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Pancreas
Superpage - Nontumor
Revised: 26 January 2013
Copyright: (c) 2001-2013, PathologyOutlines.com, Inc.
AJCC Cancer Staging Manual (7th ed)
American Journal of Clinical Pathology
American Journal of Surgical Pathology
Archives of Pathology and Laboratory Medicine
Human Pathology
Modern Pathology
Solcia: Tumors of the Pancreas (AFIP Atlas of Tumor Pathology, Series 3, Vol 20, 1997)
Websites with images: PathoPic, USCAP (virtual slides)
Please refer to these primary references for more detailed discussions and photographs
General
Normal pancreas
Reviewer: Deepali Jain, M.D. (see Reviewers
page)
Revised: 22 November 2012, last major update August 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.
General
=========================================================================
● 15 cm long, 60-140g
● Shape is compared to letter J turned sideways, with loop of J around the duodenum
● 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
Drawings
=========================================================================
Various images
Cytology images
=========================================================================
Figure 3
General
Exocrine pancreas
Reviewer: Deepali Jain, M.D. (see Reviewers
page)
Revised: 22 November 2012, last major update August 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.
General
=========================================================================
● 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
Physiology
=========================================================================
● 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)
● Pancreatic enzymes: trypsin, chymotrypsin, aminopeptidases, elastase, amylases, lipase, phospholipases, nucleases
● Cholecystokinin: promotes discharge of digestive enzymes by acinar cells; released from duodenum in response to fatty acids, peptides and amino acids
● Secretin: stimulates water and bicarbonate secretion by duct cells; is stimulated by acid from stomach and luminal fatty acids
● Trypsin: catalyzes activation of the other enzymes
● Pancreatic self-digestion: 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
Low power
Intercalary duct
Large excretory duct
Electron microscopy images
=========================================================================
Two centroacinar cells with electron-lucent cytoplasm, poor in organelles, surrounded by acinar cells rich in zymogen granules
Left: ductular cells with cell cytoplasm, some mitochondria, several elongated endosomes
Right: secondary interlobular duct has columnar cells containing juxtaluminal mucin granules with a homogeneous dense inner structure and irregularly distributed microvilli along the luminal borders
Pancreatic acinar cells
General
Endocrine pancreas
Reviewer: Deepali Jain, M.D. (see Reviewers
page)
Revised: 10 December 2012, last major update August 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.
General
=========================================================================
● 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 Pathol 2000;31:1368)
● Alpha cells: produce glucagon; peripherally 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: islets in intimate association with ducts with formation of ductuloinsular complexes
● 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 Pathol 1988;19:1215)
● Peliosis: selective congestion and dilation of vessels of islets only, not seen in vessels elsewhere
Micro images
=========================================================================
Islets in newborn: figure A-well lobulated pancreatic tissue with islet (arrows) at periphery of a lobule
figures B/C-insulin and somatostatin immunostains reveal small islet cell clusters as well as well formed islets with central insulin cells and peripheral somatostatin cells
Islets: cells with clear cytoplasm (centroacinar and ductal cells) stand out from a background of basophilic acinar cells
Adult pancreas-ordinary type islet: regular contour and compact shape is characteristic of islets rich in beta cells
Adult pancreas-irregular type islet: irregular contours and trabecular architecture are characteristic of islets rich in PP cells
Adult pancreas: distribution of islet cell types in pancreatic tail
Islet rich in PP cells in posterior part of pancreatic head
Islet hyperplasia of Beckwith-Wiedemann Syndrome: note crowding without fusion of islets inside pancreatic lobules. (Courtesy of Dr. Cesare Bordi)
Nesidioblastosis in adult with persistent adult hyperinsulinemic hypoglycemia: clustering of irregular islets in vicinity of small ductules
Positive stains
=========================================================================
● Chromogranin, synaptophysin, neuron specific enolase, neurofilament
Electron microscopy images
=========================================================================
Zymogen granules
Adult pancreatic islet cells: glucagon cell (bottom), insulin cell (upper right), somatostatin cell (left) are seen. Note the fenestrated capillary vessel at upper left
General
Embryology
Reviewer: Deepali Jain, M.D. (see Reviewers
page)
Revised: 22 November 2012, last major update August 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.
General
=========================================================================
● Forms from embryonic foregut, of endodermal origin (Univ New South Wales (Australia), Wikipedia)
● 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
● 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
Anomalies
=========================================================================
● In 2/3 of adults, pancreatic duct empties into common bile duct, not into ampulla directly
● Abnormal fusion of ventral and dorsal buds causes annular pancreas or heterotopic pancreas
Drawings
=========================================================================
Various images
Micro images
=========================================================================
10 week old fetus: primary tubules with scattered endocrine cells (A-synaptophysin) or forming buds (B-chromogranin) represent primitive islets (chromogranin+) or acini with unstained cytoplasm
10 week old fetus-dorsal pouch: individual or clustered insulin (A), glucagon (B), pancreatic polypeptide (C) and somatostatin (D) cells stained with specific hormone antibodies in primary tubules or their buds
Electron microscopy images
=========================================================================
38/39 week old fetus: an acinar cell with well-developed rough endoplasmic reticulum (bottom right), an islet B cell with partly vesicular and crystalline beta granules (center), and a primitive ductal cell with a few scattered reticulum cisternae are seen in this 170 mm long fetus
General
Cytology
Reviewer: Deepali Jain, M.D. (see Reviewers
page)
Revised: 10 December 2012, last major update August 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.
Cytology images
=========================================================================
Normal pancreatic acinar cells with eccentrically located round nuclei and abundant cytoplasm
Normal ductal cells, in sheet arrangement, showing round nuclei and relatively scarce cytoplasm
General
Minor abnormalities
Reviewer: Deepali Jain, M.D. (see Reviewers
page)
Revised: 10 December 2012, last major update August 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.
Acinar dilation
=========================================================================
● Associated with uremia, chronic pancreatitis (J Clin Pathol 1996;49:913), dehydration, severe bacterial infections (Hum Pathol 1984;15:677), bone marrow transplant
Altered acinar cells
=========================================================================
● Associated with chronic pancreatitis, alcohol, chemotherapy, pancreatic endocrine excess, tobacco
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
Ductal hyperplasia / ductal papillary hyperplasia
=========================================================================
Ductal hyperplasia: also mucinous cell hypertrophy and mild to moderate dysplasia; note the focal nuclear crowding within small papillae
Ductal papillary hyperplasia: marked papillary hyperplasia due to duct obstruction from tumor; papillae of various sizes, lined with columnar mucinous cells, project into lumen of main duct, which contains inspissated material; a few areas of flat epithelium are present between papillae
Ductal papillary hyperplasia: this interlobular duct from a patient with chronic pancreatitis shows mucous cell hypertrophy and ductular hyperplasia; epithelium exhibits slight cellular atypia
Adenomatoid ductal hyperplasia: accumulation of medium-sized pancreatic ducts, ductules, or both embedded in moderately cellular fibrous tissue
Focal fibrosis
=========================================================================
● Associated with older age or diabetes mellitus
Hemosiderin deposition
=========================================================================
● May be due to primary hemochromatosis or chronic blood transfusions
(Arch Pathol Lab Med 1985;109:996)
Lipomatosis
=========================================================================
● Associated with older age
Marked fatty atrophy
=========================================================================
● Associated with type II diabetes, obesity, pancreatitis, duct obstruction, cystic fibrosis and severe generalized atherosclerosis
● Results in malabsorption
Mucinous cell hypertrophy
=========================================================================
Nonpapillary epithelial hypertrophy characterized by replacement of normal epithelium of large and medium-sized ducts by tall mucin-producing columnar cells
Lining columnar epithelium shows mild cellular atypia characterized by some crowding of slightly enlarged nuclei; most nuclei are polarized; apical portion of cytoplasm is filled with mucin
With pyloric gland metaplasia: an area of parenchymal atrophy, chronic pancreatitis and fatty replacement of parenchyma in patient with pancreatic carcinoma; there is marked hypertrophy and hyperplasia of mucous glands of duct epithelium; a diagnosis of pyloric gland metaplasia has to be made histochemically and is suggested by PAS+ and Alcian blue (pH 2.8) negative
Electron micrograph of papillary hyperplasia in patient with cancer of head of pancreas; mucin granules have an electron-opaque matrix and a darker eccentric core
Mucinous (goblet cell) metaplasia
=========================================================================
● Associated with older age, chronic pancreatitis, carcinoma
● Differential diagnosis:
PanIN-1A
Oncocytic change
=========================================================================
● Associated with chemotherapy
Proliferation of centroacinar or intercalated duct cells
=========================================================================
● Associated with recent ductal obstruction, acute alcohol abuse, chronic pancreatitis, hyperinsulinemia or hypergastrinemia
Pseudolipomatous hypertrophy
=========================================================================
Pancreatic parenchyma consists of mature fatty tissue separated by thin fibrous septa containing isolated clusters of normal islets
Squamous metaplasia
=========================================================================
● Common, associated with chronic pancreatitis, normal pancreas, bone marrow transplant with chemotherapy
(Hum Pathol 1993;24:152)
● Micro images:
Squamous metaplasia: mucinous epithelial duct cells are partly replaced by squamous epithelium
Congenital anomalies
Agenesis
Reviewer: Deepali Jain, M.D. (see Reviewers
page)
Revised: 22 November 2012, last major update August 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.
General
=========================================================================
● Extremely rare anomaly
● Associated with severe intrauterine growth restriction, 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
● Agenesis of dorsal pancreas is also rare; either partial or complete (JOP 2012;13:108); associated with polysplenia syndrome (Br J Radiol 2011;84:e217)
Drawings
=========================================================================
Various images
Clinical images
=========================================================================
Intraoperative image of dorsal agenesis with underlying superior mesenteric vein; note the absence of pancreatic tissue left of the superior mesenteric vein (arrowhead marks most distal aspect of pancreatic tissue; thin arrow marks superior mesenteric vein)
Congenital anomalies
Annular pancreas
Reviewer: Deepali Jain, M.D. (see Reviewers
page)
Revised: 22 November 2012, last major update August 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.
General
=========================================================================
● Incidence 1 per 12,000–15,000 live births
● 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, esophageal atresia, imperforate anus, congenital heart disease, malrotation of the midgut
● Pancreatic duct is anterior, courses to the right over the duodenum, then posterior and to left behind duodenum, then near common duct
● Complications include pancreatitis, duct obstruction, peptic ulcer
● Has large number of PP cells (of ventral bud origin) in irregular shaped islets
● Portal annular pancreas is rare variant (JOP 2010;11:453)
Clinical images
=========================================================================
Development of annular pancreas
Clinical images
=========================================================================
Intraoperative images (different cases)
Congenital anomalies
Familial fibrocystic pancreatic atrophy with endocrine cell hyperplasia and pancreatic carcinoma
Reviewer: Deepali Jain, M.D. (see Reviewers
page)
Revised: 6 December 2012, last major update August 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.
General
=========================================================================
● Autosomal dominant, high penetrance, associated with diabetes mellitus, exocrine pancreatic insufficiency, characteristic imaging abnormalities
Gross description
=========================================================================
● Fibrosis, intraductal calcifications, microcysts
Micro description
=========================================================================
● 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
(Am J Surg Pathol 2001;25:1047)
Congenital anomalies
Heterotopic pancreas
Reviewer: Deepali Jain, M.D. (see Reviewers
page)
Revised: 22 November 2012, last major update August 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.
General
=========================================================================
● Pancreatic tissue outside boundaries of pancreas without anatomic or vascular connections to pancreas
● Also called ectopic 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
(Arch Pathol Lab Med 2003;127:E99),
gastroesophageal junction
(Am J Surg Pathol 1996;20:1507,
Arch Pathol Lab Med 2000;124:1165)
● Usually incidental finding but may cause ulceration, obstruction, intussusception (Hum Pathol 1994;25:169)
● Vulnerable to same diseases as normal pancreas, including pancreatic endocrine tumors (2% arise in ectopic pancreatic tissue), PanIN (Am J Surg Pathol 2007;31:1191), carcinoma (Arch Pathol Lab Med 1994;118:568,
Arch Pathol Lab Med 1999;123:707)
Case reports
=========================================================================
● 16 year old girl with pancreatic cyst in anterior mediastinum
(Mod Pathol 1996;9:210)
● 42 year old woman with ductal adnocarcinoma in hetertopic tissue in rectum (Hum Pathol 2010;41:1809)
Gross description
=========================================================================
● 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 detect radiographically)
Micro description
=========================================================================
● 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,
Arch Pathol Lab Med 2002;126:464)
● May have convoluted branching pattern mimicking invasive carcinoma
● Rarely retains mucus and resembles mucinous carcinoma
(Am J Surg Pathol 1994;18:953)
Micro images
=========================================================================
Gastroesophageal junction
Jejunum
Liver: heterotopic pancreas and ductal adenocarcinoma
Meckel’s diverticulum in Crohn’s patient-figure 3
Stomach: purely endocrine
Stomach: heterotopic pancreas tissue in muscular layer contains ducts, acinar cells and a few islets
Differential diagnosis
=========================================================================
● Pancreatic metaplasia of gastric mucosa
● Endocrine subtype of heterotopia may mimic a primary or metastatic neuroendocrine tumor
Additional references
=========================================================================
● Am J Surg Pathol 1993;17:1134,
Arch Pathol Lab Med 2003;127:e237,
Am J Surg Pathol 1998;22:100
Congenital anomalies
Nesidioblastosis
Reviewer: Deepali Jain, M.D. (see Reviewers
page)
Revised: 22 November 2012, last major update August 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.
General
=========================================================================
● Islets in intimate association with ducts, with formation of ductuloinsular complexes
● Also called congenital islet hyperplasia
● Indicates active formation of endocrine cells by multipotential cells in basal layer of ducts
Clinical features
=========================================================================
● Normal in infants, exaggerated in neonatal hyperglycemia (infants of diabetic mothers)
● In adults, is rare cause of persistent hyperinsulinemic hypoglycemia
● Associated with Beckwith-Weideman syndrome, chronic pancreatitis, cystic fibrosis, endocrine neoplasms, gastric bypass patients ((Mod Pathol 2009;22:239), Zollinger-Ellison syndrome
● May be due to increase in expression of growth factors IGF2, IGF1Ra and TGFBR3 in islets (Mod Pathol 2009;22:239)
● Must rule out mutation in HADH gene (J Clin Endocrinol Metab 2011;96:E498)
● Either focal or diffuse (Am J Surg Pathol 1989;13:766):
● 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, peliosis-type vascular ectasia
Case reports
=========================================================================
● 44 year old man with symptomatic hypoglycemia and localized nesidioblastosis (Hum Pathol 2010;41:447)
Treatment
=========================================================================
● Focal nesidioblastosis: partial pancreatectomy with excision of diseased areas; diffuse: near total pancreatectomy
Micro description
=========================================================================
● Islets in intimate association with ducts, with formation of ductuloinsular complexes
● Beta cell hypertrophy (Am J Surg Pathol 2005;29:524)
Micro images
=========================================================================
Various images
20 day old girl with persistent hypoglycemia and seizures
23 year old man with hypoglycemia mimicking an insulinoma
Left-expansion of endocrine cells from a ductal structure forming a ductulo-insular complex (arrow)
Right-irregular hyperplastic islets (arrows) in close approximation with pancreatic exocrine ductal structures
Left-chromogranin staining within irregular islets
Right-insulin staining within islets
Congenital anomalies
Pancreas divisum
Reviewer: Deepali Jain, M.D. (see Reviewers
page)
Revised: 22 November 2012, last major update August 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.
General
=========================================================================
● Most common congenital anomaly of the pancreas (3-10% of population); most patients are asymptomatic
● Incomplete fusion of dorsal and ventral pancreatic buds / ducts causes separation of ventral and dorsal pancreas as a double pancreas
● Two ductal systems drain separately to two duodenal papillae; may cause isolated dorsal or ventral pancreatitis (25%)
● Not a risk factor for acute pancreatitis (Curr Gastroenterol Rep 2011;13:150), but may be risk factor for recurrent acute pancreatitis
● Duct of Santorini provides main drainage
● Diagnose by imaging studies such as ERCP
Drawings
=========================================================================
Complete and incomplete pancreatic divisum
Various images
Pancreatitis
Acute pancreatitis
Reviewer: Deepali Jain, M.D. (see Reviewers
page)
Revised: 22 November 2012, last major update August 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.
General
=========================================================================
● Acute onset of abdominal pain due to enzymatic necrosis and inflammation of pancreas (Wikipedia)
● 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
● Complications: sterile pancreatic abscess, pancreatic pseudocyst, infected pancreatic necrosis, large vessel thrombi in nearby vessels, distant fat necrosis
● Unexpected deaths may occur in early phase of disease (Am J Forensic Med Pathol 2007;28:267)
Terminology
=========================================================================
● 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
(Arch Pathol Lab Med 1985;109:433)
● 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
Epidemiology
=========================================================================
● 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
Pathophysiology
=========================================================================
● 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
Etiology
=========================================================================
● 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)
● Infectious causes: Actinomyces, adenovirus in immunocompromised (Hum Pathol 1993;24:1145), AIDS related toxoplasmosis, Ascaris lumbricoides, aspergillus, Campylobacter jejuni, Clonorchis sinensis, CMV, coccidioides, coxsackie virus, cryptococcus, EBV, Echinococcus granulosus, Hepatitis A and B, herpes simplex, histoplasma, HIV, mumps, mycobacterium, Mycoplasma pneumoniae, nocardia, rubella, paracoccidioides, Pneumocystis jiroveci, Rocky Mountain spotted fever/Rickettsiae (Arch Pathol Lab Med 1984;108:963), Salmonella typhi, Strongyloides stercoralis, Yersinia enterocolitica
● Drugs: antiretroviral, azathioprine, estrogen, furosemide, methyldopa, pentamidine, procainamide, sulfa, thiazides
● Other: acute ischemia (thromboemboli, vasculitis, shock), anatomic abnormalities such as pancreas divisum, hyperlipidemia, hyperparathyroidism or other causes of hypercalcemia, hyperthyroidism, idiopathic (10%), SLE, trauma (including post-operative)
Diagnosis
=========================================================================
● Elevated amylase (also seen in abdominal aortic aneurysm, duodenal ulcer, gangrenous cholecystitis, mesenteric thrombosis, volvulus), elevated lipase, elevated C reactive protein, Xray (large and inflamed pancreas)
Prognostic factors
=========================================================================
● 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
Treatment
=========================================================================
● Rest the pancreas by food/fluid restriction
Gross description
=========================================================================
● Swollen, indurated, 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 description
=========================================================================
● Classified as either acute interstitial or acute hemorrhagic types
● Acute interstitial: typically an acute inflammatory cell infiltrate admixed with edema and fibrinous exudate
● Acute hemorrhagic: patchy necrosis typically in a periductal or perilobular distribution with a sparing of portions of the pancreas; diffuse interstitial edema due to microvascular leakage, fat necrosis, neutrophils, acinar and blood vessel destruction, interstitial hemorrhage
● Also acinar cell homogenization, ductal dilation with mucinous or squamous metaplasia, fibroblasts, thrombi in capillaries and venules
● Initially neutrophils are present, then macrophages and later lymphocytes
● Calcification occurs early and extensively
Micro images
=========================================================================
Hemorrhage, necrosis, fat necrosis, neutrophils
Differential diagnosis
=========================================================================
● Acute abdomen, including acute cholecystitis with rupture, appendicitis, occlusion of mesenteric vessels with bowel infarction, perforated peptic ulcer
Pancreatitis
Autoimmune pancreatitis
Reviewer: Deepali Jain, M.D. (see Reviewers
page)
Revised: 23 November 2012, last major update August 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.
General
=========================================================================
● Chronic inflammatory disease of pancreas
● Also called primary sclerosing cholangitis-like pancreatitis, non-alcoholic duct destructive chronic pancreatitis (Arch Pathol Lab Med 2000;124:1535)
● Forms mass that may constrict bile duct with dense periductal inflammatory infiltrate, and clinically is thought to be malignant
● Has 2 subtypes (Am J Surg Pathol 2011;35:26, Semin Diagn Pathol 2012;29:197)
Type 1 / lymphoplasmacytic sclerosing pancreatitis
● Pancreatic manifestation of IgG4 related systemic disease (BMC Med 2006;4:23)
● Pancreas shows hypercellular lymphoplasmacytic infiltrate of interlobular stroma (91%), storiform type fibrosis, >10 IgG4 plasma cells / high-power field (typically >50/HPF), infiltrate may extent to peripancreatic tissue
● 75% male, older patients, often presents with jaundice; may recur within and outside pancreas
● Associated with sclerosing cholangitis, Sjögren-like syndrome, obliterative phlebitis, arterial involvement
Type 2 / idiopathic duct centric pancreatitis
● Confined to pancreas (i.e. not systemic)
● Pancreas shows microabscesses and ductal ulceration (78%), granulocyte epithelial lesions, only occasional IgG4 plasma cells (<10/HPF)
● Often pancreatic tail cut-off sign by imaging (40%), disease recurrence uncommon
● No gender preference, younger patients, associated with inflammatory bowel disease, not with obliterative phlebitis
● 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
● Compared to chronic pancreatitis NOS, more foci of periductal inflammation and neutrophilic microabscesses
Treatment
=========================================================================
● Steroids (Front Physiol 2012;3:374)
● Overall prognosis is excellent
Gross description
=========================================================================
● Pancreatic mass with regional nodal swelling
● Narrowing of main pancreatic duct
Micro description
=========================================================================
Type 1:
● Prominent periductal and acinar lymphoplasmacytic infiltration and fibrosis around the pancreatic ducts
● Marked acinar atrophy, phlebitis of pancreatic and portal veins
● >10 IgG4 plasma cells / high-power field, infiltrate may extent to peripancreatic tissue
Type 2:
● Microabscesses and ductal ulceration (78%), no IgG4 plasma cells
● No calcifications, no fat necrosis, no cyst formation
Micro images
=========================================================================
Type 1 cases
Type 2: small caliber ducts with granulocytic epithelial lesions
Type 1 and type 2 cases
Cytology images
=========================================================================
Left: type 1; right: type 2 cases
Differential diagnosis
=========================================================================
● Chronic pancreatitis: often history of alcohol abuse; pancreas exhibits fat necrosis, pseudocysts, calcifications, dilated ducts with inspissated secretions; usually less periductal inflammation and neutrophilic microabscesses
● Pancreatic adenocarcinoma: marked atypia and invasion is present, may have IgG4+ plasma cells (J Gastroenterol 2012 Oct 5 [Epub ahead of print])
Pancreatitis
Chronic pancreatitis
Reviewer: Deepali Jain, M.D. (see Reviewers page)
Revised: 22 November 2012, last major update August 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.
See also subtypes below
General
=========================================================================
● Repeated attacks of pancreatic inflammation with loss of pancreatic parenchyma and replacement with fibrosis, variable pain and symptoms of pancreatic insufficiency (malabsorption, diabetes)
● May simulate or coexist with pancreatic carcinoma
● 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 (Arch Pathol Lab Med 1997;121:612)
● Attacks precipitated by alcohol, overeating, opiates, other drugs
● Biliary disease usually not a factor in chronic pancreatitis
● Other risk factors: hypercalcemia, hyperparathyroidism, hyperlipoproteinemia, pancreas divisum (seen in 12%), pancreatic neoplasm, cystic fibrosis; cigarette smoking; no known risk factor in 30%
● Also associated with mumps, polyarteritis nodosa, sarcoidosis, malakoplakia, primary sclerosing cholangitis, HIV (mild changes)
Epidemiology
=========================================================================
● Men, 40+, often alcoholics (70%)
Diagnosis
=========================================================================
● Clinical triad of steatorrhea, diabetes and pancreatic calcification on radiographic studies 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)
Gross description
=========================================================================
● Hard, shrunken, dilated ducts, visible calcified concretions (protein plugs), pseudocysts common
● 5% have obstruction due to tumor or stones
Gross images
=========================================================================
Whipple resection specimen due to chronic pancreatitis: cut surface of pancreatic head shows diffuse sclerosis with small calculi in main pancreatic duct, suggesting a "rock hard" tumor mass. Note the tubular stenosis of the bile duct in the upper pancreatic head
Main pancreatic duct in head-body region is irregularly dilated and contains calculi of varying sizes
Micro description
=========================================================================
● Loss of acini and ductal tissue 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; perineural and intraneural inflammation with hyperplasia of the nerves
● 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 (Islet aggregation) in peripancreatic adipose tissue
Micro images
=========================================================================
Focal fibrosis (upper left) was thought to be carcinoma at surgery, although no tumor was actually present
Advanced chronic pancreatitis with replacement of large areas of acinar parenchyma by sclerotic tissue and lobular aggregation of irregularly sized remaining ducts
Sclerotic area of pancreas with dilated duct (left) and clusters of remaining islets (right)
Dilated interlobular ducts containing protein plugs; surrounding tissue shows sclerosis and inflammatory reaction; note small islet at the bottom
Left: ducts are irregularly sized, but lining lacks cellular atypia; right: ducts (top) have benign appearing nuclei, islet is at bottom
Squamous metaplasia: mucinous epithelial duct cells are partly replaced by squamous epithelium
Figures 3 and 4
Positive stains
=========================================================================
● Trichrome (fibrosis), actin
Differential diagnosis
=========================================================================
● Pancreatic xanthomatous neuropathy associated with hyperlipidemia (Hum Pathol 1993;24:1023)
Additional references
=========================================================================
● Arch Pathol Lab Med 2001;125:1051, Arch Pathol Lab Med 2000;124:1302, Hum Pathol 2001;32:1174, Am J Surg Pathol 2003;27:110
Subtypes of chronic pancreatitis
Familial hereditary pancreatitis
=========================================================================
● Childhood onset, first decade, increased risk for pancreatic carcinoma
● Autosomal dominant with mutation at trypsinogen (PRSS1), codon 117 (80% cases) that removes a proteolytic cleavage site, causing persistent trypsin activation
● Other mutations in cystic fibrosis transmembrane conductance regulator (CFTR), or in the serine protease inhibitor Kazal type 1 (SPINK1)
Paraduodenal or groove pancreatitis
=========================================================================
● Also called adenomyoma/myoadenomatosis, cystic dystrophy of heterotopic pancreas, pancreatic hamartoma of pancreatic wall, or periampullary or periduodenal wall cyst
● Scar develops between head of pancreas and duodenum
● Involves an area between the pancreas, common bile duct, and duodenum, typically involves the minor papilla
● Associated with alcohol abuse, tobacco smoking, and hypertension
● Duodenal submucosa and muscularis show a prominent chronic inflammatory cell infiltrate extending to pancreas, myoid proliferation, Brunner’s gland hyperplasia
Non-alcoholic chronic tropical pancreatitis
=========================================================================
● Younger individuals, in India, southern Asia, central Africa, and Brazil
● Due to protein-calorie malnutrition, dietary cyanogen toxicity, antioxidant deficiency, genetic predisposition (mutations in pancreatic secretory trypsin inhibitor gene)
● Gross description: shrunken, firm, nodular, gritty pancreas due to calculi present diffusely in dilated ducts
● Micro description: pancreatic ducts with denuded epithelium, squamous metaplasia, periductal lymphoplasmacytic infiltrate, acinar and islets atrophy, fibrosis
Infectious pancreatitis
=========================================================================
● In immunocompromised patients
Pancreatitis
CMV pancreatitis
Reviewer: Deepali Jain, M.D. (see Reviewerspage)
Revised: 22 November 2012, last major update August 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.
Gross images
=========================================================================
Severe necrotizing pancreatitis
Micro images
=========================================================================
Acute necrotizing pancreatitis
CMV inclusions: H&E and Acute necrotizing pancreatitis
Case reports
=========================================================================
● 76 year old man with fatal acute necrotizing pancreatitis due to CMV infection after steroid administration (JOP 2011;12:158)
● Disseminated CMV infection presenting with acute pancreatitis and acalculous cholecystitis in post-chemotherapy patient (Arch Pathol Lab Med 1989;113:1287)
Pancreatitis
Eosinophilic pancreatitis
Reviewer: Deepali Jain, M.D. (see Reviewers
page)
Revised: 23 November 2012, last major update August 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.
General
=========================================================================
● Very rare (<20 cases reported)
● Usually peripheral eosinophilia and multiorgan involvement (Am J Surg Pathol 2003;27:334)
● 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
Case reports
=========================================================================
● Stillborn fetus (34 weeks) with anencephaly and diabetic mother (Gastroenterology Research 2011;4:174 (online))
● 14 year old boy with pancreatic mass (Can J Gastroenterol 2006;20:361)
● 38 year old woman (Indian J Gastroenterol 2007;26:136)
Micro description
=========================================================================
● Diffuse periductal, acinar and septal eosinophilic infiltrate affecting arteries and veins or clusters of eosinophils associated with pseudocysts
● Also fibrosis
Micro images
=========================================================================
14 year old boy: images from pancreas, duodenum, lymph node
Stillborn fetus (34 weeks) with anencephaly and diabetic mother
Hypertrophy and hyperplasia of islets with prominent septal, peri-insular and islet eosinophilic infiltrate limited to pancreatic parenchyma, with relative sparing of exocrine pancreas
Differential diagnosis
=========================================================================
● Inflammatory myofibroblastic tumor
● Langerhans’ histiocytosis
● Lymphoplasmacytic sclerosing pancreatitis: eosinophils focal
● Pancreatic allograft rejection
● Pseudocyst
● Systemic mastocytosis
Pancreatitis
Graft versus host disease (GVHD)
Reviewer: Deepali Jain, M.D. (see Reviewers
page)
Revised: 23 November 2012, last major update August 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.
General
=========================================================================
● Identified in autopsies of children with congenital immune deficiencies with GVHD of other organs (Hum Pathol 1994;25:908)
● To diagnose, must pay careful attention to pancreatic ducts
● Note: GVHD may occur post-pancreas transplant, involving skin and other organs (Transplantation 2006;82:127)
Micro description
=========================================================================
● Lymphocytes around large to medium ducts, damage to ductal epithelium (focal necrosis, reactive nuclear changes, inspissated secretions in duct lumens), and periductal edema (Histopathology 1989;14:121)
Pancreatitis
Herpes simplex pancreatitis
Reviewer: Deepali Jain, M.D. (see Reviewers
page)
Revised: 23 November 2012, last major update August 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.
General
=========================================================================
● Rare cause of acute pancreatitis; often coexists with HSV hepatitis (Eur J Gastroenterol Hepatol 2009;21:114)
Gross description
=========================================================================
● Small, discrete foci of hemorrhagic necrosis
Micro description
=========================================================================
● Parenchymal necrosis, hemorrhage, minimal fat necrosis, mild neutrophilic infiltrate compared to intensity of necrosis (Arch Pathol Lab Med 2003;127:231)
● 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
Micro images
=========================================================================
Various images
Diabetes mellitus
General
Reviewer: Deepali Jain, M.D. (see Reviewers
page)
Revised: 29 November 2012, last major update August 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.
General
=========================================================================
● Chronic disorder of carbohydrate, fat and protein metabolism due to defective or deficient insulin secretory response (Wikipedia)
Epidemiology
=========================================================================
● 3% of world population, 26 million in U.S. but only 75% are clinically diagnosed
● #7 leading cause of death in 2007 (underlying cause on 71,382 death certificates, Diabetes.org)
● Lifetime risk of diabetes: type 1 - 0.5%, type 2 - 5%
● Numerous variations, all with hyperglycemia
Etiology
=========================================================================
● Destruction of islets due to drugs (steroids, thiazides, pentamidine), hemochromatosis (“bronze diabetes” due to hemosiderin deposition in pancreas), hereditary ceruloplasmin deficiency (Hum Pathol 1997;28:499), infections (congenital rubella, CMV, coxsackievirus [Arch Pathol Lab Med 1980;104:438], enteroviruses [Diabetologia 2004;47:225]), pancreatitis, surgery, tumors, endocrinopathies (pituitary, adrenal, pregnancy) or idiopathic
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 description
=========================================================================
● 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
● Gestational diabetes: lower total insulin+ area due to smaller islets (Islets 2011;3:231)
● Infants of diabetic mothers: islet cell hypertrophy/hyperplasia
Diabetes mellitus
IDDM, insulin-dependent diabetes mellitus, type 1
Reviewer: Deepali Jain, M.D. (see Reviewers
page)
Revised: 9 December 2012, last major update August 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.
General
=========================================================================
● Chronic disease of carbohydrate, fat, and protein metabolism due to reduction in beta cell mass causing severe, absolute lack of insulin (eMedicine)
● 10% of all cases
● Without insulin, patients develop diabetic ketoacidosis (DKA), coma and death
Etiology
=========================================================================
● Presumed autoimmune cause for islet cell destruction, but precise etiology unclear (Wikipedia)
● Usually Northern European descent
● 70% concordance in identical twins, HLA-D linked
● Genetic predisposition may affect immune responsiveness to a beta cell autoantigen or method of presentation to T cells
Viruses and IDDM
● Viruses may damage beta cells, exposing antigens which trigger an autoimmune response
● May be due to molecular mimicry (immune response develops against shared amino acid sequences): GAD and Coxsackie B4 virus share a six amino acid sequence
● Retrovirus may serve as a superantigen
Autoimmune aspects
● Islet cell autoantibodies present in 70%; also CD8+ T cell infiltrate in islets
● Antigens are glutamic acid decarboxylase (GAD), islet autoantigen 2, insulin associated antibody, gangliosides
● GAD antibodies precede clinical symptoms, present in most newly diagnosed patients and 80% of first degree relatives
● GAD antibody also causes stiff man syndrome, whose patients often have a history of IDDM
● Many IDDM patients also have anti-thyroid peroxidase, anti-parietal cell and anti-adrenocortical antibodies
● Some NIDDM patients have autoantibodies, but no other features of IDDM
● Usually chronic (years)
● Clinical disease when 90% of islet cells are destroyed
Clinical features
=========================================================================
● Onset at age < 20 years, normal weight (unlike most NIDDM)
● Characterized by PPP (polyuria, polydipsia, polyphagia) and ketoacidosis (DKA)
● Polyphagia combined with weight loss is specific for IDDM; type 2 patients rarely have either
● Severe fasting hypoglycemia is due to cessation of glycogen storage in fat and muscle
● Glycosemia causes glycosuria with depletion of water and electrolytes
● 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)
● 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
● "Dead in bed syndrome": sudden death in young people with type 1 diabetes, cause unknown (Hum Pathol 2010;41:392)
Treatment
=========================================================================
● Immunosuppressive therapy is effective in children with new onset disease
Case reports
=========================================================================
● Adult with acute onset, death within 3 days, T cell pancreatic infiltrate (Arch Pathol Lab Med 1994;118:84)
● Islet inflammation with Coxsackie B5 infection (Hum Pathol 1982;13:661)
Micro description
=========================================================================
● Early insulinitis with marked islet atrophy and fibrosis and severe beta cell depletion (Islets 2011;3:131)
Micro images
=========================================================================
Normal isletss
Insulinitis
2 year old girl with recent onset diabetes
Diabetes mellitus
Non-insulin dependent diabetes mellitus
Reviewer: Deepali Jain, M.D. (see Reviewers
page)
Revised: 25 November 2012, last major update August 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.
General
=========================================================================
● Also called adult onset, Non-Insulin Dependent Diabetes Mellitus / NIDDM, type 2
● 80-90% of cases of diabetes (Wikipedia)
● Usually > 30 years old, obese (80% of cases, abdominal obesity more important than subcutaneous obesity), normal or increased blood insulin, rare diabetic ketoacidosis, no anti-islet antibodies
Pathophysiology
=========================================================================
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
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
Clinical features
=========================================================================
● 90%+ concordance in twins, apparently due to multiple genetic polymorphisms (no HLA association)
● Due to insulin resistance (associated with obesity and pregnancy) or derangement in beta cell secretion of insulin
● Associated with amyloid deposits in islets (amyloid associated with basement membrane heparan sulfate proteoglycan, Arch Pathol Lab Med 1992;116:951) and pituitary (Arch Pathol Lab Med 1995;119:1055)
Treatment
=========================================================================
● Diet, exercise, and education (eMedicine)
● Lifestyle intervention and metformin delay onset of diabetes (N Engl J Med 2012;367:1177)
Micro description
=========================================================================
● Amyloid in the islets of Langerhans is the uniform pathologic feature
Micro images
=========================================================================
Amyloid deposition in islets
Islet amyloid polypeptide (IAPP; black) and insulin-expressing cells (red) in islets
Videos
=========================================================================
Diabetes mellitus
Maturity onset diabetes of the young, MODY
Reviewer: Deepali Jain, M.D. (see Reviewers
page)
Revised: 25 November 2012, last major update August 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.
General
=========================================================================
● 1-2% of all cases of diabetes (Diabetes Metab Syndr Obes 2012;5:101)
● Also called monogenic diabetes (Wikipedia)
● Type 2 diabetes-like condition which occurs in 2+ generations, with autosomal-dominant inheritance (Diabetes Care 2011;34:1878)
● Autosomal dominant, but not a single entity - mutations in 9 genes identified to date (see diagram below)
● Common genes affected are Hepatic Nuclear Factor 1 or 4 alpha, glucokinase
● Onset before age 25, normal weight, mild hypoglycemia
● No GAD antibodies, no insulin resistance, no beta cell loss but impaired beta cell function
Single gene mutations resulting in monogenic diabetes / MODY
Diabetes mellitus
Diabetic complications
Reviewer: Deepali Jain, M.D. (see Reviewers
page)
Revised: 4 December 2012, last major update August 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.
General
=========================================================================
● 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
Formation of irreversible products called advanced glycation end products (AGEs), such as carboxymethyllysine
● 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
Diagrams
Vascular complications of diabetes
=========================================================================
● Relative risk is 100:1
● Accelerated atherosclerosis in aorta and large/medium sized vessels
● Myocardial infarction: most common cause of death, no gender preference
● Gangrene of lower extremities
Micro description:
● 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; see Kidney nontumor chapter
● Glomeruli-capillary basement membrane thickening (grade I), mesangial expansion (grade II), nodular glomerulosclerosis (grade III), diffuse glomerulosclerosis, (grade IV)
● Also renal atherosclerosis and arteriolosclerosis
● Changes to efferent arteriole are specific for diabetes
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
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
Reviewer: Deepali Jain, M.D. (see Reviewers
page)
Revised: 24 November 2012, last major update August 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.
Congenital / dysgenetic cysts
=========================================================================
● By definition are intrapancreatic, do not communicate with duct system, lined by a single layer of cuboidal, columnar, or flattened atrophic epithelium with a fibrous wall
● Most congenital pancreatic cysts are multiple, almost all are associated with underlying congenital diseases that primarily affect other organ systems (AJR Am J Roentgenol 2002;179:1375)
● Often associated with polycystic disease affecting kidney and liver, von Hippel Lindau syndrome or oral-facial-digital syndrome type I
● Single cysts may be due to abnormal duct development
● Other syndromes: Elejalde syndrome, glutaric aciduria II, Ivemark syndrome, Jeune syndrome, Meckel-Gruber syndrome, short-rib polydactyly syndrome Type 1, Trisomy 13, 14, 15, tuberous sclerosis
● Case report: multilocular cysts associated with choledochal cyst (Hum Pathol 2003;34:99)
Congenital cyst: cysts are lined by small nonmucin producing cuboidal cells and are embedded in fibrous stroma
Cysts of cystic fibrosis
=========================================================================
● Click here
Dermoid cysts
=========================================================================
● Seen in young patients (2nd-3rd decade)
● Case report: 64 year old man (World J Surg Oncol 2007;5:85)
Tail of pancreas cyst
Epidermoid cysts
=========================================================================
● May be present within an intrapancreatic spleen (Pancreas 2011;40:956)
● In tail, unilocular, typically contain concentric enzymatic concretions, may communicate with acinar system
● Squamoid cyst of pancreatic ducts; has thin wall lined by transitional/squamous cells without keratinization or granular layer
● Case report: 62 year old man with intrapancreatic spleen containing epidermoid cyst (JOP 2011;12:279)
62 year old man: intrapancreatic spleen has multiple cysts with stratified squamous epithelium that is CEA+
Foregut 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 (Am J Surg Pathol 1996;20:476)
● Case reports: 34 year old woman with pancreatic mass (JSLS 2008;12:183), 37 year old woman with acute cholangitis (JOP 2011;12:420)
Foregut cyst (0.9 cm) attached to pancreas; retroperitoneal margins are inked
Foregut cyst and immunostains of lining: a-cyst compresses bile duct (arrow); b-cyst is lined by thin epithelial layer (arrowhead) covering loose connective tissue without smooth muscle bundles or cartilage; * depicts normal pancreas; c-pseudostratified ciliated epithelium with interspersed goblet cells (arrows)
Foregut cyst attached to pancreas
Ciliated foregut cyst-FNA
Mesothelial cysts
=========================================================================
● May be multiple and involve pancreas, liver, kidney or other abdominal structures
● Case report: 36 year old man with 3 cm cyst (Ann Diagn Pathol 2006;10:371)
Pancreatic hamartoma
=========================================================================
● Initial report in 20 month old girl with 9 cm cystic mass (Hum Pathol 1992;23:1309)
● 52 year old woman with 2.5 cm mass in pancreatic head (J Korean Surg Soc 2012;83:330)
● Well demarcated and composed of cystic ductal structures embedded in focally inflamed stromal tissue (Am J Surg Pathol 2005;29:797)
Various images
Non-epithelial cysts
=========================================================================
● Includes endometrial cyst, lymphangioma, pseudocysts, parasitic cyst
Pancreatic tissue derived cysts
=========================================================================
● May appear in thorax or mediastinum, as components of gastroenteric duplication cysts, intralobar pulmonary sequestrations, teratomas or rarely from ectopic pancreatic tissue (Mod Pathol 1996;9:210)
● Paraduodenal wall cyst (cystic dystrophy): patients with paraduodenal (groove) pancreatitis, cysts may enlarge and adhere to duodenal wall, mimicking duodenal duplication; lined by granulation tissue, may be partly lined by ductal epithelium (Semin Diagn Pathol 2004;21:247)
Ectopic pancreas with cystic change in mediastinum
Paraduodenal wall cyst
Squamous cyst of pancreatic ducts
Tumors that are cystic
=========================================================================
● Cystic tumors include: ductal adenocarcinoma, IOPN, IPMN, lymphoepithelial cyst, mucinous cystic neoplasm, mucinous non-neoplastic cyst, serous cystadenoma, solid-pseudopapillary tumor
Cysts
Cystic fibrosis
Reviewer: Deepali Jain, M.D. (see Reviewers
page)
Revised: 24 November 2012, last major update August 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.
General
=========================================================================
● Autosomal recessive disorder affecting most critically the lungs; also pancreas, liver, intestines; characterized by abnormal transport of chloride and sodium across an epithelium, leading to thick, viscous secretions (Wikipedia)
● 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
● Complications: pancreatic insufficiency late in disease course in 90%, diabetes, malabsorption, pancreatitis
● Mutations also cause defective cilia and infertility; may cause meconium ileus (5-10%), intussusception
● Cysts form secondary to ductal obstruction due to thick, tenacious secretions, variable numbers of cysts range from 1 to 3 mm, very rarely entire pancreas replaced by multiple macroscopic cysts, termed “pancreatic cystosis”
Micro images
=========================================================================
At autopsy, pancreas is mucoid and slightly smaller than normal
Micro description
=========================================================================
● Grade I: accumulation of secretion
● Grade II exocrine atrophy
● Grade III atrophy with lipomatosis
● Grade IV fibrosis with total obliteration of the exocrine glands and ducts with scattered islets of Langerhans
● 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 Pathol 1984;15:278)
Micro images
=========================================================================
Abnormally viscid secretions from exocrine glands are round eosinophil masses distending and obstructing pancreatic ducts, leading to destruction of parenchyma and fibrosis
Positive stains
=========================================================================
● PAS+ diastase resistant, CEA, alpha-1-antitrypsin (Arch Pathol Lab Med 1989;113:1142)
Videos
=========================================================================
Differential diagnosis
=========================================================================
● Kartegeners: defective cilia syndrome
Cysts
Lymphoepithelial cysts
Reviewer: Deepali Jain, M.D. (see Reviewers
page)
Revised: 24 November 2012, last major update August 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.
General
=========================================================================
● Rare congenital cyst similar to branchial pouch derived structures; 0.5% of pancreatic cysts
● First describedi n 1987 (Am J Surg Pathol 1987;11:899)
● Mean age 56 years, range 35-82 years, 80% male (Mod Pathol 2002;15:492)
● Present with abdominal pain or nausea, or incidental finding
● Not associated with immunosuppression or autoimmune diseases
● Occurs anywhere in pancreas (head, body, or tail) or extrapancreatic
General
=========================================================================
● Etiology may be similar to Warthin’s tumors, in which lymphoid cells have an affinity for ductal epithelia and can induce their growth (Adv Anat Pathol 2011;18:98)
● May occasionally develop from epithelial remnants in lymph nodes (Hum Pathol 1991;22:924) or from accessory spleen in pancreas (Mod Pathol 1998;11:1171)
Clinical features
=========================================================================
● Benign, do not recur or progress
● Elevated CA19-9, CEA levels in cyst fluid (Mod Pathol 2010;23:1467)
Case reports
=========================================================================
● 60 year old man (Case Rep Gastroenterol 2012;6:604)
Gross description
=========================================================================
● Mean 5 cm (range, 1-17 cm), cysts contain keratin or clear fluid
● Often round and well-demarcated from surrounding pancreas, 60% multilocular
Gross images
=========================================================================
Well demarcated cysts
Cyst with papillary projection
Micro description
=========================================================================
● Unilocular or multilocular, lined by squamous epithelium, with lymphocytes and germinal centers in the wall
● Occasional solid lymphoepithelial islands, rarely mucinous goblet cells
● Rare sebaceous differentiation, keratin granulomas may be present
Micro images
=========================================================================
Various images
Cyst with papillary projection of squamous epithelium surrounded by lymphoid tissue
Cytology description
=========================================================================
● Numerous anucleated squamous cells, amorphous debris (Cancer 2006;108:501)
● May have mildly atypical mucinous glandular and parakeratotic epithelium
● Rare benign nucleated cells, usually no lymphocytes
Cytology images
=========================================================================
Well-differentiated squamous epithelium, keratinaceous and amorphous debris, and some lymphoid cells
Squamous cells with no/rare lymphocytes
Various images
Differential diagnosis
=========================================================================
● Clinical differential diagnosis includes mucinous cystic neoplasms, IPMN, IOPN (but different histologically)
● Histological differential diagnosis: dermoid and epidermoid cysts (younger-mean ages 29/37 years, M=F, prominent mucinous cells or respiratory mucosa in dermoid cyst), lymphangioma (positive for endothelial and lymphatic markers), pseudocyst (peripancreatic, no lymphoid stroma)
Cysts
Mucinous non-neoplastic cyst (MNC)
Reviewer: Deepali Jain, M.D. (see Reviewers
page)
Revised: 24 November 2012, last major update August 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.
General
=========================================================================
● Initially described in 2002 (Mod Pathol 2002;15:154)
● 10% of mucinous pancreatic cysts (Pancreas 2012;41:441)
● Men and women, mean age 57 years
● Does not recur after resection
● Appears to be nonneoplastic, polyclonal; may develop from acinar ductal mucinous metaplasia (Hum Pathol 2010;41:513)
Gross description
=========================================================================
● Usually unifocal, head of pancreas, thin walled cysts that don’t communicate with ductal system
Gross images
=========================================================================
Unilocular cyst containing chocolate-colored old blood
Unilocuar and multilocular cysts with no definitive connection to pancreatic duct
Micro description
=========================================================================
● 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
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Cysts are lined by single layer of cylindrical / cuboidal cells
Various images
Cytology description
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● Cuboidal/columnar cells in flat honeycomb sheets/nests (100%) with delicate/vacuolated (61%) cytoplasm, round/oval nuclei are small to slightly enlarged with 1-2 inconspicuous nucleoli, fine granular chromatin, smooth nuclear contour; also nuclear grooves (43.5%), nuclear pseudoinclusions (26%); usually thin mucin (Pancreas 2012 Jun 28 [Epub ahead of print])
Cytology images
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Comparison with IPMN
Positive stains
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● CK7, CK8, CK18, CK19, CK20, Ca 19-9, MUC1, MUC5AC
Negative stains
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● Trypsin, CEA, synaptophysin, chromogranin A, calretinin, alpha-inhibin, MUC1 (usually), MUC2 (negative in noplastic IPMN), progesterone receptor
Differential diagnosis
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● Mucinous cystic neoplasms: body/tail, women, atypia, ovarian-like stroma; similar epithelial lining and immunostaining
Cysts
Pseudocysts
Reviewer: Deepali Jain, M.D. (see Reviewers
page)
Revised: 24 November 2012, last major update August 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.
General
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● Not a true cyst because no epithelial lining
● Painful, localized collections of pancreatic secretions that develop after pancreatitis (acute or chronic), trauma, ductal calculi, obstructive neoplasms
● Complications: abscess, erosion into blood vessels and hemorrhage of splenic artery, infection (J Med Case Rep 2007 Oct 29;1:116), perforation into a hollow viscus
Treatment
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● Excise small pseudocysts in body/tail, drain pseudocysts in head
Gross description
=========================================================================
● 85% solitary, usually unilocular, in/near pancreas
● Thick, irregular wall, ragged inner surface, cloudy intraluminal contents
Gross images
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Multiseptated lesion filled with fluid
Encapsulated cystic lesion with yellow-green material
Resembling cystic neoplasm
Micro description
=========================================================================
● No epithelial lining, 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
● Fluid has high amylase content
Micro images
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Patient with chronic pancreatitis and pseudocyst; cyst lacks epithelial lining, wall contains dense collagen, chronic inflammatory cells and fat
No epithelial lining is present
Cyst contains multiple lipid droplets (Sudan Black+) and cholesterol clefts
Pseudocyst of ectopic pancreas in duodenum
Differential diagnosis
=========================================================================
● Pancreatic neoplasm, particularly if multiloculated
● Sterile abscess with liquefactive necrosis
● Serous cystadenoma with subtotal cystic degeneration: has glycogen-rich epithelial lining and prominent subepithelial capillaries (Am J Surg Pathol 2012;36:726)
End of Pancreas > Superpage > Nontumor
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