PATHOPHYSIOLOGY The cause is unknown.

Most cases of pancreatic cancer are sporadic; a small number (3%) occur in patients with an inherited predisposition. The disease is 6 times more common in diabetic than nondiabetic women (but not in diabetic men) and 2.5-5 times more common in cigarette smokers.

Carcinomas occur more often in the head (70%) and body (20%) than in the tail (10%) of the pancreas. Virtually all pancreatic carcinomas (99%) originate in duct cells and only a few (1%) in acinar cells. Pancreatic intraepithelial neoplasia and intraductal papillary mucinous tumors are thought to be precursor lesions of ductal adenocarcinoma of the pancreas. Results of molecular analyses (eg, for mutations in the proto-oncogene K-ras) suggest a monoclonal cellular origin in at least 95% of cases. Grossly, pancreatic cancer presents as an indurated infiltrating tumor that obstructs the pancreatic duct and thus often causes inflammation of the distal gland. Carcinomas of the head of the pancreas tend to obstruct the common bile duct early in their course, leading to jaundice and,
if the tumor is large, to widening of the duodenal C loop on contrast x-ray film or imaging studies. Tumors of the body and tail tend to present later in their course and thus tend to be very large when found. Pancreatic cancer frequently causes marked fibrosis in adjacent areas (desmoplastic reaction). As with other malignancies, it appears that specific molecular genetic alterations occur during development of pancreatic cancer, including overexpression of receptor-ligand systems, activation of oncogenes, inactivation of tumor suppressor genes, and mutations of DNA mismatch repair genes. For example, activating point mutations in the proto-oncogene K-ras at codon 12 have been identified in > 90% of pancreatic cancers. These mutations can be identified from cytologic brushings or from pancreatic juice obtained at the time of endoscopic retrograde cannulation of the pancreatic duct. Mutation in the TP53 tumor suppressor gene has been detected in 50-75% of adenocarcinomas of the pancreas. Concurrent loss of TP53 and K-ras function may contribute to the clinical aggressiveness of the cancer. In addition, in approximately 90% of cases, the P16 tumor-suppressor gene, located on chromosome 9p, is inactivated. Mutations in DNA mismatch repair genes can also lead to pancreatic cancer. It appears that multiple mutations must occur for pancreatic cancer to develop. Tumor suppressor genes include proteins involved in DNA damage control, cell cycle control, programmed cell death, and cell adhesion.

p16/CDKN Cell cycle 2 regulator

Melanoma, pancreatic and esophageal cancers

Mutation, deletion, methylation

Familial melanoma

Table 5-4. Phenotypic changes in the progression of neoplasia. 1. Genomic instability 1. Impaired DNA repair 2. Aberrant cell cycle checkpoint control 2. Enhanced proliferation 1. Autonomous growth 2. Abnormalities of cell cycle control 3. Exaggerated response to hormonal or growth factor stimuli 4. Lack of response to growth inhibitors or cell contact inhibition 3. Evasion of immune system 1. Antigen modulation and masking 2. Elaboration of immune response antagonistic molecules 4. Invasion of tissue and stroma 1. Attachment to extracellular matrix 2. Secretion of proteolytic enzymes 3. Recruitment of stromal cells to produce proteolytic enzymes 4. Loss of cell cohesion 5. Ability to gain access to and egress from lymphatics and bloodstream 1. Enhanced cell motility 2. Recognition of endothelial protein sequences 3. Cytoskeletal modifications 6. Establishment of metastatic foci 1. Cell adhesion and attachment 2. Tissue-specific tropism 7. Ability to recruit vascularization to support growth of primary or metastatic tumor 8. Drug resistance 1. Altered drug metabolism and drug inactivation 2. Increased synthesis of targeted enzymes 3. Enhanced drug efflux 4. Enhanced DNA damage repair

Pancreatic Neuroendocrine Tumors

Also known as islet-cell tumors, neuroendocrine tumors (NETs) are rare tumors (incidence rate, 5 cases/1,000,000 person-years) that arise from endocrine cells within or near the pancreas. NETs may occur sporadically or as part of multiple endocrine neoplasia type 1. Most primary NETs arise within the gastrinoma triangle, comprised of the joining of the cystic and common hepatic ducts, second and third portions of the duodenum, and border of the body and tail of the pancreas. Although a subset of NETs is nonfunctional, most secrete hormones that can result in various clinical syndromes. Carcinoid tumors are considered NETs but are rarely found in the pancreas. Most NETs are listed in the differential diagnosis for secretory diarrhea, although the yield of testing in this setting is extremely low. Nonfunctional tumors are most often indolent but may demonstrate malignant behavior, including metastases. Table 1: Pancreatic Neuroendocrine Tumors

Tumor Type Insulinoma

Number Secretory (%) * 40-60 Products Insulin

Clinical Features Hypoglycemia; symptoms of

Laboratory Tests Insulin level, C-reactive protein; 72-hr inpatient

Symptomatic Treatment Dietary measures; octreotide;

catecholamine excess; fasting, with monitoring of diazoxide 90% benign Gastrinoma 20-50 Gastrin Peptic ulcer disease; GERD; secretory glucose and insulin levels Fasting serum gastrin; gastric pH analysis; Proton pump inhibitor; octreotide

diarrhea; most common gastrin provocation NET in MEN-I; 60%90% malignant Glucagonoma Rare Glucagon Glucose intolerance; migratory necrolytic erythema; weight loss; anemia; 90% malignant Somatostatinoma Rare Somatostatin Diabetes; gallstones; secretory diarrhea Clinical and pathologic diagnoses; increased somatostatin-like immunoreactivity in resected tumor VIPoma Rare Vasoactive Cholera-like, secretory Serum VIP Octreotide testing (calcium or secretin challenge) Serum glucagon Octreotide; insulin; zinc supplement (rash); TPN (malnutrition) Octreotide

intestinal peptide diarrhea; hypokalemia;

hypochlorhydria
* Percentage among neuroendocrine tumors. GERD, gastroesophageal reflux disease; MEN-I, multiple endocrine neoplasia type I; NET, neuroendocrine tumor; TPN, total parenteral nutrition; VIP, vasoactive intestinal polypeptide.

When a NET is suspected, imaging tests are important to locate the primary tumor and determine the presence of metastases (Fig. 3). NETs may be difficult to localize. Contrast-enhanced CT and MRI may be used as initial tests; however, they have a low yield for small tumors. EUS is a more sensitive test for detecting small pancreatic neuroendocrine tumors and allows simultaneous FNA for tissue diagnosis. Nuclear imaging after administration of radio-labeled octreotide can help locate most neuroendocrine tumors. Insulinomas are not well visualized with octreotide scans because they do not possess high concentrations of somatostatin receptors.

NETs confined to the pancreas should be surgically resected after symptoms of hormonal excess have been treated and controlled (see Table 1 ). Patients with metastatic disease can be managed medically with octreotide, chemotherapy (streptozocin), or radiographic embolization of the primary tumor and metastases. Debulking of primary and metastatic disease may also be considered for patients with debilitating symptoms related to tumor secretory products.