17. Acute and chronic pancreatitis. Tumours of the pancreas

Introduction

The exocrine part of the pancreas accounts for 99% of the organ. The exocrine pancreas is composed of ductules, ducts and acinar cells that produce digestive enzymes. These enzymes are secreted in pro-enzyme form inside zymogen granules, so that they aren’t activated before they reach the lumen of the duodenum. The enzymes include trypsin, phospholipase, elastase and lipase.

The pancreas has multiple mechanisms to prevent premature activation of the digestive enzymes:

• They are synthesized as inactive proenzymes
• Their activation requires conversion of trypsinogen to trypsin by duodenal enteropeptidase
• The acinar cells also secrete trypsin inhibitors
• The acinar cells are very resistant to the digestive effects of the activated digestive enzymes
• Trypsin cleaves and inactivates itself as a negative feedback mechanism.

Autodigestion of the pancreas occurs when these enzymes are prematurely activated in the pancreas. This process is the background of pancreatitis.

Acute pancreatitis

Acute pancreatitis is a reversible inflammatory condition of the pancreas that varies in intensity from just oedema and adiponecrosis to widespread parenchymal necrosis. It occurs when something causes the digestive enzymes to be activated in the pancreas itself, which self-digest the organ. The disease has a significant mortality, around 5%.

In most patients the disease is mild and patients recover after a few days. However, 20% develop severe (necrotising) pancreatitis with complications or organ failure, which has a high mortality.

Etiology

Acronym GET SMASHED

• Gallstones
• Ethanol (Alcoholism)
• Trauma
• Steroids
• Mumps (and Coxsackie) Virus
• Autoimmune
• Scorpion venom
• Hypercalcaemia, Hyperlipidemia
• ERCP
• Drugs

Other causes are Vascular (shock, arteroembolism, polyarteritis nodosa), mutations (PRSS1, SPINK1), idiopathic, etc.

The most common causes are alcoholism and gallstones in the biliary tract distal to the pancreatic duct. These two factors are responsible for 80% of all cases of acute pancreatitis.

Pathomechanism

Alcohol increases the viscosity of the pancreatic juice while also increasing the tone of the sphincter of Oddi. This decreases the outflow of the pancreatic juice, which increases the risk that the enzymes will be activated inside the pancreas. Gallstones stuck in the biliary tract distal to the pancreatic duct block outflow of the pancreatic juice.

As the digestive enzymes are activated elastase will start to digest the vasculature. This causes leakage of fluid into the parenchyme, causing oedema. Further digestion of vessels causes interstitial haemorrhage.

Digestive enzymes destroy the pancreatic parenchyme and cause necrosis. As the enzymes reach the intrapancreatic and peripancreatic fat the pancreatic lipases will digest the triacylglycerols inside the adipocytes. This forms free fatty acids that will combine with calcium to form soap. This process is adiponecrosis. As the disease progresses mesenterial and subcutaneous fat may also be digested.

The severe necrosis recruits inflammatory cells, causing an acute inflammation.

The basic alterations in acute pancreatitis can therefore be summarized as (1) Microvascular leakage causing oedema, (2) Proteolytic destruction of pancreatic parenchyma, (3) Adiponecrosis, (4) Acute inflammatory reaction and (5) interstitial hemorrhage.

Pathology

We distinguish two forms of acute pancreatitis, oedematous type and necrotising/haemorrhagic type.

Oedematous acute pancreatitis accounts for 80% of cases and is the mildest of the two. Histologically we can see interstitial oedema, inflammatory cell infiltrate, and adiponecrosis but no haemorrhage or interstitial necrosis. It has an almost zero percent mortality rate.

Necrotising or haemorrhagic acute pancreatitis is more severe and accounts for 20% of cases. Histologically we can see patchy necrosis, interstitial oedema, adiponecrosis, inflammatory cell infiltrate, and interstitial haemorrhage. The necrosis may become infected, which worsens the prognosis.

Complications

Acute peripancreatic fluid collections are possible early (< 4 weeks) complications of oedematous acute pancreatitis. These fluid collections do not contain necrosis and are non-encapsulated.

Pseudocysts are possible late (> 4 weeks) complications of oedematous acute pancreatitis. The pseudocyst is formed when liquefied areas of necrotic pancreatic tissue becomes walled off by fibrous tissue. It’s not a true cyst as it’s not lined by epithelium. These cysts may resolve themselves, become infected or compress adjacent structures.

Acute necrotic collection is a non-encapsulated necrotic fluid collection which can occur in the first weeks after necrotising acute pancreatitis. They may become infected.

Walled-off necrosis is similar to acute necrotic collection, but it’s encapsulated and occurs later (> 4 weeks). They may also become infected.

Diagnosis

Elevated pancreatic enzymes, especially amylase and lipase suggest acute pancreatitis. CT and ultrasound are also useful.

Clinical features

Patients usually have severe pain in the upper abdomen which radiates to the back. Nausea and vomiting are also common. In necrotising acute pancreatitis there may be frank organ failure.

Treatment

Treatment is mostly supportive. Giving fluid is important to prevent development of shock. Denying oral feeding is important to prevent stimulating more pancreatic secretions.

Chronic pancreatitis

Chronic pancreatitis is characterised by chronic inflammation of the pancreas with replacement of normal parenchyme by fibrotic scar tissue, which causes chronic abdominal pain and pancreatic insufficiency.

Etiology

The causes of chronic pancreatitis are classified using a system termed TIGAR-O, which is also an acronym.

• Toxic-metabolic factors
  • Alcohol abuse
  • Tobacco smoking
  • Hypertriglyceridaemia
• Idiopathic
• Genetic (hereditary pancreatitis, cystic fibrosis)
• Autoimmune
• Recurring acute pancreatitis
• Obstructive chronic pancreatitis
  • Tumour of papilla of Vater
  • Duct sclerosis
  • Ductal stones

Symptoms

The most common symptoms of chronic pancreatitis are also epigastric abdominal pain radiating to the back and nausea/vomiting.

Complications

Chronic pancreatitis may lead to chronic malabsorption and steatorrhoea due to the loss of exocrine pancreas function, and diabetes mellitus due to loss of endocrine pancreas function.

Pancreatic neoplasms

Neoplasms of the pancreas may originate from the endocrine cells (endocrine tumours) or the exocrine cells (exocrine tumours).

The exocrine neoplasms may be either cystic or solid. Some of these are benign and some are among the most lethal of all malignancies.

The cystic neoplasms are:

• Serous cystadenomas
• Mucinous cystadenomas
• Intraductal papillary mucinous neoplasms

The solid neoplasms are:

• Solid pseudopapillary neoplasm/solid papillary cystic neoplasia
• Pancreatic adenocarcinoma

Pancreatic adenocarcinoma

Definition and epidemiology

Pancreatic adenocarcinoma is what’s commonly referred to as “pancreatic cancer”. It has one of the highest mortality rates of all cancers, as it’s aggressive, causes no early symptoms, and is difficult to treat. It’s a disease of elderly: people in their 60s – 80s are most commonly affected.

Etiology

• Smoking
• Chronic pancreatitis
• Alcoholism
• Obesity

Pathology

Pancreatic adenocarcinoma accounts for almost all malignant exocrine pancreatic cancer (the remaining being acinar adenocarcinoma and mucinous cystadenocarcinoma). Adenocarcinomas originate from epithelial cells of the pancreatic tubules.

60% of cases are located in the head of the pancreas, with the remaining 40% being spread evenly throughout the body and tail.

Clinical features

Those cases where the tumor in the head have the best prognosis, simply because they cause symptoms first and are therefore the first to be discovered. Tumors of the body and tail produce symptoms very late and are therefore often not found until the late stage. Common symptoms include:

• Belt-shaped epigastric pain
• Posthepatic (obstructive) jaundice
• Courvoisier’s sign – enlarged but nontender gallbladder that is palpable
• Trousseau’s sign – recurring migratory thrombophlebitis (superficial venous blood clots)

Prognosis

Pancreatic adenocarcinoma is very aggressive. Metastases are often present upon diagnosis. It frequently invades local structures and can even invade the portal vein itself. If the tumor invades other structures locally is it frequently considered inoperable. The 5-year survival rate is less than 5%.

Pancreatic endocrine tumours

Pancreatic endocrine tumours are neuroendocrine tumours, which produce hormones. They originate from the Langerhans islets cells. They account for < 5% of pancreatic tumours and are therefore quite rare.

These tumours are predominantly benign but may be malignant as well. However, their disruptive potential comes rather from their hormone-producing properties rather than their mass effect or invasion.

A few percent of endocrine pancreatic tumours are associated with multiple endocrine neoplasia (MEN) type 1.

The tumours are named after the hormone they produce:

• Insulinoma
• Gastrinoma
• VIPoma
• Glucagonoma
• Somatostatinoma

Insulinomas cause hypoglycaemia, gastrinomas cause severe peptic ulcer disease, VIPomas cause secretory diarrhoea, and so on.

Benign pancreatic tumours

Benign pancreatic tumours are rare and frankly not that important to know.

Serous cystadenomas are the most common cystic neoplasm of the pancreas. They occur most frequently in older and female patients. They are almost always benign. They’re associated with mutations in the VHL tumor suppressor gene.

Mucinous cystadenomas are almost exclusively found in women are usually found in the body or tail of the pancreas. The cysts are filled with thick mucin. Up to one third of these neoplasms have dysplasia and therefore can become malignant.

Intraductal papillary mucinous neoplasms (IPMN) (or intraductal papillary cystic neoplasm according to the lecture) grow in the larger ducts of the pancreas. These neoplasms are more common in males than in females. Up to two thirds of these neoplasms have mutations that give them the possibility to turn malignant.

Solid pseudopapillary neoplasm is an epithelial tumor with low malignant potentional that is usually found in the body or tail. Mainly young females are affected. This tumor is locally aggressive, but doesn’t metastasise.