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Pancreas Pathology (Congenital Abnormalities (Pancreas divisum (most…
Pancreas Pathology
Congenital Abnormalities
Pancreas divisum (most common)
- Due to failure of fusion of the fetal pancreatic duct systems of the dorsal and ventral pancreatic primordia --> results in a very short duct of Wirsung
- Majority of the pancreas drains through minor pancreatic duct (duct of Santorini) into the duodenum through the minor duodenal papilla
- Complication: Chronic pancreatitis
Annular Pancreas
- Band-like ring of normal pancreatic tissue that completely encircles the 2nd part of the duodenum
- Complications: Duodenal obstruction (leading to gastric distention and vomiting)
Ectopic Pancreas
- Aberrantly situated pancreatic tissue usually found in stomach, duodenum, jejunum, Meckel diverticula & ileum
- Complications:
- Localised inflammation (pain and bleeding)
- Ectopic pancreatic endocrine neoplasms may arise
-
Diabetes Mellitus
- A group of metabolic disorders having in common disordered carbohydrate, fat and protein metabolism characterized by fasting hyperglycemia (≥126 mg/dL or 7mmol/L) and glycosuria
• Secondary change in kidneys, eyes, nerves and blood vessels
Types
Primary (Idiopathic)
Type I
- Genetic Involvement:
- 50% concordance in twins
- HLA-D linked
- Characteristic cause:
- Absolute insulin deficiency
- Pathogenesis:
- Autoimmunity:
- Genetic factors
- Viral infection (molecular mimicry)
- Beta cell damage
- Producing self-reactive T lymphocytes and autoantibodies
- Severe insulin deficiency results from beta cell destruction
- Clinical Features:
- Polyuria and Glycosuria
- Polydipsia
- Polyphagia
- Weight loss
- Diabetic ketoacidosis
- Histological features:
- Marked reduction in number and size of islets
- Insulitis (leukocytic infiltration of islets)
Type II
- Genetic involvement:
- 90-100% concordance in twins
- No HLA association
- Characteristic cause:
- Insulin resistance with relative insulin deficiency
- Pathogenesis:
- Obesity-induced peripheral insulin resistance:
- Increased levels of plasma free FAs reduces insulin signaling and increases gluconeogenesis
- Decreased adipokines (anti-hyperglycaemic hormones elaborated by adipocytes which increase peripheral insulin sensitivity)
- Exhaustion of beta cells:
- Due to increasing peripheral insulin resistance
- Confounded by primary genetic beta cell defect predisposing to beta cell decompensation
- Clinical Features:
- May have polyuria, polydipsia, weight loss
- Hyperosmolar non-ketotic coma (typically in physically incapacitated elderly unable to rehydrate adequately)
- Histological Features:
- Moderate reduction in number and size of islets
- Amyloid replacement of islets
Secondary DM:
- Chronic pancreatitis and post-pancreatectomy
- Hormonal tumours (eg. pheochromocytoma, pituitary tumours)
- Drugs (exogenous corticosteroids)
- Hemochromatosis
- Genetic disorders
- Gestational DM
Complications of Diabetes
- Macrovascular Diseases
- Due to accelerated atherosclerosis
- Affects various systemic arteries:
- Cerebral: stroke
- Coronary: acute MI
- Limbs: peripheral vascular disease
- Microvascular Diseases
- Retinopathy
- Neovascularization due to hypoxia-induced VEGF production in retina (causing blindness)
- Increased risk of cataract and glaucoma
- Nephropathy
- Glomerular lesions (basement membrane thickening + diffuse mesangial sclerosis + nodular glomerulosclerosis aka Kimmelstiel-Wilson lesions)
- Renal vascular lesions (atherosclerosis)
- Pyelonephritis
- Neuropathy
- Peripheral neuropathy
- Lower extremities first, more sensory than motor deficits
- Autonomic neuropathy
- Disturbances in bowel and bladder movements, may have impotence
- Mononeuropathy
- Manifests as a sudden wrist drop, foot drop or cranial nerve palsies
- Increased susceptibility to infections
- Due to vascular compromise and decreased leukocyte function
- Common infections seen in diabetic patients:
- Skin infections
- Tuberculosis
- Pneumonia
- Pyelonephritis
Pathogenesis of Chronic ComplicationsMechanisms resulting from sustained hyperglycaemia:1. Non-enzymatic glycosylation
- Glucose chemically attaches to the amino group of proteins w/o the aid of enzymes --> forming irreversible advanced glycosylation end products (AGEs)
- AGEs can directly cross-link with collagen and albumin --> contribute to thickening of basement membranes
- AGE-modified matrix components enhance trapping of LDLs --> accelerates atherosclerosis
- AGEs can bind to AGE receptors found on certain cell types (macrophages, endothelial cells, mesangial cells) which induces:
- Release of cytokines and growth factors
- Increased endothelial permeability
- Proliferation and synthesis of ECM
2. Intracellular hyperglycemia
- Affects tissues not dependant on insulin for glucose transport (nerves, lens, kidneys, blood vessels)
- Hyperglycaemia causes increased intracellular glucose levels in such tissues
- Increased intracellular glucose causes disturbances of the poll pathway by providing increased substrate (glucose) for conversion to sorbitol (by aldose reductase), then to fructose
- Accumulation of fructose increases cellular osmolarity --> causing osmotic cell injury + cataracts
- Also, conversion process utilizes NADPH, which, when depleted by increased conversion, results in decreased glutathione regeneration, increasing cellular susceptibility to oxidative damage
Neoplasms
-
Pancreatic Carcinoma
- Infiltrating ductal adenocarcinoma of pancreas
- 60-80 years old
- Very aggressive cancer with high mortality
Etiologies and Associations:
- Smoking
- Fat-rich diet
- Diabetes mellitus
- Chronic pancreatitis
Pathogenesis:
- Pancreatic intraepithelial neoplasm (PIN - precursor lesions in small bile ducts) --> invasive carcinoma sequence
- Progressive mutations:
- Telomere shortening
- K-RAS mutations
- p16 tumour suppressor gene inactivation
- p53, SMAD4, BRCA2 gene inactivation
Symptoms:
- Silent
- Abdominal pain
- Weight loss
- +/- Obstructive jaundice
- +/- Migratory thrombophlebitis (Trousseau sign)
- Tumor markers in serum: CA19-9 carcinoembryonic antigen (CEA)
Histological Subtypes:
- Adenocarcinoma (usual form)
- Squamous cell carcinoma
- Cystuadenocarcinoma
- Acinar cell carcinoma
- Prominent acinar cell differentiation
- Production of exocrine enzymes
- May cause metastatic fat necrosis due to lipases released into circulation
- Undifferentiated carcinoma
- May have osteoclast-like giant multinucleated cells
- Pancreatoblastoma
- Rare, found in children age 1-15 years
- Squamous islands admixed with acinar cells
Sites
- Head of pancreas (60%)
- Better prognosis in general due to earlier detection due to obstruction of bile duct which passes through the head of the pancreas
- Entire pancreas (20%)
- Body (15%)
- Tail (5%)
Pathological Effects and Complications:
- Generally poor prognosis (one of the highest mortality
rates amongst all cancers)
- Biliary obstruction (for tumours of head of pancreas)
- Obstructive jaundice
- Ascending cholangitis
- Cholecystitis
- Gastrointestinal bleeding
- Migratory thrombophlebitis (Trousseau’s sign)
- Due to tumour-elaborated procoagulants & platelet aggregating factors
-
Pancreatitis
- Inflammation of the pancreas associated with injury to the exocrine pancreas
- Ranges from a transient attack to a permanent loss of function
Acute Pancreatitis
- Reversible pancreatic parenchymal injury asc with inflammation
Causes:
- Obstruction of pancreatic duct system:
- Cholelithiasis
- Periampullary neoplasms
- Pancreas divisum
- Choledochal cysts
- Parasites
- Alcoholism
- Infections:
- Mumps virus, Ascaris lumbricoides, Clonorchis sinensis
- Acute ischemia:
- Shock, thrombosis, embolism, vasculitis
- Drugs:
- Furosemide, azathioprine, oestrogen
- Hyperlipoproteinemia
- Hypercalcemia
- Mechanical causes:
- Hereditary pancreatitis:
- AD form: trypsinogen mutation rendering trypsin resistant to inactivating cleavage by another trypsin
- AR form: trypsin inhibitor mutation
Pathogenesis
- Initiating Event:
- Due to causes of pancreatic duct obstruction leading to interstitial oedema which impairs blood flow --> resulting in ischemic damage. And also due to accumulation of lipases causing local fat necrosis
- Due to causes of direct acinar cell injury, resulting in release of intracellular proenzymes and lysosomal hydrolyses, which activate enzymes
- Either way, initiating events leads to further acinar cell injury, which results in local activation of pancreatic enzymes, leading to:
- Interstitial oedema and inflammation
- Proteolysis (proteases)
- Fat necrosis (lipases, phospholipase)
- Haemorrhage (elastase)
Morphology
- Gross:
- Haemorrhage and necrosis
- Fat necrosis of adipose tissue (within pancreas, peripancreatic fat, omentum and mesentery)
- Fat saponification (when fat necrosis is combined with calcium salt)
- Chicken broth peritoneal fluid (due to fat necrosis releasing fat globules into peritoneal fluid)
- Histology:
- Inflammatory infiltrate
- Interstitial edema
- Areas of fat necrosis
Clinical Features:
- Signs and symptoms:
- Intense, constant abdominal pain, often referred to the upper back or even to the left shoulder
- Laboratory findings:
- Raised serum amylase and lipase
- Conjugated hyperbilirubinemia (if obstruction is common to pancreatic and biliary ducts)
- Glycosuria (due to damage to endocrine pancreas)
- Hypocalcemia (due to draining of calcium in fat saponification, poor prognostic sign)
Pathological Effects and Complications:
- Systemic organ failure
- Shock, ARDS, acute renal failure
- Pancreatic abscess formation
- Pancreatic pseudocyst formation
- A pseudocyst has no true epithelial lining, just a focus of necrotic material walled off by fibrous/granulation tissue
- Cannot be excised, has to be drained
- May be subsequently infected by gut microbes
- May lead to chronic pancreatitis
- Duodenal obstruction
Chronic Pancreatitis
- Inflammation of the pancreas with irreversible destruction of the exocrine parenchyma, fibrosis and in the late stages, destruction of the endocrine parenchyma
Causes:
- Long term alcohol abuse (most common cause)
- Long-standing pancreatic duct obstruction
- Pseudocysts
- Calculi
- Trauma
- Pancreas divisum
- Neoplasms
- Hereditary causes (same as those for acute pancreatitis)
- Cystic fibrosis
- Autoimmune (lymphoplasmacytic sclerosing pancreatitis)
Pathogenesis:
- Progressive destruction of pancreas by repeated flare-ups of mild and subclinical types of acute pancreatitis
Morphology
- Atrophy of acini
- Dilated ducts containing protein plugs
- Interlobular fibrosis and chronic inflammatory infiltrate
- Calcifications
- Pseudocysts
- Remaining surviving islets embedded in a sclerotic background
Pathological Effects and Complications:
- Chronic malabsorption
- Due to deficiency in exocrine pancreatic enzymes required for digestion of food
- Diabetes mellitus
- Due to loss of islets of Langerhans