1. The Pathology of Pancreas

2. Exocrine Component of Pancreas

3. The most significant disorders of the exocrine pancreas are
Congenital anomalies
Cystic fibrosis (Mucoviscidosis)
Pancreatitis (acute & chronic)
Tumors

4. Congenital Anomalies Agenesis Aberrant (ectopic) pancreas Hypoplasia
Stomach, duodenum, jejunum, Meckel’s 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

5. 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.

6. 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)

7. Manifestations: 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

8. The bronchial epithelium:
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

9. Salivary glands: Bile ducts: Bowel: The sweat 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)
The sweat glands:
Perform normally, but chloride is not reabsorbed through the sweat ducts
These children's sweat is excessively salty

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

11. Pancreatitis Acute pancreatitis Mild form Severe 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

12. Etiology Metabolic Mechanical Vascular Infectious Hypercalcemia
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

13. 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 ...

14. activates clotting and complement

15. ... 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

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

17. 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

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

20. Chronic Pancreatitis
The disease occurs in the same type of patient likely to develop acute pancreatitis–most 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

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

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

23. Tumors of the Exocrine Pancreas
Benign
Cystic Tumors
1. SEROUS CYSTADENOMA
2. MUCINOUS CYSTADENOMA
Malignant
Adenocarcinoma
60% head
15% body
5% tail
20% diffuse

24. 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

25. 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)

26. Microscopy 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

29. Endocrine Component of Pancreas

30. ß cells a cells

31. Islets of Langerhans Beta (70%) Alpha (5%-20%) Delta (5%) PP (1% - 2%)
Cell Type (%)
Beta (70%)
Alpha (5%-20%)
Delta (5%)
PP (1% - 2%) EC D1
Hormone
Insulin
Glucagon
Somatostatin
Pancreatic Polypeptide
Serotonin
VIP

32. Blood Glucose & Various Hormones
Hormone
Insulin
Glucortocoids
Glucagon
Growth Hormone
Epinephrine
Action
 Glucose
 Glucose
Diabetic
Syndrome

33. 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

35. 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

36. Primary Diabetes mellitus
Insulin-dependent diabetes mellitus (IDDM):
Type I diabetes
(juvenile-onset diabetes)
<20 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)
>30 y/o
Obesity
N /  Insulin
No islet cell abnormalities
Insulin Resistance
Relative Insulin Deficiency
Ketoacidosis – rare

37. 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

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

39. Insulitis – Type I

41. 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

42. Relative Insulin Deficiency
Pathogenesis of Type II DM
ß cell defect
Genetic
Environment
Obesity
Abnormal Secretion
Insulin resistance
Relative Insulin Deficiency
ß cell
exhaustion
IDDM
Type II DM

43. Loss of ß cells
Amyloid deposits
Hyalinization
Islets in Type II

44. 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

45. Increased Intracellular Glucose - Polyol Pathways
Non-Insulin
Requiring Cells
Schwann Cells  Neuropathy
Retinal Pericytes  Retinal Microaneurysms
Lens Lens Opacities
Sorbitol
Sorbitol
Fructose
Sorbitol

49. 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

51. Diabetes Mellitus - Mortality
Myocardial Infarction
Renal Failure
Atherosclerotic Heart Disease
Cerebrovascular Accident (CVA)
Infection
Gangrene
Hypoglycemia/Ketoacidosis

52. 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.

53. 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

54. Macrosomia

55. Macrosomia

56. Endocrine tumors of Pancreas

57. 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)

58. Islet-cell adenoma

59. 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

60. Macroscopy: Histology: 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

61. Insulinoma

62. 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)

64. 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