Pancreas Patho B 2

PATHOLOGY 2BPATHOLOGY 2B

PANCREASPANCREAS

ROBERTO D. PADUA JR.,MD,DPSPROBERTO D. PADUA JR.,MD,DPSP

DEPARTMENT OF PATHOLOGYDEPARTMENT OF PATHOLOGY

FATIMA COLLEGE OF MEDICINEFATIMA COLLEGE OF MEDICINE

Organ ConsiderationsOrgan ConsiderationsGreek Greek pankreaspankreas means “all flesh” means “all flesh”Endocrine and exocrine functionsEndocrine and exocrine functionsRetroperitoneal locationRetroperitoneal location20 cm in length20 cm in length90 grams in men; 85 grams in women90 grams in men; 85 grams in womenHas 3 parts = head, body, and tailHas 3 parts = head, body, and tailPancreatic duct system:Pancreatic duct system:

– Duct of Wirsung = main pancreatic duct that Duct of Wirsung = main pancreatic duct that drains into the duodenum at the papilla of Vaterdrains into the duodenum at the papilla of Vater

– Duct of Santorini = accessory pancreatic duct Duct of Santorini = accessory pancreatic duct that drains into the duodenum through a separate that drains into the duodenum through a separate minor papillaminor papilla

Organ ConsiderationsOrgan ConsiderationsEmbryologically arises from the fusion of Embryologically arises from the fusion of dorsal and ventral outpouchings of the dorsal and ventral outpouchings of the foregutforegut

Exocrine pancreasExocrine pancreasConstitutes 80-85% of the pancreasConstitutes 80-85% of the pancreas

Composed of acinar cellsComposed of acinar cells

Produce digestive enzymesProduce digestive enzymes

Endocrine pancreasEndocrine pancreasComposed of islets of Langerhans that Composed of islets of Langerhans that constitutes only 1-2% of the pancreasconstitutes only 1-2% of the pancreas

Secretes insulin, glucagon, and somatostatinSecretes insulin, glucagon, and somatostatin

Normal pancreatic anatomy

Congenital AnomaliesCongenital Anomalies

AgenesisAgenesisTotal absence of the pancreasTotal absence of the pancreas

Rare; associated with widespread severe Rare; associated with widespread severe malformation malformation

incompatible with lifeincompatible with life

Homozygous mutations in the Homozygous mutations in the IPF1IPF1 gene on gene on chromosome 13q12.1chromosome 13q12.1

Congenital AnomaliesCongenital Anomalies

Pancreas DivisumPancreas DivisumMost common congenital anomalyMost common congenital anomaly

Incidence : 3-10%Incidence : 3-10%

Failure of the fetal duct systems of the Failure of the fetal duct systems of the dorsal and ventral pancreatic primordia to dorsal and ventral pancreatic primordia to fusefuse

Predisposes to development of chronic Predisposes to development of chronic pancreatitispancreatitis

Congenital AnomaliesCongenital AnomaliesAnnular PancreasAnnular Pancreas

Ventral primordium of the pancreas fails to rotate Ventral primordium of the pancreas fails to rotate properlyproperly

Congenital abnormalities of the GIT can be seenCongenital abnormalities of the GIT can be seen

Down syndrome is a predisposing conditionDown syndrome is a predisposing condition

Encirclement of the duodenum by pancreatic Encirclement of the duodenum by pancreatic parenchyma parenchyma constriction of the duodenal lumen constriction of the duodenal lumen

Contains large number of PP cells in its many Contains large number of PP cells in its many irregularly shaped isletsirregularly shaped islets

Presents with duodenal obstructionPresents with duodenal obstruction

Congenital AnomaliesCongenital AnomaliesHeterotopic PancreasHeterotopic Pancreas

Most common in the duodenum (2Most common in the duodenum (2ndnd portion) portion)

Seen in the stomach, jejunum, ileum, Meckel’s Seen in the stomach, jejunum, ileum, Meckel’s diverticulum, gastric and intestinal diverticula, GB and diverticulum, gastric and intestinal diverticula, GB and bile ducts, large bowel, spleen, omentum, abdominal bile ducts, large bowel, spleen, omentum, abdominal wallwall

Grossly, resembles normal pancreas Grossly, resembles normal pancreas firm, yellow, firm, yellow, lobulated nodules measuring up to 4 cm, sharply lobulated nodules measuring up to 4 cm, sharply circumscribed from the surrounding tissuescircumscribed from the surrounding tissues

Central umbilication is present corresponding to the Central umbilication is present corresponding to the central duct that opens into the lumen (important central duct that opens into the lumen (important diagnostic sign)diagnostic sign)

Microscopically, acinar and ductal tissues are always Microscopically, acinar and ductal tissues are always present; islet tissue is found only in 1/3 of casespresent; islet tissue is found only in 1/3 of cases

Acute PancreatitisAcute PancreatitisGroup of reversible lesions characterized by Group of reversible lesions characterized by inflammation of the pancreas ranging in severity inflammation of the pancreas ranging in severity from edema and fat necrosis to parenchymal necrosis from edema and fat necrosis to parenchymal necrosis with severe hemorrhagewith severe hemorrhage

Incidence rate : 10-20 cases/100,000 (Western)Incidence rate : 10-20 cases/100,000 (Western)

Approximately 80% of cases = biliary tract disease or Approximately 80% of cases = biliary tract disease or alcoholismalcoholism

Gallstones present in 35-60% of cases of acute Gallstones present in 35-60% of cases of acute pancreatitspancreatits

Severe alcoholoc intake = 65% in the USSevere alcoholoc intake = 65% in the US

Idiopathic = 10-20% of casesIdiopathic = 10-20% of cases

Acute PancreatitisAcute PancreatitisGenetic alterationsGenetic alterations

1.1. Cationic Trypsinogen (PRSS1)Cationic Trypsinogen (PRSS1)

> point mutation with G to A transitions > point mutation with G to A transitions resulting in an arginine (R) to histidine resulting in an arginine (R) to histidine (H) (H) substitution ( called R122H) substitution ( called R122H)

> affects a site on the cationic trypsinogen > affects a site on the cationic trypsinogen molecule essential for the molecule essential for the

cleavage cleavage (inactivation) of trypsin by trypsin (inactivation) of trypsin by trypsin itself itself resistant inactivation resistant inactivation abnormally abnormally active active trypsin activates other digestive trypsin activates other digestive

proenzymes proenzymes pancreatitis pancreatitis

Acute PancreatitisAcute Pancreatitis

Genetic alterationsGenetic alterationsCationic Trypsinogen (PRSS1)Cationic Trypsinogen (PRSS1)

> hereditary pancreatitis > hereditary pancreatitis

> autosomal dominant disease with > autosomal dominant disease with

80% penetrance 80% penetrance

> recurrent attacks of severe > recurrent attacks of severe

pancreatitis usually beginning in pancreatitis usually beginning in

childhoodchildhood


Genetic alterationsGenetic alterations2. Serine Protease Inhibitor, Kazal Type 1 2. Serine Protease Inhibitor, Kazal Type 1

(SPINK1)(SPINK1)

> the gene codes for a pancreatic > the gene codes for a pancreatic trypsin inhibitortrypsin inhibitor

> mutations in the SPINK1 gene > mutations in the SPINK1 gene pancreatitispancreatitis


Morphology – GrossMorphology – GrossGross changes vary from a swollen and Gross changes vary from a swollen and edematous well-preserved organ to a edematous well-preserved organ to a hemorrhagic and necrotic mass of tissue hemorrhagic and necrotic mass of tissue

Pancreatic substance exhibits areas of red-Pancreatic substance exhibits areas of red-black hemorrhage interspersed with foci of black hemorrhage interspersed with foci of yellow-white, chalky fat necrosisyellow-white, chalky fat necrosis

Foci of fat necrosis may also be found in Foci of fat necrosis may also be found in the extrapancreatic fat depots, (omentum, the extrapancreatic fat depots, (omentum, mesentery, subcutis)mesentery, subcutis)


Morphology - GrossMorphology - GrossPeritoneal cavity contains serous, slightly Peritoneal cavity contains serous, slightly turbid, brown-tinged fluid in which globules turbid, brown-tinged fluid in which globules of fat can be identifiedof fat can be identified

Hemorrhagic pancreatitisHemorrhagic pancreatitisMost severe formMost severe form

Extensive parenchymal necrosis Extensive parenchymal necrosis accompanied by diffuse hemorrhage within accompanied by diffuse hemorrhage within the substance of the glandthe substance of the gland

Acute PancreatitisAcute PancreatitisMorphology - MicroscopicMorphology - Microscopic

Ranges from trivial inflammation and Ranges from trivial inflammation and edema to severe extensive necrosis and edema to severe extensive necrosis and hemorrhagehemorrhageMorphologic changesMorphologic changes

Microvascular leakage causing edemaMicrovascular leakage causing edemaNecrosis of fat by lipolytic enzymesNecrosis of fat by lipolytic enzymesAn acute inflammatory reactionAn acute inflammatory reactionProteolytic destruction of pancreatic Proteolytic destruction of pancreatic parenchymaparenchymaDestruction of blood vessels with subsequent Destruction of blood vessels with subsequent interstitial hemorrhageinterstitial hemorrhage


Morphology – MicroscopicMorphology – Microscopic

Earlier changes are represented by acinar Earlier changes are represented by acinar cell homogenization, ductal dilatation with cell homogenization, ductal dilatation with epithelial degeneration, diffuse interstitial epithelial degeneration, diffuse interstitial edema, leukocytic infiltration, and edema, leukocytic infiltration, and fibroblastic reactionfibroblastic reaction extensive necrosis extensive necrosis and hemorrhage of pancreatic tissueand hemorrhage of pancreatic tissue


PathogenesisPathogenesisRemains controversialRemains controversial

Anatomic changes strongly suggest Anatomic changes strongly suggest autodigestion of the pancreatic substance autodigestion of the pancreatic substance by inappropriately activated pancreatic by inappropriately activated pancreatic enzymesenzymes

Activation of trypsin is an important Activation of trypsin is an important triggering event in acute pancreatitistriggering event in acute pancreatitis

Trypsin

Trypsinogen

Activate other proenzymes

Phospholipase Proelastase

Disintegration of fat cells

Damage elastic fibers of b.v.

Acute Pancreatitis

Prekallikrein Kallikrein

Kinin system

Hageman factor

Clotting system

Complement system

Inflammation

Small vessel thromboses

Acute PancreatitisAcute PancreatitisClinical FeaturesClinical Features

Cardinal manifestation = abdominal painCardinal manifestation = abdominal painPain is constant and intense and is often Pain is constant and intense and is often referred to the upper backreferred to the upper back

Full-blown acute pancreatitis is a medical emergency Full-blown acute pancreatitis is a medical emergency of the first magnitudeof the first magnitude

Symptoms are due to release of toxic enzymes, Symptoms are due to release of toxic enzymes, cytokines, and other mediators with explosive cytokines, and other mediators with explosive activation of the systemic inflammatory response activation of the systemic inflammatory response leukocytosis, hemolysis, DIC, fluid sequestration, leukocytosis, hemolysis, DIC, fluid sequestration, ARDS, and diffuse fat necrosisARDS, and diffuse fat necrosis

Peripheral vascular collapse and shock with acute Peripheral vascular collapse and shock with acute renal tubular necrosis may occurrenal tubular necrosis may occur


Clinical FeaturesClinical FeaturesPancreatic necrotic foci can undergo Pancreatic necrotic foci can undergo secondary infection secondary infection infected pancreatic infected pancreatic necrosisnecrosis

– Currently regarded as the most common, most Currently regarded as the most common, most severe, and most lethal of the infectious severe, and most lethal of the infectious complicationscomplications

– Occurs in 40-60% of patients with acute Occurs in 40-60% of patients with acute necrotizing pancreatitisnecrotizing pancreatitis

– Usually involves Gram-negative organisms from Usually involves Gram-negative organisms from the alimentary tractthe alimentary tract

can evolve into a chronic formcan evolve into a chronic form


Clinical FeaturesClinical FeaturesLaboratory findingsLaboratory findings

Serum amylase level elevation in the first 24 Serum amylase level elevation in the first 24 hourshours

Elevation of serum lipase within 72 to 96 hoursElevation of serum lipase within 72 to 96 hours

Glycosuria occurs in 10% of cases Glycosuria occurs in 10% of cases

Elevated serum C-reactive protein is a reliable Elevated serum C-reactive protein is a reliable marker for the presence of pancreatic necrosismarker for the presence of pancreatic necrosis

Hypocalcemia – a poor prognostic signHypocalcemia – a poor prognostic sign

results from results from precipitation of calcium precipitation of calcium soaps in soaps in the fat necrosisthe fat necrosis

Acute PancreatitisAcute PancreatitisClinical FeaturesClinical Features

ManagementManagement““Resting” the pancreas by total restriction of Resting” the pancreas by total restriction of food and fluids and by supportive therapyfood and fluids and by supportive therapyMedical (4-6 hrs) Medical (4-6 hrs) deteriorate deteriorate emergency emergency laparotomylaparotomyOthers : emergency endoscopic retrograde Others : emergency endoscopic retrograde cholangiopancreatography with or w/o cholangiopancreatography with or w/o endoscopic papillotomyendoscopic papillotomyPresence of an upper abdominal mass Presence of an upper abdominal mass suspected of being pseudocyst and persistent suspected of being pseudocyst and persistent rising jaundice are indications for surgical rising jaundice are indications for surgical interventionintervention

SEQUELAE OF ACUTE PANCREATITIS

Chronic PancreatitisChronic PancreatitisCharacterized by inflammation of the Characterized by inflammation of the pancreas with destruction of exocrine pancreas with destruction of exocrine parenchyma, fibrosis, and, in the late parenchyma, fibrosis, and, in the late stages, the destruction of endocrine stages, the destruction of endocrine parenchymaparenchyma

Irreversible impairment of pancreatic Irreversible impairment of pancreatic functionfunction

Prevalence : 0.04-5%Prevalence : 0.04-5%

Chronic PancreatitisChronic PancreatitisEtiologic factorsEtiologic factors

Long-term alcohol abuseLong-term alcohol abuseLong-standing obstruction of the pancreatic Long-standing obstruction of the pancreatic ductductTropical pancreatitisTropical pancreatitis

Attributed to malnutritionAttributed to malnutritionSeen in Africa and AsiaSeen in Africa and Asia

Hereditary pancreatitisHereditary pancreatitisMutations in the Mutations in the PRSS1PRSS1 and and SPINK1SPINK1 genes genes

Idiopathic chronic pancreatitisIdiopathic chronic pancreatitisMutations in cystic fibrosis transmembrane Mutations in cystic fibrosis transmembrane conductance regulator (conductance regulator (CFTRCFTR) gene) gene

Chronic PancreatitisChronic PancreatitisEtiologic factors (Rosai and Ackerman, 9Etiologic factors (Rosai and Ackerman, 9thth ed) ed)

– Obstruction of the ductal system by carcinoma or Obstruction of the ductal system by carcinoma or stonesstones

– Chronic alcoholism Chronic alcoholism most common most common– HyperparathyroidismHyperparathyroidism– Genetic factorsGenetic factors– Polyarteritis nodosaPolyarteritis nodosa– MumpsMumps– A “tropical” formA “tropical” form– TBTB– SarcoidosisSarcoidosis– MalakoplakiaMalakoplakia– Secondary extension of sclerosing cholangitisSecondary extension of sclerosing cholangitis– HIVHIV

Chronic PancreatitisChronic Pancreatitis

Pathogenesis – HypothesesPathogenesis – HypothesesDuctal obstruction by concretionsDuctal obstruction by concretions

Alcohol Alcohol increase protein concentrations in increase protein concentrations in the pancreatic juice the pancreatic juice ductal plugs ductal plugs obstruct obstruct the pancreatic ductsthe pancreatic ducts

Toxic-metabolicToxic-metabolicToxins including alcohol and its metabolites Toxins including alcohol and its metabolites can exert toxic effect on acinar cells can exert toxic effect on acinar cells accumulation of lipids in acinar cells accumulation of lipids in acinar cells acinar acinar cell loss cell loss parenchymal fibrosis parenchymal fibrosis


Pathogenesis – HypothesesPathogenesis – HypothesesOxidative stressOxidative stress

Alcohol-induced oxidative stress Alcohol-induced oxidative stress generate generate free radicals in acinar cells free radicals in acinar cells membrane lipid membrane lipid oxidation and activation of transcription oxidation and activation of transcription factors (AP1 and NFfactors (AP1 and NFκβκβ) ) expression of expression of chemokines chemokines attracts mononuclear cells attracts mononuclear cells

Promotes fusion of lysosomes and zymogen Promotes fusion of lysosomes and zymogen granules, acinar cell necrosis, inflammation, granules, acinar cell necrosis, inflammation, and fibrosisand fibrosis

Chronic PancreatitisChronic PancreatitisPathogenesis – HypothesesPathogenesis – Hypotheses

Necrosis-fibrosisNecrosis-fibrosisAcute pancreatitis Acute pancreatitis perilobular fibrosis, duct perilobular fibrosis, duct distortion, and altered pancreatic secretions distortion, and altered pancreatic secretions over time and with multiple episodes over time and with multiple episodes loss of loss of pancreatic parenchyma and fibrosispancreatic parenchyma and fibrosis

******Chemokines have been identified in chronic Chemokines have been identified in chronic pancreatitis (IL-8, MCP-1) plus TGF-pancreatitis (IL-8, MCP-1) plus TGF-ββ, PDGF , PDGF induce the activation and proliferation of induce the activation and proliferation of periacinar myofibroblasts (pancreatic stellate periacinar myofibroblasts (pancreatic stellate cells) cells) deposition of collagen deposition of collagen fibrosis fibrosis


Morphology – GrossMorphology – GrossGland is hardGland is hard

Extremely dilated ductsExtremely dilated ducts

Visible calcified concretionsVisible calcified concretions

Chronic PancreatitisChronic PancreatitisMorphology – MicroscopicMorphology – Microscopic

Parenchymal fibrosisParenchymal fibrosis

Reduced number and size of acini with relative Reduced number and size of acini with relative sparing of the islets of Langerhanssparing of the islets of Langerhans

Variable dilation of the pancreatic ductsVariable dilation of the pancreatic ducts

Chronic inflammatory infiltrate around lobules and Chronic inflammatory infiltrate around lobules and ductsducts

Interlobular and intralobar ducts are dilated with Interlobular and intralobar ducts are dilated with protein plugs in their lumensprotein plugs in their lumens

Ductal epithelium is atrophied or hyperplastic or may Ductal epithelium is atrophied or hyperplastic or may show squamous metaplasiashow squamous metaplasia

Ductal concretions may be evidentDuctal concretions may be evident


Clinical FeaturesClinical FeaturesS/Sx varies = recurrent attacks of abdominal S/Sx varies = recurrent attacks of abdominal pain/back painpain/back pain

May be entirely silent until pancreatic May be entirely silent until pancreatic insufficiency or DM developsinsufficiency or DM develops

Attacks are precipitated by alcohol abuse, Attacks are precipitated by alcohol abuse, overeating, or the use of opiates and other overeating, or the use of opiates and other drugs that increase the tone of the sphincter drugs that increase the tone of the sphincter of Oddiof Oddi

Diagnosis requires a high degree of Diagnosis requires a high degree of suspicionsuspicion

Chronic PancreatitisChronic PancreatitisClinical FeaturesClinical Features

Attack of abdominal pain Attack of abdominal pain mild fever and mild fever and mild to moderate elevation of serum mild to moderate elevation of serum amylase (absent with destruction of acinar amylase (absent with destruction of acinar cells)cells)Gallstone-induced obstructionGallstone-induced obstruction

JaundiceJaundiceElevation of alkaline phosphataseElevation of alkaline phosphataseCT and UTS – visualize calcificationCT and UTS – visualize calcification

Weight loss and hypoalbuminemic edema Weight loss and hypoalbuminemic edema from malabsorption caused by exocrine from malabsorption caused by exocrine pancreatic insufficiencypancreatic insufficiency


Acinar necrosis and acute inflammation are Acinar necrosis and acute inflammation are seen more often in patients with persistent seen more often in patients with persistent pain than in those who are free of painpain than in those who are free of pain

Treatment Treatment – Pancreatic duct drainage (through Pancreatic duct drainage (through

pancreacojejunostomy or endoscopic removal of pancreacojejunostomy or endoscopic removal of ductal stones)ductal stones)

– Partial pancreatic resectionPartial pancreatic resection– Near-total pancreatectomy with or without islet Near-total pancreatectomy with or without islet

autotransplantationautotransplantation


PrognosisPrognosisNot an immediately life-threatening Not an immediately life-threatening condition, long term outlook is poorcondition, long term outlook is poor

20-25 year mortality rate of 50%20-25 year mortality rate of 50%

Hereditary pancreatitis – 40% lifetime risk of Hereditary pancreatitis – 40% lifetime risk of developing pancreatic cancer; unclear for developing pancreatic cancer; unclear for other forms other forms

SEQUELAE OF CHRONIC PANCREATITIS

Pancreatic TransplantationPancreatic Transplantation

Two main indicationsTwo main indicationsChronic pancreatitisChronic pancreatitis

Insulin-resistant diabetes mellitusInsulin-resistant diabetes mellitus

At present, pancreatic graft survival rates At present, pancreatic graft survival rates approach 90% at 1 yearapproach 90% at 1 year

Two complicationsTwo complications““graft pancreatitis”graft pancreatitis”

Pancreatic thrombosisPancreatic thrombosis

AbscessAbscess

Most often seen as complications of acute Most often seen as complications of acute pancreatitispancreatitis

Characterized by the presence of pus and Characterized by the presence of pus and the microbiologic identification of bacteria in the microbiologic identification of bacteria in over 90% of casesover 90% of cases

Non-Neoplastic CystsNon-Neoplastic CystsCongenital CystsCongenital Cysts

Result from anomalous development of the Result from anomalous development of the pancreatic ductspancreatic ductsMay be associated with polycystic disease May be associated with polycystic disease and and von Hippel-Lindau diseasevon Hippel-Lindau diseaseRange from microscopic lesions to 3-5 cm in Range from microscopic lesions to 3-5 cm in diameterdiameterLined by a glistening duct type cuboidal Lined by a glistening duct type cuboidal epithelium or by a completely attenuated epithelium or by a completely attenuated cell layercell layer enclosed in a thin fibrous capsule filled with enclosed in a thin fibrous capsule filled with clear to turbid mucoid or serous fluidclear to turbid mucoid or serous fluid

Non-Neoplastic CystsNon-Neoplastic Cysts

Pseudocysts Pseudocysts Related to pancreatitis, trauma, and rarely, Related to pancreatitis, trauma, and rarely, to neoplastic obstruction of large ductsto neoplastic obstruction of large ducts

They can become very large, and spread They can become very large, and spread beyond the substance of the pancreasbeyond the substance of the pancreas

MicroscopicMicroscopic– Lack of epithelial liningLack of epithelial lining

GrossGross– Wall is thick and irregularWall is thick and irregular– Inner surface is raggedInner surface is ragged– Intraluminal content is cloudy or bloodyIntraluminal content is cloudy or bloody

Non-Neoplastic CystsNon-Neoplastic CystsPseudocysts Pseudocysts

Complications = perforation and hemorrhage (splenic Complications = perforation and hemorrhage (splenic artery)artery)TreatmentTreatment

– Small pseudocysts located in the body or tail of Small pseudocysts located in the body or tail of the pancreas = excisionthe pancreas = excision

– External drainage (preferred for the infected External drainage (preferred for the infected cysts)cysts)

Contraindicated if the cysts connect with the Contraindicated if the cysts connect with the ductal systemductal system

– Internal drainageInternal drainageTransgastric cystgastrostomyTransgastric cystgastrostomyCystojenunostomy to a Roux-en-Y loop of Cystojenunostomy to a Roux-en-Y loop of jejunum jejunum

Cystic NeoplasmsCystic Neoplasms

Only 5-15% of pancreatic cysts are Only 5-15% of pancreatic cysts are neoplasticneoplastic

5% of all pancreatic neoplasms5% of all pancreatic neoplasms

Can be benign, borderline malignant, or Can be benign, borderline malignant, or malignantmalignant

Cystic NeoplasmsCystic NeoplasmsSerous cystadenomasSerous cystadenomas

Benign cystic neoplasms consists of glycogen-rich Benign cystic neoplasms consists of glycogen-rich low-cuboidal cells surrounding small cystslow-cuboidal cells surrounding small cysts

Contains clear, thin, straw-colored fluidContains clear, thin, straw-colored fluid

Account for about 25% of all cystic neoplasms of the Account for about 25% of all cystic neoplasms of the pancreaspancreas

Occurs twice in women than in men; 7Occurs twice in women than in men; 7thth decade of life decade of life

Non-specific S/Sx like abdominal pain or palpable Non-specific S/Sx like abdominal pain or palpable abdominal massabdominal mass

Treatment : surgical resectionTreatment : surgical resection

Cystic NeoplasmsCystic Neoplasms

Mucinous cystic neoplasmsMucinous cystic neoplasmsAlmost always arise in womenAlmost always arise in women

Can be benign, borderline malignant, or Can be benign, borderline malignant, or malignantmalignant

Arises in the body or tail Arises in the body or tail

Present as painless, slow-growing massesPresent as painless, slow-growing masses

Cysts are lined by columnar mucinous Cysts are lined by columnar mucinous epithelium containing thick, tenacious mucinepithelium containing thick, tenacious mucin

Diagnosis is only done after removalDiagnosis is only done after removal

Treatment is distal pancreatectomyTreatment is distal pancreatectomy

Cystic NeoplasmsCystic NeoplasmsIntraductal papillary mucinous Intraductal papillary mucinous neoplasms (neoplasms (IPMNsIPMNs))

Produce cysts containing mucinProduce cysts containing mucinCan be benign, borderline malignant, or Can be benign, borderline malignant, or malignantmalignantOccurs more frequently in menOccurs more frequently in menInvolve the head of the pancreas more often Involve the head of the pancreas more often than the tailthan the tailCharacteristic FeaturesCharacteristic Features

Lack the dense “ovarian” stroma Lack the dense “ovarian” stroma Arise in the main pancreatic ductsArise in the main pancreatic ducts

Cystic NeoplasmsCystic NeoplasmsSolid-pseudopapillary tumorSolid-pseudopapillary tumor

Seen mainly in adolescent girls and young womenSeen mainly in adolescent girls and young womenLarge, well-circumscribed masses with solid and Large, well-circumscribed masses with solid and cystic areascystic areasCystic areas are filled with hemorrhagic debris and Cystic areas are filled with hemorrhagic debris and neoplastic cells grow in solid sheets or as papillary neoplastic cells grow in solid sheets or as papillary projectionsprojectionsCan present with abdominal discomfort because of Can present with abdominal discomfort because of their large sizetheir large sizeAlteration of the Alteration of the ββ-catenin/adenomatous polyposis -catenin/adenomatous polyposis coli genetic pathwaycoli genetic pathwayLocally aggressiveLocally aggressiveTreatment : surgical resectionTreatment : surgical resection

Pancreatic CarcinomaPancreatic Carcinoma85% of all cases of pancreatic malignancy85% of all cases of pancreatic malignancy

44thth most common cause of death from cancer most common cause of death from cancer (US)(US)

Incidence is increasing, particularly in womenIncidence is increasing, particularly in women

Risk factors : B-naphthylamine or benzidine Risk factors : B-naphthylamine or benzidine exposure, cigarette smoking, diet rich in fats, exposure, cigarette smoking, diet rich in fats, chronic pancreatitis, and DMchronic pancreatitis, and DM

10% show familial aggregation consistent 10% show familial aggregation consistent with genetic susceptibilitywith genetic susceptibility

Most patients are elderly (60-80 y/o), with Most patients are elderly (60-80 y/o), with slight male preponderance (1.6:1 ratio)slight male preponderance (1.6:1 ratio)

Pancreatic CarcinomaPancreatic CarcinomaDiagnosis is made when tumor becomes Diagnosis is made when tumor becomes relatively large (about 5 cm) and has relatively large (about 5 cm) and has extended beyond the pancreas (85% of extended beyond the pancreas (85% of cases)cases)Carcinomas of the body and tail grow Carcinomas of the body and tail grow insidiously and often have already insidiously and often have already metastasized at the time of diagnosismetastasized at the time of diagnosis

Associated with peripheral venous thrombi in Associated with peripheral venous thrombi in 25% of patients25% of patients

Diagnosis : CT-scan, MRI, celiac Diagnosis : CT-scan, MRI, celiac angiography, UTZ, ERCP, seleno-methionine angiography, UTZ, ERCP, seleno-methionine scan, duodenal aspirate, serum testscan, duodenal aspirate, serum testTumor markers : SPan1 and CA19-9 antigenTumor markers : SPan1 and CA19-9 antigen

Pancreatic CarcinomaPancreatic Carcinoma

Molecular CarcinogenesisMolecular CarcinogenesisK-RASK-RAS

K-RASK-RAS gene is the most commonly altered gene is the most commonly altered oncogene oncogene

Activated by point mutation Activated by point mutation impair impair GTPase activity of GTPase activity of K-ras K-ras gene gene active active protein protein Ras activates several intracellular Ras activates several intracellular transduction pathways transduction pathways activation of activation of transcription factors fos and juntranscription factors fos and jun

Pancreatic CarcinomaPancreatic CarcinomaMolecular CarcinogenesisMolecular Carcinogenesisp16p16

p16p16 gene (chromosome 9p) is the most frequently gene (chromosome 9p) is the most frequently inactivated tumor suppressor gene in pancreatic inactivated tumor suppressor gene in pancreatic cancercancerInactivated in 95% of casesInactivated in 95% of casesp16 plays a critical role in the control of the cell cyclep16 plays a critical role in the control of the cell cycle

p53p53Inactivation of the Inactivation of the p53p53 tumor suppressor gene tumor suppressor gene (chromosome 17p) seen in 50-70% of pancreatic Ca(chromosome 17p) seen in 50-70% of pancreatic CaGene product is nuclear DNA-binding protein that Gene product is nuclear DNA-binding protein that acts both as a cell cycle checkpoint and as inducer of acts both as a cell cycle checkpoint and as inducer of cell death (apoptosis)cell death (apoptosis)


Molecular CarcinogenesisMolecular CarcinogenesisSMAD4SMAD4

Tumor suppressor gene (chromosome 18q) Tumor suppressor gene (chromosome 18q) is inactivated in 55% of pancreatic cancersis inactivated in 55% of pancreatic cancers

Also known as Also known as DPC4DPC4, codes for protein that , codes for protein that plays an important role in signal plays an important role in signal transduction from the transduction from the TGF-TGF-ββ family of cell family of cell surface receptorssurface receptors

Normal function of this gene is to suppress Normal function of this gene is to suppress growth and promote apoptosisgrowth and promote apoptosis

Pancreatic CarcinomaPancreatic CarcinomaMolecular CarcinogenesisMolecular CarcinogenesisGenes amplifiedGenes amplified

AKT2AKT2 gene gene

MYBMYB gene gene

Inactivated tumor suppressor genesInactivated tumor suppressor genesAIB1AIB1 gene gene

BRCA2 geneBRCA2 gene

LKB1/STK11 genesLKB1/STK11 genes

MKK4 geneMKK4 gene

TGFTGFββ-R1 and R2 genes-R1 and R2 genes

RB1 geneRB1 gene


Molecular CarcinogenesisMolecular CarcinogenesisMethylation abnormalitiesMethylation abnormalities

Hypermethylation of the promoter of a Hypermethylation of the promoter of a number of suppressor genes is associated number of suppressor genes is associated with transcriptional silencing of the geneswith transcriptional silencing of the genes

Gene expressionGene expressionIdentified a number of genes that are highly Identified a number of genes that are highly overexpressed in pancreatic cancersoverexpressed in pancreatic cancers

Potential targets for therapeutics and may Potential targets for therapeutics and may form the basis for future screening testsform the basis for future screening tests

Pancreatic CarcinomaPancreatic CarcinomaLocation : head of the pancreas (60%), body (15%) or Location : head of the pancreas (60%), body (15%) or tail (5%)tail (5%)

Multiple tumors are found in 20% of casesMultiple tumors are found in 20% of cases

Majority are ductal adenocarcinomasMajority are ductal adenocarcinomas

Poorly delineated and firm, with a yellow cut-surfacePoorly delineated and firm, with a yellow cut-surface

May undergo massive cystic degenerationMay undergo massive cystic degeneration

Duodenal wall is invaded by direct extension in Duodenal wall is invaded by direct extension in tumors involving the head of the pancreas causing tumors involving the head of the pancreas causing obstruction of the distal CBDobstruction of the distal CBD

Involved pancreatic ducts are dilated and plugged Involved pancreatic ducts are dilated and plugged with necrotic tumorwith necrotic tumor

A cross-section through the head of the pancreas and adjacent CBD showing both an ill-defined mass in the pancreatic substance and the green discoloration of the duct resulting from total obstruction to bile flow.

Pancreatic CarcinomaPancreatic CarcinomaMicroscopic featuresMicroscopic features

Graded as well-differentiated, moderately Graded as well-differentiated, moderately differentiated, and poorly differentiateddifferentiated, and poorly differentiated

LPO = glands are well formed, have a large LPO = glands are well formed, have a large lumen, and are lined by one or few layers of lumen, and are lined by one or few layers of cylindrical or cuboidal epitheliumcylindrical or cuboidal epithelium

Their overall LPO appearanace may be be Their overall LPO appearanace may be be particularly suggestive of carcinoma except particularly suggestive of carcinoma except for the irregularities in the shape and for the irregularities in the shape and distribution of the glands and the peculiar distribution of the glands and the peculiar concentric desmoplastic stroma that concentric desmoplastic stroma that surrounds themsurrounds them

Perineural invasion – 90% of cases Perineural invasion – 90% of cases

Poorly formed glands are present in densely fibrotic stroma within the pancreatic substance with presence of some inflammatory cells.


Histochemical and Histochemical and Immunohistochemical featuresImmunohistochemical features

Positive for mucin stainsPositive for mucin stains

Consistent reactivity for keratins and EMAConsistent reactivity for keratins and EMA

Glycoprotein MUC1 is expressed in over 60% Glycoprotein MUC1 is expressed in over 60% of conventional invasive ductal carcinomaof conventional invasive ductal carcinoma

Others : CEA, CA19-9, B72.3, DUPAN-2, Others : CEA, CA19-9, B72.3, DUPAN-2, YPan-1, SPan-1, Tn and sialosyl-Tn antigens, YPan-1, SPan-1, Tn and sialosyl-Tn antigens, DF3DF3


Spread and metastasisSpread and metastasisTends to metastasize to multiple LN located Tends to metastasize to multiple LN located around the organaround the organ

Most commonly involved the LN around the Most commonly involved the LN around the common hepatic artery, hepatoduodenal common hepatic artery, hepatoduodenal ligament, posterior pancreaticoduodenal, ligament, posterior pancreaticoduodenal, around the superior mesenteric artery, para-around the superior mesenteric artery, para-aortic, and anterior pancreatico-duodenalaortic, and anterior pancreatico-duodenal

Microscopic metastasis were found in T1 and Microscopic metastasis were found in T1 and T2 lesionsT2 lesions


Spread and metastasisSpread and metastasisMost common sites of distant metastasis are Most common sites of distant metastasis are liver, peritoneum, lung, adrenal, bone, liver, peritoneum, lung, adrenal, bone, distant LN groups, skin, and CNSdistant LN groups, skin, and CNS

Supraclavicular LN metastasis is sometimes Supraclavicular LN metastasis is sometimes the first manifestation of pancreatic the first manifestation of pancreatic carcinomacarcinoma


DiagnosisDiagnosisCytologyCytology

Duodenal secretionDuodenal secretion

Pancreatic juicePancreatic juice

FNABFNAB

percutaneouspercutaneous

intraoperativeintraoperative

Frozen sectionFrozen section


TreatmentTreatmentSurgicalSurgical

PrognosisPrognosisOverall 5-year survival rate = 4% or less with Overall 5-year survival rate = 4% or less with over 90% of patients dying within 1 year of over 90% of patients dying within 1 year of diagnosisdiagnosis

Mean survival of 3 months for untreated Mean survival of 3 months for untreated patientspatients

Even if the tumor is confined at the pancreas Even if the tumor is confined at the pancreas at the time of diagnosis, the 5-year survival at the time of diagnosis, the 5-year survival rate does not exceed 15%rate does not exceed 15%


Prognostic FactorsPrognostic FactorsTumor stage – most important prognostic Tumor stage – most important prognostic indicatorindicator

Microscopic grade – well-differentiated Microscopic grade – well-differentiated tumor have longer survival ratetumor have longer survival rate

Tumor size - <4.5 cm have better chance of Tumor size - <4.5 cm have better chance of curative operationcurative operation

Blood vessel invasion and retroperitoneal Blood vessel invasion and retroperitoneal margin of resection – decreased survivalmargin of resection – decreased survival

LN metastasisLN metastasis


Prognostic FactorsPrognostic FactorsDNA ploidyDNA ploidy

TGF-B1TGF-B1 expression – associated with well- expression – associated with well-differentiated tumordifferentiated tumor

American Joint Committee for Cancer American Joint Committee for Cancer Staging for Carcinoma of the PancreasStaging for Carcinoma of the Pancreas

TNM classification criteria

T1 No direct extension of the primary beyond the pancreas

T2 Limited direct extension to the duodenum, bile duct, or stomach

T3 Advanced direct extension incompatible with surgical resection

TX Direct extension not assessed

N0 Regional nodes not involved

N1 Regional nodes involved

NX Regional LN not assessed

American Joint Committee for Cancer American Joint Committee for Cancer Staging for Carcinoma of the PancreasStaging for Carcinoma of the Pancreas

TNM classification criteria

M0 No distant metastasis

M1 Distant metastasis present

MX Distant metastasis not assessed

TNM Stages

Stage I T1-2, N0, M0

Stage II T3, N0, M0

Stage III T1-T3, N1, M0

Stage IV Any T or N, M1

PancreatoblastomaPancreatoblastomaMost common form of pancreatic neoplasia Most common form of pancreatic neoplasia in childhood, but can also occur in adultsin childhood, but can also occur in adults

Reported in patients with Beckwith-Reported in patients with Beckwith-Wiedemann syndrome and familial Wiedemann syndrome and familial adenomatous polyposis of the colonadenomatous polyposis of the colon

Bimodal age distribution = mean of 2.4 and Bimodal age distribution = mean of 2.4 and 33 years33 years

No sex predilectionNo sex predilection

Mean tumor size is 10 cm and partial Mean tumor size is 10 cm and partial encapsulation is the ruleencapsulation is the rule

PancreatoblastomaPancreatoblastomaMicroscopicMicroscopic

Very cellular tumors, made up of uniform Very cellular tumors, made up of uniform epithelial cells arranged in solid sheets and epithelial cells arranged in solid sheets and nests, admixed with well-formed acinar nests, admixed with well-formed acinar structures and occasional ductular formationsstructures and occasional ductular formations

““Squamoid corpuscles” are a constant and Squamoid corpuscles” are a constant and characteristic findingcharacteristic finding

ImmunochemistryImmunochemistryPositivity for pancreatic enzymes, endocrine Positivity for pancreatic enzymes, endocrine markers, and CEAmarkers, and CEA

Alpha-fetoprotein may be produced by the Alpha-fetoprotein may be produced by the tumortumor

PancreatoblastomaPancreatoblastoma

Treatment :Treatment : Surgical resection Surgical resection

ENDOCRINE PANCREASENDOCRINE PANCREAS

ROBERTO D. PADUA JR.,MD,DPSP

DEPARTMENT OF PATHOLOGY

FATIMA COLLEGE OF MEDICINE

Endocrine PancreasEndocrine PancreasConsists of about 1 million microscopic Consists of about 1 million microscopic clusters of cells, the islets of Langerhansclusters of cells, the islets of Langerhans

Aggregate weight of 1-1.5 gramsAggregate weight of 1-1.5 grams

Four major cell typesFour major cell typesΒΒeta cells – 68%; insulineta cells – 68%; insulin

Alpha cells – 20%; glucagonAlpha cells – 20%; glucagon

Delta cells – 10%; somatostatinDelta cells – 10%; somatostatin

PP cells – 2%; pancreatic polypeptide that PP cells – 2%; pancreatic polypeptide that exerts its effect on the GIT exerts its effect on the GIT stimulation of stimulation of secretion of gastric and intestinal enzymes secretion of gastric and intestinal enzymes and inhibition of intestinal motilityand inhibition of intestinal motility

Endocrine PancreasEndocrine Pancreas

Two minor cell typesTwo minor cell typesD1 cells – elaborates VIP, a hormone that D1 cells – elaborates VIP, a hormone that induces glycogenolysis and hyperglycemia; induces glycogenolysis and hyperglycemia; stimulates gastrointestinal fluid secretion and stimulates gastrointestinal fluid secretion and causes secretory diarrheacauses secretory diarrhea

Enterochromaffin cells – synthesize serotonin Enterochromaffin cells – synthesize serotonin and are sources of pancreatic tumors that and are sources of pancreatic tumors that cause the carcinoid syndromecause the carcinoid syndrome

Diabetes MellitusDiabetes MellitusA group of metabolic disorder sharing the A group of metabolic disorder sharing the common underlying feature of common underlying feature of hyperglycemiahyperglycemia

Hyperglycemia results from defects in Hyperglycemia results from defects in insulin secretion, insulin action, or bothinsulin secretion, insulin action, or both

Causes multi-organ damage affecting the Causes multi-organ damage affecting the kidneys, eyes, nerves, and blood veselskidneys, eyes, nerves, and blood vesels

SYMPTOMS OF DIABETESSYMPTOMS OF DIABETESSYMPTOMS OF DIABETESSYMPTOMS OF DIABETES

PolyuriaPolyuriaPolyuriaPolyuriaPolydipsiaPolydipsiaPolydipsiaPolydipsia

PolyphagiaPolyphagiaPolyphagiaPolyphagia

Poor Wound Poor Wound HealingHealing

Poor Wound Poor Wound HealingHealing

Weight LossWeight LossWeight LossWeight Loss

Weakness and Weakness and FatigueFatigue

Weakness and Weakness and FatigueFatigue

Blurring of Blurring of VisionVision

Blurring of Blurring of VisionVision

SYMPTOMS OF DIABETESSYMPTOMS OF DIABETESSYMPTOMS OF DIABETESSYMPTOMS OF DIABETES

RISK FACTORS FOR DIABETES RISK FACTORS FOR DIABETES RISK FACTORS FOR DIABETES RISK FACTORS FOR DIABETES

Heredity Heredity

Old Old AgeAge

Obesity Obesity

Mothers Mothers of large of large babies babies

ADA 2004

Criteria for diagnosis of DMCriteria for diagnosis of DMCriteria for diagnosis of DMCriteria for diagnosis of DM

Note: criteria should be confirmed by repeat testing on a different day.

CRITERIA FOR DIAGNOSIS OF DIABETES CRITERIA FOR DIAGNOSIS OF DIABETES MELLITUSMELLITUS

CRITERIA FOR DIAGNOSIS OF DIABETES CRITERIA FOR DIAGNOSIS OF DIABETES MELLITUSMELLITUS

American Diabetes American Diabetes AssociationAssociation

8 hr Fasting 8 hr Fasting Blood SugarBlood Sugar

2 hours after 2 hours after

75g glucose 75g glucose (OGTT)(OGTT)

NORMALNORMAL < 100 mg/dL< 100 mg/dL < 140 mg/dL< 140 mg/dL

IMPAIRED FASTING IMPAIRED FASTING GLYCEMIA (IFG)GLYCEMIA (IFG)

100 and < 126 100 and < 126 mg/dLmg/dL

------

IMPAIRED IMPAIRED GLUCOSE GLUCOSE

TOLERANCE (IGT)TOLERANCE (IGT)

------ 140 and < 200 140 and < 200 mg/dLmg/dL

DIABETES DIABETES MELLITUSMELLITUS

126 mg/dL126 mg/dL 200 mg/dL 200 mg/dL

Symptoms of diabetes and Random Blood Symptoms of diabetes and Random Blood Sugar of Sugar of 200 mg/dL 200 mg/dL

“prediabetics” – risk for developing type 2 DM (40% risk

over 5yrs) & CV disease

Level of glycemia at which diabetic chronic complications

occur

Etiology of DMEtiology of DMEtiology of DMEtiology of DM

Insulin:Insulin:– Insulin secretion defect Insulin secretion defect – Insulin action defect (insulin resistance/ Insulin action defect (insulin resistance/

receptor defect)receptor defect)

Excess counter-regulatory hormones Excess counter-regulatory hormones (glucagon, catecholamines, cortisol, (glucagon, catecholamines, cortisol, growth hormone)growth hormone)

Etiologic Classification of DMEtiologic Classification of DMEtiologic Classification of DMEtiologic Classification of DM

exocrineI.

II.

III. IV.

Based on pathologic process that leads to hyperglycemia


I.

II.

III. IV.

Previous terms: juvenile-onset DM, IDDMPrevious terms: juvenile-onset DM, IDDM

absolute insulin deficiency due to autoimmune beta absolute insulin deficiency due to autoimmune beta cell destructioncell destruction

Triggered by infectious or environmental stimulusTriggered by infectious or environmental stimulus

Pathology: “insulitis” pancreas infiltrated by Pathology: “insulitis” pancreas infiltrated by lymphocyteslymphocytes

Major susceptibility gene: HLA on chrom6Major susceptibility gene: HLA on chrom6

TYPE IATYPE IA : presence of immunologic markers (islet : presence of immunologic markers (islet cell autoAbs, anti-GAD, anti-insulin abs)cell autoAbs, anti-GAD, anti-insulin abs)

TYPE IBTYPE IB : idiopathic, immunologic markers absent : idiopathic, immunologic markers absent

Ketosis proneKetosis prone

Needs insulin therapyNeeds insulin therapy

Diabetes Mellitus Type 1Diabetes Mellitus Type 1

Mechanisms of B-cell dysfunctionMechanisms of B-cell dysfunctionT lymphocytes react against B-cell antigens T lymphocytes react against B-cell antigens and cause cell damageand cause cell damage

Locally produced cytokines damage Locally produced cytokines damage ββ cells cellsIFN-IFN-γγ, TNF, IL-1, TNF, IL-1

Autoantibodies against islet cells and insulin Autoantibodies against islet cells and insulin are also detected in the blood of 70-80% of are also detected in the blood of 70-80% of patientspatients


I.

II.

III. IV.

90% of cases 90% of cases Previous names: Previous names: NIDDM, adult-onset DMNIDDM, adult-onset DMpolygenicpolygenicStrong genetic Strong genetic componentcomponent

• Visceral Obesity common (contributes to insulin resistance)

Diabetes Mellitus Type 2Diabetes Mellitus Type 2

ββ-cell dysfunction-cell dysfunctionInability to adapt to the long-term demands Inability to adapt to the long-term demands of peripheral insulin resistance and of peripheral insulin resistance and increased insulin secretionincreased insulin secretion

Loss of normal pulsatile, oscillating pattern Loss of normal pulsatile, oscillating pattern of insulin secretion and attenuation of the of insulin secretion and attenuation of the first phase of insulin secretion triggered by first phase of insulin secretion triggered by elevation in plasma glucoseelevation in plasma glucose

Reflected by a decrease in Reflected by a decrease in ββ-cell mass, islet -cell mass, islet degeneration, and deposition of islet degeneration, and deposition of islet amyloid (amylin)amyloid (amylin)

11. . >> 45 yrs, if normal, repeat at 3-year intervals 45 yrs, if normal, repeat at 3-year intervals

2. Check at a younger age:2. Check at a younger age:

- have a first-degree relative with diabetes- have a first-degree relative with diabetes

- - high-risk ethnic population (e.g., African- high-risk ethnic population (e.g., African- American, Hispanic American, Native American, American, Hispanic American, Native American, Asian-American, Pacific Islander)Asian-American, Pacific Islander)

- - are obese are obese - have delivered a baby > 9 lb - have delivered a baby > 9 lb

- have been diagnosed with GDM- have been diagnosed with GDM

- IGT or IFG- IGT or IFG

- hypertensive (- hypertensive (>> 140/90) 140/90)

- have HDL - have HDL << 35 mg/dl and/or triglyceride 35 mg/dl and/or triglyceride >> 150 150 mg/dl mg/dl

- cardiovascular, cerebrovascular diseases- cardiovascular, cerebrovascular diseases

Recommendations for DM Testing (ADA Recommendations for DM Testing (ADA 2004)2004)

1American Diabetes Association. Diabetes Care 2004; 27:S15–S35. 2American Diabetes Association. Diabetes Care 2002; 25:S35–S49.

3American Association of Clinical Endocrinologists. Endocrine Pract 2002; 8 (Suppl. 1):40–82.4European Diabetes Policy Group. Diabet Med 1999; 16:716–730.

Fasting/pre-prandial plasma glucose

< 140< 180Postprandial plasma glucose

< 11090–130

Biochemical index AACE3ADA1,2

mg/dl mmol/l mg/dl mmol/l

5.0–7.2

< 10.0

< 6.5 < 7HbA1c (%)

< 6.0

< 7.8

Glycemic goalsGlycemic goals

HBA1cHBA1c

Excess blood sugar non-enzymatically Excess blood sugar non-enzymatically binds to portion of Hgb (irreversible) binds to portion of Hgb (irreversible)

A1C levels provide a 2- to 3-month index A1C levels provide a 2- to 3-month index of glycemic controlof glycemic control

Assess overall blood glucose controlAssess overall blood glucose control

Albumin Albumin Fructosamine (1-2 weeks) Fructosamine (1-2 weeks)

1. Pickup JC. In: Pickup JC, Williams G, eds. Textbook of Diabetes. 3rd ed. Boston, Mass: Blackwell Science; 2003.

2. Clark N. In: Leahy JL, Cefalu WT, eds. Insulin Therapy. New York, NY: Marcel Dekker, Inc.; 2002.3. Cefalu WT. In: Leahy JL, Cefalu WT, eds. Insulin Therapy. New York, NY: Marcel Dekker, Inc.;

2002.

It cannot be cured. It cannot be cured.

But it can be But it can be controlled by controlled by keeping blood keeping blood

sugar level within sugar level within normal range. normal range.

Diabetes Diabetes MellitusMellitus

Diabetes Diabetes MellitusMellitus

Morphology of DiabetesMorphology of Diabetes

PancreasPancreasReduction in the number and size of isletsReduction in the number and size of islets

Leukocytic infiltration of the islets (insulitis)Leukocytic infiltration of the islets (insulitis)

ββ-cell degranulation by EM-cell degranulation by EM

Subtle reduction in islet cell mass – DM 2Subtle reduction in islet cell mass – DM 2

Amyloid replacement of islets – DM 2Amyloid replacement of islets – DM 2

Islet cell hyperplasia in newborns of diabetic Islet cell hyperplasia in newborns of diabetic mothersmothers

Diabetic NephropathyDiabetic Nephropathy

Renal failure is 2Renal failure is 2ndnd only to MI as a cause of only to MI as a cause of deathdeath

Three lesions encounteredThree lesions encountered glomerular lesionsglomerular lesions

renal vascular lesions – arteriosclerosisrenal vascular lesions – arteriosclerosis

pyelonephritis and necrotizing papillitispyelonephritis and necrotizing papillitis

Diabetic NephropathyDiabetic NephropathyGlomerular lesionsGlomerular lesions

Capillary basement membrane thickeningCapillary basement membrane thickeningOccur throughout their entire lengthOccur throughout their entire lengthDetected by EM within a few years of onsetDetected by EM within a few years of onset

Diffuse mesangial sclerosisDiffuse mesangial sclerosisDiffuse increase in mesangial matrix and is Diffuse increase in mesangial matrix and is always associated with basement membrane always associated with basement membrane thickeningthickeningSeen in most patients with disease of Seen in most patients with disease of >10years>10yearsManifest with nephrotic syndrome Manifest with nephrotic syndrome proteinuria, hypoalbuminemia, edemaproteinuria, hypoalbuminemia, edema

Nodular glomerulosclerosisNodular glomerulosclerosis


Glomerular lesionsGlomerular lesionsNodular glomerulosclerosis Nodular glomerulosclerosis

Kimmeltiel-Wilson lesion -- ball-like deposits of Kimmeltiel-Wilson lesion -- ball-like deposits of a laminated matrix situated in the periphery of a laminated matrix situated in the periphery of the glomerulusthe glomerulus

PAS positive containing trapped mesangial PAS positive containing trapped mesangial cellscells

Seen in 15-30% of long-term diabeticsSeen in 15-30% of long-term diabetics

Major cause of morbidity and mortalityMajor cause of morbidity and mortality


Renal vascular lesionsRenal vascular lesionsRenal atherosclerosis and arteriosclerosisRenal atherosclerosis and arteriosclerosis

Hyaline arteriosclerosis affects both the Hyaline arteriosclerosis affects both the afferent and efferent arteriolesafferent and efferent arterioles

POORLY-CONTROLLEDPOORLY-CONTROLLEDDIABETICS are …DIABETICS are …

POORLY-CONTROLLEDPOORLY-CONTROLLEDDIABETICS are …DIABETICS are …

2-4 times more prone to HEART 2-4 times more prone to HEART DISEASE DISEASE

25 times more prone to BLINDNESS25 times more prone to BLINDNESS 90 times more prone to 90 times more prone to

NEUROPATHY NEUROPATHY 5 times more prone to GANGRENE5 times more prone to GANGRENE 17 times more prone to KIDNEY 17 times more prone to KIDNEY

DISEASEDISEASE

Pancreatic Endocrine NeoplasmsPancreatic Endocrine Neoplasms

Islet cell tumorsIslet cell tumors

Account for 2% of all pancreatic neoplasmsAccount for 2% of all pancreatic neoplasms

Most common in adultsMost common in adults

Occur anywhere along the length of the Occur anywhere along the length of the pancreaspancreas

Propensity to elaborate pancreatic Propensity to elaborate pancreatic hormoneshormones

3 most distinctive clinical syndrome3 most distinctive clinical syndromeHyperinsulinismHyperinsulinism

HypergasrinemiaHypergasrinemia

MEN syndromesMEN syndromes

Hyperinsulinism (Insulinoma)Hyperinsulinism (Insulinoma)Most common of the pancreatic endocrine Most common of the pancreatic endocrine neoplasmsneoplasms

Clinical triadClinical triadAttacks of hypoglycemia occur with blood Attacks of hypoglycemia occur with blood glucose levels below 50mg/dlglucose levels below 50mg/dl

The attacks consist principally of such CNS The attacks consist principally of such CNS manifestations of confusion, stupor, and loss manifestations of confusion, stupor, and loss of consciousnessof consciousness

The attacks are precipitated by fasting or The attacks are precipitated by fasting or exercise and are promptly relieved by feeding exercise and are promptly relieved by feeding or parenteral administration of glucoseor parenteral administration of glucose

Hyperinsulinism (Insulinoma)Hyperinsulinism (Insulinoma)MorphologyMorphology

Generally benign (90%), solitary, arises within Generally benign (90%), solitary, arises within the pancreasthe pancreas

Small (<2cm), encapsulated, pale to red-Small (<2cm), encapsulated, pale to red-brown nodulesbrown nodules

Microscopically, giant islets with preservation Microscopically, giant islets with preservation of the regular cords of monotonous cells and of the regular cords of monotonous cells and their orientation to the vasculaturetheir orientation to the vasculature

Immunohistochemistry, insulin positive tumor Immunohistochemistry, insulin positive tumor cellscells

Zollinger-Ellison Syndrome Zollinger-Ellison Syndrome (Gastrinomas)(Gastrinomas)

Marked hypersecretion of gastrin by a Marked hypersecretion of gastrin by a gastrin-producing tumorgastrin-producing tumorAssociation of pancreatic islet cell lesion Association of pancreatic islet cell lesion with hypersecretion of gastric acid and with hypersecretion of gastric acid and severe peptic ulceration (90-95% of severe peptic ulceration (90-95% of patients)patients)May arise in the pancreas, peripancreatic May arise in the pancreas, peripancreatic region, or the wall of the duodenumregion, or the wall of the duodenumMore than half are locally invasive or have More than half are locally invasive or have already metastasized at the time of already metastasized at the time of diagnosisdiagnosisMay be associated with MEN syndromeMay be associated with MEN syndrome

Other Pancreatic Endocrine Other Pancreatic Endocrine NeoplasmNeoplasm

Alpha-cell tumors (Glucagonoma)Alpha-cell tumors (Glucagonoma)Associated with increased serum levels of Associated with increased serum levels of glucagonglucagon

Presents with mild DM, characteristic skin Presents with mild DM, characteristic skin rash (necrolytic migratory erythema), and rash (necrolytic migratory erythema), and anemiaanemia

Occur most frequently in pre- and Occur most frequently in pre- and postmenopausal women postmenopausal women


Delta-cells tumors Delta-cells tumors (Somatostatinomas)(Somatostatinomas)

Associated with DM, cholelithiasis, Associated with DM, cholelithiasis, steatorrhea, and hypochlorydriasteatorrhea, and hypochlorydria

Difficult to localized pre-operativelyDifficult to localized pre-operatively

Requires high plasma level of somatostatin Requires high plasma level of somatostatin for diagnosisfor diagnosis


VIPomaVIPomaWatery diarrhea, hypokalemia, achlorydria, Watery diarrhea, hypokalemia, achlorydria, or WDHA syndromeor WDHA syndrome

Associated with increased release of Associated with increased release of vasoactive intestinal polypeptide (VIP) from vasoactive intestinal polypeptide (VIP) from a tumora tumor


Pancreatic carcinoid tumorsPancreatic carcinoid tumorsProduces serotonin Produces serotonin

RareRare

Endocrinologically asymptomatic despite the Endocrinologically asymptomatic despite the presence of high levels in plasmapresence of high levels in plasma

Pancreas Patho B 2

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