Pancreatic Pathology Flashcards
What is the exocrine function of the pancreas?
What cells/structures are involved?
secretion of digestive enzymes which require activation
- trypsin
- lipase
- phospholipase
- elastase
- amylase (marker of pancreatic inflammation)
involves glands, ducts and the duodenum
Why are exocrine products secreted as enzymatically inert?
How are they activated and suppressed?
if they were not enzymatically inert, the pancreas would digest itself
activation requires conversion of trypsinogen into trypsin in the duodenum
trypsin inhibitors (e.g. SPINK-1) are present in the acinar and ductal cells
What are acinar cells?
pyramidal shaped epithelial cells arranged around a central lumen into which enzymes are secreted
What % of the pancreas is made from endocrine and exocrine cells?
85% of the pancreas is exocrine
1-2% of the pancreas is endocrine
What cells are involved in the endocrine function of the pancreas?
What is this function?
1 million clusters of cells - islets of Langerhans
they secrete peptide hormones into the blood
(e.g. insulin and glucagon)
What is pancreatitis and what is it associated with?
inflammation of the pancreas
associated with injury to the exocrine parenchyma
What is the main difference between acute and chronic pancreatitis?
acute:
- gland reverts to normal if the underlying cause is removed
chronic:
- irreversible loss of the pancreatic tissue
What are the causes (aetiology) of acute pancreatitis?
- gallstones (50% cases)
- alcohol (25% cases)
- rare causes (<5% cases)
- vascular insufficiency
- viral infections - mumps & coxsackie B
- hypercalcaemia
- ERCP
- inherited causes
- idiopathic (10% cases)
What is the male : female ratio like in acute pancreatitis?
How common is it?
male to female ratio varies with cause
1 M : 3F in biliary disease, 6M : 1F in alcoholism
it is relatively common - 10-20 per 100,000 in Western countries
What % of patients with gallstones have acute pancreatitis?
35-60% of patients with acute pancreatitis have gallstones
5% of patients with gallstones have pancreatitis
What is hereditary pancreatitis?
What are the 2 different mutations that can cause it?
recurrent attacks of severe pancreatitis that usually begins in childhood
- PRSS1 inherited mutations - autosomal dominant
- SPINK-1 gene - autosomal recessive
What is the result of having a PSSR1 inherited mutation?
- PRSS1 mutations alter a site on the cationic trypsinogen molecule that is essential for inactivation of trypsin by trypsin itself
- mutations result in trypsin being resistant to cleavage by another trypsin molecule
- small amounts of trypsin activation results in activation of other digestive enzymes causing pancreatitis
What is the SPINK-1 gene?
What is its function?
serine protease inhibitor Kazal type 1
it codes for a trypsin inhibitor which helps prevent autodigesiton of the pancreas by activated trypsin
What are the clinical features of acute pancreatitis?
What is a poor prognostic sign?
usually presents as an emergency requiring hospital admission
- sudden onset of severe abdominal pain, radiating to the back
- nausea & vomiting
- raised serum amylase / lipase (> 3x normal)
it may be mild (recovery within 5-7 days) but can be serious with high mortality
persistent hypocalcaemia is a poor prognostic sign
What is involved in the pathogenesis of acute pancreatitis?
it varies according to aetiology
- leakage and activation of pancreatic enzymes
- amylase released into the blood
e.g. obstruction (stones) damages duct lining resulting in leakage and activation of pancreatic enzymes
hypoxia affects the acinar cells at the periphery of the lobules
What is the difference in pathogenesis in mild and severe acute pancreatitis?
mild pancreatitis:
- swollen gland with fat necrosis
severe pancreatitis:
- swollen, necrotic gland with fat necrosis and haemorrhage
- Grey Turner’s sign - haemorrhage into the subcutaneous tissues of flank
- Cullen’s sign - periumbilicus
Why does fat necrosis occur in pancreatitis?
chalky white material containing calcium salts which have been freed up by lipase-mediated cleavage of fatty acids
What are some other factors involved in the pathogenesis of acute pancreatitis?
- hypocalcaemia (fatty acids bind calcium ions)
- hyperglycaemia
- abscess formation
- pseudocysts
What are the complications of acute pancreatitis?
What do most of them relate to?
- shock
- intravascular coagulopathy
- haemorrhage
- pseudocysts (collections of pancreatic juice secondary to duct rupture)
many of the systemic features are related to the release of toxic enzymes, cytokines and other mediators into the circulation
this results in activation of the systemic inflammatory response
What is chronic pancreatitis?
What does it lead to?
a progressive inflammatory disorder in which parenchyma of the pancreas is destroyed and replaced by fibrous tissue
irreversible destruction of the exocrine tissue, followed by destruction of the endocrine tissue
leads to malnutrition and diabetes
Why are acute and chronic pancreatitis not two distinct diseases but a continuum?
- recurrent acute can develop chronic pancreatitis
- overlap in causative factors
- both genetic and environmental
- experimental protocols can be modified to induce each condition
What are the symptoms of chronic pancreatitis?
What can it mimic?
- intermittent abdominal pain
- back pain
- weight loss
- fibrosis of exocrine tissue can mimic carcinoma macroscopically and microscopically
What is the incidence of chronic pancreatitis?
26 per 100,000 in Europe
70 per 100,000 in UK
What is the TIGARO acronym for the causes of chronic pancreatitis?
Toxic:
- alcohol, cigarette smoke, drugs
- hypercalcaemia, hyperparathyroidism, infections
Idiopathic
Genetic:
- CFTR, PRSS1, SPINK1 mutations
Autoimmune
Recurrent acute pancreatitis
Obstruction of main duct:
- cancer, scarring
What is involved in the pathogenesis of chronic pancreatitis?
it is not well understood
it involves ductal obstruction by concretions (protein plugs)
there are direct toxic effects e.g. alcohol
What are the characteristics of chronic pancreatitis?
- localised, irregular involvement of the gland early on then later global atrophy
- dilated and distorted ducts
- calculi, especially in alcohol induced
- fatty replacement - fibrosis
- pseudocyst formation
What are the complications of chronic pancreatitis?
What is the mortality rate?
- malabsorption of fat (lack of lipases)
- steatorrhoea
- impairment of fat soluble vitamin absorption - A, D, E , K
- diarrhoea, weight loss & cachexia
- diabetes (late feature)
- pseudocysts (10%)
- stenosis of common bile duct / duodenum
- severe chronic pain
mortality rate is nearly 50% within 20-25 years of disease onset
What % of cancers are pancreatic adenocarcinoma?
What is 5 year survival and who is usually affected?
3% of all cancers (10th most common)
5 year survival is 4%
it is rare before 40 years and affects 60-80 year olds
ratio is 1.3M : 1 F
What is involved in the epidemiology of pancreatic adenocarcinoma?
it is complex and multifactorial
- cigarette smoking (20% cases, 2.3x risk) drops with abstinence
- family history (10% cases)
- heavy alcohol intake
- diet rich in red meats
- obesity
- chronic pancreatitis
- hereditary (10%)
cigarette smoking and family history (9x increase in 1st degree relatives) are the most important
What hereditary cancer syndromes may be present in 5-10% of cases of pancreatic adenocarcinoma?
- HNPCC - DNA mismatch repair
- FAMMM - p16/cdkn2A
- familial breast cancer - BRCA2
- ataxia-telangiectasis - ATM
- von Hippel-Lindau - VHL
- familial pancreatitis - cationic trypsinogen, SPINK1
- Peutz-Jeghers - LKB1 / STK11
What is involved in the progression model for adenocarcinoma of the pancreas?
What is the most common neoplastic precursor?
the most common neoplastic precursor to invasive carcinoma is PanIN
- K-ras mutations occur early on
- p16 inactivation occurs as an intermediate step
- inactivation of suppressor genes occurs later
What is shown here?
pancreatic intraepithelial neoplasia (PanIN)
Where does pancreatic intraepithelial neoplasia usually happen?
- 60-70% head of pancreas
- 5-15% body of pancreas
- 10-15% tail of pancreas
- 5-15% diffuse involvement
What does PaIN look like?
What type of response does it elicit?
grossly - hard, grey-white, poorly defined masses
it is highly invasive and elicits a desmoplastic response
this is an intense non-neoplastic host reaction composed of fibroblasts, lymphocytes and extracellular matrix
How long does someone tend to have pancreatic carcinoma before they present?
early cancer is silent
most patients with symptoms have advanced disease
it is usually present for at least a decade before it is detected
What are the non-specific symptoms of pancreatic carcinoma?
- epigastric pain, radiating to the back
- weight loss
- painless jaundice
- pruritis
- nausea
- diabetes - both increases risk and can be a presenting complication
What 2 “signs” are looked for in pancreatic carcinoma?
Trousseau’s syndrome:
- migratory thromboplebitis
- this is episodes of blood vessel inflammation due to a blood clot which are recurrent and appear in different locations over time
Courvoisier’s sign:
- palpable gallbladder without pain
Where may distant metastases be seen in pancreatic carcinoma?
liver, peritoneum and lung
What is the survival like for pancreatic carcinoma with and without treatment?
it is almost universally fatal (incidence nearly equals mortality)
mean survival untreated is 3-5 months
survival is 10-20 months post-surgery but only 10-20% are resectable at time of diagnosis
What are the poor prognostic factors for pancreatic adenocarcinoma?
- extension of tumour outside the pancreas
- metastatic spread to local lymph nodes
- vascular and perineural invasion
- poor differentiation
- positive margins on resection
What are pancreatic neuroendocrine tumours derived from?
How common are they?
they are uncommon and are < 3% of pancreatic neoplasms
they are derived from islet cells
Are pancreatic neuroendocrine tumours malignant?
How do they present?
they have a spectrum of behaviour ranging from benign to malignant
they present with a wide range of clinical symptoms depending upon their endocrine effects
What is the incidence of pancreatic neuroendocrine tumours like?
Who is at increased risk?
incidence is < 1 per 100,000 per year
equally affects males and females
seen in 20-60 years
increased risk with MEN1
(pituitary adenoma, parathyroid adenoma, islet cell tumour of pancreas)
What are the 2 main different types of pancreatic neuroendocrine tumours?
- well differentiated neuroendocrine tumour
- poorly differentiated neuroendocrine carcinoma
Who tends to be affected by a well-differentiated neuroendocrine tumour?
What effects do these have on the body?
they are uncommon, 1-2% of pancreatic neoplasms
- affects any age but rare in children
- 7-13% have multiple (MEN1)
- 15-35% non functioning
- single tumours usually produce multiple hormones but usually single hyperfunctional syndrome
Who tends to be affected by a poorly-differentiated neuroendocrine carcinoma?
What is prognosis like?
- rare and <1% of all pancreatic tumours
- affects more males than females
- 40-75 years of age
- advanced disease at presentation
- prognosis without treatment is 1-2 months, but up to 50 months with chemotherapy
What are the 6 main types of functioning neuroendocrine tumour?
- insulinoma
- glucagonoma
- gastrinoma
- somatostatinoma
- VIPoma
- PP-cell PEN
What cells are affected in an insulinoma?
What syndrome does this produce and what are the clinical findings?
affects beta cells producing insulinoma syndrome
produces hypoglycaemia due to the hypersecretion of insulin
patient develops confusion, psychiatric disturbances and possibly coma
hypoglycaemia can produce permanent cerebral damage so diagnosis is urgent
What type of cell is affected in glucagonoma?
What syndrome does this produce and what are the clinical findings?
alpha cell is affected producing glucagonoma syndrome
clinical findings:
- stomatitis
- rash
- diabetes
- weight loss
What type of cell is affected in gastrinoma?
What syndrome does this produce and what are the clinical findings?
the G cell is affected producing Zollinger-Ellison syndrome
clinical findings:
- peptic ulcer
- diarrhoea
What type of cell is affected in somatostatinoma?
What syndrome does this produce and what are the clinical findings?
the delta cell producing somatostatinoma syndrome
clinical findings:
- diabetes
- cholelithiasis
- hypochlorhydria
What type of cell is affected in VIPoma?
What syndrome does this produce and what are the clinical findings?
the type of cell affected is unknown but it produces Verner-Morrison syndrome
clinical findings:
- diarrhoea
- hypokalaemia
- achlorydria
What type of cell is affected in PP-cell PEN?
What syndrome does this produce and what are the clinical findings?
it affects PP cells
there is no syndrome or clinical findings
What do pancreatic neuroendocrine tumours look like?
How big are they and where are they found?
- usually well circumscribed, sometimes encapsulated
- solid
- 10 - >50mm
- occur anywhere in the pancreas
- can be multiple
