The Pathology of Pancreas

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The Pathology ofPancreas
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Exocrine Component of Pancreas
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• The most significant disorders of the exocrine
  pancreas are
• Congenital anomalies
• Cystic fibrosis (Mucoviscidosis)
• Pancreatitis (acute chronic)
• Tumors

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Congenital Anomalies

• Agenesis
• Aberrant (ectopic) pancreas
• Stomach, duodenum, jejunum, Meckels
  diverticulum, ileum
• Hypoplasia
• endocrine and exocrine elements
• Annular pancreas
• the head of the pancreas may encircle the
  duodenum as a collar
• cause subtotal duodenal obstruction

• Ductal anomalies
• Pancreas divisum ducts of Wirsung and of
  Santorini (accessory pancreatic duct) may both
  persist as totally separate structures, with
  separate duodenal orifices

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Cystic Fibrosis (Mucoviscidosis)

• Genetic pediatric disorder
• autosomal recessive
• the locus for the disease is chromosome 7q
• Common (1/2500 births)
• Often fatal in childhood and young adult life
• This defect results in
• (1) increased salt content of sweat
• (2) decreased water content of respiratory,
  intestinal, and pancreatic exocrine secretion,
  leading to increased viscosity.

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• Cystic fibrosis is caused by
• Lack of a membrane component essential to proper
  chloride transport across membranes of the
  mucus-producing exocrine glands and eccrine sweat
  glands in response to cAMP (Cyclic-Adenosine
  monophosphate)

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• Changes in the pancreas and mucous salivary
  glands
• ducts plugged by viscous mucus
• cysts" form behind the plugs
• "fibrosis atrophy" ensues after years of
  obstruction

• Manifestations
• recurrent pulmonary infections leading to chronic
  lung disease
• pancreatic insufficiency
• steatorrhea
• malnutrition
• hepatic cirrhosis
• intestinal obstruction
• male infertility

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• The clinical syndrome is complex and reflects the
  underlying pathophysiology.
• The bronchial epithelium
• Lumens become plugged by thick mucus
• Lung infections
• Staph. aureus
• Pseudomonas aeruginosa
• Pneumonias
• Lung abscesses
• Bronchiectasis
• Airway ulcers

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• The sweat glands
• Perform normally, but chloride is not reabsorbed
  through the sweat ducts
• These children's sweat is excessively salty

• Salivary glands
• Produce mucus (all but the parotid)
• Some degree of plugging and atrophy
• Bile ducts
• Mucus plugs
• Cirrhosis
• Bowel
• Obstruction due to thick mucus (meconium ileus)

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• The pancreatic ductal epithelium
• Chloride secretion disorders
• Plugged pancreatic ducts
• Atrophy
• Malabsorption
• Vitamin deficiencies (vitamin A and K)

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Pancreatitis

• Acute pancreatitis
• Mild form
• Accompanied by edema and limited necrosis of
  pancreatic tissue
• Severe form
• acute hemorrhagic pancreatitis, or necrotizing
  pancreatitis,
• extensive fat necrosis
• hemorrhage into the parenchyma of the pancreas

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Etiology

• Metabolic
• Alcohol
• Hyperlipoproteinemia
• Hypercalcemia
• Drugs (glucocorticoids, pentamidine,
  azathioprine)
• Mechanical
• Gallstones (migrating)
• Trauma
• Surgery
• Parasitic diseases

• Vascular
• Shock
• Embolism
• P. Nodosa
• Infectious
• Mumps
• Coxsackievirus
• Mycoplasma pneumonia
• Hypercalcemia
• Anatomic anomalies

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• Pathophysiology of acute pancreatitis
• Autodigestion by inappropriately activated
  enzymes (trypsin) ?
• Trypsin activates various digestive enzymes and,
  clotting and complement (see next slide)
• Small vessel thrombosis
• Obstruction (gallstones or alcohol associated
  concretions) increases ? intraductal pressure ?
  enzyme-rich interstitial fluid ? fat necrosis ...?

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activates clotting and complement
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• ...? Fat Necrosis attracts neutrophils ? release
  cytokines ? cause interstitial edema ? impairs
  blood flow ?causes ischemia and acinar cell
  injury
• Infections, drugs, trauma, shock? premature
  release of proenzymes and lysosomal hydrolases?
  acinar cell injury

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• Pancreas undergoes
• proteolysis (proteases)
• lipolysis (lipase)
• eventually with hemorrhage (elastases damage
  vessels)
• This produces considerable acute inflammation
• neutrophils
• edema
• Alcohol ? reactivate chronic pancreatitis

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• Pathology
• (1) Proteolytic destruction of pancreatic
  substance
• (2) necrosis of blood vessels with subsequent
  hemorrhage
• (3) necrosis of fat
• (4) an accompanying inflammatory reaction

• Very early stages
• interstitial edema
• Soon after
• focal and confluent areas of frank necrosis
• neutrophilic infiltration
• interstitial hemorrhage
• The most characteristic histologic lesions
• focal areas of fat necrosis in the pancreatic and
  peripancreatic fat tissue

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• Distrophic
• calcification
• Amorphous basophilic calcium precipitates may be
  visible within the necrotic focus

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Chronic Pancreatitis

• The disease occurs in the same type of patient
  likely to develop acute pancreatitismost
  commonly
• the middle-aged
• male
• Chronic alcoholism
• Biliary tract disease
• Alcohol ? reactivate chronic pancreatitis

• Hypercalcemia (hyperparathyroidism)
• Hyperlipidemia
• Pancreas divisum (stenosis of the duodenal
  papilla).
• Uncertain etiology
• nonalcoholic tropical pancreatitis
• familial hereditary pancreatitis

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• Macroscopy
• Small, firm, white pancreas (partial or total)
• Calcifications
• Microscopy
• Chronic inflammatory infiltrate (lymphocytes)
• Loss of acinar cells
• Dilated ducts (contain protein plugs)
• Fibrosis

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• PANCREATIC CYSTS
• PANCREATIC PSEUDOCYST
• CONGENITAL CYSTS
• NEOPLASTIC CYSTS
• 1. SEROUS CYSTADENOMA
• 2. MUCINOUS CYSTADENOMA CYSTADENOCARCINOMA

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Tumors of the Exocrine Pancreas

• Benign
• Cystic Tumors
• 1. SEROUS CYSTADENOMA
• 2. MUCINOUS CYSTADENOMA

• Malignant
• Adenocarcinoma
• 60 head
• 15 body
• 5 tail
• 20 diffuse

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Adenocarcinoma

• Risk factors
• (1) smoking
• (2) exposure to chemicals (chemists and garage
  workers)
• (3) hereditary pancreatitis
• (4) consumption (abuse) of fats and meat
• (5) partial gastrectomy

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• Location Findings
• Head of the pancreas ? the ampulla of Vater ?
  obstructive biliary symptoms (early)
• Body or tail of the pancreas ? grows silently ?
  invasion to adjacent structures ? metastatic
  dissemination ? obstructive biliary symptoms
  (late)

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• Grossly
• Carcinomas of the head
• may be fairly small mass lesions
• may be totally inapparent on external examination
  
• increased consistency and irregular nodularity
• Carcinomas of the body or tail
• up to 10 cm in diameter
• gray-white/scirrhous
• homogenous
• infiltrates the lobular architecture
• larger tumors invade the duodenum and common bile
  duct (biliary obstruction)

• Microscopy
• Poorly differentiated adenocarcinoma
• Deeply infiltrative growth pattern
• Dense stromal fibrosis
• Perineural invasion
• Mucus production

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Endocrine Component of Pancreas
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ß cells a cells
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Islets of Langerhans

• Cell Type ()
• Beta (70)
• Alpha (5-20)
• Delta (5)
• PP (1 - 2)
• EC
• D1

Hormone Insulin Glucagon Somatostatin Pancreatic
Polypeptide Serotonin VIP
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Blood Glucose Various Hormones
?

• Hormone
• Insulin
• Glucortocoids
• Glucagon
• Growth Hormone
• Epinephrine

Action ? Glucose ? Glucose ? Glucose ? Glucose ?
Glucose
Diabetic Syndrome
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Diabetes mellitus

• Diabetes mellitus is a common chronic disease
  characterized by relative or absolute deficiency
  of insulin, resulting in glucose intolerance.
• A chronic metabolism disorder of
• carbohydrate
• fat
• protein
• Characterized by
• Polyuria, Polydypsia, Polyphagia
• Absolute or relative insulin deficiency
• hyperglycemia
• glycosuria

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• Types of Diabetes Mellitus
• Type I
• Autoimmune and idiopathic there is an absolute
  insulin lack
• Type II
• Defects in insulin secretion, and/or a relative
  lack of insulin, and/or insulin resistance
• Type III
• Damage to the pancreas (pancreatitis, tumors,
  hemochromatosis, cystic fibrosis)
• Type IV
• Gestational diabetes

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Primary Diabetes mellitus

• Insulin-dependent diabetes mellitus (IDDM)
• Type I diabetes
• (juvenile-onset diabetes)
• lt20 y/o
• Normal Weight
• ? Insulin
• Islet cell abnormalities
• Autoimmunity
• Severe Insulin Deficiency
• Ketoacidosis common

• Noninsulin-dependent diabetes mellitus (NIDDM)
• Type II diabetes
• (adult-onset diabetes)
• gt30 y/o
• Obesity
• N / ? Insulin
• No islet cell abnormalities
• Insulin Resistance
• Relative Insulin Deficiency
• Ketoacidosis rare

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Picture of the Islet Cells

• Type I
• Insulitis Early
• Atrophy, Fibrosis
• Beta-Cell Depletion
• Genetic Predisposition
• 95 HLA DR3/DR4
• Autoimmunity
• T-Cell Mediated
• Selective Islet Cells
• Islet Cell Antibodies
• Environmental
• Coxsackie - B Virus (GAD)

• Type II
• No Insulitis
• Focal Atrophy, Amyloid
• Mild Beta-Cell Depletion
• Genetic Susceptibility
• 20-40 Concordance in First Degree Relatives
• No HLA Linkage
• Autoimmunity
• None
• Environmental
• None

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Pathogenesis of Type I DM
Environment Viral infections
Genetic HLA-DR3/DR4
Autoimmune Insulitis
ß cell Destruction
Severe Insulin deficiency
Type I DM
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Insulitis Type I
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Type II

• Deranged Insulin Secretion
• Increased Insulin Secretion
• Delayed Insulin Secretion
• Deficiency of Insulin Secretion
• Obesity
• 80 Obese
• ? Insulin
• Insulin Resistance
• ? Number of Receptors
• Postreceptor Defects
• Reduced GLUTS
• Amyloid
• Accumulation

Glucose Transporters
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Pathogenesis of Type II DM
Environment Obesity
ß cell defect Genetic
Insulin resistance
Abnormal Secretion
Relative Insulin Deficiency
ß cell exhaustion
IDDM
Type II DM
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Loss of ß cells Amyloid deposits Hyalinization
Islets in Type II
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Complications

• Short term Complications (metabolic)
• Hypoglycemia
• Diabetic Ketoacidosis
• Non Ketotic hyperosmolar diabetic coma
• Lactic acidosis
• Long term Complications (microangiopathic)
• Angiopathy
• Retinopathy
• Nephropathy
• Neurophathy

See PATHOPHYSIOLOGY_Long term Complications in
Diabetes Mellitus
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Increased Intracellular Glucose - Polyol
Pathways Non-Insulin Requiring Cells Schwann
Cells ----------------? Neuropathy Retinal
Pericytes ----------? Retinal Microaneurysms Lens
---------------?Lens Opacities
Sorbitol
Sorbitol
Fructose Sorbitol
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Other problems of Diabetics

• Hepatic fatty change
• Complications of pregnancy
• Macrosomia (hyperglycemia, growth factor)
• Birth defects (preventable by euglycemia through
  pregnancy)

• Infections
• Bacterial
• Fungal (mucor, candida)
• Gallstones
• Cholesterol
• Altered platelet function
• Skin lesions
• Diabetic xanthomas
• lipid-laden macrophages
• Necrobiosis
• focal necrosis (dermis)
• necrobiosis lipoidica diabeticorum

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Diabetes Mellitus - Mortality

• Myocardial Infarction
• Renal Failure
• Atherosclerotic Heart Disease
• Cerebrovascular Accident (CVA)
• Infection
• Gangrene
• Hypoglycemia/Ketoacidosis

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Gestational Diabetes

• Pathophysiologically type II DM
• Pregnancy is a state of insulin resistance
• Increased Insulin needs in pregnancy
• Insulin release is enhanced in pregnancy ?
• increased insulin ? hunger ? over eating
• When the pregnancy is over and the insulin needs
  return to normal, the diabetes usually disappears.

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Gestational Diabetes Complications

• Fetal
• macrosomia
• neural tube defects
• neonatal hypoglycemia
• hypocalcemia
• hyperbilirubinemia Neonatal Jaundice
• birth trauma
• childhood/adolescent obesity

• Maternal
• higher risk of hypertension
• pre-eclampsia
• infections
• cesarean section
• future diabetes

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Macrosomia
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Macrosomia
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Endocrine tumors of Pancreas
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Islet Cell Tumors

• Clinical syndromes associated with hyperfunction
  of the islets of Langerhans
• (1) Hyperinsulinism and hypoglycemia (insulinoma)
  caused by diffuse hyperplasia of the islets of
  Langerhans
• (2) Zollinger-Ellison syndrome (gastrinoma)
• caused by benign adenomas that occur singly or
  multiply
• (3) Multiple Endocrine Neoplasia (malignant islet
  tumors)

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Islet-cell adenoma
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Insulinomas Beta cell tumors

• Most common of islet cell tumors
• Paroxysmal hypoglycemia (? Glucose
  ? Insulin)
• CNS - confusion, unconsciousness
• Relief with glucose administration
• Massively obese patients

• Whipple's triad
• (1) low measured plasma glucose
• (2) mental changes especially related to fasting
  or exercise
• confusion
• stupor
• loss of consciousness
• (3) attacks relieved by glucose administration

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• b-cell tumors inducing hyperinsulinism
• 70 are solitary adenomas
• 10 are multiple adenomas
• 10 are hyperplasia
• 10 are metastasizing

• Macroscopy
• encapsulated
• firm
• yellow-brown nodules
• Histology
• cords and nests of well-differentiated beta cells

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Insulinoma
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Zollinger-Ellison Syndrome (Gastrinoma)

• G-cell tumors
• Gastrin Secretory Cell
• Most common in the pancreas
• 10 to 15 in the duodenum
• 60 of gastrinomas are malignant
• Striking gastric hypersecretion

• A syndrome of
• multiple bleeding ulcers
• diarrhea (malabsorption)
• Ulcers
• Stomach
• Duodenum (first and second portions)

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Islet cell tumors (rare ones)

• Alpha-two cell tumors (glucagonoma)
• mild diabetes
• sore tongue
• necrolytic migratory erythema
• Delta-cell tumors (somatostatinoma)
• diabetes mellitus
• cholelithiasis
• steatorrhea
• hypochlorhydria

• VIPoma (diarrheogenic islet cell tumor)
• watery diarrhea
• hypokalemia
• achlorhydria