Pathology of pancreas MARKÉTA HERMANOVÁ Exocrine pancreas The exocrine pancreas produces trypsin, lipase, phospholipase, amylase, elastase. These enzymes, with the exception of lipase, are in a form of inactive proenzymes and they are activated in the duodenum Most of the proenzymes are activated by trypsin, which itself is activated from inactive trypsinogen by enteropeptidase in the duodenum Acinar and ductal cells produce protease inhibitors Congenital anomalies of pancreas Usually as a result of failure of migration and fusion of dorsal and ventral parts of the pancreas May cause stenosis of duodenum, increase the risk of pancreatitis - Annular pancreas - Pancreas divisum - Ectopic pancreas (stomach, duodenum, jejunum,...) - Congenital/dysgenetic cysts of pancreas - Cystic fibrosis (mucoviscidosis) • AR inherited disease caused by the presence of mutations in the CFTR gene (7q 31.2) • CFTR gene encodes the chloride channel protein, it also participates in the regulation of other ion channels (Na, K) and cellular processes (transport of ATP, bicarbonate and mucus secretion) • Leads to abnormal transport of ions and water through membranes • Effect of CFTR is tissue-specific: - Sweat glands: chloride and sodium reabsorption; loss of CFTR function → hypertonic sweat (with excessive NaCl – „children with salty-tasting skin“) - Respiratory and instestinal epithelium: CFTR ensures active luminal chloride secretion; loss of CFTR function → reduction of luminal choride secretion and increased reabsorption of sodium and water from the lumen → dense viscous mucus which obstructs ducts of the glands Cystic fibrosis (mucoviscidosis) Disorder with a wide degree of phenotypic variation 5 classes of mutations of CFTR gene: - combination of 2 „severe mutations“ → severe („classic“) phenotype of CF - combination of less severe mutations → mild phenotype of CF + modifier genes (e.g. polymorphisms in genes, whose products modulate neutrophil function in response to bacterial infections) Cystic fibrosis (mucoviscidosis): pathological features in organs Pancreas - viscous mucus obstructs ducts, which leads to dilatation of ducts, atrophy of the parenchyma and fibrosis - exocrine pancreatic insufficiency (fat malabsorption and avitaminosis A,D,E,K) - endocrine pancreatic insufficiency (diabetes associated with cystic fibrosis) Lungs - airway obstruction, recurrent and persistent infections - bronchitis, bronchiectasis, bronchopneumonia, abscess - Pseudomonas aeruginosa, Haemophilus influenzae, Staphylococcus aureus, Burkholderia cepacia, Strenotrophomonas maltophilia, atypic mycobakteria Meconium ileus Bile ducts obstruction (with the development of biliary cirrhosis) Impairment of salivary glands (analogical to pancreatic impairment) Azoospermia and infertility (resulting from congenital bilateral abscence of vas deferens) Impairment of sweat glands Pancreatitis • Acute (AP) Systemic inflammatory response to autodigestion of the pancreas and peripancreatic tissue by inappropriate release and activation of its own enzymes. • Chronic (CP) Prolonged inflammation of the pancreas, during which functional parenchyma is gradually replaced by fibrotic tissue with the development of irreversible destruction of exocrine, later endocrine pancreas. Etiology of acute pancreatitis pancr Initation of AP: Inappropriate and massive activation of trypsinogen Activation of elastase and phospholipase → damage of cell membranes and hemorrhage, ARDS (phospholipases interact with the surfactant) Activation of other enzymes, activation of complement, kallikrein-kinin system, coagulation and fibrinolytic system → DIC, shock (with mortality of 2-4 %) Main pathways of pathogenesis of AP: - duct obstruction - primary acinar cell injury - primary defective intracellular transport of proenzymes The most common causes of AP are alcoholism and billiary tract disease Acute pancreatitis – etiologic factors 80 % of acute pancreatitides is associated with alcoholism and disorders of bile ducts Metabolic - Alcoholism - Hyperlipoproteinemia (type I a V) - Hypercalcemia (hyperparathyroidism etc.) - Drugs (thiazide diuretics, azathioprine, estrogens, sulfonamides, furosemide, metyldopa, pentamidine, procainamide) -Genetic Mechanical -Trauma -Obstruction (gallstones, pancreas divisum, tumors, parasites(Ascaris lumbricoides)), spasms -Iatrogenic injury (perioperative injury, ERCP) Vascular, ischaemic -Shock, trombosis, embolism -Vasculitis – polyarteriitis nodosa - Infectious -Mumps -Coxsackievirus -Mycoplasma pneumoniae Focal oedema and necrosis of fat tissue Diffuse necrosis of pancreatic parenchyma and hemorrhage + idiopatic AP (10-20 %) Acute pancreatitis The basic alterations of morphology of the pancreas include: • Interstitial oedema caused by microvascular leakage • Necrosis of fat caused by lipolytic enzymes • Acute inflammatory reaction • Protelolytic destruction of pancreatic parenchyma • Destruction of blood vessels caused by elastase with interstitial hemorrhage • Clinical features Pain in the upper abdomen, anorexia, nausea, emesis; severe cases cause acute abdomen DIC, ARDS, shock Hypocalcemia, elevated levels of amylase and lipase in plasma Postnecrotic pseudocysts, secondary infections, abscess Clinical-pathological subtypes of AP • Acute interstitial pancreatitis moderate inflammation, interstitial oedema and focal necrosis of fat tissue of pancreas and peripancreatic tissue • Acute necrotizing pancreatitis necrosis of fat tissue of pancreas and peripancreatic tissue (Balser‘s fatty necrosis, Ca bound to necrotic tissues, hypocalcemia of blood), colliquation of necrotic areas, destruction of structures of exocrine and endocrine pancreas, interstitial hemorrhage • Hemorrhagic pancreatitis Extensive necrosis of pancreatic parenchyma, hemorrhage Acute pancreatitis pancreas-acute-hemorrhagic-pancreatitis-surf Necrotizing acute pancreatitis pancreas-enz-necrosis Necrotizing acute pancreatitis s7-3-pancreas-ak-nekr-40x-he Necrosis adipose tissue of omentum peritoneum-omentum-fat-necrosis-panceratitis-392g Chronic pancreatitis (CP) Pathogenesis of CP Obstructive causes Toxic-metabolic causes Oxidative stress Necrosis-fibrosis Etiology of chronic pancreatitis– classification TIGARO Toxic-metabolic (alcohol (alcoholic CP), nicotine, hyperlipidemia, drugs, uremia, toxins…) Idiopathic Genetic - hereditary pancreatitis, AD (mutation in gene PRSS1 (trypsinogen 1)), high risk of development of pancreatic carcinoma - genetically induced pancreatitis (alterations in genes CFTR, SPINK1 (trypsin inhibitor),…) - alpha-1 antitrypsin deficiency Autoimmune (imitates carcinoma!) Recurrent (repeated episodes of acute pancreatitis) Obstructive (gallstone obstruction, tumor,...) Clinical features and aftermath: Atrophy and insufficiency of exocrine and endocrine pancreas, fibrosis. Chronic pain in the upper abdomen, weight loss, icterus Pancreatogenic malabsorption syndrome An increased risk of cancer (pancreatic ductal adenocarcinoma (PDAC)) Chronic pancreatitis (CP) Associated with extensive architectonical and cytological alterations of pancreas Destruction of acinar cells Perilobular and intralobular fibrosis Distortion of persistent ductal elements → morphologically looks like well-differentiated pancreatic ductal adenocarcinoma (PDAC) – diff. dg. PDAC x CP!!! Reactive cytonuclear changes of epithelium Dysplastic ductal lesions – pancreatic intraepithelial neoplasia (PanINs) in CP Clinical diff. dg. of CP and pancreatic ductal adenocarcinoma (PDAC) Age (PDAC is rare in younger age (<40 years)) Long-term history of clinical problems of patient with CP Chronic alcoholic, hereditary and so-called paraduodenal pancreatitis → development on the bases of recurrent acute pancreatitis; formation of pseudocyst Icterus -CP - usually after years of progressive CP -PDAC - sudden manifestation of icterus PDAC: disease of older adults (>50 years), without history of CP or alcoholism * Different in autoimmune pancreatitis! Gross description (CP in surgical material) Unevenly distributed fibrosis with foci of fibrotization and lobular parenchyma in CP (alcoholic and hereditary) Consistency is more elastic in CP, impairment of pancreas is more diffuse Pseudocyst in CP Calcificated mucoprotein plugs in CP Progression of stenosis of major pancreatic duct in CP Paraduodenal pancreatitis (inflammatory, fibrous and cystic changes in loci of predilection) Autoimmune pancreatitis (grossly looks like PDAC, predominantly in pancreatic head, diffuse impairment, stenosis of the major pancreatic duct and damage of extrahepatic bile ducts) Alcoholic chronic pancreatitis in resection specimen 05a 05 Alcoholic chronic pancreatitis 06-11-23-1-7 06-11-23-1-6 Hereditary pancreatitis Mutations in genes encoding pancreatic enzymes or their inhibitors → increased autoactivation of trypsinogen or resistance to inactivation → autodigestion of pancreatic tissue, recurrent pancreatitis PRSS1 (cationic trypsinogen gene), AD SPINK1 (serum protease inhibitor), AR Fibrosis - perilobular, periductal, sometimes intralobular; diffuse X focal Dilatation of ducts, inspissation of luminal mucus, calcification (similarity with ACP), hyperplasia, metaplasia and dysplasia of ductal epithelium. 50-70x increased risk of development of pancreatic carcinoma (vs 2-5x increased risk in sporadic CP) Autoimmune pancreatitis 2 clinicopathologic subtypes of autoimmune pancreatitis: ◦ lymphoplasmacytic sclerosing pancreatitis (LPSP, type 1) ◦ often associated with other IgG4-related sclerosing lesions ◦ ◦ idiopathic ductocentric pancreatitis (IDCP, type 2) ◦ also known as AIP with granulocytic epithelial lesion ◦ ◦ usually occurs solitary ◦ rarely associated with ulcerative colitis ◦ ◦ dense periductal inflammation with neutrophilic infiltration and destruction of ductal epithelium ◦ ◦ absence or low IgG4+ plasmocyte count LPSP (AIP w/o GEL) IDCP (AIP with GEL) Alcoholic CP Infiltration Lymphoplasmacytic + eosinophilic + neutrophilic Lymphoplasmacytic + neutrophilic (ducts, acinar cells) Few chronic inflammatory cells Ducts Dense periductal infiltration w/o destruction Dense periductal infiltration + GEL Distortion of ducts, dilatation, w/o infiltration Mucoprotein plugs and Ca No No Often Lobuli Infiltration of acinar cells with destruction Focal infiltration with neutrophils Focal lobular atrophy and fibrosis Veins Phlebitis obliterans Rarely phlebitis obliterans W/o phlebitis obliterans Arteries Rarely intensive arterial impairment Usually w/o arterial impairment W/o arterial impairment Pseudocysts No No Yes Involvement of peripancreatic adipose tissue Common Minimal, inflammation restricted to pancreatic tissue Loci of necrosis IgG4 IHC >10 IgG4+ plasmocytes/HPF few or none IgG4+ plasmocytes few or none IgG4+ plasmocytes Clinical features M >F IgG4 sclerosing lesions M=F, younger AIP+UC Clinical features of AIP Obstructive icterus Abdominal pain Imaging methods – diffuse/focal enlargement of pancreas ERCP – diffuse irregular major pancreatic duct with stenosis and stenosis of ductus choledochus Responds to steroid therapy Autoimmune pancreatitis (IDCP, type 2) Hermanova_OBR8 1. Dense periductal inflammation 2. Destruction of ductal epithelium by neutrophils 1 2 IgG4-related sclerosing lesions Autoimmune pancreatitis Sclerosing cholangitis Lymphoplasmacytic sclerosing cholecystitis Sclerosing sialadenitis (Küttner tumor) Idiopathic retroperitoneal fibrosis (M. Ormond) Inflammatory pseudotumor of liver, lungs and pituitary gland IgG4-related tubulointerstitial nephritis IgG4-related interstitial pneumonia Sclerosing prostatitis Sclerosing thyroiditis Hypophysitis Pachymeningitis Sclerosing dacryoadenitis (Mikulicz disease)………. - M>F; respond to steroid therapy, lymphadenopathy; mimic neoplastic lesions - sclerosing lesions with diffuse lymphoplasmacytic infiltration, irregular fibrotisation - may be present: eosinophils, phlebitis obliterans, dense infitration of IgG4+ plasmacytes - increased risk of development of malignant lymphoma Obstructive pancreatitis diffuse perilobular and intralobular fibrosis dilatation of ducts w/o obstruction, irregularity or signs of destruction of ductal epithelium w/o signs of inspissation of luminal mucus and calcifications in ducts hyperplasia of ductal epithelium necrosis and pseudocysts not present Paraduodenal pancreatitis Also known as: cystic dystrophy of heterotopic pancreas (the residue of the dorsal part of pancreas in duodenal wall), periampullary duodenal wall cyst, „groove“ pancreatitis, pancreatic hamartoma of duodenal wall,... Alcohol comsumption Clinical features associated with duodenal stenosis, loss of weight, icterus in 20 % of cases Changes in region of minor duodenal papilla (obstruction, pancreas divisum) + impairment of pancreatic head + paraduodenal cystic changes (between the duodenal wall and the pancreas) Prolonged inflammation in submucosa and wall of the duodenum and the adjacent pancreas, foci of necrosis, myofibroblast proliferation, pseudocystic lesions, granulation tissue, granulomatous response, Brunner gland hyperplasia „Idiopathic chronic pancreatitis“ 3-9 % of all case of CP Mutation in CFTR gene (cystic fibrosis transmembrane conductance regulator gene) Mutation v SPINK1 gene (PSTI – pancreatic secretory trypsin inhibitor) + external factors (smoking, alcohol) Dysfunction of sphincter of Oddi Pancreas divisum Cysts of pancreas Congenital cysts - unilocular - multilocular (AD polycystic disease (cysts of kidney, liver, pancreas), syndrome von Hippel-Lindau) - (dermoid (mature teratoma)) Benign lymphoepithelial cyst Mucinous non-neoplastic cyst (v.s. mucinous cystic neoplasm (MCN)??) Periampullary duodenal wall cyst (in heterotopic pancreas) Enterogenous cyst Retention cyst Endometrial cyst - endometriosis Parasitic cysts (Ecchinococcus granulosus) Pseudocysts - associated with pancreatitis - the result of trauma -Abscesses Benign lymphoepithelial cyst of pancreas 06-05-22-1 06-05-22-1-1 06-05-22-1-2 06-05-22-1-3 Pancreatic tumors Epithelial Non-epithelial Secondary (metastatic) tumors Type of neoplasm Incidence Location Features Ductal adenocarcinoma (PDAC) 85-90 % H˃T solid, poorly defined masses, desmoplastic stroma Highly agressive Intraductal papillary-mucinous neoplasm 3-5 % H˃T Cystic, intraductal, progression into carcinoma Neuroendocrine neoplasia (NEN)/ Tumors of the endocrine pancreas 1-2 % H=T Solid, pseudocystic*, different degrees of malignancy, see classification of NEN GIT; hormonally active Mucinous cystic neoplasm 1-2 % T˃˃H Cystic, absence of communication with ducts, , progression into carcinoma, female predominance Serous cystic neoplasm 1-2 % H=T Cystic, absence of communication with ducts, benign Acinar cell carcinoma 1-2 % H=T Solid, pseudocystic*, agressive Solid pseudopapillary neoplasm 1-2 % H=T Solid, pseudocystic*, young women, low malignant potential Pancreatoblastoma ˂1 % H=T Solid, in children, malignant H - head; T - tail; * often with pseudocystic degeneration Risk factors Exogenous risk factors Endogenous risk factors Age Familial occurrence Smoking Hereditary syndromes Alcohol* Chronic pancreatitis Diet (especially high-fat), obesity Diabetes mellitus Exposition to organic substances or radiation * Indirect impact by induced chronic pancreatitis Genetic syndromes associated with PDAC Syndrome Type of inheritance Gene Lynch sy (hereditary nonpolyposis colorectal cancer) AD MSH2, MLH1,… Familial breast cancer; genes of Fanconi anemia AD BRCA2, PALB2, FANCC, PANCG, (BRCA1) Familial pancreatic cancer AD Unknown Familial Atypical Multiple Mole Melanoma syndrome (FAMMM) AD CDKN2A (p16) Hereditary pancreatitis AD (PRSS1) AR (SPINK1) PRSS1 SPINK1 Peutz-Jeghers sy AD STK11 Features of PDAC § 85-90% of all pancreatic neoplasms § very poor prognosis, the five-year relative survival rate is about 5 %, mortality almost equals to incidence § incidence is increasing, the highest incidence of pancreatic cancer in Czech republic § 5th leading cause of cancer related death in Western countries (2nd among GIT malignancies) § causes of this unfavorable state: absence of effective screening diagnosis often made in advanced stage of the disease due to lack of symptoms molecular-biologic characteristics of PDAC § radical resection – favourably increases survival rate of patients; at time of diagnosis only 10-15 % patients with PDAC meet criteria for resection; 70 % of patients are presented with metastases in regional lymph nodes. Despite radical resection, reccurence of PDAC in about 90 % of patients within two years after surgery. Pancreatic cancer incidence source: NOR ČR Malignant tumor of pancreas Progress in time Mortality Precursor lesions of pancreatic cancer Pancreatic intraepithelial neoplasms (PanIN) – precursor of PDAC Mucinous cystic neoplasms (MCN) Intraductal papillary-mucinous neoplasms (IPMN) - multistage process of histologic and genetic progress into invasive cancer - different clinico-pathological and genetic features Pancreatic cancer Disease induced by germline or acquired mutations of germ or somatic cells Multiple alterations of numerous genes responsible for progression of pancreatic cancer Knowledge of molecular basis of the disease – revelation of effective marker for early diagnosis + potential target for therapy Precursor lesions: helpful tool for study of molecular basis of pancreatic cancer Potentially successfull therapeutic strategy: combination of drugs targeted for pancreatic tumor stem cells and their microenvironment and conventional chemotheurapeutic agents ??? Microenvironment of pancreatic cancer – role of fibrogenesis in pancreatic cancer Tumor stroma – intergral component of cancerogenesis; provides communication between tumor and stroma cells Role of activated pancreatic stellate cells (stromal cells with similar behaviour as myofibroblasts): -Production of extracelular matrix proteins a matrix metalloproteinases (MMPs) -Source of cytokines and growth factors -Effect on tumor and other cells favouring tumor progression and fibrosis Role of proteases produced by stromal cells in DM a ↓BMI -Biopeptides of glucose homeostasis (+ neuropeptide Y, peptide YY, proline) substrates of these proteases -Fusion products ↓active/inactive → induction of diabetes associated with pancreatic cancer and loss of body weight (↓BMI) Stimulation of pancreatic cancer progression by mediators derived from stromal cells -Induction of cell proliferation -Inhibition of apoptosis -Chemoresistance -Invasive growth Evolution of therapy targeted on pancreatic stellate cells - Signs of PDAC Mostly located in the head of pancreas (2/3) Abdominal pain, loss of weight, suddenly emerged painless icterus, pruritus Thrombophlebitis migrans Signs caused by metastates or by affected sorrounding organs Oncomarkers (CA 19-9, CEA,…non-specific) DM associated with PDAC (atypical) - suddenly in advanced age - absence of obesity, rapid progression requiring insulin therapy - reccurence of infections including mycotic - disbalance of homeostasis with repeated hyperglycemia and tendency towards ketoacidosis and kachexia Ductal adenocarcinoma (head of the pancreas) _pancreas-adenocarcinoma PDAC dissemination Lymphatic metastases in regional lymph nodes Hematogenous metastases in liver, lungs, bones Peritoneal carcinomatosis Perineural invasion Ductal adenocarcinoma and perineural invasion 06-11-23-1-1 06-11-23-1-4 Pancreatic Cystic Neoplasms Mucinous cystic tumors Mucinous cystic neoplasm (MCN) Intraductal papillary-mucious neoplasm (IPMN) Benign, however can progress into carcinoma. Serous cystic tumors Almost always benign; some might be associated with Von Hippel-Lindau disease. Mucinous cystic neoplasms (MCN) Unilocular or multilocular, no communication with ducts, columnar mucin-producing epithelium supported by ovarian like stroma 90 % in women (5th - 6th decades); body-tale localisation - Noninvasive (excellent prognosis) - Invasive (60 % five-yers survival rate) - Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact help@nature.com or the author • Genetic alteration in progression of MCN: - Early mutation of oncogene KRAS - Inactivation of TSG TP53 and DPC4 in invasive MC carcinomas Intraductal papillary mucinous neoplasms (IPMN) Mucin producing, growing within the main pancreatic duct or its major branches, papillary architecture M/F = 60:40; 6th decade 75 % in the head of pancreas; 20 % body and tail + diffuse infiltration Precursor lesions: IPMN with low grade and high grade dysplasia Malignant lesions: IPMN associated with invasive carcinoma Three morphologic types: -Intestinal type (MUC2+) -Pancreatobilliary type (MUC1+) -Gastric type (MUC5AC+; „branch duct type“) - + intraductal oncocytic papillary neoplasm + intraductal tubulopapillary neoplasm IPMN obrázek 5 Hermanová IPMN-MNCK-01 Mucinous noncystic carcinoma (2/3) Better prognosis Tubular (PDAC-like) adenocarcinoma (1/3) Poor prognosis IPMN Intestinal type IPMN Pancreatobilliary type IPMN ? Gastric type IPMN ? Genetic alterations in progression of IPMN: - early mutation of KRAS - late inactivation of p16 a TP53 - inactivation of DPC4 only in 10 % of IPM invasive carcinomas - inactivation of STK11/LKB1 in 1/3 IPMN Acinar cell carcinoma, trypsine+ pankreas-acin-cell-ca-meta-perit-10521-04-40x-tryp Solid and acinar architecture M>F; adults, rare in children Circumscribed, multinodular, necrosis, cystic degeneration Granular eosinonophilic cytoplasm – zymogen granules Variants: - acinar cell cystadenocarcinoma - mixed acinar-endocrine carcinoma (30 % proportion of more than 1 cell type). - acinární karcinom0002 Serous pancreatic neoplasms 06-11-23-1-14 06-11-23-1-15 Usually cystic, lined by glycogen-rich, ducular type epithelial cells Serous cystadenoma: ◦benign; tail, body > head; central stellate scar; microcystic ◦ Serous cystadenocarcinoma: ◦Extremely rare ◦ + variants: -Macrocystic serous cystic neoplasm -Solid serous neoplasm -SCN associated with Von Hippel-Lindau sy -Mixed serous neuroendokcrine neoplasm Solid pseudopapillary neoplasm low grade malignancy, with favourable biologic behaviour Young women Monomorphic cells forming solid and pseudopapillary structures; haemorrhagic-cystic changes Variable expression of epithelial, mesenchymal and endocrine markers 85-95 % cured with surgical resection HE400x01 PAS600x Pancreatic neuroendocrine tumors Functioning (hormonally active) - insulinoma - glucagonoma - somatostatinoma - gastrinoma - VIP-producing tumor - serotonin-producing tumor - others – producing ectopic hormones (ACTH, calcitonin,…) Non-fuctioning (clinically asymptomatic without association with hormonal syndrome) Note: tumors smaller than 0,5 cm – microadenoma – usually clinically asymptomatic Classification of neuroendocrine neoplasms of GIT valid even for pancreas Neuroendocrine tumor - NET G1/G2/G3 well differentiated neuroendocrine tumor; low grade (G1/G2) and high grade (G3) (previously called carcinoids and atypical, malignant carcinoids) Neuroendocrine carcinoma - NEC G3 poorly differentiated neuroendocrine neoplasm (neuroendocrine carcinomas, high grade malignant tumors) - Small cell neuroendocrine carcinoma - Large cell neuroendocrine carcinoma - Mixed neuroendocrine nonneuroendocrine neoplasm (MiNEN) (previously called MANEC) WHO 2010: NET G1/G2; NEC; MANEC) WHO 2019: NET G1/G2/G3; NEC; MiNEN) Pancreatic neuroendocrine tumor. _pancreas-islet-cell-tumor-malignant Pancreatic neuroendocrine tumor. Clinical syndromes associated with functioning neuroendocrine tumors 1) Insulinoma/hyperinsulinism…..hypoglycemia 2) Gastrinoma/Zollinger-Ellison syndrome……peptic ulcers in atypical localisations 3) Glukagonoma….diabetes, erythema migrans, anemia 4) Somatostatinoma…diabetes, cholelithiasis, steatorhea, hypochlorhydria 5) VIPoma/WDHA syndrome….(„watery diarrhoea, hypokalemia, achlorhydria) 6) Carcinoid/carcinoid syndrome + tumors with ectopic production of ACTH..Cushing syndrome, MSH..hyperpigmentation, ADH..diabetes insipidus Amyloid formation in insulinoma. FNAB – cytology of pancreatic neuroendocrine tumor. NE tumor 357606 Thank you for your attention….