Pancreas

Divided into head (right of left border of superior mesenteric vein; contains uncinate process), body (between left border of superior mesenteric vein and left border of aorta) and tail

A retroperitoneal organ, lies within duodenal curve, close to superior mesenteric artery and portal vein

Anterior body of pancreas touches posterior wall of stomach; posterior of pancreas touches aorta, splenic vein and left kidney

Pancreatic tail extends to the splenic hilum

Has large functional reserve of cells

Exocrine Pancreas

Acini comprise 80% of pancreas; composed of columnar to pyramidal epithelial cells with minimal stroma

Basophilic due to prominent rough endoplasmic reticulum; have well developed Golgi complex

Cells form apical oriented secretory complex with zymogen granules containing digestive enzymes (PAS+)

After stimulation, zymogen granules migrate to apical plasma membrane and release contents into lumen

Luminal border has prominent microvilli

Centroacinar cells: in center of acini, occasionally in clusters, with pale cytoplasm and oval nuclei

Intercalated duct: drains acini via intralobular ducts (cuboidal epithelium), to interlobular ducts lined by mucin secreting columnar cells

Pancreas produces 2 liters/day of bicarbonate rich fluid containing digestive enzymes and proenzymes, regulated by neural stimulation (vagus nerve) and humoral factors (secretin, cholecystokinin)

Secretin: stimulates water and bicarbonate secretion by duct cells; is stimulated by acid from stomach and luminal fatty acids

Cholecystokinin: promotes discharge of digestive enzymes by acinar cells; released from duodenum in response to fatty acids, peptides and amino acids

Pancreatic enzymes: trypsin, chymotrypsin, aminopeptidases, elastase, amylases, lipase, phospholipases, nucleases

Trypsin: catalyzes activation of the other enzymes

Pancreatic self-digestion is prevented by: packaging of most proteins as inactive proenzymes, enzyme sequestration in zymogen granules, proenzymes activated only by trypsin which is activated only by duodenal enterokinase, trypsin inhibitors are present in ductal and acinar secretions, intrapancreatic release of trypsin activates enzymes which degrade other digestive enzymes before they can destroy pancreas, lysosomal hydrolases can degrade zymogen granules to prevent auto destruction if acinar secretion is impaired, acinar cells themselves are highly resistant to trypsin, chymotrypsin and phospholipase A2

Endocrine Pancreas

Consists of islets of Langerhans, represents 1% of pancreas (percentage higher at birth)

Round, compact, highly vascularized with scanty connective tissue; more irregular outline and trabecular arrangement in posterior head of pancreas with cells producing pancreatic polypeptide

Size of islets usually 0.1 to 0.2 mm, endodermal origin, one million islets present in pancreas

Islet composition: beta cells (68%), alpha cells (20%), delta cells (10%), PP cells (2%), serotonin cells (rare)

Post-gastrectomy, may get islet hypertrophy, then beta cell proliferation, then atrophy and amylin deposits, Hum Path 2000; 31:1368

Alpha cells: produce glucagon; peripheral dense and round on EM

Beta cells: produce insulin and islet cell amyloid polypeptide (amylin), crystalline appearance on EM with surrounding halo

Delta cells: produce somatostatin (represses release of insulin and glucagon), large pale granules on EM

D1 cells: produce vasoactive intestinal polypeptide (VIP), which induces glycogenolysis and hyperglycemia, stimulates GI fluid secretion and causes secretory diarrhea

Enterochromaffin cells: synthesize serotonin, produce carcinoid syndrome

Gastrin cells: pancreas usually lacks gastrin producing cells, although gastrinomas are common

PP cells: produce pancreatic polypeptide, which stimulates secretion of gastric and intestinal enzymes and inhibits intestinal motility; present in islets and scattered in exocrine pancreas; more PP cells in posterior head of pancreas (from ventral bud)

Nesidioblastosis (see below under congenital anomalies)

Nesidiodysplasia: loss of the usual centrilobular concentration of larger islets, with increased small irregularly distributed aggregates of islet cells; also increase in beta cell nuclear size and DNA content; may be associated with endocrine neoplasms, Hum Path 1988;19:1215

Peliosis: selective congestion and dilation of vessels of islets only, not seen in vessels elsewhere

Positive islet immunostains: chromogranin, synaptophysin, neuron specific enolase, neurofilament

Embryology

Pancreas forms from ventral and dorsal buds that rotate and fuse

Ventral bud (anlage) develops from hepatic duct, forms posterior/inferior head and uncinate process

Dorsal bud (anlage) develops from foregut and extends into dorsal mesentery; forms body, tail, anterior head

Fusion of ducts at week 7 creates main pancreatic duct (Wirsung) which extends to papilla of Vater, usually with common bile duct

Abnormal fusion of ventral and dorsal buds causes annular pancreas or heterotopic pancreas

In 2/3 of adults, pancreatic duct empties into common bile duct, not into ampulla directly

Proximal portion of dorsal duct persists as accessory duct of Santorini, empties into minor duodenal papilla

Usually are numerous anastomotic connections between ducts of Wirsung and Santorini; if not, get pancreas divisum (10% of individuals), in which duct of Santorini is major drainage duct

Percentage of acinar cells decreases after birth

Congenital anomalies

Agenesis

Usually associated with severe malformations, not compatible with life

Annular pancreas

Incidence 1 per 7000

Head of pancreas circles duodenum as a collar and may constrict lumen

Due to failure of ventral bud to rotate properly

Associated with Down’s syndrome

Pancreatic duct is anterior, courses to the right over the duodenum, then posterior and to left behind

duodenum, then near common duct

Associated with pancreatitis, duct obstruction, peptic ulcer

Has large number of PP cells (of ventral bud origin) in irregular shaped islets

Heterotopic pancreas

Aka ectopic pancreas

Pancreatic tissue outside boundaries of pancreas without anatomic or vascular connections to pancreas

Present in 0.5% to 14% of autopsies; due to displacement of pancreatic tissue during embryonic development

Often in gastric antrum, duodenum, jejunum, Meckel’s diverticulum (Archives 2003;127:E99), gastroesophageal junction (AJSP 1996;20:1507, Archives 2000;124:1165)

Case report of pancreatic cyst in anterior mediastinum, Mod Path 1996;9:210

Usually incidental findings but may cause ulceration, obstruction, intussusception, Hum Path 1994;25:169

Vulnerable to same diseases as normal pancreas (2% of islet cell tumors arise in ectopic pancreatic tissue), may undergo malignant transformation, Archives 1994;118:568, Archives 1999;123:707

Gross: 0.2 to 3 cm, resembles normal pancreas with firm, yellow, well-circumscribed, lobulated nodules, may have central umbilication due to a central duct if below a mucosa (can be detected radiographically)

Micro: usually in submucosa, almost always acinar cells and ducts, islets present in 1/3; may be pyloric-type mucous glands

4 histologic types: total (all cell types), ducts only (canalicular), exocrine (acinar) only, islet cells only / endocrine (very rare, Archives 2002;126:464); may have convoluted branching pattern mimicking invasive carcinoma; rarely retains mucus and resembles mucinous carcinoma, AJSP 1994;18:953

DD in stomach: pancreatic metaplasia of gastric mucosa; endocrine subtype of heterotopia may mimic a primary or metastatic neuroendocrine tumor

References: AJSP 1993;17:1134, Archives 2003;127:e237 (case report), AJSP 1998;22:100 (presence in children)

Nesidioblastosis

Aka congenital islet hyperplasia

Islets in intimate association with ducts, with formation of ductuloinsular complexes; indicates active formation of endocrine cells by multipotential cells in basal layer of ducts

Normal in infants, exaggerated in neonatal hyperglycemia (infants of diabetic mothers); very rare in adults with hyperinsulinemic hypoglycemia; also associated with Zollinger-Ellison syndrome, cystic fibrosis, chronic pancreatitis, endocrine neoplasms

In infants, not due to abnormal beta cell proliferation, Mod Path 1998;11:444

Focal or diffuse patterns

Focal: nodular hyperplasia of islet-like cell clusters, including ductuloinsular complexes and hypertrophied insulin cells with giant nuclei

Diffuse: involves entire pancreas; irregularly sized islets and ductuloinsular complexes present, both contain hypertrophied insulin cells

Treatment: partial pancreatectomy with excision of the diseased areas for most patients with focal nesidioblastosis, near-total pancreatectomy for diffuse nesidioblastosis

References: AJSP 1989;13:766

Pancreas divisum

3-10% of population

Incomplete fusion of dorsal and ventral pancreatic buds / ducts; diagnose by imaging studies

Duct of Santorini provides main drainage

May predispose to recurrent acute pancreatitis

Pancreatitis

Acute pancreatitis

Acute onset of abdominal pain due to enzymatic necrosis and inflammation of the pancreas

Demographics: 20 cases/100,000 in US, 80% associated with biliary tract disease or alcoholism

Note: 1/3 to 2/3 of patients have gallstones, but only 5% with gallstones develop pancreatitis

75% of gallstone related cases occur in women; 86% of alcohol related cases occur in men

Alcoholism associated: 2/3 of all cases in US, 5% in UK

Causes: common channel between common bile duct and main pancreatic duct due to migrating gallstone, biliary sludge, spasm of sphincter of Oddi; although 50% of normals also have a common channel

Less common causes: trauma (including post-operative), infection (mumps, coxsackievirus, Mycoplasma pneumonia, adenovirus in immunocompromised, Hum Path 1993;24:1145, Rocky Mountain spotted fever /Rickettsiae, Archives 1984;108:963, AIDS related toxoplasmosis, Ascaris lumbricoides, Clonorchis sinensis; acute ischemia (thromboemboli, vasculitis, shock), drugs (thiazides, azathioprine, estrogen, sulfa, furosemide, methyldopa, pentamidine, procainamide), hyperlipidemia, hyperparathyroidism or other causes of hypercalcemia, hyperthyroidism, 10% idiopathic

Symptoms: abdominal pain, high white blood count, DIC, ARDS, diffuse fat necrosis, peripheral vascular collapse, acute tubular necrosis, shock (blood loss, electrolyte disturbances, endotoxemia, release of cytokines), hypocalcemia, hyperglycemia

DD: acute abdomen (appendicitis, perforated peptic ulcer, acute cholecystitis with rupture, occlusion of mesenteric vessels with bowel infarction)

Diagnosis: elevated amylase (also seen in duodenal ulcer, volvulus, gangrenous cholecystitis, abdominal aortic aneurysm, mesenteric thrombosis), elevated lipase, elevated C reactive protein, Xray (pancreas large and inflamed)

Treatment: rest the pancreas by food/fluid restriction

Complications: sterile pancreatic abscess, pancreatic pseudocyst, infected pancreatic necrosis; large vessel thrombi in nearby vessels, distant fat necrosis

Outcome: 5% die of shock during first week; overall mortality is 20% (10% if swollen/edematous) vs. 50% if hemorrhagic/necrotic

Acute respiratory distress syndrome or acute renal failure are poor prognostic factors

Gross: swollen, edematous or hemorrhagic/necrotic, yellow nodules represent fat necrosis in pancreas, mesenteric and peritoneal fat; may spread to colon and cause ileus, stenosis, perforation, fistulas

Micro: diffuse interstitial edema due to microvascular leakage, fat necrosis, neutrophils, acinar and blood vessel destruction, interstitial hemorrhage; also acinar cell homogenization, ductal dilation, fibroblasts, thrombi in capillaries and venules; initially neutrophils are present, then macrophages and later lymphocytes; calcification occurs early and extensively

Physiology of acute pancreatitis:

Due to autodigestion by inappropriately activated enzymes

Trypsin activates digestive enzymes as well as prekallikrien, which activates clotting and complement

systems, amplifying small vessel thrombosis

Obstruction from gallstones or alcohol associated concretions increases intraductal pressure, causing enzyme-

rich interstitial fluid to accumulate, which causes fat necrosis, which attracts neutrophils that release cytokines and cause interstitial edema, which impairs blood flow and causes ischemia and acinar cell injury

Acinar cell injury also caused by infections, drugs, trauma, shock, premature release of proenzymes and

lysosomal hydrolases

Obstruction or alcohol cause proenzymes to be delivered in an intracellular compartment with lysosomal

hydrolases, which may activate them prematurely

Alcohol may also reactivate chronic pancreatitis due to secretion of protein-rich pancreatic fluid, which causes

deposition of inspissated protein plugs, causing obstruction of small pancreatic ducts

Acute interstitial pancreatitis: mild, with edema and fat necrosis only

Acute necrotizing pancreatitis: more severe, may get hemorrhagic pancreatitis as well as fat necrosis

Bile pancreatitis: Bile reflux through common bile duct into pancreatic duct due to abnormal junction, Archives 1985 May;109(5):433-6

Infected pancreatic necrosis: secondary infection of necrotic foci

Postoperative pancreatitis: due to trauma of exploration of common bile duct, gastric resection, papillary stenosis plus sphincterotomy

Chronic pancreatitis

Repeated attacks of pancreatic inflammation with loss of pancreatic parenchyma and replacement with fibrosis, variable pain, symptoms of pancreatic insufficiency (malabsorption, diabetes)

May simulate or coexist with pancreatic carcinoma

Demographics: Attacks precipitated by alcohol, overeating, opiates, other drugs

Men, 40+, often alcoholics; biliary disease usually not a factor in chronic pancreatitis

Other risk factors: hypercalcemia, hyperparathyroidism, hyperlipoproteinemia, pancreas divisum (seen in 12%), pancreatic neoplasm, cystic fibrosis; no known risk factor in 30%

Also associated with mumps, polyarteritis nodosa, sarcoidosis, malakoplakia, primary sclerosing cholangitis, HIV (mild changes)

Diagnosis: requires high degree of suspicion; mildly elevated amylase during attacks; CT scan shows calcifications; weight loss, intractable abdominal pain, hypoalbuminemia and associated edema due to pancreatic insufficiency

Treatment: pancreatic duct drainage, Whipple resection (relieves pain in 50% of patients with pain)

Complications: pseudocysts in 10%, also pseudoaneursyms, polyarthropathy, avascular bone necrosis; rarely causes widespread metastatic fat necrosis (from liberation of lipase) affecting legs, mediastinum, pleura, pericardium, bone marrow, liver, skin (erythema nodosum like lesions), localized portal hypertension due to fibrosis of splenic vein in alcoholic hepatitis (Archives 1997;121:612)

Gross: hard, dilated ducts, visible calcified concretions (protein plugs), pseudocysts common; 5% have obstruction due to tumor or stones

Micro: loss of acini with relative sparing of islets, irregularly distributed bland periductal fibrosis, variable obstruction of pancreatic ducts of all sizes; chronic inflammation (including mast cells) around lobules and ducts; dilated ducts with concretions; ductal epithelium is atrophic, hyperplastic or undergoes squamous metaplasia; islets may become sclerotic and disappear; associated with Brunner gland hyperplasia in duodenum; may have islet cell proliferation with invasive-like pattern

Positive stains: trichrome, actin

DD (clinically): pancreatic xanthomatous neuropathy associated with hyperlipidemia, Hum Path 1993;24:1023

References: Archives 2001;125:1051, Archives 2000;124:1302, Hum Path 2001;32:1174

Subtypes of chronic pancreatitis

Familial hereditary pancreatitis

top

Childhood onset, increased risk for pancreatic carcinoma

Autosomal dominant with mutation at trypsinogen codon 117 that removes a proteolytic cleavage site, causing persistent trypsin activation

Groove pancreatitis

top

Scar develops between head of pancreas and duodenum

Non-alcoholic tropical pancreatitis

top

Due to protein-calorie malnutrition

CMV pancreatitis

top

Case report of disseminated CMV infection presenting with acute pancreatitis and acalculous cholecystitis in post-chemotherapy patient, Archives 1989;113:1287

Eosinophilic pancreatitis

top

Very rare (<20 cases reported)

Usually peripheral eosinophilia and multiorgan involvement; may have elevated serum IgE

May have hypereosinophilic syndrome: eosinophil count >1500 cells/mm³ sustained over ≥6 months, history of allergic manifestations such as rhinitis and bronchial asthma, involvement of other organ systems such as skin, heart, GI tract, no other recognizable cause for eosinophilia, including parasitic infections and leukemia

May present as a pancreatic mass or common bile duct obstruction simulating malignancy

Micro: diffuse periductal, acinar and septal eosinophilic infiltrate affecting arteries and veins or clusters of eosinophils associated with pseudocysts; also fibrosis

DD: pancreatic allograft rejection, pseudocyst, lymphoplasmacytic sclerosing pancreatitis (eosinophils focal), inflammatory myofibroblastic tumor, Langerhans’ histiocytosis, systemic mastocytosis

References: AJSP 2003;27:334

Graft versus host disease (GVHD)

top

Associated with autopsies of children with congenital immune deficiencies with GVHD of other organs

To diagnose, must pay careful attention to pancreatic ducts

Micro: lymphocytes around large to medium ducts, damage to ductal epithelium (focal necrosis, reactive nuclear changes, inspissated secretions in duct lumens), and periductal edema

References: Hum Path 1994;25:908

Herpes simplex pancreatitis

top

Gross: small, discrete foci of hemorrhagic necrosis

Micro: parenchymal necrosis, hemorrhage, minimal fat necrosis, mild neutrophilic infiltrate compared to intensity of necrosis; atrophic acinar cells; numerous eosinophilic intranuclear inclusions with clear halos (Cowdry type A), many multinucleated giant cells with hyperchromatic irregular nuclei and eosinophilic cytoplasm; some nuclei have basophilic, ground-glass/smudged appearance

References: Archives 2003;127:231

Lymphoplasmacytic sclerosing pancreatitis

Aka PSC-like pancreatitis, non-alcoholic duct destructive chronic pancreatitis

Resembles primary sclerosing cholangitis involving the pancreas

Forms mass that may constrict bile duct with dense periductal inflammatory infiltrate, and clinically is thought to be malignant

May have allergic history or be associated with other autoimmune disorders (ulcerative colitis, primary sclerosing cholangitis)

Mean age 57 years, range 19 to 87 years, usually male

By definition, no known cause for chronic pancreatitis, and features of classic chronic pancreatitis (fat necrosis, pseudocysts, calcifications, dilated ducts with inspissated secretions) are absent

Treatment: steroids

Gross: pancreatic mass with regional nodal swelling; narrowing of main pancreatic duct

Micro: prominent periductal and acinar lymphoplasmacytic infiltration and fibrosis around the pancreatic ducts; marked acinar atrophy, phlebitis of pancreatic and portal veins; may have focal eosinophilic infiltrates; similar changes in bile duct and gallbladder; no calcifications, no fat necrosis, no cyst formation

DD: pancreatic adenocarcinoma

References: Hum Path 1991;22:387, AJSP 2003;27:110, Archives 2000;124:1535

Miscellaneous

Minor Abnormalities

Acinar dilation is associated with uremia, dehydration, severe bacterial infections, bone marrow transplant

Altered acinar cells is associated with tobacco, alcohol, pancreatic endocrine excess, chemotherapy;

3 patterns: (a) small groups of cells with reduced cytoplasm, less basophilia, more vacuolation, condensed nuclei, resemble islets; (b) normal sized cells without basophilia with basal nuclei; (c) cells with variable size and occasional large irregular nuclei

Focal fibrosis is associated with older age or diabetes mellitus

Hemosiderin deposition may be due to primary hemochromatosis or chronic blood transfusions, Archives 1985;109:996

Lipomatosis is associated with older age

Marked fatty atrophy is associated with type II diabetes and severe generalized atherosclerosis

Mucinous (goblet cell) metaplasia is associated with older age, chronic pancreatitis, carcinoma (DD: PanIN-1A)

Oncocytic change is associated with chemotherapy

Proliferation of centroacinar or intercalated duct cells is associated with recent ductal obstruction, acute

alcohol abuse, chronic pancreatitis, hyperinsulinemia or hypergastrinemia

Squamous metaplasia is common, associated with chronic pancreatitis, normal pancreas, bone marrow transplant with chemotherapy, Hum Path 1993;24:152

Pancreas transplantation

Indications: chronic pancreatitis, IDDM (type 1 diabetes)

Early complications: graft pancreatitis, pancreatic thrombosis, endothelialitis of capillaries and venules

Late complications: recurrence of original disease, rejection (vasculitis, obliterative endarteritis, periductal

lymphocytic infiltrate), mononuclear inflammation which preferentially destroys beta cells

Poor prognosis: moderate to severe acinar inflammation, acinar tissue loss, fibrosis, vascular luminal narrowing, AJSP 1992;16:1098

Note: Transplanted islets produce more glucagon than insulin

Acute pancreas allograft rejection vs. posttransplantation lymphoproliferative disease (PTLD)

Distinction important since diagnoses have opposite treatments

Rejection: >75% mixed small and large T lymphocytes, fewer mature plasma cells, variable eosinophils; <10% atypical cells; inflammation of acini, veins, arteries, ducts; associated with acinar cell damage

PTLD: nodular and expansile infiltrates, mostly atypical, plasmacytoid B cells, occasional Reed-Sternberg-like cells; random involvement of parenchyma, no apparent affinity for the acinar tissue; extensive infiltration of peripancreatic soft tissues is common, no involvement of arterial walls unless concurrent acute vascular rejection; positive in-situ hybridization for Epstein-Barr virus encoded RNA

Rejection and PTLD both demonstrate necrosis, infiltration of venous walls with associated endothelialitis Specimens with rejection and PTLD have combinations of these features, Hum Path 1998;29:569

Diabetes mellitus - general

Chronic disorder of carbohydrate, fat and protein metabolism due to defective or deficient insulin secretory response

Demographics: 3% of world population, 13 million in U.S. but only 50% are clinically diagnosed

54,000 deaths/year in U.S., #7 leading cause of death

Lifetime risk: type 1 – 0.5%, type 2 – 5%

Numerous variations, all with hyperglycemia

Causes: destruction of islets due to pancreatitis, tumors, drugs (steroids, thiazides, pentamidine), hemochromatosis (“bronze diabetes” due to hemosiderin deposition in pancreas), hereditary ceruloplasmin deficiency (Hum Path 1997;28:499), surgery, infections (congenital rubella, CMV, coxsackievirus [Archives 1980;104:438]), endocrinopathies (pituitary, adrenal, pregnancy), gestational diabetes or idiopathic

Long term complications: damage to blood vessels in kidneys (nodular Kimmelstiel-Wilson glomerulopathy, pyelonephritis, papillary necrosis), eyes (exudative and proliferative retinopathy), nerves (symmetric polyneuropathy); peripheral vascular disease and coronary artery disease are major causes of morbidity / death

Diagnosis: high fasting glucose or impaired glucose tolerance (without diabetes, oral glucose loads cause only slight rise in blood glucose due to brisk insulin response; with diabetes, blood glucose rises markedly for a sustained period)

Micro: Type 1 - inconsistent reduction in number and size of islets, uneven insulinitis (T lymphocytes)

Type 2 - subtle reduction in islet cell mass, amyloid replacement of islets due to amylin fibrils (also seen in

aging nondiabetics); associated with marked fatty replacement

Infants of diabetic mothers – islet cell hypertrophy/hyperplasia

IDDM, insulin-dependent diabetes mellitus

Aka juvenile onset, IDDM; formerly called Type 1; 10% of all cases

Due to reduction in beta cell mass causing severe, absolute lack of insulin

Without insulin, patients develop diabetic ketoacidosis (DKA), coma and death

Onset at age < 20 years, normal weight, decreased blood insulin, anti-islet cell antibodies present, DKA common

Islet cell destruction: due to genetic predisposition, autoimmunity, environmental insult; initially with mononuclear cell infiltrates

Genetic predisposition: usually Northern European descent; 70% concordance in identical twins, HLA-D linked; may affect immune responsiveness to a beta cell autoantigen or method of presentation to T cells

Autoimmunity: usually chronic (years); clinical disease when 90% of islet cells are destroyed

Associated with CD8+ T cell infiltrate

Islet cell autoantibodies seen in 70% of patients; antigens are glutamic acid decarboxylase (GAD), islet autoantigen 2, insulin associated antibody, gangliosides; GAD antibodies precede clinical symptoms

GAD antibody: in most newly diagnosed patients, 80% of first degree relatives;

GAD antibody causes stiff man syndrome, whose patients often have a history of IDDM

Immunosuppressive therapy ameliorates IDDM in animals and children with new onset disease

Some NIDDM patients have autoantibodies, but no other features of IDDM

Many IDDM patients also have anti-thyroid peroxidase, anti-parietal cell and anti-adrenocortical antibodies

Case report of acute onset in an adult with T cell pancreatic infiltrate and death within 3 days, Archives 1994;118:84

Environmental factors: may explain variations in rates – 60 x higher incidence in Finnish vs. Korean children

Viruses may damage beta cells, exposing antigens which trigger an autoimmune response

Molecular mimicry (immune response develops against shared amino acid sequences): GAD & Coxsackie B4

virus share a six amino acid sequence

Case report of islet inflammation with Coxsackie B5 infection, Hum Path 1982;13:661

Retrovirus may serve as a superantigen

Clinical: characterized by PPP (polyuria, polydipsia, polyphagia) and DKA

Severe fasting hypoglycemia is due to cessation of glycogen storage in fat and muscle

Glycosemia causes glycosuria with depletion of water and electrolytes

Polyphagia combined with weight loss is specific for diabetes

Also: low/absent plasma insulin, high plasma glucagon, unstable glucose tolerance (very sensitive to changes

in insulin, diet, exercise, infection, stress), presence of free fatty acids (due to breakdown of adipose stores), which produces ketone bodies (acetoacetic acid and beta-hydroxybutyric acid)

NIDDM patients rarely have polyphagia or weight loss; may get hyperosmotic nonketotic coma - dehydration due to hyperglycemic diuresis with failure to drink enough fluids to compensate, often in an elderly person with diabetes and stroke/infection

Micro: early insulinitis with marked islet atrophy and fibrosis and severe beta cell depletion

Non-insulin dependent diabetes mellitus

Aka adult onset, NIDDM; formerly called type 2

80-90% of cases of diabetes

Usually > 30 years old, obese (80% of cases, abdominal obesity more important than subcutaneous obesity),

normal or increased blood insulin, no anti-islet antibodies, rare diabetic ketoacidosis

90%+ concordance in twins, but no HLA association; apparently due to multiple genetic polymorphisms

Relative insulin deficiency is due to insulin resistance or derangement in beta cell secretion of insulin

Early: normal insulin secretion and plasma levels, but loss of pulsatile, oscillating pattern of secretion; also loss of rapid first phase of insulin secretion triggered by glucose; NO insulinitis is present

Later: mild/moderate insulin deficiency, may be due to beta cell damage; beta cells may be “exhausted” due to chronic hyperglycemia and persistent beta cell stimulation

Insulin resistance in peripheral tissues also seen in obesity and pregnancy

Amylin: 37 amino acid peptide, normally produced by beta cells, packaged and cosecreted with insulin; in NIDDM patients, tends to accumulate outside beta cells and resembles amyloid

Amyloid present is associated with basement membrane heparan sulfate proteoglycan, Archives 1992;116:951

Note: NIDDM is associated with amyloid deposits in pituitary, confirmed by anti-amyloid lambda light chain and P components, Archives 1995;119:1055

Maturity onset diabetes of the young, MODY

<5% of all cases of diabetes, mild hyperglycemia

Autosomal dominant, due to genetic defects in beta cell function

Onset before age 25, normal weight

Defects in Hepatic Nuclear Factor (HNF) 1 or 4 alpha, glucokinase, mitochondrial DNA (associated with

deafness)

No GAD antibodies, no insulin resistance, no beta cell loss but impaired beta cell function

Diabetic complications

Main complications are microangiopathy, retinopathy, nephropathy, neuropathy – all due to hyperglycemia

Kidneys transplanted into diabetic patients develop nephropathy within 3-5 years but kidneys from diabetic

patients transplanted into normal patients have remission of nephropathy

Strict control of diabetes delays progression of microvascular complications

Complications are due to nonenzymatic glycosylation and disturbances in polyol pathways

Nonenzymatic glycosylation

Glucose + protein => Schiff base (protein - NH = CH (CHOH)4-CH2OH) => Amadori product

(protein-NH-CH2-C=0-(CHOH)3-CH2OH => protein-protein cross linking via N-C-N bonding

Early reactions are reversible, and related to HbA1c level; advanced glycosylation end products (AGE) are not reversible

AGE traps LDL in blood vessels, enhances cholesterol deposition, accelerating atherosclerosis

AGE inhibition antagonizes diabetic complications in experimental models

Polyol pathways

Important in tissues that don’t require insulin for glucose transport, i.e. nerves, lens, kidneys, blood vessels

High intracellular glucose plus aldose reductase produces sorbitol and later fructose, causing water influx and osmotic cell injury

In lens, causes swelling and opacity

Inhibition of sorbitol may reduce formation of cataracts and neuropathy

Vascular complications of diabetes

Accelerated atherosclerosis in aorta and large/medium sized vessels

Myocardial infarction: most common cause of death, M=F

Gangrene of lower extremities; relative risk is 100:1

Micro: hyaline arteriolosclerosis, associated with hypertension, more common/severe in diabetes but not specific; amorphous hyaline thickening in arteriolar wall; related to severity of disease and hypertension

microangiopathy: diffuse basement membrane thickening with protein leakage in capillaries of skin, skeletal muscle, retina, renal glomeruli, renal medulla, renal tubules, Bowman capsule, peripheral nerves, placenta

Diabetic nephropathy

#2 cause of death in patients with diabetes after myocardial infarction

Glomeruli - capillary basement membrane thickening, diffuse glomerulosclerosis, nodular glomerulosclerosis

Nodular glomerulosclerosis: ball-like deposits of laminated matrix within mesangial core of lobule; push capillary loops to periphery, may have perinodular halos; called Kimmelstiel-Wilson lesion and may contain trapped mesangial cells; low sensitivity (10-35%) but highly specific for diabetes mellitus

Diffuse glomerulosclerosis: diffuse increase in mesangial matrix, mesangial cell proliferation, basement membrane thickening; seen in most patients with diabetes mellitus after 10 years; when marked, causes nephrotic syndrome; not specific

Also renal atherosclerosis and arteriolosclerosis; changes to efferent arteriole are specific for diabetes

Pyelonephritis: more common and more severe with diabetes mellitus; necrotizing papillitis also more common

Ocular

#4 cause of blindness in US

Associated with retinopathy, cataracts, glaucoma

Neuropathy

Peripheral, symmetric neuropathy of lower extremity most common, sensory more common than motor

Cysts

True cysts

Congenital cysts often associated with polycystic disease affecting liver and kidney, von Hippel Lindau syndrome or oral-facial-digital syndrome type I ; also Meckel-Gruber syndrome; Ivemark syndrome of renal, hepatic, and pancreatic cystic dysplasia; trisomy 13, 14, and 15; Jeune syndrome; short-rib polydactyly syndrome of Saldino-Noonan; Elejalde syndrome; glutaric aciduria II; tuberous sclerosis; single cysts may be due to abnormal duct development

Case report of multilocular cysts associated with choledochal cyst, Hum Path 2003;34:99

Cysts of cystic fibrosis (below)

Dermoid cysts: seen in young patients

Epidermoid cysts: may be present within an intrapancreatic spleen

Esophageal cysts attached to pancreas: rare; unilocular, smooth surfaced with clear mucoid material, ciliated epithelium resembles bronchogenic cyst, but no respiratory glands, no cartilage and had two smooth muscle layers, AJSP 1996;20:476

Mesothelial cysts: may be multiple and involve pancreas, liver, kidney or other abdominal structures, case report with elevated CA19-9 Archives 2001;125:944

Multicystic pancreatic hamartomas: rare, Hum Path 1992;23:1309

Non-epithelial cysts: includes lymphangioma

Tumors that are cystic: includes serous cystadenomas and mucinous cystic neoplasms (cysts due to intraluminal secretions), IPMN and IOPN (copious secretions of intraductal neoplasms cause massive cystic dilation of native ducts seen as cysts on CT/MR scans), usual pancreatic ductal adenocarcinoma and solid-pseudopapillary tumors (cysts due to degeneration), mucinous non-neoplastic cysts (newly described entity, below)

Pancreatic tissue derived cysts: may appear in thorax or mediastinum, as components of gastroenteric duplication cysts, intralobar pulmonary sequestrations, teratomas or rarely from pure pancreatic tissue, Mod Path 1996;9:210

Cystic fibrosis

Incidence: 1 in 20 in U.S. are carriers; most common mutation is #708 (seen in 70% with disease)

Mutations cause reduced chloride ion in secretions, thicker respiratory secretions, upper respiratory infections

Get pancreatic insufficiency late in disease course

Mutations also cause defective cilia and infertility

Meconium ileus seen in 5-10% of patients; also intussusception

Cysts form secondary to ductal obstruction due to thick, tenacious secretions

Micro: pancreatic ducts diffusely dilated and filled with numerous lamellated concretions; associated with fibrosis;

nondiabetic patients have fibrocystic changes with normal islets, prominent nesidioblastosis, some persisting exocrine tissue; young adult diabetic patients have total loss of exocrine pancreas with fat replacement, no nesidioblastosis, reduced islets, Hum Path 1984;15:278

Positive stains (mucus globules): PAS+ diastase resistant, CEA, alpha-1-antitrypsin

DD: Kartegeners (defective cilia syndrome)

References: Archives 1989;113:1142

Lymphoepithelial cysts

A type of congenital cyst similar to branchial pouch derived structures

80% male; mean age 56 years, range 35-82 years

Present with abdominal pain or nausea, or as incidental findings

Not associated with immunosuppression or autoimmune diseases

In some cases, may develop from epithelial remnants in lymph nodes or an accessory spleen located in the pancreas, Mod Path 1998;11:1171

May arise similar to Warthin’s tumors, in which lymphoid cells have an affinity for ductal epithelia and can induce their growth

Benign, do not recur or progress

Gross: mean size 5 cm (range, 1-17 cm), cysts contain keratin or clear fluid; often round and well-demarcated from surrounding pancreas

Micro: unilocular or multilocular, lined by squamous epithelium, with lymphocytes and germinal centers in the wall; occasional solid lymphoepithelial islands, rarely mucinous goblet cells; keratin granulomas may be present

DD (clinical-but all lack lymphoid stroma): mucinous cystic neoplasms, IPMN, IOPN

DD (histologic): dermoid and epidermoid cysts (mean ages 29 and 37 years, M=F, prominent mucinous cells or respiratory mucosa in dermoid cyst), lymphangiomas (positive for endothelial and lymphatic markers), pseudocysts (peripancreatic, no lymphoid stroma)

References: Mod Path 2002;15:492, AJCP 1992;98:188; AJSP 1987;11:899, Archives 1990;114:85, Hum Path 1991;22:924

Mucinous non-neoplastic cyst

Recently described in Mod Path 2002;15:154

Men and women, mean age 57

No recurrences after 2 year mean follow-up; may be nonneoplastic

Gross: usually unifocal, head of pancreas, thin walled cysts that don’t communicate with ductal system

Micro: cuboidal/columnar mucin producing cells with small amount of dense fibrous stroma; no ovarian type stroma; no cellular atypia or increased proliferation; no communication with duct or biliary system