Session 30 Pancreas Pathology

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Lecture Notes

Session 30: Pancreas Pathology

Felician Sikujua (MD)

Learning tasks

At the end of this session, students are expected to be able to:

Explain pathological changes in acute pancreatitis.

Explain pathological changes in chronic pancreatitis.

Describe pancreatic neoplasia.

Diseases of the exocrine pancreas

Diseases of the exocrine pancreas include

Congenital anomalies.

Acute and chronic pancreatitis.

Neoplasms.

Cystic fibrosis.

Congenital anomalies

These include

Agenesis.

Pancreas divisum.

Annular pancreas.

Ectopic pancreas.

Congenital pancreatic cysts.

Pancreatitis

In acute pancreatitis, function can return to normal if the underlying cause of inflammation is removed.

By contrast, chronic pancreatitis is defined by irreversible destruction of exocrine pancreatic parenchyma.

Acute pancreatitis

Reversible inflammatory disorder that varies in severity, ranging from focal edema and fat necrosis to widespread hemorrhagic parenchymal necrosis.

Caused by the destructive effect of enzymes released from pancreatic acini.

Approximately 80% of cases are attributable to either biliary tract disease or alcoholism.

Roughly 5% of patients with gallstones develop acute pancreatitis.

Etiologic factors in acute pancreatitis

Metabolic

Alcoholism

(Most common cause)

Hyperlipoproteinemia

Hypercalcemia Drugs (e.g., azathioprine).

Genetic

Infectious

Mumps

Coxsackievirus

Mechanical

Gallstones

Trauma

Iatrogenic injury

Perioperative injury

Endoscopic procedures with dye injection

Vascular

Shock

Atheroembolism

Polyarteritis nodosa

Other causes of acute pancreatitis

Non–gallstone-related obstruction of the pancreatic ducts.

Medications including anticonvulsants, cancer chemotherapeutic.

Metabolic disorders, including hypertriglyceridemia.

Ischemia due to vascular thrombosis, embolism.

Trauma, both blunt force and iatrogenic during surgery.

Inherited mutations.

Idiopathic.

Morphology: Acute pancreatitis

The basic alterations in acute pancreatitis are

Microvascular leakage causing edema.

Necrosis of fat by lipases.

An acute inflammatory reaction.

Proteolytic destruction of pancreatic parenchyma.

Destruction of blood vessels leading to interstitial hemorrhage.

Morphology: Acute pancreatitis cont…

In milder forms, histologic alterations include interstitial edema and focal areas of fat necrosis in the pancreatic substance and peripancreatic fat.

Fat necrosis results from enzymatic destruction of fat cells.

The released fatty acids combine with calcium to form insoluble salts that precipitate in situ.

Morphology: Acute pancreatitis cont…

In more severe forms such as acute necrotizing pancreatitis, necrosis of pancreatic tissue affects acinar and ductal tissues as well as the islets of Langerhans.

Vascular damage causes hemorrhage into the parenchyma of the pancreas.

Macroscopically: Pancreas exhibits red-black hemorrhagic areas interspersed with foci of yellow-white, chalky fat necrosis.

Morphology: Acute pancreatitis cont…

Fat necrosis also can occur in extrapancreatic fat, including the omentum and bowel mesentery, and even outside the abdominal cavity (e.g., in subcutaneous fat).

In most cases the peritoneum contains a serous, slightly turbid, brown-tinged fluid with globules of fat (derived from enzymatically digested adipose tissue).

In the most severe form, hemorrhagic pancreatitis, extensive parenchymal necrosis is accompanied by diffuse hemorrhage within the substance of the gland.

Pathogenesis:Acute pancreatitis

Activation of trypsin is a critical triggering event in acute pancreatitis.

If trypsin is inappropriately generated from its proenzyme trypsinogen, it can activate itself as well as other proenzymes (e.g., phospholipases and elastases) that can then take part in the process of autodigestion.

Trypsin also converts prekallikrein to its activated form, thus sparking the kinin system, and, by activation of factor XII (Hageman factor), also sets in motion the clotting and complement systems.

Pathogenesis:Acute pancreatitis cont…

Three pathways can incite the initial enzyme activation that may lead to acute pancreatitis:

Pancreatic duct obstruction.

Primary acinar cell injury.

Defective intracellular transport of proenzymes within acinar cells.

Pathogenesis:Acute pancreatitis cont…

Pancreatic duct obstruction: Impaction of a gallstone distal to the site of union of a common bile duct and pancreatic duct results in:

Reflux of bile up pancreatic duct causing toxic injury to pancreatic acini

Increased intraductal pressure leading to enzymatic leakage from pancreatic ducts.

Chronic alcohol ingestion may also produce increased intraductal pressure due to production of a protein-rich pancreatic fluid, which can form solid plugs in smaller pancreatic ducts.

Pathogenesis:Acute pancreatitis cont…

Direct acinar injury: Less common causes of pancreatitis (e.g. viruses, drugs and trauma) may produce direct acinar damage.

The three (3) patterns of pancreatic necrosis are

Periductal—necrosis of acinar cells adjacent to ducts. Typically caused by duct obstruction, particularly associated with gallstones and alcohol

Perilobular—necrosis of the periphery of lobules. Caused by poor vascular perfusion usually as a result of shock

Panlobular—necrosis affects all portions of the pancreatic lobule. This often develops from initial periductal or perilobular necrosis.

Pathogenesis:Acute pancreatitis cont…

Irrespective of the cause of pancreatitis, acinar damage leads to liberation of lytic enzymes (proteases and lipases) causing necrosis of normal tissue.

Lipases cause fat necrosis.

Proteases cause destruction of pancreatic parenchyma.

Endocrine destruction results in hyperglycaemia

Elastase and other enzymes cause vascular damage with haemorrhage into pancreas or peritoneum.

Extensive haemorrhage is known as acute haemorrhagic pancreatitis.

Alcohol consumption may cause pancreatitis by:

Alcohol consumption may cause pancreatitis by

Alcohol transiently increases pancreatic exocrine secretion and contraction of the sphincter of Oddi

Alcohol also has direct toxic effects on acinar cells which leads to membrane damage.

Chronic alcohol ingestion results in the secretion of protein-rich pancreatic fluid, which leads to the deposition of inspissated protein plugs and obstruction of small pancreatic ducts.

Clinical features and Complications of Acute pancreatitis

Abdominal pain is the cardinal manifestation of acute pancreatitis.

Characteristically, the pain is constant and intense and often is referred to the upper back.

Suspected acute pancreatitis is diagnosed primarily by the presence of elevated plasma levels of amylase and lipase and the exclusion of other causes of abdominal pain.

Sequelae include sterile or infected pancreatic “abscesses” or pancreatic pseudocysts.

Chronic pancreatitis

Chronic pancreatitis is characterized by

Long-standing inflammation.

Fibrosis.

Destruction of the exocrine pancreas.

In its late stages, the endocrine parenchyma also is lost.

By far the most common cause of chronic pancreatitis is long-term alcohol abuse.

Middle-aged men constitute the bulk of patients in this etiologic group.

Other causes of chronic pancreatitis

Less common causes of chronic pancreatitis include

Long-standing pancreatic duct obstruction (e.g., by pseudocysts, calculi, neoplasms, or pancreas divisum)

Tropical pancreatitis, a poorly characterized heterogeneous disorder seen in Africa and Asia, with a subset of cases having a genetic basis

Hereditary pancreatitis due to mutations.

Chronic pancreatitis associated with CFTR mutations.

As many as 40% of persons with chronic pancreatitis have no recognizable predisposing factors.

Morphology:Chronic pancreatitis

Chronic pancreatitis is characterized by

Parenchymal fibrosis.

Reduced number and size of acini.

Variable dilation of the pancreatic ducts.

There is a relative sparing of the islets of Langerhans.

Chronic pancreatitis cont…

Although the pathogenesis of chronic pancreatitis is not well defined, several hypotheses are proposed:

Ductal obstruction by concretions.

Toxic-metabolic.

Oxidative stress.

Pancreatic neoplasms

Pancreatic neoplasms can be exocrine or endocrine.

Pancreatic exocrine neoplasms can be cystic or solid.

Some tumors are benign, while others are among the most lethal of all malignancies.

Cystic Neoplasms

It include

Serous cystadenoma.

Mucinous cystic neoplasms.

Intraductal papillary mucinous neoplasms.

Pancreatic Carcinoma

Pancreatic cancer probably arises from noninvasive precursor lesions developing by progressive accumulation of characteristic mutations of oncogenes.

Typically, these neoplasms are ductal adenocarcinomas that produce an intense desmoplastic response.

Most pancreatic cancers are diagnosed at an advanced stage, accounting for the high mortality rate.

Obstructive jaundice is a feature of carcinoma of the head of the pancreas.

Many patients also experience debilitating pain.

Morphology: Cancer of the Pancreas

Approximately 60% of pancreatic cancers arise in the head of the gland, 15% in the body, and 5% in the tail.

In the remaining 20%, the neoplasm diffusely involves the entire organ.

Carcinomas of the pancreas usually are hard, graywhite, stellate, poorly defined masses.

The vast majority of carcinomas are ductal adenocarcinomas, recapitulating to some degree the normal duct epithelium by forming glands and secreting mucin.

Morphology: Cancer of the Pancreas cont…

Two (2) features are characteristic of pancreatic cancer

It is highly invasive (even “early” invasive pancreatic cancers invade peripancreatic tissues extensively)

It elicits an intense non-neoplastic host reaction composed of fibroblasts, lymphocytes, and extracellular matrix (desmoplastic response).

Morphology: Cancer of the Pancreas cont…

Most carcinomas of the head of the pancreas obstruct the distal common bile duct as it courses through the head of the pancreas.

In 50% of such cases, there is marked distention of the biliary tree, and patients typically exhibit obstructive jaundice.

In marked contrast, carcinomas of the body and tail of the pancreas do not impinge on the biliary tract and hence remain silent for some time.

Morphology: Cancer of the Pancreas cont…

They may be quite large and widely disseminated by the time they are discovered.

Pancreatic cancers often extend through the retroperitoneal space, entrapping adjacent nerves (thus, accounting for the pain).

Occasionally invade the spleen, adrenals, vertebral column, transverse colon, and stomach.

Peripancreatic, gastric, mesenteric, omental, and portahepatic lymph nodes frequently are involved.

Morphology: Cancer of the Pancreas cont…

Liver often is enlarged as a consequence of metastatic deposits.

Distant metastases may occur, principally to the lungs and bones.

On microscopic examination

Pancreatic carcinoma usually is a moderately to poorly differentiated adenocarcinoma.

Abortive tubular structures or cell clusters and exhibiting aggressive, deeply infiltrative growth.

Morphology: Cancer of the Pancreas cont…

Dense stromal fibrosis accompanies tumor invasion, and there is a proclivity for perineural invasion within and beyond the organ.

Lymphatic invasion also is commonly seen.

Pancreatic neuroendocrine tumors

Pancreatic neuroendocrine tumors (PanNETs), also known as islet cell tumors, are rare in comparison with tumors of the exocrine pancreas, accounting for only 2% of all pancreatic neoplasms.

PanNETs are most common in adults and may be single or multifocal.

When they are malignant, the liver is the most common site of organ metastases.

These tumors have a propensity to elaborate pancreatic hormones, but some are nonfunctional.

Insulinomas

Benign tumors.

Beta cell tumors (insulinomas) are the most common type of PanNET and may be responsible for the elaboration of sufficient insulin to induce clinically significant hypoglycemia.

The characteristic clinical picture is dominated by attacks of hypoglycemia, which occur when plasma blood glucose levels fall below 50 mg/dL.

Insulinomas cont…

The attacks consist principally of such central nervous system manifestations as confusion, stupor, and loss of consciousness.

They are precipitated by fasting or exercise and are promptly relieved by feeding or parenteral administration of glucose.

Most insulinomas are cured by surgical resection.

Gastrinomas

Benign tumors

Marked hypersecretion of gastrin usually has its origin in gastrin-producing tumors (gastrinomas), which are just as likely to arise in the duodenum and peripancreatic soft tissues as in the pancreas (the so-called gastrinoma triangle).

Associated by Zollinger-Ellison syndrome.

In this condition, hypergastrinemia from a pancreatic or duodenal tumor stimulates extreme gastric acid secretion, which in turn causes peptic ulceration.

Gastrinomas cont…

The duodenal and gastric ulcers often are multiple; although they are identical to those found in the general population.

They often are unresponsive to usual therapy.

In addition, ulcers may occur in unusual locations such as the jejunum; when intractable jejunal ulcers are found, Zollinger-Ellison syndrome should be considered.

More than half of the affected patients have diarrhea.

Key points

Chronic alcoholism is associated with pancreatitis.

Fat necrosis is seen in acute pancreatitis.

Acute pancreatitis causes abdominal pain is which is referred to the upper back.

Presence of elevated plasma levels of amylase and lipase is seen in acute pancreatitis.

Obstructive jaundice is a feature of carcinoma of the head of the pancreas.

Insulinoma is benign tumor producing sufficient insulin to induce clinically significant hypoglycemia.

Gastrinoma is gastrin-producing tumors associated with Zollinger-Ellison syndrome.

Review questions

List five (5) risk factors for acute pancreatitis.

How does alcohol cause acute pancreatitis?

List five (5) morphological features seen in acute pancreatitis.

Mention three (3) morphological features seen in chronic pancreatitis.

Outline five (5) characteristic features of cancer of the pancreas.

References

Kumar V. ; Abbas A. K. ; Aster J. C.;(2013): Robbins and Contran Pathologic Basis of Disease (9th Ed.) Elsevier Saunders, USA. Pg. 646-652.

Mohan H.;(2010): Text book of Pathology (6th Ed.) Jaypee Brothers Medical Publishers, India. Pg. 644-648.

Xiu P.;(2012): Crash Course Pathology (4th Ed.) Elsevier Saunders, USA. Pg. 140-142.

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Session 30 Pancreas Pathology

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Lecture Notes