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

Micro images: image1, intercalary duct, large excretory duct

Cytology: figure 3

Exocrine Pancreas

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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

Micro images: acinar cells

Endocrine Pancreas

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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

Micro images: islets #1, #2

EM images: zymogen granules

Embryology

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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

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Usually associated with severe malformations, not compatible with life

Annular pancreas

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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

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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

Micro images: jejunum, Meckel’s diverticulum in Crohn’s patient-figure 3, stomach-purely endocrine#1, #2, gastroesophageal junction, acinar cell carcinoma in jejunum, ductal carcinoma in jejunum

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

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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

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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

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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

Gross images: fat necrosis

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

Micro images: image1

Physiology of acute pancreatitis:

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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

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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

Micro images: figures 3/4

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, AJSP 2003;27:110

Subtypes of chronic pancreatitis

Familial hereditary pancreatitis

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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

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Scar develops between head of pancreas and duodenum

Non-alcoholic tropical pancreatitis

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Due to protein-calorie malnutrition

CMV pancreatitis

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

Eosinophilic pancreatitis

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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)

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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

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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

Gross/micro images: image1

References: Archives 2003;127:231

Lymphoplasmacytic sclerosing pancreatitis

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Also called autoimmune pancreatitis, PSC-like pancreatitis, non-alcoholic duct destructive chronic pancreatitis; recently described as example of “hyper-IgG4” disease (BMC Med 2006;4:23)

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 (i.e. no alcohol abuse), and features of classic chronic pancreatitis (fat necrosis, pseudocysts, calcifications, dilated ducts with inspissated secretions) are absent

Laboratory: elevated serum IgG4

Treatment: steroids; overall prognosis is excellent

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

Micro images: various images #1; #2; #3

DD: pancreatic adenocarcinoma

References: Hum Path 1991;22:387, AJSP 2003;27:110, Archives 2000;124:1535, AJSP 2003;27:334, Archives 2005;129:1148

Miscellaneous

Minor Abnormalities

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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