THE EXOCRINE PANCREASCONGENITAL ANOMALIES
Pancreas divisum is the most common clinically significant congenital anomaly resulting from failure of fusion of pancreatic ducts. This leads to the main pancreatic duct draining only a small portion of the head, while the bulk of the pancreas drains through a minor duct. This creates a state of inadequate drainage for the bulky pancreatic secretions thus predisposes to chronic pancreatitis.
Annular pancreas results from abnormal pancreatic fusion due to failure of ventral bud to rotate properly; head of pancreas encircles duodenum as a collar and may constrict lumen
completely. It can lead to duodenal obstruction.
Ectopic Pancreas is uncommon; favored sites are the stomach and duodenum. The ectopic tissue is small and submucosal in location. It can cause localized inflammation, or mucosal bleeding.
Congenital cysts: the kidney, liver, and pancreas can all contain cysts ( polycystic disease).
Acute Pancreatitis is relatively common in developed countries. Causes implicated include
1. Gallstones and excessive alcohol intake; these are the main offenders.
2. Non-gallstone obstruction of the pancreatic ducts e.g. by periampullary tumors
3. Medications as with thiazide & frusemide diuretics
4. Trauma, both blunt and iatrogenic during surgery or endoscopy
5. Others such as metabolic disorders, ischemia and infections as with mumps
In up to 20% of patients there is no identifiable cause (idiopathic pancreatitis).
In milder forms there is edema & congestion of the organ with foci of fat necrosis. Fat necrosis results from enzymatic destruction of fat cells; the released fatty acids combine with calcium to form insoluble salts that precipitate locally and appear as yellow-white chalky deposits within & outside the pancreas e.g. in the omentum and mesentery.
The peritoneal cavity contains a brown-tinged fluid with fat globules.
In the most severe forms there is extensive parenchymal necrosis accompanied by diffuse hemorrhage.
These parallel the gross changes of edema, acute inflammation, and focal fat necrosis.
In more severe forms, necrosis involves all tissue constituents including islets of Langerhans
Vascular damage causes hemorrhage into the parenchyma of the pancreas.
The microscopic changes favor autodigestion of the pancreatic substance by activated pancreatic enzymes. Trypsin seems to have a central role because it can activate other enzymes (e.g. phospholipases and elastases) that can participate in the process of autodigestion. Trypsin can also leads to activation of the kinin system & factor XII and thus the clotting and complement systems.
Pancreatic duct obstruction causes an increase in intraductal pressure, thus allowing accumulation of an enzyme-rich interstitial fluid that causes tissue injury. Edema further compromises local blood flow, causing vascular insufficiency and ischemic injury to acinar cells.
The role of alcohol as a cause of pancreatitis is still unknown, proposed mechanisms include contraction of the sphincter of Oddi and direct toxic effects on acinar cells.
Inherited mutations in genes important for normal pancreatic exocrine function are investigated.
The manifestations of severe acute pancreatitis are attributable to systemic release of digestive enzymes and explosive activation of the inflammatory response. Patients show increased vascular permeability, leukocytosis, DIC, ARDS (due to alveolar capillary injury), and diffuse fat necrosis. Shock can occur rapidly due to electrolyte disturbances and loss of blood volume. These catastrophic events can be complicated by endotoxemia resulting from infection of the necrotic debris by gram-negative organisms as there is break down of barriers between gastrointestinal, pancreas and blood stream.
Laboratory findings include markedly elevated serum amylase during the first 24 hours, followed (within 3-4 days) by rising serum lipase levels. Hypocalcemia can result from precipitation of calcium in the extensive areas of fat necrosis. The enlarged inflamed pancreas can be visualized by CT or MRI. Although most individuals with acute pancreatitis eventually recover, some die from shock; ARDS and acute renal failure. In those who survive complications include pancreatic abscesses or pancreatic pseudocysts.
Pancreatic Pseudocyst is the most common cystic lesion of the pancreas and a common complication of acute pancreatitis. Liquefied necrotic pancreatic tissues become surrounded by fibrous tissue wall to form a cystic space, lacking an epithelial lining ("pseudo"). Drainage of pancreatic secretions into this space over months to years (from damaged pancreatic ducts) can cause massive enlargement of the cyst (up to 30 cm in diameter). They can become secondarily infected, and larger pseudocysts can compress or even perforate into adjacent structures. It is commonly attached to the surface of the gland and may involve peripancreatic tissues.
Chronic Pancreatitis is characterized by longstanding inflammation and fibrosis with destruction of the exocrine pancreas; in the late stages, the islets are also lost.
Causes of chronic pancreatitis include
Chronic alcoholism (the most common cause).
Long-standing pancreatic duct obstruction (e.g., by pseudocysts, calculi, neoplasms)
Tropical pancreatitis: seen in Africa and Asia, and attributed to malnutrition
Hereditary pancreatitis due to mutations of genes, some encoding trypsin inhibitor.
In some cases there is no obvious cause (idiopathic); as with acute pancreatitis, a growing number of these cases are associated with inherited mutations in genes concerned with normal pancreatic exocrine function.
Gross features: the gland is hard, sometimes with extremely dilated ducts and visible calcifications
Parenchymal fibrosis, reduced number and size of acini, and variable dilation of the ducts.
A chronic inflammatory infiltrate around remaining lobules and ducts.
Islets of Langerhans are relatively spared but eventually they disappear.
This is still not established with certainity. However, several hypotheses are proposed:
1. Ductal obstruction by concretions: alcohol increases the protein concentration of pancreatic secretions; these can form ductal plugs.
2. Toxic: alcohol can exert a direct toxic effect on acinar cells leading to their destruction
3. Oxidative stress induced by alcohol generates free radicals in acinar cells, which lead to fusion of lysosomes and zymogen granules with resulting acinar cell necrosis, inflammation, and fibrosis.
4. Necrosis-fibrosis due to recurrent episodes of acute pancreatitis
Chronic pancreatitis can present with repeated bouts of jaundice, persistent or recurrent abdominal and back pain. It may be entirely silent until pancreatic insufficiency and diabetes develop.
Chronic pancreatitis may present as attacks of abdominal pain with some elevation of serum amylase. Gallstone-induced obstruction may cause jaundice &/or elevation in serum alkaline phosphatase. A helpful finding is visualization of calcifications within the pancreas by CT or ultrasonography. Weight loss and hypoalbuminemia with edema from malabsorption can also occur.
Some of these are entirely benign (e.g., serous cystadenoma); others, such as mucinous cystic neoplasms, can be benign but frequently have malignant potential.
Pancreatic Carcinoma has a very poor prognosis in that the 5-year survival rate is less than 5%.
Pathogenesis: like all cancers, it arises as a consequence of inherited and acquired mutations in cancer-associated genes. There is a progressive accumulation of genetic changes in pancreatic epithelium as it proceeds from non-neoplastic, to noninvasive lesions in small ducts and ductules, to invasive carcinoma. Antecedent lesions are called "pancreatic intraepithelial neoplasias" (PanINs). They are often found adjacent to infiltrating carcinomas and share with the latter a number of the same genetic mutations. The more common molecular alterations in pancreatic carcinogenesis affect K-RAS (oncogene), and the tumor suppressor genes p16, SMAD4, and p53.
Carcinoma is primarily a disease of the elderly (60 and 80 years). Smoking has the strongest environmental influence. Chronic pancreatitis and diabetes mellitus are also associated with an increased risk. Familial clustering of pancreatic cancer has been reported, and familial pancreatitis (related to mutations in a trypsinogen gene) is associated with up to 80-fold increased risk.
The head is most commonly involved (60%), whereas the tail is the least common site (5%)
The cancer is usually hard, gray-white, poorly defined mass.
Most carcinomas of the head obstruct the distal common bile duct leading to distention of the biliary tree, and obstructive jaundice.
In marked contrast, carcinomas of the body and tail do not interrupt the biliary tract and hence remain silent for some time. They may be quite large and widely disseminated by the time of the diagnosis.
The regional lymph nodes & the liver are often involved by metastases as are the lungs & bones.
Most carcinomas are ductal adenocarcinomas .
Two features are characteristic of pancreatic cancer:
1. It is highly invasive; even in the early stages, thus infiltrates peripancreatic tissues extensively
2. It elicits an intense fibroblastic (desmoplastic) response.
Perineural and lymphatic invasions are commonly seen.
Migratory thrombophlebitis (Trousseau syndrome) occurs in about 10% of patients. Endoscopic ultrasonography and CT, are helpful in diagnosis and in performing guided percutaneous needle biopsy.