Pancreatic Cancer

Definition

More than 90% of pancreatic tumors are adenocarcinomas that arise from the ductal epithelium. Other major tumors of the pancreas include acinar cell, intraductal papillary mucinous neoplasm, mucinous cystic neoplasm, mixed histology, endocrine malignancies, carcinoid tumors, lymphomas, and a variety of rare sarcomas.

Epidemiology

Pancreatic ductal adenocarcinoma has one of the highest mortality-to-incidence ratios of any disease. Although it represents the tenth leading cause of cancer in the United States, it is the fourth leading cause of cancer-related deaths because most patients will die from their disease. By the year 2030, pancreatic cancer is expected to be the second leading cause of cancer-related death behind only lung cancer. Each year in the United States, approximately 50,000 individuals die from pancreatic adenocarcinoma or its complications. The incidence of pancreatic cancer is slowly increasing based on the changing demographics of the U.S. population. In the United States, Blacks have a higher incidence and mortality from pancreatic cancer compared with Whites, although the incidence rate is not increasing as fast in Blacks as in Whites. The risk of developing pancreatic adenocarcinoma increases with age, with a mean onset at age 71 years. The risk is equivalent in men and women, with an average lifetime risk for developing pancreatic adenocarcinoma of about 1 in 78. Globally, 70% of all pancreatic cancer cases occur in people living in advanced economies, with about 470,000 worldwide deaths in 2020.

Smoking tobacco, as well as passive exposure to tobacco smoke in the environment, contributes significantly to the development of pancreatic adenocarcinoma and is also associated with a reduction in survival among patients with pancreatic cancer. Occupational hazards that have been associated with an enhanced risk of developing pancreatic adenocarcinoma include exposure to chlorinated hydrocarbon solvents and heavy metals.

Most pancreatic adenocarcinoma cases are sporadic and occur without a history of the disease in first-degree relatives. Germline mutations in cancer susceptibility genes are commonly identified, even in patients without a significant family history of cancer. Some pancreatic adenocarcinomas occur in association with other cancers or diseases, but most do not occur in association with a defined syndrome.

However, approximately 10% of pancreatic adenocarcinomas occur in families with a history of pancreatic adenocarcinoma. In such families, the risk of developing pancreatic adenocarcinoma is increased seven-fold compared with the general population. Premalignant cystic lesions of the pancreas also occur in families with pancreatic cancer. In addition to mutations of the PALB2 gene in 3% of these families, mutations have also been identified in ATM or BRCA2 , which are critical partners in the DNA damage repair pathway, as well as in p16 .

Chronic pancreatic inflammation from alcohol misuse or genetic anomalies significantly increases the risk of being diagnosed with pancreatic adenocarcinoma. Pro-inflammatory cytokines contribute to the progression from premalignant lesion to advanced tumor.

New-onset insulin-dependent diabetes after age 50 years is associated with about a 4-fold increased risk of pancreatic cancer and can be an indicator of pancreatic cancer. Long-standing type 1 and type 2 diabetes mellitus also may increase the risk of pancreatic adenocarcinoma by about 1.5-fold. For example, the increase in obesity in the U.S. population and the concomitant increase in associated diabetes mellitus are strongly associated with an enhanced lifetime risk of developing pancreatic adenocarcinoma. Epidemiologic studies also note a relationship between type 3c diabetes (diabetes related to pancreatic disease and characterized by a severe deficiency of all glucoregulatory hormones) and the development of pancreatic adenocarcinoma. Patients with type 3c diabetes appear to have the highest associated risk of developing pancreatic adenocarcinoma, especially in the setting of coexisting chronic pancreatitis. Type 3c diabetes is also a consequence of pancreatic adenocarcinoma in approximately 30% of patients.

Pathobiology

Pancreatic cancer is caused by inherited (germline) and acquired (somatic) mutations in cancer-causing genes. Oncogenes and tumor suppressor genes contribute to the growth of the tumor itself as well as to the surrounding microenvironment. A major advance in understanding the development of pancreatic cancer has been the appreciation that the majority of pancreatic adenocarcinomas progress sequentially from histologically normal ductal epithelium to low-grade pancreatic intraepithelial neoplasia, to high-grade pancreatic intraepithelial neoplasia, to invasive carcinoma. This process is associated with the accumulation of specific gene alterations ( Fig. 180-1 ).

The KRAS oncogene, located on chromosome 12, is the most frequently mutated oncogene in pancreatic cancer in (>90% of tumors). It encodes a membrane-bound protein that has GTP-ase activity and is involved in signal transduction. When activated by mutation, typically a point mutation in codon 12, the functions of KRAS are independent of growth factor control, thereby leading to chronic activation of its downstream signaling partners ( PI3K , MAPK , and RAF ), the inhibition of apoptosis, the activation of the cell cycle, migration, angiogenesis, cytoskeletal remodeling, and unchecked proliferation. KRAS oncogenic dose variation plays an important role in pancreatic cancer tumorigenesis, progression, and metastasis.

The tumor suppressor CDKN2A/TP16 , which is a cell cycle control gene, is commonly inactivated in pancreatic cancer, with 80 to 95% loss of activity leading to increased cell cycle progression. TP53 is activated by DNA damage to stop cell cycle progression and repair damaged DNA or initiate apoptosis. Mutations in this tumor suppressor gene are commonly found in 50 to 75% of pancreatic tumors. Inactivation of SMAD4 (DPC4), which is involved in regulating cell cycle progression through the transforming growth factor (TGF)-β pathway, is observed in over 50% of pancreatic cancers and is associated with worse prognosis and the development of metastases. Inactivation of RB1 (in <10% of pancreatic cancers) and STK11 (responsible for Peutz-Jeghers syndrome) is also observed.

Several major signaling pathways are involved in pancreatic tumorigenesis. Hedgehog (Hh) signaling, critical in embryogenesis, regulates the cell cycle and apoptosis, aids in the formation of tumor stroma, and is often upregulated and abnormal in pancreatic cancers. The NOTCH pathway, which is also important in normal embryogenesis to prevent terminal differentiation of cells until appropriate, can be abnormally activated in pancreatic cancer, thereby allowing cells to remain in an undifferentiated state that contributes to tumor growth. When the Wnt pathway is activated, β-catenin is stabilized and migrates into the nucleus, where it activates its target genes. The epidermal growth factor receptor (EGFR), TGF-β, and JAK/STAT pathways are also abnormal in pancreatic cancer cells and lead to the promotion of cell growth, proliferation, differentiation, and survival. Epigenetic modification, the process by which gene expression is altered by mechanisms other than changes in the actual DNA sequence, also has a role in pancreatic cancer tumorigenesis. Shortening of telomeres and overexpression of microRNAs lead to chromosomal instability and dysregulation of gene expression, respectively.

In addition to cancer cells themselves, the tumor microenvironment is composed of stromal cells, inflammatory cells, and endothelial cells that all play a particularly important role in the growth of pancreatic cancer. Cancer cells secrete growth factors, including insulin-like growth factor (IGF)-1, fibroblast growth factor (FGF), TGF-β, vascular endothelial growth factor (VEGF), and platelet-derived growth factor (PDGF), that stimulate pancreatic stellate cells (also called myofibroblasts) to secrete excess amounts of extracellular matrix. In turn, the matrix and its stromal cells secrete cytokines and growth factors that promote the growth, invasion, and dissemination of cancer cells. This matrix also protects pancreatic cancer cells from apoptosis and generates a desmoplastic reaction that interferes with the delivery of chemotherapy to the tumor site. The local presence of TGF-β also leads to decreased activity of helper T-cells and thereby suppresses the body’s immune reaction against pancreatic cancer cells.

Clinical Manifestations

Many pancreatic tumors are asymptomatic when they are diagnosed by an imaging study obtained for an unrelated reason. The symptoms of early pancreatic adenocarcinoma are often subtle and include nonspecific gastrointestinal complaints (nausea, vague abdominal pain), fatigue, and weight loss of undetermined etiology. Epigastric pain and obstructive jaundice often prompt the initial diagnostic work-up of the biliary tree but are frequently late symptoms that are associated with advanced local or regionally disseminated disease. Because approximately 75% of pancreatic carcinomas are located in the head of the pancreas, clinical presentations are often related to compression or invasion of the biliary tree or pancreatic ducts. Deep or superficial venous thrombosis (Trousseau syndrome) is not infrequent, either early or late in the presentation of pancreatic adenocarcinoma. Observation of a palpably distended gallbladder (from obstruction of the distal common bile duct), or Courvoisier sign, is uncommon.

The laboratory abnormalities that accompany pancreatic adenocarcinoma at presentation include anemia and elevations of serum levels of bilirubin, alkaline phosphatase, and aminotransferases. A majority of patients eventually develop signs of obstructive jaundice as well as hyperglycemia, which reflects associated diabetes mellitus.

Early pancreatic intraepithelial neoplasia lesions are asymptomatic, and cystic lesions of the pancreas often remain asymptomatic. Some are discovered on abdominal imaging performed for other purposes, with some estimates that 2 to 15% of patients undergoing abdominal magnetic resonance imaging (MRI) may have unsuspected pancreatic cysts. Most small lesions do not cause symptoms and otherwise would remain undetected unless they later caused acute symptoms that would precipitate an abdominal computed tomographic (CT) scan. Large cysts may cause vague symptoms, but obstructive jaundice is uncommon. Most intraductal papillary mucinous neoplasms are asymptomatic, but some patients present with obstructive jaundice or with pancreatitis.

Diagnosis