaundice. Tumors localized in the tail of the pancreas present very late with abdominal and low back pain due to infiltration of nerves.

The most common type of pancreatic cancer is ductal adenocarcinoma. Ductal carcinomas are poorly demarcated tumors composed of atypical cells arranged in irregular, often complex and incomplete, tubular or glandular structures, embedded in dense desmoplastic tumor stroma. Chronic pancreatitis (infiltrates of inflammatory cells, fibrosis, and atrophy of normal exocrine pancreatic structures) is a frequent finding. The rate of cell proliferation is often high and mitotic figures are easy to find. Necrotic cellular debris can often be found inside cancerous glands and ducts. Invasion into tiny vessels or into perineural lymphatics is a common feature. Grading of ductal carcinomas into well, moderately or poorly differentiated carcinomas dependens on the morphology. The tumor grade has not proven helpful in the prognosis of patients with pancreatic cancer. In addition to the typical ductal carcinoma, there are uncommon variants of pancreatic cancer, including adenosquamous carcinoma, mucinous carcinoma, papillary carcinoma, and acinar cell carcinoma. Moreover, mucinous cystadenocarcinoma and tumors corresponding to the endocrine compartment of the pancreas also exist.

Invasive ductal adenocarcinoma develops from its precursors: pancreatic intraepithelial neoplasia, intraductal papillary mucinous neoplasm, and mucinous cystic neoplasm. Cancer develops in a stepwise manner affecting several common cancer-associated genes (KRAS, TP53, CDKN2A, SMAD4).

Diagnosis of ductal carcinoma is usually based on morphological features. Immunohistochemistry has a role in the diagnosis of metastatic pancreatic cancer or in the detection of neuroendocrine differentiation in pancreatic cancers. Ductal carcinoma shows the expression of various keratins and mucins (e.g. KRT7, MUC5AC) but specifically has loss of expression of SMAD4. Molecular investigations have role in the diagnosis of genetic mutations in inherited cancers. In addition, detection of mutations in BRCA genes enables the selection of patients for the treatment with PARP inhibitors.

Treatment of patients depends on the tumor stage. Radiation and chemotherapy are the main treatment, especially in advanced diseases. Surgical treatment in localized disease has a potentially curative effects but it is more frequently used to relieve symptoms or prevent complications in advanced disease. Patients with BRCA mutated cancers can be treated with agents targeting DNA damage repair such as PARP inhibitors.