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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Associated with severe intrauterine growth retardation, early onset of diabetes mellitus without ketoacidosis, failure to thrive due to pancreatic insufficiency and malformations of the biliary system and the heart (Klin Padiatr 2005;217:76)

High mortality

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

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 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, micro image1, Hum Path 1993;24:152

Pancreas transplantation

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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

Diabetes mellitus - general

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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

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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

Micro images: image1

Non-insulin dependent diabetes mellitus

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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

Micro images: amyloid deposition

Maturity onset diabetes of the young, MODY

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<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

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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

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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

Micro images: image1

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

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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; AJSP 2003;27:110

Lymphoepithelial cysts

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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

Gross images: image1

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

Micro images: image1, image2, image3, image4, image5, image6, image7

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

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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

Gross images: image1

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

Micro images: image1

Positive stains: CK 7, CK 8, CK 18, CK 19, CK20, Ca 19-9, MUC5AC

Negative stains: trypsin, CEA, synaptophysin, chromogranin A, calretinin, alpha-inhibin, MUC1 (usually), MUC2, progesterone receptor

DD: mucinous cystic neoplasms (body/tail, women, atypia, ovarian-like stroma; similar epithelial lining and immunostaining)

Pseudocysts

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Localized collections of pancreatic secretions that develop after pancreatitis (acute or chronic), trauma, ductal calculi, obstructive neoplasms

Painful, may cause hemorrhage of splenic artery, infection, perforation

Treatment: excise small pseudocysts in body/tail, drain pseudocysts in head

Complications: abscess, erosion into blood vessels and hemorrhage, perforation into a hollow viscus

Gross: 85% solitary, usually unilocular, in/near pancreas; thick, irregular wall, ragged inner surface, cloudy intraluminal contents

Micro: no epithelial lining, fluid has high amylase content, cyst arises from drainage of pancreatic secretions from damaged ducts into interstitial tissue, which becomes walled off by fibrous tissue; cyst wall contains histiocytes, giant cells, granulation tissue, rarely eosinophils; cyst may communicate with ductal system

DD: pancreatic neoplasm, particularly if multiloculated; sterile abscess with liquefactive necrosis

References: AJSP 2003;27:110, AJSP 2003;27:334

Tumors of pancreas

Ductal, endocrine or acinar origin; defined based on line of differentiation, not cell of origin

Ductal adenocarcinoma, NOS

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also known as Usual Ductal Adenocarcinoma (UDA), tubular type

85% of pancreatic cancers are ductal adenocarcinoma not otherwise specified (NOS)

#5 cause of cancer death in US after lung, colon, breast, prostate

Risk factors: smoking, alcohol abuse (particularly African-Americans), obesity, beta-naphthylamine or benzidine exposure, familial relapsing pancreatitis, older age

Uncertain risk factors: chronic pancreatitis, diabetes (may be secondary to carcinoma), male (M/F = 1.6:1)

Familial syndromes: hereditary nonpolyposis colorectal carcinoma (MIM 114500, MLH-1 or MSH-2 mismatch repair genes), familial atypical mole-melanoma syndrome (MIM 600160, p16 mutations); familial AD gene recently identified at 4q32-34 (Am J Hum Genet 2002;70:1044), BRCA2 (MIM 600185), Peutz-Jeghers syndrome (MIM 602216, STK11/LKB1 gene, Hum Path 1986;17:97), hereditary pancreatitis (MIM276000, cationic trypsinogen gene at 7q35), ataxia telangiectasia

Genetics: 90% have point mutations at codon 12 of Kras, a signal transducer for tyrosine kinase; may be early event, but Kras screening not clinically useful to date (Kras mutations in 40% of chronic pancreatitis patients, Hum Path 1999;30:602); 30-40% have c-myc structural alterations by immunostaining or FISH, Mod Path 2002;15:462

Other associated mutations: DPC4/SMAD4 gene (deleted in 50% of pancreatic carcinoma), p16 (#9p) in >95%, p21, Rb

60% have p53 mutations (present in 2/3 of PanIN lesions), 50% overexpress HER2

Clinical: 60% of tumors are in head, 15% in body, 5% in tail, 20% diffusely involve pancreas

Head tumors: tumor invades ampulla, obstructs bile flow, 50% have distention of biliary tree and progressive jaundice, 50% have pain, 85% have extension beyond pancreas at diagnosis

Body/tail tumors: large at diagnosis since don’t cause symptoms until late, 25% have peripheral venous thrombi, metastases common at diagnosis

Coexisting pancreatitis in 10%; may delay diagnosis while pancreatitis is treated

Symptoms: pain, weight loss, anorexia, malaise, weakness

Trousseau sign: migratory thrombophlebitis, in 10% due to tumor or tumor necrosis producing platelet-aggregating factors and procoagulants; causes arterial and venous thrombi, including pulmonary thromboemboli

Serum tests: SPan-1, CA19-9

Metastases: local lymph nodes (microscopic metastases found in 75% with T1, T2 disease); distant to liver, lung, peritoneum, adrenal, bone, distal nodes; supraclavicular node metastases may be presenting symptom

Tumor may track along biopsy needle path (also seminoma, pleomorphic adenoma)

Metastases to ovary may simulate primary mucinous ovarian tumors, AJSP 1989;13:748

Treatment (curative): distal pancreatectomy for body/tail tumors, Whipple resection (subtotal pancreaticoduodenectomy) for head/periampullary tumors; resect retroperitoneal nerves and nodes if Stage I/II to reduce local recurrence

Whipple perioperative mortality ~ 2%

Most (85%) tumors are not amenable to curable surgery; palliative treatment includes bypass operations, radiation therapy and chemotherapy

Treatment information by stage from National Cancer Institute

Prognosis: 5 year survival 2-4%, 90% die within 1 year; 5 year survival of 20% if localized non-metastatic (median survival 15-20 months), 6-10 months if locally advanced non-metastatic, 3-6 months if metastatic disease

Dependent on stage, size (<4.5 cm for resectable tumors), ? tumor grade, SMAD4 status (19 vs. 15 months, Clin Cancer Res 2001;7:4115)

Kras mutations detected by PCR in paraaortic lymph nodes is poor prognostic indicator, AJSP 2002;26:1578

Ductal adenocarcinoma (continued)

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Gross: poorly delineated (hard to measure size), gritty, gray-white, hard masses, infiltrates locally, 25% of head tumors extend to duodenal wall; if advanced, may be difficult to determine site of origin between pancreas, ampulla or common bile duct; 20% have multiple tumors

Gross images: figure 1

Micro: individual tubular glands surrounded by stroma; typically good architectural differentiation with marked atypia and extensive desmoplasia; mucin production is specific for ductal origin

Normal pancreas may show atrophic changes, chronic inflammatory infiltrate, fibrosis, ductal dilation beyond tumor mass

Well differentiated: pink apical band composed of mucin granules; basal cytoplasm has mucinous vacuoles; may appear benign but has irregular shape and distribution, desmoplasia, marked nuclear pleomorphism with nucleoli, loss of polarity, mitotic figures

Moderate/poorly differentiated: most tumors; abortive tubular structures, deeply infiltrative growth pattern

Micro images: image1, image2, CK7/CK20 (figures E/F)

Micro images (Mod Path subscribes): MUC1

Perineurial invasion: present in 90%, but also associated with benign epithelial inclusions and chronic pancreatitis; tumor invades along nerve tract, typically with better differentiated glands; causes back pain, predicts poor prognosis

Angiolymphatic invasion: in 50%

High grade PanIN: in 20%, may be distant from main tumor mass or at margin

Low grade PanIN: in 30%

Squamous metaplasia, pyloric gland metaplasia, focal epithelial hypertrophy – seen in tumors and controls

“Insular pancreas”: islets are preserved but acini are destroyed due to duct obstruction

Cytology: duodenal secretions are 80% sensitive in head tumors, 33% sensitive in tail tumors, ERCP juice is 50-85% sensitive, FNA is 90% sensitive; brushings are 50% sensitive (repeat if inconsistent with clinical or radiologic findings, Archives 2000;124:387); aspirates are cellular, without acinar cells, with atypical ductal cells in sheets, clusters or singly; enlarged nuclei; mitotic figures; may be adjacent to benign ductal cells

Positive stains: mucin (gastric, small intestinal types), keratin, EMA, CEA, B72.3 (cannot use to differentiate tumor from chronic pancreatitis), CA19-9, Dupan-2, CK7, CA125 (48%)

Negative stains: CK20, estrogen receptor, MUC2, loss of DPC4 seen in 50%-specific for malignancy (in-situ or invasive) but only 50% sensitive, AJCP 2001;116:831

EM: mucigen granules on EM

Molecular: Kras mutations occur early during carcinogenesis, are present in 90% of tumors, associated with poor prognosis (Cancer 2007;109:1561); Kras mutation analysis of FNAs facilitates risk stratification of patients with a pancreatic mass (J Clin Gastroenterol 2007;41:906)

DD: chronic pancreatitis (normal architecture at low power with central ectatic branched ductules and clusters of round ductules surrounded by cuff of stroma vs. haphazard architecture of UDA with occasional glands immediately adjacent to adipocytes; UDA has cell-to-cell variability of 3-4 x difference in nuclear size, loss of cell polarity, perineurial invasion, individual cell infiltration, budding into lumen)

DD of hepatic lesions: bile duct adenomas in liver may contain bile but have normal architecture and uniform cytology vs. UDA metastatic to liver

Reference: AJSP 2002;26:1578

Familial fibrocystic pancreatic atrophy with endocrine cell hyperplasia and pancreatic carcinoma

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Autosomal dominant, high penetrance, associated with diabetes mellitus, exocrine pancreatic insufficiency, characteristic imaging abnormalities

Gross: fibrosis, intraductal calcifications, microcysts

Micro: lobulocentric patchy to diffuse fibrocystic changes (collagenization, microcysts) with stromal fibrosis, acinar atrophy, endocrine cell hyperplasia resembling nesidioblastosis, multifocal PanIN 2-3; minimal background pancreatitis; malignancies often unusual histology: small cell, giant cell anaplastic, cystadenocarcinoma, AJSP 2001;25:1047

Exploration and frozen section of possible pancreatic adenocarcinoma

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First check for metastatic disease in peripancreatic nodes, liver, peritoneum

Intraoperative pancreatic FNA minimizes hemorrhage, pancreatitis, tumor seeding

Highly suspicious for tumor if dilation of common bile duct and jaundice but no biliary tract stones

Frozen section: look for disorganized duct distribution, variation in nuclear size of at least 4:1, incomplete duct lumen; minor criteria are infiltrating single cells, perineurial invasion, mitotic figures, necrotic glandular debris

Micro images: image1

Note: for patients with colloid carcinoma (larger tumors, typically in head, mucin lakes microscopically), avoid incisions into the tumor to prevent thromboemboli or tumor dissemination

DD: chronic pancreatitis

References: Archives 2002;126:1169, AJSP 1981;5:179

Adenosquamous carcinoma

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Malignant squamoid and glandular components

Rare, M/F = 2:1, mean age 65

May resemble adenoacanthomas (benign squamous component), well differentiated squamous cell carcinoma with keratinization, poorly differentiated squamous cell carcinoma without keratinization, basaloid carcinoma

Worse prognosis (mean survival 6 months) than usual ductal adenocarcinoma of pancreas, Mod Path 2001;14:443

CK903 and CD44 highlight squamoid portion of tumor; otherwise similar immunostaining and Kras mutations as usual ductal adenocarcinoma

Pancreatic “squamous cell” carcinoma may be adenosquamous carcinoma with exuberant squamous component

Metastases may contain only glandular component

Aspirates show extensive necrosis with dense blue globules, squamous ghosts, anucleate squames, atypical single cells, enlarged pyknotic nuclei

Micro images: image1, image2, image3, image4, mucicarmine, CK5/6

References: Archives 2000;124:212

Colloid (mucinous noncystic) carcinoma

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Aka pure mucinous or gelatinous carcinoma

Tumors composed predominantly (80%+) of scanty malignant epithelial cells floating in nodular extracellular mucin lakes with muconodular invasive component of 1 cm or more; mucin tends to be retained during histologic processing

Mean age 61; M=F, usually in head of pancreas

Associated with IPMN, ampullary/duodenal tubulovillous adenomas, mucinous cystic neoplasm

Commonly see perineurial invasion and regional lymph node metastases

Compared to UDA, are larger tumors (5.5 cm), lower stage, better survival

Physiology: inverse polarization of cells (mucin glycoproteins in stroma-facing surfaces vs. luminal surface or diffuse in usual ductal adenocarcinoma), lack of external lamina or basement membrane, and expression of MUC2 (rare in UDA) may cause accumulation of extracellular mucin, which contains tumor spread

Survival: 5 year survival 57% (vs. 5% for usual ductal carcinoma); long survival even with nodal metastases, perineurial invasion, vascular invasion; but see AJSP 2002;26:56 (similar survival to usual ductal carcinoma using 50% as the minimal required colloid component)

All patient deaths in one study associated with surgical incision into the tumor or core biopsy; incisional biopsy may contribute to thromboembolism or tumor dissemination

Gross: soft, mean 5 cm

Micro: tumor cells are highly atypical and found within mucin, tended to be cribriform/stellate clusters, signet-ring cells (not in stroma), small tubules; tumor cells may also line the mucin lakes; perineurial invasion common

Usually arise in association with IPMN or tubular/tubulovillous adenoma; most of tumor consists of mucin lakes

Micro images: MUC2

Cytology: difficult to spread thinly on slides due to abundant mucus; malignant cells may be rare

Positive stains: MUC2+ (marker of indolent mucin, UDA usually MUC2-), CEA

Negative stains: MUC1

Molecular: Kras mutations detected in 4 of 12; p53 in 2 of 9

EM: mucigen granules on stromal surface, no basement membrane

DD: usual ductal adenocarcinoma (some mucin but no mucin lakes), IPMN and mucinous cystic neoplasms (smooth contours, well-attached complete epithelium, mucin lost in processing)

References: AJSP 2001;25:26, AJSP 2003;27:571, Mod Path 2002;15:1087

Foamy gland pattern of pancreatic adenocarcinoma

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Deceptively benign-appearing pattern with prominent microvesicular (foamy) cytoplasm; also described in prostate

May be misinterpreted as benign mucinous ducts

Tumors are malignant architecturally and metastasize; clinical course, p53 and Kras mutations similar to usual ductal adenocarcinoma

Micro: well formed glands with bland cells but subtle infiltration; cells have microvesicular (white and crisply foamy) cytoplasm with distinct pink brush border like zone at the luminal portion of the cell; nuclei are basal oriented, dense or wrinkled (raisinoid)

Note: apical cytoplasmic folds in benign mucinous ducts should be differentiated from brush border-like zone

Foamy material is due to evenly sized mucigen granules that are mucin negative

Positive stains (brush border-like zone): mucicarmine, Alcian blue and high iron diamine, AJSP 2000;24:493; tumor cells positive for CEA, CK8, p53

Negative stains (brush border-like zone): PAS, MUC2

Intraductal oncocytic papillary neoplasm

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First recognized in 1996, AJSP 1996;20:980

M=F; mean age 62

Low malignant potential; surgery may be curative

Invasive in 20%, usually limited in extent with nested oncocytic pattern

Gross: usually in head; mean 6 cm; mucin filled cysts with nodular papillary projections; often with dilated ducts communicating with main tumor

Micro: papillary ducts composed of arborizing papillary structures with focal cribriform pattern, papillae lined by stratified and pseudostratified oncocytic cuboidal cells with intraepithelial lumina (highly specific, may contain mucin), abundant finely granular pink cytoplasm (due to mitochondria), prominent eccentric nuclei, microcystic spaces of 1-3 cell size; architecturally complex with atypical cytology, mitotic figures

Intraductal papillae may fuse and form large solid areas replacing the papillary architecture

Invasive component, if present, may resemble intraductal component

Positive stains: mucin in intraepithelial lumina, PTAH, 111-3 for mitochondria; B72.3 (uniformly), CEA (focal); focal apical MUC1+, dispersed MUC2+

Negative stains: p53, acinar cell markers (lipase, trypsin, chymotrypsin), neuroendocrine markers

Molecular: no Kras, p53 or SMAD4 mutations

EM: cells frequently packed with mitochondria

References: AJSP 2001;25: 942, AJSP 2002;26:1071

IPMN v IOPN:

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IPMN more often invasive (50% v 20%)

IPMN invades with a ductal or colloid pattern, not the oncocytic pattern of IOPN

IPMN usually have intestinal papillae, not the pancreaticobiliary type of IOPN

IOPN have intraepithelial lumina and are oncocytic

Intraductal papillary mucinous neoplasm (IPMN)

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Aka IPMT; first named in 1995, Archives 1995;119:209

Papillary proliferation of ductal epithelium with excessive mucin production, usually oozing from Ampulla of Vater, with ductal dilation

To diagnose, must detect endoscopically or radiologically or see gross cyst or mass (i.e. at least 1 cm in size)

May present with acute pancreatitis, Archives 1996;120:981

Multicentric with cytologic atypia; associated with Kras mutations

More common in men age 60+ at head of pancreas

Invasive tumors containing foci of IPMN have better behavior than usual ductal; must differentiate invasion from epithelial extension, Hum Path 2001;32:834

Somewhat indolent; 30% associated with invasive carcinoma, which is often colloid carcinoma; type of invasion depends on histology and MUC1/MUC2 pattern (see micro below), chart, Mod Path 2002;15:1087

Resection often is accompanied by frozen sections, since most lesions are contiguous

Prognosis often unpredictable, perhaps because presence of IPMN may indicate invasion elsewhere in gland

Treatment: resect entire tumor, sample extensively (> 50 blocks) to rule out invasion or atypia

Gross: May present as multilocular cystic masses

Gross images: figure 8

Micro: complex papillary fronds of mucin-producing epithelial cells; ductal fibrosis, acinar atrophy but well preserved islets; associated with chronic pancreatitis; no ovarian-type stroma

Micro images: image1, non-invasive in figure 4, invasive in figure 9

Reference: AJSP 2002;26:56

3 patterns of papillae:

Intestinal-type: more common, resemble colonic villous adenomas, may exhibit pale apical mucin reminiscent of gastric foveolar cells, MUC1-, MUC2+; when invasive, associated with colloid carcinoma (also MUC1-, MUC2+)

Pancreaticobiliary type: rare, complex arborizing papillae with 2-5 cell layers and cuboidal cells with prominent nucleoli, MUC1+, MUC2 negative/focal, less mucinous; more cytologic atypia; when invasive, associated with usual ductal adenocarcinoma (also MUC1+, MUC2-)

Oncocytic type: MUC1+, MUC2+

Note: benign or non-neoplastic pancreas is MUC1-; PanIN and invasive ductal NOS are usually MUC2-

Positive stains: often p27 positive

Grade as benign, borderline, malignant (invasive or not) based on cytologic atypia

DD: mucinous cystic neoplasms, PanIN (resembles small IPMN), IOPN (see below).

References: AJSP 2001; 25: 942, Mod Path 1999;12:518

IPMN in secondary ducts only

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Patients are slightly younger (median 55 vs. 64 years), associated with mild dilation of main duct

In-situ carcinoma in only 15%, no invasive carcinoma

Management is uncertain

References: AJSP 2000; 24: 1372

MCN versus IPMN

F >> M M > F

40-50 60-70

Tail Head

Not in duct In duct

Ovarian stroma No ovarian type stroma

Large duct pattern

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Ducts are clustered with irregular contours, may have desmoplastic stroma, usually is no cystic change

Focal microcystic appearance may be due to marked ectasia of infiltrating neoplastic glands, particularly near duodenal muscularis propria

Prognosis is similar to usual ductal adenocarcinoma

DD: Mucinous cystic neoplasm, IPMN, IOPN

Medullary carcinoma

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Associated with microsatellite instability, colonic adenocarcinoma

Gross: soft (since minimal desmoplastic stroma)

Micro: syncytial growth of poorly differentiated tumor cells accompanied by chronic inflammatory infiltrate, minimal desmoplastic stroma, pushing (expanding) border and extensive necrosis

Molecular: usually no Kras mutations, but 20% have inactivation of DNA mismatch repair system

Microglandular carcinoma

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Rare tumor, AJCP 1996;105:727

Micro: neuroendrocrine features; small uniform cells in sheets mixed with small microglandular / cribriform structures; cells with scan cytoplasm, small nucleoli

Positive stains: CAM5.2

Negative stains: chromogranin, synaptophysin, NSE, peptide hormones

EM: abortive glandular lumens, lined by imperfectly formed microvilli, well-developed junctional complexes; no dense core secretory granules or zymogen granules

DD: neuroendocrine tumors of pancreas (primary, metastatic)

Mucinous cystic neoplasm (MCN)

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Almost always women, mean age 45 (young), better prognosis than usual ductal adenocarcinoma

Present with abdominal pain or mass

Metastases usually restricted to abdominal cavity; metastases to ovary may simulate primary ovarian tumors

Can also occur in the liver

Cystic fluid has high CEA content and viscosity, low amylase compared to microcystic adenoma and pseudocysts, lower elastase I than pseudocysts; values may vary within different loculi of same neoplasm, AJCP 1993;100:425, Archives 1985;109:375

Rarely associated with anaplastic carcinoma, Archives 1997;121:1104, Archives 1997;121:533, or sarcomatous stroma with aggressive behavior; molecular analysis suggests monoclonal origin with subsequent divergence, Mod Path 2000;13:86; AJSP 1997; 21:70

Note: sample extensively to rule out an invasive component (Hruban claims benign if completely resect and entirely examine and no invasive component, AJSP 1999;23:1320

Classification: invasive mucinous cystadenocarcinoma (destructive stromal invasion, usually UDA type, rarely colloid type), MCN with carcinoma in situ (severe cytologic atypia, cribriform or bridging structures without fibrovascular cores), borderline MCN (moderate cellular and architectural atypia and papillary complexity) or mucinous cystadenoma (minimal atypia)

Gross: large (mean 10 cm); usually in body/tail, multilocular (occasionally unilocular) megacysts that don’t communicate with ductal system unless fistula are present; cyst wall is papillary, trabecular or thickened; has mucoid/watery cyst contents; must sample solid areas within the cyst

Micro: lined by tall mucin-producing cells, often forming papillae; intestinal or gastric foveolar-type features; calcification common; ovarian type stroma present which recapitulates fetal pancreatic mesenchyme around ducts (ER/PR+, inhibin+); may have mural nodules with features of giant cell tumor, MFH or anaplastic carcinoma; endocrine cells often scattered among columnar lining cells

Micro images: image1, MCN with sarcomatous stroma

Positive stains: MUC5AC, DPC4 present in in-situ areas (usually lost in invasive disease; AJSP 2000;24:1544); p53, EGFR

Negative stains: MUC1 (except in invasive components), MUC2 (except for faint staining of goblet cells)

Molecular: Kras mutations noted in in-situ or invasive areas

DD: IPMN (usually head, communicates with duct system), ovarian mucinous tumors (similar clinical and histologic appearance), pancreatic pseudocyst (MCN lining may be denuded so small biopsy may be falsely negative), cystic ductal adenocarcinoma

References: AJSP 1999;23:1320, AJSP 1999;23:410; AJSP 2002;26:466, AJSP 1987;11:11

Mucinous pancreatic tumors

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UDA has intracellular mucin with scattered mucicarmine positive cells

Tumors with stromal mucin are either UDA with marked mucin formation OR colloid type adenocarcinoma with large well-defined pools of mucin and few cells

Tumors with intraluminal mucin are either mucinous cystic neoplasms or IPMN

PanIN (pancreatic intraepithelial lesions)

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Premalignant lesions (except for PanIN-1A), first described in 1998, AJSP 1998;22:163

See http://pathology.jhu.edu/pancreas_panin

Note: click on description for microscopic images

Applies only to small caliber ducts, not the main pancreatic duct; for lesions too small to be seen grossly or by radiologic imaging

Chart: progression model of PanIN and pancreatic cancer

Normal: The normal ductal and ductular epithelium is a cuboidal to low-columnar epithelium with amphophilic cytoplasm. Mucinous cytoplasm, nuclear crowding and atypia are not seen
Squamous (transitional) metaplasia: Normal cuboidal ductal epithelium is replaced by mature squamous or transitional epithelium without atypia
PanIN-1A: Flat epithelial lesions composed of tall columnar cells with basally located nuclei and abundant supranuclear mucin. Nuclei are small, round to oval. If oval, the nuclei are perpendicular to the basement membrane. Also designated PanIN/L-1A to reflect that the neoplastic nature of many cases is not established. May demonstrate Kras mutations, although they are present in 70% of normal pancreata at autopsy
PanIN-1B: Epithelial lesions with a papillary, micropapillary or basally pseudostratified architecture, but otherwise identical to PanIN-1A

PanIN-2: Flat or papillary mucinous epithelial lesions with some nuclear abnormalities (some loss of polarity, nuclear crowding, enlarged nuclei, pseudo-stratification and hyperchromasia), but less than PanIN-3. Rare mitoses are non-luminal (not apical) and not atypical. Usually no true cribriforming luminal necrosis or marked cytologic abnormalities
PanIN-3: Papillary or micropapillary, rarely flat. True cribriforming, budding off of small clusters of epithelial cells into the lumen and luminal necroses suggests PanIN-3. Loss of nuclear polarity, dystrophic goblet cells (goblet cells with nuclei oriented towards the lumen and mucinous cytoplasm oriented toward the basement membrane), mitoses which may be abnormal, nuclear irregularities and prominent (macro) nucleoli

Additional micro images: image1, MUC1

Grade PanIN based on the highest grade component of a lesion.

Papillary high-grade PanIN associated with improved survival in invasive ductal adenocarcinoma patients with stage I-III disease in one study, Hum Path 2001;32:834

Ki-67 immunostaining increases with PanIN grade, image1, Mod Path 2002;15:441

PanIN associated with ampullary adenomas and adenocarcinoma, Mod Path 2001;14:139

Positive stains: MUC1

Negative stains: MUC2

References: AJSP 2001;25:579, Mod Path 2002;15:1087

DD:

Cancerization of ducts: Infiltrating carcinomas can extend into pancreatic ducts and ductules, mimicking PanIN-3. An infiltrating carcinoma close to a duct lesion and an abrupt transition from a highly atypical lesion to normal duct epithelium suggests cancerization of the duct or ductule. Serial sections may be helpful.
IPMNs are larger than PanIN, usually visible grossly or by radiologic imaging. IPMNs may extend into small ducts. Serial sections may be helpful.
Mucinous cystic neoplasms have ovarian stroma, NO connection to the duct system and larger size.

Reactive changes: consider if significant inflammatory cell infiltrates, particularly neutrophils

Signet ring/cord-like pattern

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Resembles mammary lobular carcinoma with targetoid pattern, signet ring cells, linear infiltration

Vacuolated/cribriform adenocarcinoma

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High grade tumors with gland-in-gland arrangement

Tumor cells form cribriform nests with multiple large vacuoles or microcysts containing cellular debris and mucin

May resemble fat necrosis; have necrotic material in lumen

Note: this pattern is rare in non-pancreatic adenocarcinomas, may be helpful in determining site of origin of metastases

DD: lipogranuloma, adenomatoid tumor, mesonephric adenoma, treated prostate cancer (metastatic), treated breast cancer (metastatic), vacuolated adenocarcinoma, signet-ring cells

Undifferentiated carcinoma - general

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7% of non-endocrine pancreatic malignancies

Anaplastic, osteoclastic giant cell tumor, sarcomatoid and carcinosarcoma variants

Usually involve body/tail, not head, M > F

Undifferentiated carcinoma - anaplastic

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Variant of ductal adenocarcinoma with distinctive appearance and extremely poor prognosis

Patients usually present with widely disseminated disease

Micro: pleomorphic tumor with discohesive, bizarre, multinucleated giant cells (not osteoclast-like); resembles giant cell carcinomas of lung, adrenal, liver; dense inflammatory infiltrate with emperipolesis (neutrophils in tumor cells)

Positive stains: EMA, keratin

Undifferentiated carcinoma - Osteoclastic giant cell tumor

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Different morphologically from anaplastic carcinoma, with better prognosis

Occasionally coexists with anaplastic carcinoma

Tumor cells (undifferentiated) appear to induce osteoclasts

Similar tumor in the liver

Resembles giant cell tumor of bone, Hum Path 1991;22:618

Gross: large, hemorrhagic

Micro: contain 5 cellular components - osteoclast-like giant cells, pleomorphic large cells, histiocyte-like mononuclear cells, atypical mononuclear cells (nucleus resembles pleomorphic large cells), ductal carcinoma cells

Positive stains:

Osteoclast-like giant cells: CD68+, keratin negative, no Kras mutation; non-neoplastic

Pleomorphic large cells (not always present): CD68-, often have Kras mutations

Histiocyte-like mononuclear cells: CD68+, keratin+, often have Kras mutations

Atypical mononuclear cells: CD68-, often have Kras mutations

Ductal carcinoma cells: CD68-, same Kras mutations as pleomorphic large cells and mononuclear cells

Molecular: osteoclast-like giant cells lack Kras mutations, but mononuclear cells have similar Kras mutations as ductal carcinoma cells, AJSP 1998;22:1247, Hum Path 2000;31:1223, Archives 1998;122:266

Undifferentiated carcinoma - carcinosarcoma / sarcomatoid carcinoma

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Rare, <10 cases reported through 2003

Mean survival 6 months

Biphasic with epithelial/glandular and sarcomatoid components

Heterologous differentiation (cartilage, bone, striated muscle) may be present

Case report with usual type adenocarcinoma and MFH, Archives 2002;126:1114

Micro images: image1

Pancreatic endocrine neoplasms

Pancreatic endocrine neoplasms - general

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3-5% of pancreatic neoplasms

“Islet cell tumors” is inaccurate, as they are believed to arise from pluripotential ductal cells that have the capacity to differentiate along neuroendocrine lines

All are considered malignant except microadenomas (less than 5 mm, usually incidental at autopsy), since are no definite histologic criteria to differentiate benign and malignant (except for metastases); no TNM staging exists for these tumors

One proposal: classify as low grade if no necrosis and 0-1 MF/50 HPF; as intermediate grade if necrosis OR 2+ MF/50 HPF

80% occur in MEN1 patients, usually age 50-60

Most tumors are functional and secrete multiple hormones (AJSP 1996;20:1378), hCG more common in malignant tumors

Usually occurs in adults in body/tail

Tumors are either syndromic or not; non-syndromic may produce hormones so don’t call “non-functional”

Tumors are hypervascular and circumscribed with octreotide scan (highlights somatostatin receptors),

Usually slow growing, metastases to nodes, liver, bone; recommend resection of metastases for palliative relief

Gross: pink (resemble spleen, lymph node), no well defined capsule, variable fibrous tissue, calcium, bone, cysts (see below)

Gross images: image1, image2

Micro: nests of polygonal cells with moderate to abundant eosinophilic cytoplasm resembling carcinoid tumors due to delicate vasculature, salt and pepper chromatin.

Solid, gyriform, trabecular and glandular patterns with minimal to moderate fibrosis but NO desmoplasia

Architecture is associated with type: Solid – any type; gyriform – alpha cells, beta cells, PP types; glandular –

gastrin, VIP

Amyloid is produced by insulin-secreting tumors (from amylin or somatostatin)

Cells are less polarized than acinar cell carcinoma

Rarely exhibits true glandular formations

No necrosis, minimal mitotic figures and low Ki-67 counts (if high mitoses or Ki-67, question the diagnosis)

May display endocrine atypia with marked nuclear enlargement and cytomegaly, but there is preservation of

N/C ratio, even chromatin and even nuclear membranes, no necrosis or increased mitotic activity

Rarely mucin, clear cell change, psammoma bodies, oncocytes, focal rhabdomyosarcomatous metaplasia

Stains do NOT correlate with secretion; immunostains NOT necessary for diagnosis

Features to report: tumor size, location, mitotic figures, vascular or capsular invasion, Archives 2000;124:30

Micro images: image1, image2, image3, image4, CD31

Positive stains: chromogranin, synaptophysin, peptides, insulin, glucagon, somatostatin, pancreatic polypeptide, gastrin, vasoactive intestinal polypeptide, CEA; often acinar markers (no prognostic importance, AJSP 2002;26:893)

EM: dense-core neurosecretory granules (not specific, size overlaps with zymogen granules of acinar cell tumors), usually randomly distributed, lack the well-developed secretory apparatus of acinar cell tumors (rough ER, mitochondria)

DD: usual ductal adenocarcinoma (has marked nuclear atypia), chronic pancreatitis with islet cell hyperplasia

DD: pseudoneoplastic islet cell lesions (islets aggregate while rest of pancreas atrophies; islets at tail are compact, islets in head are diffuse and may appear infiltrative, usually have trabecular pattern and are pancreatic polypeptide positive; usually no perineurial invasion)

Poor prognostic factors for pancreatic endocrine neoplasms

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Tumor size > 3 cm; invasion of stroma, capsule, vessels or adjacent organs; glandular/solid pattern; > 2 MF/10 HPF; aneuploidy; older age, high proliferation index (Ki-67 of 5% or more, Hum Path 1996;27:1124, Archives 2003;127:196)

Micro images: Ki-67

Cystic endocrine tumors

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Associated with MEN1 (younger patients, often multiple, in tail and secreting) or sporadic (solitary, non-secreting)

By imaging have peripheral hypervascular rim and images of cyst into cyst

Confirm by octreoscan scintigraphy; excise since may be malignant

Micro: thick cyst wall with nests of neuroendocrine cells; also neuroendocrine cells grouped in vesicular structures surrounded a fluid filled cavity, AJSP 2001;25:752

Malignant pancreatic endocrine tumor with sarcomatous differentiation

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Micro images: image1, image2, image3, chromogranin

Only 2 cases reported, Mod Path 2001;14:1187

Tumors in MEN1 patients

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Usually produce glucagon, insulin or pancreatic polypeptide; tendency towards multiple tumors in same patient, often microscopic, which often produce different hormones; associated with nesidioblastosis in 30% of cases, AJSP 1996;20:1378

Tumors with rhabdoid features

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Micro: sheets of monotonous tumor cells with uniform round nuclei, dispersed chromatin, abundant densely eosinophilic cytoplasmic inclusions that displaced the nuclei toward the periphery; rhabdoid elements merge with conventional neuroendocrine areas

Positive stains (rhabdoid tumor cells): chromogranin, synaptophysin, cytokeratin

EM: inclusions composed of large whorls of intermediate filaments

References: AJSP 2003;27:642, Archives 1997;121:1104

ACTH-secreting tumors

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Rare; produce adrenocorticotrophic hormone (ACTH), and cause Cushing syndrome: central obesity, muscle weakness, glucose intolerance, hypertension

Carcinoid tumors

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Rare, arise from Kultschitsky (serotonin secreting) cells normally present in pancreas

Strongly argentaffinic

May be associated with carcinoid syndrome (flushing, diarrhea)

Grading systems for gut neuroendocrine tumors include Capella (high grade and low grade) and WHO (high grade, typical carcinoid, atypical carcinoid); unclear if subdividing low grade tumors has prognostic value, although mitotic activity may be helpful, Hum Path 2002;33:1126

Clear cell pancreatic endocrine tumor

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Clear cell change is specific for von Hippel-Lindau disease, AJSP 2001; 25:602

Rarely associated with hypercalcemia, Archives 2003;127:241

Gross: solid, multinodular, golden-yellow; may be cystic

Micro: clear cells in nests, cords and tubules with central hemorrhage and associated thin walled vessels; also cords and gyriform pattern suggestive of endocrine tumors; vascular invasion common; may have adjacent serous cystadenoma-like areas

Micro images: image1

Positive stains: chromogranin, synaptophysin, pancreatic polypeptide

DD: metastatic renal cell carcinoma (negative for neuroendocrine markers and neurosecretory granules), low grade mucinous adenocarcinomas, serous microcystic adenoma, adrenal tumors, steroid secreting tumors of ovary/testis, clear cell hepatocellular carcinoma

Gastrinoma (G cell tumor)

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Associated with hypersecretion of gastric acid and severe peptic ulceration

Causes ulcers in 90% - 85% duodenal/jejunal, 15% gastric; intractable to medical therapy

50% of patients with gastrinomas have diarrhea

Tumors usually in pancreas, also duodenum, peripancreatic soft tissue, gastric antrum (opposite of G cell distribution)

Tumors also in ovary, mesentery, liver, intra-abdominal lymph nodes (? ectopic pancreatic tissue or metastases)

50% are locally invasive or metastatic at diagnosis

Zollinger-Ellison syndrome tumors are usually solitary, malignant, located in pancreas

MEN 1 cases: less likely to be malignant, arise in duodenal wall, often multicentric

Treatment: H2 blockers, surgical resection of tumor (if cannot resect, some advocate total gastrectomy)

Micro: Non-neoplastic pancreas shows large islets and nesidioblastosis; malignant tumors are histologically bland; associated with pancreatic polypeptide cell hyperplasia, Hum Path 1997;28:149

EM: granules similar to VIP, normal gastrin producing cells: small, electron dense

Primary lymph node gastrinoma

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Gastrin producing tumors in lymph nodes, with no GI or pancreatic primary

Occur in “gastrinoma triangle” - from the cystic and common bile ducts to the second and third portion of the duodenum to neck and body of the pancreas

Apparently due to gastric secreting neuroendocrine cells within these nodes, Archives 2000;124:832

Glucagonoma (alpha cell tumors)

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Adult females, age 40+

2 types

(a) Glucagonoma syndrome: adult women with large, solitary tumors, nondescript microscopic pattern, atypical granules on EM, few immunoreactive tumor cells, high incidence of malignancy

Clinical features are due to markedly elevated glucagon: abnormal glucose tolerance test; normochromic, normocytic anemia; necrolytic migratory erythema (skin rash of legs, perineum, groin; rash becomes blisters with central clearing, heals with hyperpigmentation but without scarring in 7-14 days, AJSP 1986;10:445); sore red tongue; angular stomatitis; severe weight loss; depression; deep venous thromboses; may develop overwhelming infection

(b) Multiple small tumors with gyriform growth pattern, strongly immunoreactive for glucagon, typical granules on EM, nearly always benign

Micro images: glucagon immunostaining in incidental tumor discovered at autopsy

EM: large, dense peripheral nucleoid

High grade neuroendocrine carcinomas

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Aggressive, resemble small cell carcinoma of lung, with infiltrative growth pattern, numerous mitotic figures and necrosis

Represent less than 5% of pancreatic neuroendocrine tumors

May produce ACTH, are associated with hypercalcemia

Grading systems for gut neuroendocrine tumors include Capella (high grade and low grade) and WHO (high grade, typical carcinoid, atypical carcinoid)

DD: PNET in young, metastasis from lung primary

Insulinoma (beta cell tumor)

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Only 7-10% behave malignantly (perhaps because most are detected when very small due to symptoms)

Functional status is NOT an independent prognostic factor

Associated with hyperinsulinemia; usually adults; <10% associated with MEN1 syndrome

Case report of widely metastatic tumor with focal rhabdomyosarcomatous areas, AJSP 1989;13:422

Whipple’s triad: symptoms of hypoglycemia (stupor, confusion, loss of consciousness), glucose < 50 mg/dl, symptoms relieved by glucose or symptoms caused by fasting or exercise

Laboratory: high insulin levels and high insulin/glucose ratio; hypoglycemia is mild in 80% of cases

Diagnosis: high insulin levels, intravenous tolbutamide administration detects serum proinsulin

Use arteriography (60% successful) or ultrasound to locate small tumors

Treatment: surgical exploration or subtotal pancreatectomy

Benign (90%): solitary, encapsulated, 1.5 cm or less; solid/gyriform, no glands

Malignant (10%): based on local invasion or metastases; usually causes more pronounced hypoglycemia

Note: amyloid may be derived from somatostatin and not amylin, AJSP 1998;22:360

Micro: solid or gyriform patterns, usually without glands; in children are associated with nesidioblastosis (direct transformation of ductal epithelium into neoplastic islet tissue); amyloid present, Archives 1978;102:227

Positive stains: insulin (less than normal beta cells), proinsulin (50%), chromogranin, amylin

Micro images: insulin immunostain#1, #2

EM: round secretory granules with irregular crystals separated from enclosing membrane by a distinct halo; granules do NOT imply functional activity

DD of hyperinsulinism: diffuse hyperplasia of the islets in infants of diabetic mothers

DD of hypoglycemia: insulin sensitivity, diffuse liver disease, glycogenoses, solitary fibrous tumor of pleura / peritoneum (tumor cells secrete insulin like growth factor II), hepatocellular carcinomas

Pancreatic polypeptide-secreting tumors

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Asymptomatic despite high levels of the hormone in plasma

Rare, although PP cells common in pancreatic endocrine tumors of other types

Somatostatinoma

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Aka delta cell tumors

Associated with diabetes, cholecystolithiasis, steatorrhea, hypochlorhydria

Hard to localize preoperatively; may be in duodenal wall; may have psammoma bodies

Diagnose by high plasma somatostatin levels

Micro images: somatostatin immunoreactive cells

VIPoma

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Aka Verner-Morrison tumors

Secretes vasoactive intestinal peptide (VIP)

Diarrhea (cholera-like), hypokalemia, achlorhydria

Resemble G cell tumors without gastrin immunoreactivity

Also contain pancreatic polypeptide, calcitonin, alpha chain of hCG

May be locally invasive or metastastic

DD: neural crest tumors (ganglioneuroma, neuroblastoma, neurofibroma, pheochromocytoma) produce similar symptoms

Acinar cell and mixed tumors

Acinar cell cystadenoma

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First described in 2002 (AJSP 2002;26:698)

Rare benign cystic neoplasm of the pancreas (Pancreas 2008;37:254)

70% women, ages 16 to 66 years

Benign behavior

Case reports: Case of the Week #136

Treatment: excision

Gross: mean 6 cm, unilocular or multilocular cysts with watery fluid, cysts usually not connected with ductal system

Micro: well circumscribed cystic spaces composed of mature acinar cells with abundant eosinophilic granular cytoplasm and round, basal nuclei; cyst may be lined by flattened cells resembling normal ductal epithelium, but with focal acinar cells and admixed with dilated acini; may be adjacent to mucinous ductal epithelium; eosinophilic secretions form oval plugs; no papillary projections or solid areas, no ovarian type stroma, no PanIN lesions; no atypia, no mitotic activity, no vascular invasion, no relationship to major ductal system

Micro images: Case of the Week - #1; #2; #3; trypsin

Positive stains: PAS, lipase, trypsin, chymotrypsin, CK7

Negative stains: Ki-67

EM: image

DD: acinar cell cystadenocarcinoma (more complex epithelium, nuclear atypia, prominent nucleoli; often necrosis, solid nests of tumor cells, mitotic figures, infiltration into surrounding stroma), PanIN (no acinar cells, variable atypia)

References: Mod Pathol 2007;20 Suppl 1:S71

Acinar cell carcinoma

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Aggressive tumors, resemble parotid gland tumors and acinar structures of normal pancreas

1-2% of pancreatic malignancies

Typical patient is 60-69 years old white man with intraabdominal mass; rare in children, 85% men; AJSP 1992;16:815

10% have lipase hypersecretion syndrome (subcutaneous fat necrosis, polyarthralgias, occasional eosinophilia, nonbacterial thrombotic endocarditis) due to lipase secretion by tumor; these patients usually have liver metastases

Tumors may secrete alpha-fetoprotein (AFP)

50% have metastases at diagnosis (liver and regional lymph nodes); 5 year survival is only 10%

Kras and p53 mutations uncommon

Most AFP+ pancreatic neoplasms are acinar cell carcinomas or pancreatoblastoma, Hum Path 2000;31:938, Hum Path 1992;23:828

Gross: well circumscribed, soft/fleshy (since minimal stroma) with fibrous septa, large (mean 11 cm), hemorrhage and necrosis common

Gross images: image1

Micro: highly cellular with minimal stroma and without desmoplasia; solid, nesting, glandular or acinar patterns with sharp luminal space outlines; monotonous uniform polarized cells with abundant eosinophilic granular apical cytoplasm due to zymogen granules (scanty in solid tumors), basal nuclei and single prominent nucleoli; moderate nuclear atypia, variable mitoses; vascular invasion often present; no mucin

Note: solid or trabecular pattern resembles endocrine tumors; 30-50% have minor endocrine component based on immunohistochemistry

Note: must document pancreatic enzymes to be considered an acinar cell tumor

Micro images: image1, image2, image3

Positive stains: PAS (diastase resistant) for granules, trypsin and chymotrypsin (90%+ sensitive), lipase (50% sensitive), amylase, elastase, butyrate esterase (75% sensitive, indicates lipase), keratin

Note: staining is often in the apical portion of the tumor cells

Negative stains: mucin, CD56

EM: well-developed microvilli, abundant granular (rough) ER, numerous mitochondria, zymogen like granules (300-600 nm, apical, homogenous), irregular fibrillary granules (up to 3500 nm with fibrillary internal structures, resemble zymogen granules in developing pancreas),

DD: pancreatic endocrine tumor (no acinar differentiation, PAS-, uniform nuclear morphology, fibrous stroma), solid pseudopapillary tumor (young women, cystic and hemorrhagic, solid and pseudopapillary patterns, CD56+, CD10+), pancreatoblastoma (children, squamoid bodies), ductal adenocarcinoma (mucicarmine+, CEA+)

References: Archives 2002;126:985 (case report), Archives 2001;125:1127 (case report), Hum Path 1985;16:746 (case report)

Acinar cell cystadenocarcinoma

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Typically large tumors up to 17 cm containing multiple cysts

Marked atypia, frequent mitotic activity

DD of cellular, stroma-poor tumors:

Pancreatic endocrine neoplasm: rare mitoses, no polarization, indistinct nucleoli, amyloid stroma, trabeculae, stippled chromatin, although acinar cell may contain scattered endocrine cells and mixed tumors are common

Acinar cell hyperplasia: common, resembles islets, may have minor atypia, may be pre-malignant

Acinar cell adenoma: may not exist; may be a well differentiated acinar cell carcinoma or pancreatoblastoma in children

Mixed tumors

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At least 25% of each component

Mixed ductal-endocrine

Presence of mixed metastases in one case ruled out trapped ducts within an endocrine tumor

Behavior resembles ductal adenocarcinomas, Archives 2000;124:284

Micro images: image1

Mixed acinar-endocrine tumor

Behaves like acinar cell carcinoma

Diagnosis should be based on morphology, not immunohistochemistry, AJSP 2002;26:893, AJSP 1994;18:765

Resembles pancreatoblastoma

Mixed acinar, ductal, islet cell tumor

Use immunohistochemistry to define

Tumors of indeterminate origin

Pancreatoblastoma

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Most common pancreatic tumor of infancy/early childhood; bimodal age distribution (peaks at ages 2 and 33), M=F

Most children survive and do well with chemotherapy if no metastases; 50% are cured after excision; those with metastases often die

Adults have mean survival of 18 months

Note: resembles acinar cell carcinoma except for squamoid corpuscles; behavior of both in children is similar

Gross: partially encapsulated, often lobulated, mean size 10 cm

Micro: geographic (varies with the field since mixtures of acini, squamoid corpuscles and less endocrine, ductal); very cellular, uniform epithelial cells in sheets and nests with acini/ducts; squamoid corpuscles (circumscribed whorled nests of plump spindle cells with a squamous appearance and occasional keratinization) are common and specific

Squamoid corpuscles: a growth pattern, not a line of differentiation

Pediatric cases often have hypercellular stroma, occasionally with bone/cartilage

Note: optically clear nuclei may cause false positive immunohistochemical staining with ABC (biotin) technique

Positive stains: pancreatic enzymes (acinar areas), CEA and mucin in luminal secretions of small acini, alpha-fetoprotein (18%), keratin

Negative stains: neuroendocrine markers (rare cells may be positive)

EM: acinar cell features

DD: solid pseudopapillary neoplasms

References: Archives 1986;110:650; Archives 2003;127:1501 (ampullary tumor)

Serous cystadenoma

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Aka microcystic adenoma, glycogen rich cystadenoma

Mean age 66, 70% women, associated with von Hippel Lindau syndrome, diabetes (if tumor destroys enough islets)

Symptoms: variable (none, local discomfort/pain or obstruction if in pancreatic head)

Excision almost always curative

Case reports of coexisting pancreatic adenocarcinoma, AJSP 1990;14:352, pancreatic endocrine neoplasm, AJSP 1996;20:471

Gross: large (mean 11 cm) multiloculated mass, sharply outlined, cysts filed with clear fluid; spongy; resembles infantile polycystic kidney; often has central stellate scar; rarely is multicentric, usually in tail or body; either macrocystic (megacystic, oligocystic, usually < 10 cysts, Hum Path 1992;23:871) or microcystic (1-3 mm)

Gross images: circumscribed, sponge-like cut surface with central stellate scar

Gross images contributed by Dr. Hanni Gulwani, New Delhi (India): 76 year old man with incidental pancreatic mass - image #1; #2

Micro: small cystic spaces lined by small cuboidal cells with clear cytoplasm (glycogen), minimal mucin, myoepithelial layer present, round hyperchromatic central nuclei; minimal papillae, has islets between lobules which may calcify (radiating pattern), tumor is vascular (seen by selective angiography); rarely has oncocytic change; occasionally has papillary features (Archives 2001; 125: 1591)

Fluid has low CEA content compared to mucinous cystic neoplasms

Micro images: clear glycogen rich cells without atypia; various images; papillary variant

Micro images contributed by Dr. Hanni Gulwani, New Delhi (India): 76 year old man with incidental pancreatic mass - image #1; #2; #3; #4

Positive stains: EMA, low molecular weight keratin, PAS without diastase

Negative stains: CEA, trypsin, chromogranin, synaptophysin, S100, desmin, vimentin, Factor 8

EM: prominent microvilli, glycogen granules, epithelial cells connected by occluding junctions and belt desmosomes resting on a basement membrane; no neurosecretory or zymogen granules

Molecular: may be aneuploid, Archives 1991;115:563

DD: lymphangioma (Factor 8+, lymphocytes present, epithelial cells lack glycogen), mucinous cystic neoplasms (larger cystic spaces, CEA+, mucin+), solid pseudopapillary tumor (pseudopapillary features)

References: AJSP 1988;12:251, AJSP 1986;10:365

Serous/microcystic adenocarcinoma

One case reported, histologically benign, but metastasized to stomach and liver and invaded spleen, AJSP 1989;13:61

Solid variant

Rare, similar microscopically to serous cystadenoma but no cystic spaces

Cells arranged in nests, sheets and trabeculae separated by thick fibrous bands

Cells contain glycogen (PAS+)

Benign behavior in case report, AJSP 1996;20:1401

DD: sugar tumor of pancreas, clear cell carcinoma, clear cell pancreatic endocrine neoplasm, metastatic renal cell carcinoma

Solid pseudopapillary tumor of pancreas

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Also called papillary and solid epithelial neoplasm, papillary cystic neoplasm, Gruber-Frantz tumor

1-2% of non-endocrine pancreatic neoplasms

Young (mean 30-35 years), 90% women, not associated with any clinical syndrome

Not truly papillary or truly cystic

Appears to be unique to the pancreas, but origin is unclear, as it lacks clear evidence of ductal, acinar or endocrine differentiation (Mod Path 2007;20:S71)

Low proliferative neoplasm with evidence of dysregulation of activating cyclins and inhibitory proteins (Mod Path 2001;14: 47); may derive from pluripotent indifferent stemcells capable of endocrine and exocrine differentiation

Poor prognostic factors: venous invasion, high nuclear grade, “necrobiotic nests”; metastases in 10-15% to liver or peritoneum are associated with venous invasion, high nuclear grade and necrosis; patients usually survive even with metastases

Xray images: CT scan

Case reports: Case of the Week #121, 38 year old woman with liver metastases #1 (Archives 1995;119:268), #2 (Archives 1984;108:723), 43 year old woman (Archives 2001;125:971), 44 year old woman (Archives 2002;126:985)

Treatment: wide excision, with excellent prognosis (J Surg Oncol 2007;95:304)

Solid pseudopapillary tumor of pancreas (continued)

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Gross: large (mean 9 cm), usually encapsulated, hemorrhagic, necrotic, rarely multifocal (Archives 1991;115:958)

Gross images: inhomogeneous solid and cystic mass; multilocular cystic mass

Micro: cellular (resembles islet cell tumor and ependymoma); pseudopapillae with hyalinized fibrovascular cores lined by several layers of bland fragile epithelial cells with clear to eosinophilic cytoplasm, variable intracytoplasmic PAS+ hyaline globules; also round/oval nuclei, finely stippled chromatin, nuclear grooves, indistinct nucleoli, few mitoses; foam cells, clusters of lipid/cholesterol crystals surrounded by foreign-body giant cells; fibrovascular core contains mucinous changes; tumor friable but not necrotic; may have pseudocystic areas; pseudopapillae due to solid nests minus cells degenerating away from the small vessels; look like rosettes in cross section; tumor cells infiltrate without any stromal reaction

Micro images: #1; #2; #3; #4; #5; #6; #7; #8; solid and pseudopapillary patterns; CD10+, CD56+, vimentin+, PR+, alpha-1-antitrypsin+

Positive stains: vimentin, CD10, CD56 (intense, diffuse, AJSP 2000;24:1361); also estrogen and progesterone receptors, focal neuroendocrine markers; also chymotrypsin and trypsin (AJSP 1987;11:85), nuclear and cytoplasmic beta-catenin, cyclin D1 overexpression, nuclear E-cadherin

Negative stains: chromogranin, CEA, acinar and ductal markers (keratin may be patchy)

EM: large electron dense granules with complex internal membranous and granular inclusions and alpha-1-antitrypsin

Solid pseudopapillary tumor of pancreas (continued)

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Molecular: almost always mutations in exon 3 of the beta-catenin gene, causes abnormal immunostaining patterns for beta-catenin (nuclear and cytoplasmic, compared to membranous staining in normal pancreas) and overexpression of cyclin D1 (Am J Pathol 2002;160:1361); also nuclear localization of E-cadherin with absence of membranous and cytoplasmic localization, which may account for dyscohesive tumor cells (AJSP 2008;32:1)

DD: pancreatic pseudocyst (may be grossly similar, but no epithelial cells lining the cystic structures, even after careful search, patients are usually older and male, and have a history of pancreatitis), pancreatic endocrine tumor (no degenerative pseudopapillae, intracytoplasmic hyaline globules or longitudinal nuclear grooves; chromogranin+, CD10-, negative for nuclear beta-catenin), adrenal cortical tumors (positive for inhibin, vimentin, keratin), acinar cell carcinoma (typically has acinar formations, prominent nucleoli and mitotic activity, immunostaining for trypsin, chymotrypsin, and lipase, Mod Path 2007;20:S94).

Miscellaneous tumors

Clear cell “sugar” tumor

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Rare, case report at AJSP 1996;20:722

Resembles clear cell “sugar” tumor of lung

Tumor arises from perivascular epithelioid cells, which also cause lymphangiomyomatosis, angiomyolipoma

Micro: large epithelioid cells, clear or eosinophilic granular cytoplasm containing glycogen with nuclear pleomorphism but no mitotic activity

Positive stains: HMB45, actin

Negative stains: cytokeratin, NSE, chromogranin A, lipase, amylase

EM: membrane bound granules

DD: clear cell carcinoma

Inflammatory myofibroblastic tumor

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Rare, resembles a malignancy (forms a mass, may constrict bile duct); more common in lung

Similar to lymphoplasmacytic sclerosing pancreatitis

Probably not EBV-related

Associated with development of second similar tumor

Micro: spindled cells, collagen, and variable lymphocytes and plasma cells; rarely has prominent eosinophils

Positive stains: smooth muscle actin, vimentin

Negative stains: S100, CK, CD35, LMP, EBER

DD: inflammatory fibrosarcoma, follicular dendritic cell tumor

Reference: AJSP 2003;27;334

Leukemia

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Case report of plasma cell leukemia presenting as pancreatic mass, Archives 1993;117:844

Lymphoid hyperplasia

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Case report of benign lymphoid hyperplasia presenting as a mass causing obstructive jaundice,

Hum Path 1991;22:724

Lymphoma

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Primary disease is rare (<200 cases reported); usually in elderly

Disease may originate in peripancreatic or retroperitoneal lymph nodes

Presenting complaints of abdominal pain and jaundice due to common bile duct obstruction or abdominal masses

Usually intermediate to high grade; 50% die within 12 months

Often involved by mediastinal diffuse large cell lymphoma, AJSP 1986;10:176

Case report of advanced angiocentric T cell lymphoma (peripheral T cell lymphoma, NOS) of pancreas and eye presenting as advanced diabetes mellitus with diabetic retinopathy, Hum Path 2001;32:741

References: AJSP 1997;21:484

Perivascular epithelioid cell tumor (PEComa)

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Concept of perivascular epithelioid cell tumor first proposed in 1992 (AJSP 1992;16:307)

Tumor family includes angiomyolipoma (renal and extrarenal), clear cell “sugar” tumor (lung and extrapulmonary), lymphangioleiomyomatosis, related tumors of the falciform ligament / ligamentum teres, skin (Histopathology 2005;46:498), uterus (Mod Path 2005;18:1336) and other viscera and soft tissue

Origin: no known normal counterpart to perivascular epithelioid cell.

Case reports: 37 year old woman (Case of Week #143)

Micro images: malignant tumor - #1; #2; #3; #4; #5; #6; #7

Micro: malignant appearing tumors may have large zones of necrosis and nests of malignant cells with marked cellular pleomorphism and mitotic activity; cells are epithelioid and spindled, have clear to eosinophilic cytoplasm, large vesicular nuclei, prominent eosinophilic nucleoli; may have brown “dusty” pigment suggestive of melanin; no glandular growth or sarcomatous features

Positive stains: Melan A and HMB-45, also actin (Int J Surg Pathol 2009 Jan 4 [epub ahead of print]), CD1a (Pathol Int 2008;58:169); variable EMA, variable S100

Negative stains: CD68, Pan-keratin, LCA, CD117, inhibin

Differential diagnosis: melanoma, GIST tumors, clear cell sarcoma of soft parts, alveolar soft part sarcoma, leiomyosarcoma and even paraganglioma (AJSP 2009;33:475) - recommended to thoroughly sample tumor, use melanocytic markers, other immunostains, possibly molecular markers

Primitive neuroectodermal tumor (PNET)

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Mean 18 years (range 6 to 25 years)

Small round blue cell tumor with evidence of neuroectodermal differentiation

Account for 1% of all sarcomas

Usually in soft tissue or bone of children/young adults, rare in pancreas

At all sites, 5 year survival is 50%

Gross: tumors in head of pancreas, 3.5 to 9.0 cm

Micro: sheets and lobules of small round cells with scant cytoplasm; prominent nuclear molding, frequent mitotic activity; often infiltrate into peripancreatic soft tissue; variable tumor necrosis; usually no rosettes

Positive stains: CD99 (O13/MIC2), cytokeratin, neuroendocrine markers (chromogranin, synaptophysin, NSE)

Negative stains: desmin

Molecular: t(11;22)(q24;q12)

DD: neuroendocrine carcinoma, small cell carcinoma (higher mitotic rate, numerous karyorrhectic bodies, focal glandular differentiation, no t(11;22), usually elderly population), pancreatoblastoma (usually age 10 or less, acinar formations, squamoid corpuscles, no t(11;22)), pancreatic endocrine neoplasms (usually adults, no molding, negative for neuroendocrine markers, slow growing tumors), neuroblastoma (younger patients, produce catecholamines, no t(11;22)), lymphoblastic lymphoma (CD99+ but TdT+ also), rhabdomyosarcoma, metastatic PNET to pancreas, intraabdominal desmoplastic small round cell tumor (dense fibrous stroma, strong desmin staining, different t(11;22) than PNET)

References: Mod Path 1994;7:200, AJSP 2002;26:1040

Pyloric gland adenoma

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Rare, case report in main pancreatic duct

May have codon 12 Kras mutation (also seen in usual type pancreatic ductal adenocarcinoma) and dysplasia; AJSP 1999;23:227

Gross: polypoid mass

Micro: well-demarcated nodule composed of closely packed tubular glands lined by columnar, mucin-secreting cells with abundant clear cytoplasm and basally oriented nuclei; focal mild atypia present; pyloric metaplasia and focal papillary hyperplasia present in adjacent ductal epithelium

Positive stains: PAS with and without diastase

Negative stains: Alcian blue, chromogranin, synaptophysin

Sarcoma

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Rare (0.1%), may resemble sarcomatoid carcinoma, anaplastic carcinoma, extension of retroperitoneal or gastroduodenal sarcomas

Case report of leiomyosarcoma causing death within 1 year, micro images, Archives 2001;125:152

Case report of MFH with post-operative death, Hum Path 1989;20:1215

Schwannoma

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Rare, mean age 60, M=F, 2/3 partially cystic, typical histology, Mod Path 1998; 11:1178

Metastatic tumors to pancreas

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Usually secondary tumors of the pancreas occur by direct extension

Primary site of metastases often bowel; also kidney, prostate, lung, leukemia / lymphoma

Metastases usually are multifocal and lack fibrosis

Miscellaneous

Grossing

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Ink common bile duct margin, pancreatic duct margin, retroperitoneal margin, other soft tissue margins, duodenum, stomach

Retroperitoneal margin: soft tissue adjacent to right lateral border of superior mesenteric artery, site of most local recurrences

Margins should be sectioned perpendicular to the inked margin

Staging

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Same classification for clinical and pathological staging, as most patients don’t have resections

Primary Tumor (T)

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TX: Primary tumor cannot be assessed

T0: No evidence of primary tumor

Tis: Carcinoma in situ (includes PanIn III)

T1: Tumor limited to the pancreas, 2 cm or less in greatest dimension

T2: Tumor limited to pancreas, more than 2 cm in greatest dimension

T3: Tumor extends beyond the pancreas but without involvement of the celiac axis or the superior mesenteric artery

T4: Tumor involves the celiac axis or the superior mesenteric artery (unresectable primary tumor)

Regional Lymph Nodes (N)

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NX: Regional lymph nodes cannot be assessed

N0: No regional lymph node metastasis

N1: Regional lymph node metastasis

Distant metastasis (M)

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M0: No distant metastasis

M1: Distant metastasis

Anatomic stage / prognostic groups

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Stage 0: Tis N0 M0

Stage IA: T1 N0 M0

Stage IB: T2 N0 M0

Stage IIA: T3 N0 M0

Stage IIB: T1-3 N1 M0

Stage III: T4 Any N M0

Stage IV: Any T Any N M1

Features to Report:

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Tumor size

Tumor location

Histopathologic type

Histologic grade (well, moderate, poor or undifferentiated)

Perineurial invasion

Angiolymphatic invasion

Margins (common bile duct, pancreatic duct, retroperitoneal margin [soft tissue adjacent to superior mesenteric artery], surgical margin)

Involvement of adjacent structures

Lymph nodes

Presence of PanIN (including marginal involvement)

Findings in remaining pancreas (pancreatitis)

Endocrine tumors (Archives 2000;124:30)

Tumor size

Tumor location

Histopathologic type

Perineurial invasion

Angiolymphatic invasion

Margins

Mitotic activity, necrosis, pleomorphism, amyloid

Involvement of adjacent structures

Lymph nodes

Presence of PanIN (including marginal involvement)

Findings in remaining pancreas (pancreatitis, nesidioblastosis)

End of pancreas chapter

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