j0305257 Systemic Pathology Hepatobiliary, pancreas,diabetes mellitus, endocrine system j0305257 Morphology of hepatic injury û hepatocyte degeneration and/or pathologic intracellular accumulation (i. e. fatty liver, pigment, …) ûhepatocyte necrosis, apoptosis ûinflammation ûregeneration ûfibrosis û j0305257 Fatty liver disease - steatosis ûgross: ð enlarged, paler, in extreme cases yellow, softer consistency ð ûmicro: ð small or confluent droplets in cytoplasm ð ûcauses: ð alcohol ð other toxins (drugs, organic substances) ð diabetes mellitus + metabolic syndrome ð excessive fat intake ð infection (hepatitis C, …) ð hypoxia ð û j0305257 Fatty liver - steatosis û = pathological accumulation of lipids in form of intracytoplasmatic vesicles û û without inflammatory reaction reversible process û with inflammation (steatohepatitis) – possible progression to cirrhosis û û microvesicular x macrovesicular ðvesicle < or > than hepatocyte nucleus ðvariable distribution (diffuse, zonal, focal), may help to the etiological diagnosis j0305257 sejmout0003 sejmout0004 Fatty liver disease - steatosis j0305257 Alcoholic fatty liver steatóza jater 200x 1 Lipid vesicle in cytoplasm of hepatocytes 2 Hepatocyte nucleus pushed to periphery 2 1 1 j0305257 Fatty liver, satellitosis of neutrophils j0305257 Alcoholic hepatitis : steatohepatitis, cholestasis, Mallory hyaline 39mr j0305257 Cholestasis û Causes: ðhepatocellular dysfunction (inborn, acquired) ðbiliary obstruction (intra-, extrahepatic) ð û Signs: ðpruritus - itching(↑ serum bile acids) ðhyperlipidemia → skin xanthomas (focal cholesterol accumulation) ðmalabsorption → ↓ fat soluble vitamins (A; D; K) ð↑ ALP (serum alkaline phophatase) ð j0305257 Cholestasis MORPHOLOGY ûGross: ð green-brown (olive) discoloration ûMicro: ð bile pigment accumulation in hepatocytes / canaliculi („bile plugs“) ð edema, periductal neutrophilic infiltrates in portal spaces ð chronic obstruction → portal fibrosis → biliary cirrhosis j0305257 obstr Cholestasis in HCC 1Bile accumulation 2 Hepatocyte 1 1 2 2 j0305257 Hepatic venous congestion ûGROSS: ðenlarged, heavy liver ðdark – reddish brown color ðcardiac fibrosis (induration) ðcombination with chronic hypoxemic steatosis – nutmeg liver j0305257 Hepatic venous congestion (“nutmeg” liver) j0305257 Hepatic venous congestion ûMICRO: ðcentral veins and sinusoidal dilatation • ðcentrolobular hepatocytic atrophy, necrosis • ð„lines“ of congestion • j0305257 Hepatic venous congestion městnání v játrech 20x 1 2 2 1 1 1 Portal spaces 2 Congestive lines (severe congestion with hepatocyte necrosis) --- pseudolobule: confluent remnants of 3 lobules, centrally portal space j0305257 Hepatitis ûinfectious ðacute, chronic ðviral • most common • primary hepatotropic - hepatitis viruses • systemic – EBV, CMV, HSV, yellow fever, enteroviruses, … ðbacterial •pyogennic bacteria, TBC, salmonella – typhoid fever, leptospirosis,… ðparasitic •ecchinococcus, schistosoma, … ðprotozoal •amebiasis ð j0305257 Hepatitis ûNon-infectious û (acute, chronic) û ð autoimmune (AIH) ð metabolic • hemochromatosis, NASH ð toxic/drug induced ð cryptogenic j0305257 Chronic hepatitis û Asymptomatic / clinical symptoms û Laboratory signs of progressive/relapsing liver disease (> 6 months, 12 months in HCV) û Etiology: ð Viruses • HBV, HBV+HDV, HCV ð AIH ð metabolic (inborn, NASH) ð toxic/ drug induced (alcoholic) ð cryptogenic j0305257 Chronic hepatitis - pathology ûGross: ð non-charakteristic, commonly enlarged liver of firmer consistency û û Micro: ðDisease activity: grade of necroinflammatory changes in portal spaces and lobules (interface activity; type, grade and localisation of necrosis; grade of inflammatory infiltrate) j0305257 Chronic hepatitis - pathology û Disease stage: ðstage of fibrosis and architectural changes (portal fibrotic expansion, bridging fibrosis, nodularity → cirrhosis) j0305257 Chronic hepatitis 29mr 1 Portal spaces with inflammatory infiltrate 2 Hepatocytes 3 Interface activity 1 2 3 3 j0305257 NASH: non-alcoholic steatohepatitis û Spreading silent epidemics: ûPatients with metabolic syndrome: û „male-type“ obesity (intraabdominal fat accumulation – waist size) ûhyperlipidemia ûDM of II type, hyperglycaemia j0305257 Liver fibrosis ûResponse to inflammation ûMostly irreversible ð(under favorable conditions reversible to some extent) ûDeposition of collagen ðà effects on hepatic metabolism and blood flow ûBegins around portal tracts or central veins à spreads à links other regions (bridging fibrosis) ûBasic lobular architecture partially preserved û j0305257 Advanced liver disease (cirrhosis) û Complete loss of original architecture ðRegenerating groups of hepatocytes surrounded by fibrotic scar tissue ðReorganisation of vascular architectecture ðIntrahepatic biliary trackt changes, incl. ductular hyperplasia û ûDue to continued parenchymal injury and fibrosis ûAdvanced stage of liver disease, may be partially reversible û j0305257 Advanced liver disease (cirrhosis) û Etiology: ðmassive acute necrosis ðchronic hepatitis ðbiliary diseases: • inborn (atresia) • acquired: – autoimmune (primary biliary cirrhosis, prim. sclerosing cholangitis), secondary biliary cirrhosis (chronic obstruction) ðcryptogenic cirrhosis ð ûGross: liver usually diminished in size ðmicronodular ðmacronodular j0305257 Image075 Cirrhosis - macronodular j0305257 Cirrhosis - micronodular j0305257 Advanced liver disease (cirrhosis) 43mr j0305257 CT scan with contrast of the abdomen in transverse view demonstrates a small liver with cirrhosis. The spleen is enlarged from portal hypertension copy Advanced liver disease (cirrhosis) j0305257 Advanced liver disease (cirrhosis) j0305257 Cirrhosis – fibrotic septa (Van Gieson staining) cirhoza VG20x 1Nodules 2 Fibrotic septa 1 1 1 2 2 2 j0305257 Cirrhosis - ductules cirhoza 100x 1 Nodulus 2 Ductular hyperplasia 3 Portal tract with lymphocytes 1 2 2 2 3 j0305257 Complications of cirrhosis û Insufficiency of liver functions: ð ↓ synthesis (proteins incl. clotting factors etc.) ð ↓ detoxication – hepatic coma ð ↓ Kupffer cells function ð û Portal hypertension: ð splenomegaly, intestinal venous congestion (! infarsation, inflammation) ð ascites (! peritonitis) ð portocaval anastomoses (oesophageal varices) ð û Carcinoma ðmostly hepatocellular j0305257 Focal lesions and tumors ûTumor-like lesions ûBenign tumors ûMalignant tumors: ðprimary, secondary j0305257 Tumor-like lesions ûFocal nodular hyperplasia ûNodular regeneratory hyperplasia (lack of fibrosis) ûCysts ûBiliary hamartoma (von Meyenburg complex) j0305257 Focal nodular hyperplasia ûLocalized benign hepatocellular nodules with central stellate fibrous scar ûSingle or multiple ûMore common in females, oral contraceptives – estrogenes ûDiff. dg. x tumors û û j0305257 FNH – fibrotic scar j0305257 Benign tumors ûAdenoma ûhepatocellular ðlack of portal tracts, regular trabeculae ûcholangiocellular ð biliary , accumulation of regular ducts, lack of bile production, less than 1cm, subcapsular ûcystadenoma ðmucinous, rare û ûHaemangioma ûcavernous ð û û j0305257 û hamartoma, commonly multiple û 2 mm – 15 cm û risk of rupture + bleeding, consumption coagulopathy û common regressive changes – atypical US, CT, dif. dg. x malignancy û dark spongiotic demarcated focus û fibrous septa + vascular spaces Cavernous haemangioma j0305257 Cavernous haemangioma (in micronodular liver cirrhosis) kavernozní hemangiom jatra 20x 1 Liver nodules 2 Dilated vascular spaces filled with red blood cells 3 Chronic inflammatory infiltrate 1 1 2 2 2 3 j0305257 Cavernous haemangioma 1 Dilated vascular spaces filled with red blood cells 2 Fibrous septa with endothelial cells 1 1 1 2 2 j0305257 Malignant tumors ûPrimary ðHepatocellular carcinoma (90%) ðCholangiocarcinoma ðHepatoblastoma • children ðAngiosarcoma • associated with vinyl chloride, arsenic, or Thorotrast exposure j0305257 Malignant tumors ûSecondary ðMetastatic carcinomas • most common liver malignancy (GIT, lung, breast, kidney,…) ð Direct spread of adjacent malignant tumors •gall bladder, pancreas ðOther metastasing tumors •melanoma, sarcomas etc. ðHaemopoetic neoplasms • leukemia infiltrates, lymphomas û j0305257 Preneoplastic changes ûLiver cell dysplasia ð low grade, high grade ðusually in cirrhosis ð small foci or nodules, microcellular – smaller cells with less cytoplasm + bigger nuclei û Diff. dg. x well diff. HCC û j0305257 Hepatocellular carcinoma û World-wide 5th most common malignancy in males, 8th in females û Possible primary prevention û Different incidence due to geography / cause ð High-income countries: now lower incidence, usually in cirrhosis (alcohol), ↑ (NASH, HCV) ð Eastern Asia (HBV) + Africa (aflatoxin) – 80% of cases j0305257 Hepatocellular carcinoma û Single or more nodules different from adjacent tissue ðmultifocal start or intrahepatic metastases û Micro ð trabecular, acinar +/- pseudoglandular, solid ð enlarged nuclei + nucleoli, ↑ mitotic activity, atypias; eosinophilic – pale cytoplasm û Possible steatosis, bile production j0305257 Hepatocellular carcinoma û angioinvasion ð mostly venous û metastases ð lung, bones, LN û small solitary (→3) focus ð excision, transplantation û large, multiple ð ablation, bad prognosis û secondary prevention ðregular check-up of cirrhotic patients j0305257 Image081 Hepatocellular carcinoma j0305257 60mr HCC j0305257 HCC 100x HCC j0305257 HCC j0305257 Cholangiocarcinoma ûFrom intrahepatic biliary ducts û↑ risk in PSC, HCV cirrhosis, … ûmucin secterion, no bilirubin pigment ûirregular ducts, strands of cells ûdiff. dg. x metastatic or direct spread – gallbladder, pancreas, colorectal ca ûmostly bad prognosis û j0305257 56mr Cholangiocarcinoma 1 Cholangiocarcinoma 2 Liver parenchyma 1 2 j0305257 Cholangiocarcinoma (IHC CK7) Æ CK7 positive ductal cells (brown) j0305257 Colorectal ca metastasis 1 Tubular formations of colorectal adenocarcinoma 2 Liver parenchyma 1 1 2 j0305257 64mr Cholecystolithiasis Æ Gallbladder filled with stones j0305257 Cholecystitis ûAcute calculous ðObstruction of GB neck or cystic duct ðLocal pain radiating to right shoulder ðFever, nausea, leukocytosis ðPotential surgical emergency ûempyema of gallbladder ûgangrenous cholecystitis j0305257 Cholecystitis ûAcute acalculous ðless common, ischemic (postoperative, trauma, burns, sepsis,…) ûChronic ðRecurrent attacks of pain ðNausea and vomiting ðAssociated with fatty meals û ð û j0305257 Cholecystitis 1 Inflammatory infiltrate ÆMucosa 1 1 j0305257 Cholecystitis 1 Inflammatory infiltrate ÆMucosa 1 j0305257 Gangrenous cholecystitis gangrena zlucniku 20x 1 necrosis 2 bacterias 3 inflammatory infiltrate Æ fibrin 3 1 2 2 j0305257 Chronic cholecystitis û Fibroproduction ðthickening of the wall, adhesion, diff. dg. x ca ûChronic inflammation ûReactive epithelial atypias and metaplasia Possible dysplasia ð ↑ ca risk ûDystrophic calcification ûGallbladder hydrops j0305257 63mr Chronic cholecystitis 1 Inflammatory infiltrate ÆMucosa 1 1 j0305257 Gallbladder carcinoma ûSeventh decade ûF>M ûDiscovered at late stage, usually accidental ûAdenocarcinoma, other types ûLocal extension into liver, cystic duct, portal LN ûMean 5 yrs survival 1% ðbetter prognosis if accidental finding in CHCE in incipient stage j0305257 Gallbladder carcinoma D:\Rosai\images\14FF14.jpg D:\Rosai\images\14FF16.jpg j0305257 Pathology of pancreas û Exocrine û Endocrine 00000041 00000042b j0305257 Acute pancreatitis û etiological factors: ð Metabolic - Alcohol - Hyperlipoproteinemia (type I and V) - Hypercalcemia (hyperparatyreoidismus) - Drugs - Genetics ð Mechanic - Obstruction (lithiasis), spasms - Iatrogenic damage (ERCP, perioperative) ð Vascular, ischemic - Shock, trombosis, embolia - Vasculitis – polyarteriitis nodosa ð Infections - mumps - Coxsackieviruses - Mycoplasma pneumoniae ð j0305257 Acute pancreatitis û clinical features: ð severe abdominal (epigastric) pain, nausea and vomitting – acute abdomen ð ð DIC ð ð shock, multiorgan failure, ARDS, renal failure ð ð elevation of serum amylases, lipases, hypocalcaemia ð ð infective complications ð ð pseudocysts û j0305257 Acute pancreatitis û Morphology: ð serous and haemorrhagic exsudate in the peritoneal cavity ð ð swollen pancreas ð ð necroses, colliquation, haemorrhages ð ð Balzer´s fat necroses • û û j0305257 Acute pancreatitis pancreas-enz-necrosis 1. Fatty necroses with haemorrhagic rim 2. Adjacent pancreatic parenchyma 1 2 1 2 j0305257 Balzer´s fat necroses peritoneum-omentum-fat-necrosis-panceratitis-392g 1. Balzer´s fat necrosis in the omentum 2. Surrounding fatty tissue 1 2 j0305257 Acute pancreatitis s7-3-pancreas-ak-nekr-40x-he 1. Necrosis 2. Demarcation/leucocytes 3. Adjacent pancreatic tissue 1 2 3 j0305257 Acute pancreatitis ak pankreatitis 100x 1. Necrosis 2. Demarcation/leucocytes 1 2 j0305257 Chronic pancreatitis û TIGAR-O classification (2001): ð Toxic/metabolic (alcohol, uremia, drugs) ð ð Idiopathic ð ð Genetic (hereditary) ð ð Autoimmune ð ð Recurrent acute ð ð Obstructive ð j0305257 Alcoholic pancreatitis û histologic features: ð chronic calcifying pancreatitis ð ð fibrotisation of pancreas, mostly perilobular ð ð autodigestive necroses and postmalatic pseudocysts ð ð dilated and irregular ducts ð ð protein plugs in ducts, calcifications ð ð hyperplasia and metaplasia of ductal epithelium ð ð increased risk of pancreatic cancer in chronic pancreatitis ð j0305257 Alcoholic pancreatitis 06-11-23-1-3 1. Dilated ducts, protein plugs in ducts 2. Perilobular fibrotisation 3. Lobular architecture of pancreas 1 2 3 j0305257 Alcoholic pancreatitis 06-11-23-1-6 1. Perilobular fibrotisation 2. lympho-plasmocellular inflammatory infiltration 3. Lobular architecture of the pancreas 1 2 3 j0305257 Autoimmune pancreatitis û adults affected ð rare in 2nd and 3rd decade û û M>F ð û clinical and radiological features mimic pancreatic cancer ð û associated with other autoimmune disorders ð û j0305257 Obstructive pancreatitis û Obstructive pancreatitis – histological features: ð diffuse perilobular and intralobular fibrosis ð ð dilated ducts without obstruction, irregularities or signs of destruction of ductal epithelium ð ð no protein plugs or calcifications in ducts ð ð hyperplasia of ductal epithelium ð ð necroses and pseudocysts absent ð j0305257 Tumours of the pancreas û epithelial û û non-epithelial ð û secondary - metastatic j0305257 Epithelial tumours û classified according to biological behavior: ð benign: • serous cystadenoma • acinar cell cystadenoma • ðPremalignant lesion: •pancreatic intraepithelial neoplasia grade 3 (PanIN-3) •mucinous cystic neoplasm with low- or intermediate grade dysplasia •mucinous cystic neoplasm with high grade dysplasia •intraductal papillary mucinous neoplasm with low- or intermediate grade dysplasia •intraductal papillary mucinous neoplasm with high grade dysplasia •intraductal tubulopapillary neoplasm • ð malignant: •Ductal adenocarcinoma !! (PDAC) •mucinous cystic neoplasm associated with invasive carcinoma •intraductal papillary mucinous neoplasm associated with invasive carcinoma •acinar cell carcinoma •acinar cell cystadenocarcinoma •serous cystadenocarcinoma •pancreatoblastoma •solid-pseudopapillary neoplasm •mixed acinar-ductal carcinoma •mixed acinar-neuroendocrine carcinoma •mixed acinar-neuroendocrine-ductal carcinoma •mixed neuroendocrine-ductal carcinoma j0305257 Precursor lesions of invasive pancreatic cancer û Pancreatic intraepithelial neoplasia (PanIN) ð microscopic precursor of PDAC û û Mucinous cystic neoplasm (MCN) û û Intraductal papillary mucinous neoplasm (IPMN) ð gross cystic precursor lesions j0305257 Pancreatic intraepithelial neoplasia (PanIN) PANIN_86 PANIN_19 PANIN_29 PANIN_42 1A 1B 2 3 j0305257 Ductal adenocarcinoma û ductal adenocarcinoma - 85-90% of all pancreatic neoplasias û û 5th most frequent cancer-related death ðin GIT 2nd after colorectal cancer ð û risk factors: ð higher age ð genetic factors ð environemntal factors: • smoking, high fat diet, obesity and low physical activity, chemicals ð chronic pancreatitis (both hereditary and sporadic); (CP) ð diabetes mellitus ð alcohol (indirectly, induces CP) û j0305257 Ductal adenocarcinoma û clinical features: ð 60-70 % in the pancreatic head ð ð abdominal and back pain ð ð weight loss ð ð icterus, pruritus, diabetes mellitus ð ð migratory thrombophlebitis ð ð symptoms related to liver metastasis and/or invasion of adjacent organs ð j0305257 Ductal adenocarcinoma û biologiccal behavior ð lymphogennous metastasis (regional lymph nodes) ð ð haematogennous metastasis (liver, lungs, bones) ð ð carcinomatosis of peritoneum ð ð perineural spreading û j0305257 Ductal adenocarcinoma û Gross: ð usually solid mass in the pancreatic head ð ð mean diameter 2-3 cm ð ð common bile duct and/or main pancreatic duct stenosis ð ð necrosis rare ð ð absence of calcifications and pseudocysts j0305257 Ductal adenocarcinoma û Micro: ð grade of differentiation: • grade 1: well differentiated –ductal and tubular formation in desmoplastic stroma, columnar mucin producing cell, distinct small nucleoli, low mitotic activity, low degree of pleomorphism/atypia – • grade 2: moderately differentiated – ductal, tubular, microglandular, cribriform formation, desmoplasia, irregular mucin production, prominent nucleoli, higher pleomorhism – • grade 3: poorly differentiated –irregular glandular structure, solid aggregates, squamoid foci, spindle cells, anaplastic, pleomorphic structures, mitotic activity j0305257 Ductal adenocarcinoma in the head of pancreas pancreas-ca-head-4-394g 1.Carcinoma of pancreatic head 2.Pancreatic body and tail 1 2 j0305257 Ductal adenocarcinoma PDAC 40x 01 1. Neoplastic ductal formations 2. Focal duct ruptures with macrophages and detritus intraluminally 1 1 2 j0305257 Ductal adenocarcinoma – well differentiated (G1) PDAC WD 19148-07-40x 1. Neoplastic ductal formations 2. Stromal desmoplasia 1 1 2 j0305257 Ductal adenocarcinoma– poorly differentiated (G3) PDAC PD 7387-04 100x 1. Solid tumour parts 2. Cribriform formations 1 1 2 j0305257 Differential diagnosis of ductal adenocarcinoma and chronic pancreatitis – clinical features û Adenocarcinoma: ð older patients • rare under 40 • ð no pancreatitis and alcoholism in medical history ð ð sudden painless icterus ð ð û Chronic pancreatitis: ð often in younger patiens ð ð medical history: • long term – recurrent acute pancreatitis • alcohol abuse ð ð icterus after long term duration of disease ð ð ð ð j0305257 Differential diagnosis of ductal adenocarcinoma and chronic pancreatitis – gross features û Adenocarcinoma: ð solid mass in the pancreatic head, mean diameter 2-3 cm ð common bile duct stenosis ð ð usually without necrosis, calcifications, pseudocysts û Chronic pancreatitis: ð more diffuse ð ðAlternation of lobular parenchyma and areas of fibrosis ð ð protein plugs and calcifications in ducts ð ð extrapancreatic pseudocysts ð j0305257 Differential diagnosis of ductal adenocarcinoma and chronic pancreatitis – microscopic features û Adenocarcinoma: ð haphazard distribution of irregular ductal structures ð ð ducts perineurally, in extrapancreatic fatty tissue ð ð hypercellular condensation of stroma around neoplastic ducts, stromal desmoplasia ð ð enlarged nuclei, pleomorphism, hyperchromasia, mitoses, prominent nucleoli, loss of nuclear polarity ð ð dense acidophilic cytoplasm, apical condensation of cytoplasm û Chronic pancreatitis ð (organoid) lobular arrangement ð ð ducts intrapancreatically ð ð smooth contours of the ducts, roud/oval lumens ð ð dense hyalinized stroma ð ð uniform nuclei, inconspicious nucleoli, no mitoses ð ð cytoplasm normochromophilic, absence of apical condensation j0305257 Differential diagnosis of ductal adenocarcinoma and chronic pancreatitis – microscopic features Hermanova_OBR2 1. Haphazard distribution of irregular ducts 2. Stromal desmoplasia 1. Lobular arrangement 2. Dense hyalinized stroma 1 1 2 1 2 j0305257 Neuroendocrine neoplasms of the pancreas û synonyms: pancreatic NETs, islet cell tumor, APUDoma û 1 – 2 % of all pancreatic tumors û 3rd-6th decade û classification: ð neuroendocrine tumour (NET) - nonfunctional NET (NET G1, G2) - NET G1 - NET G2 - ð neuroendocrine carcinoma (NEC) - large cell NEC - small cell NEC ð j0305257 Neuroendocrine neoplasms of pancreas û Functional (hormonally active) ð insulinoma ð glucagonoma ð somatostatinoma ð gastrinoma ð VIPoma ð serotonin producing NET ð others – with ectopic hormone production (ACTH, calcitonin,…) ð û Nonfunctional (with no association with hormonal syndrome) û û Pancreatic neuroendocrine microadenomas ð <0,5 cm ð usually clinically silent j0305257 Neuroendocrine neoplasms of pancreas ûGross: ð partially or totally circumscribed/encapsulated; usually solitary ð ð ð white, yellow or pink-brown ðhaemorrhages, necrosis can occur; cystic tumors rare ð – j0305257 Neuroendocrine neoplasms of pancreas û Micro: ð nesting, trabecular, glandular, acinar, tubuloacinar, pseudorosette,…arrangements of their cells ð ðcells uniform, round, finely granular amphophilic to eosinophilic cytoplasm, coarsely clump chromatin („salt and pepper“) ð ðVariable amount of stroma ð ð IHC: • CEA, synaptophysin, chromogranin, NSE, CD56 • peptide hormones: – insulin, glucagon, serotonin, somatostatin, gastrin ð ð j0305257 Neuroendocrine neoplasms of pancreas _pancreas-islet-cell-tumor-malignant j0305257 Neuroendocrine neoplasms of pancreas 1.Trabecular formation of tumour cells 2.Dense fibrotic stroma 1 1 2 j0305257 Diabetes mellitus û Group of complex metabolic lesions û Multifactorial etiology û Common sign: ð glucose metabolism dysregulation → glucose intolerance - hyperglycaemia û Causes: ð insulin secretion disorders ð disorders of insulin action / response to insulin ðcombination of both û j0305257 Diabetes mellitus û Other metabolic disorders: ð lipolysis • hyperlipidaemia (loss of weight), ketoacidosis ð hyperglycaemia • osmotic diuresis (polyuria, dehydratation, thirst) ð diminished protein synthesis j0305257 Diabetes mellitus - classification û Primary DM: ð DM type 1 • insulin-dependent • destruction of β-cells, autoimunne, idiopathic • ð DM type 2 •non-insulin dependent • ð Genetic defects of β-cells function • MODY – maturity-onset diabetes of the young, etc. û Now possible 5 DM types j0305257 Diabetes mellitus - classification û Secondary DM: ðExocrine pancreas defects • (chron. pancreatitis, cystic fibrosis, hemochromatosis, tumor) ð Endocrinopathies • (Cushing sy, hyperthyreosis, acromegaly, etc.) ð Infections • (CMV, coxsackie B, congenital rubella) ð Drugs • (glucocorticoids, proteases inhibitors, …) û Gestational DM j0305257 Diabetes mellitus û Atypical glucose bond on proteins ð glycation→ change of normal characteristics/functions, i.e. in vessels BM; monitoring - glycosylated hemoglobin HbA1c ð û Polyol pathways ð atypical metabolisation of glucose by reductases to sorbitol + fructose i.e. in kidneys, nerves, eye lens → oedema and cell damage ð û Free radicals formation ð oxidative stress û j0305257 Diabetes mellitus - complications û Long-term consequences similar in all types: ð microangiopathy (neuropathy, retinopathy) ð diabetic glomerulosclerosis ð accelerated atherosclerosis ð immune defect, mostly nonspecific (bacterias, fungi) ð diabetic ketoacidosis, hyperosmolar coma ð hypoglycaemia/coma due to insulin overdose j0305257 Diabetes mellitus – morphology ûPancreas û DM type1 ð more specific changes ð insulinitis with lymfocytic infiltration of islets + ↓ of their size and number û DM type 2 ð possible amyloid deposition or islet fibrotisation j0305257 Diabetes mellitus – morphology ûLarge vessels û AS, changes non-specific û AS complications (MI, gangrene) sooner and more often û accelerated hyaline arteriolosclerosis and hypertension → intracerebral haemorrhage, nephrosclerosis j0305257 Diabetes mellitus – morphology ûSmall vessels û Microangiopathy ð diffuse thickening of BM, but BM more leaky for proteins û Nephropathy û Retinopathy û Neuropathy j0305257 Diabetic nephropathy û Diabetic glomerulosclerosis ð diffuse x nodular û Renal vascular lesions ð arteriolosclerosis û Pyelonephritis incl. papillary necrosis û û Common progression to renal insufficiency j0305257 Glomerulosclerosis + arteriolosclerosis j0305257 Papillary necrosis ûAcute necrotizing papillitis in the setting of focal ischaemia nekrpapil j0305257 Diabetes mellitus – morphology û Ocular lesions: ð retinopathy (neovascularization) ð cataract formation (opaque lens) ð glaucoma (intra-ocular hypertension) • j0305257 Diabetes mellitus – morphology û Neuropathy ûsegmental demyelinization ð distal polyneuropathy • mostly motoric + sensitive in lower extremities – incl. ↓ pain perception (→ ulceration) ð autonomic neuropathy • functional disorders of intestines, bladder, sexual j0305257 Diabetes mellitus – morphology û Skin ð increased susceptibility to infections incl. protracted mycotic i., gangrene ð granuloma annulare (foci of collagen degeneration + inflammatory infiltrate) ð necrobiosis lipoidica ð j0305257 Diabetes mellitus – morphology û Pregnancy ð pre-eclampsia ð large babies (already in utero) ð neonatal hypoglycaemia j0305257 Metabolic syndrome û abdominal obesity („male type“) û insulin resistance û hyperlipidemia + abnormal lipid spectrum û ûConsequences û cardiovascular lesions û non-alcoholic steatohepatitis j0305257 Pathology of other endocrine organs (selected) û Hyperfunction û Hypofunction û Neoplasia (+ event. functional changes) j0305257 pit-ad-ma Pituitary adenoma ÆAdenoma copy j0305257 Thyroid gland û HYPERTHYROIDISM - thyrotoxicosis û overproduction, ↑ release into the blood, extrathyroidal secretion û hyperplasia ð Graves-Basedow disease, nodular goitre û hyperfunctional tumor ð adenoma, ca û incipient autoimmune thyroiditis û endocrine axis dysregulation j0305257 Thyroid gland ûThyrotoxicosis û hypermetabolic state + overactivity of sympathetic nervous system û û Exophthalmos û Weight loss, diarrhoea, tremor, anxiety, insomnia û Tachycardia, palpitations, arrhytmia - atrial fibrillation → thyrotoxic cardiomyopathy, hypertension û Sweating, heat intolerance û Osteoporosis û Possible thyroid storm, heart failure j0305257 Thyroid gland û HYPOTHYROIDISM û congenital (cretinism), û û û ð geographic iodine deficiency (endemic cretinism), individual factors (hypoplasia, ectopy, genetic /metabolic defects) ð thyroid hormones necessary to fetal brain development → severe neurologic defects incl. mental retardation ð coarse facial features + hypomimia, protruding tongue, disorders of dentition + growth, sexual retardation û j0305257 Thyroid gland û MYXEDEMA û hypothyroidism developing in older child/adult û M:F 1:10 û slowing of physical/mental activity û accumulation of mucoid matrix substances in dermis, myocardium, vessels, …), hypercholesterolemia, AS acceleration û cool skin, cold intolerance, constipation + overweight, fatigue, dyspnoea, decreased exercise capacity û secondary oligo- amenorrhoea û cardiovascular insufficiency û j0305257 thyr-Io-scan radioactive iodine uptake 1.norm 2.diffuse hyperplasia 3.„hot“ nodule – usually adenoma 4.„ cold“ nodule - ca Thyroid gland - scintigraphy j0305257 Thyroiditis û Acute inflammations uncommon ð purulent bacterial (abscess), tbc û Subacute granulomatous – giant cell thyroiditis (de Quervain‘s) ?viral ð painful enlargement, micro mixed inflammatory infiltrate + giant cell reaction û Chronic sclerosing t. (Riedel‘s) ðdense fibrotisatin, diff. dg. x ca j0305257 Chronic thyroiditis chrthyr-ma j0305257 Hashimoto‘s thyroiditis û organ-specific autoimmune inflammation û variable auto-antibodies ð x peroxidase, thyroglobulin, etc. û early stage - enlargement + hyperfunction û later hypofunction û ↑ risk of other autoimmune diseases (DM, SLE,..) û ↑ risk of malignancies ðMALT lymphomas, papillary thyroid carcinoma j0305257 Hashimoto‘s thyroiditis û Gross: ð non-homogennous, firm, small paler foci û Micro: ð dense lymphoplasmocellular infiltrate, incl. germinal centres ð thyroid follicles atrophy, onkocytic transformation of follicular epithelium (Hürtle cells) • eosinophilic cytoplasm, enlarged nucleus, distinctive nucleolus ð variable grade of fibrosis j0305257 Hashimoto‘s thyroiditis Hashimoto 100x 1Follicles 2Germinal centre Æ Inflammatory infiltrate 2 1 1 j0305257 Hashimoto‘s thyroiditis Hashimoto 200x 1Follicles 2Lymphocytes + plasma cell infiltrate Æ Oncocytes 1 1 2 2 j0305257 Thyroid gland hyperplasia û Autoimmune Graves-Basedow disease û û Diffuse parenchymatous thyrotoxic goiter (> 60g) + exophthalmos û û IgG auto-antibody to the TSH receptor – LATS (long-acting thyroid stimulator) û ûAdenomatoid nodules ð in the setting of nodular goiter, unencapsulated, diff. dg. x true adenoma may be difficult û j0305257 Thyroid gland hyperplasia û Gross: ð symmetric diffuse enlargement, red-brown, „fleshy“ û Micro: ð tall hyperplastic follicular cells, papillary formations, ↓ amount of colloid, numerous resorptive vacuoles, focal lymphocytic infiltration j0305257 Thyroid hyperplasia thyr-hyperpl-ma j0305257 Thyroid hyperplasia Basedow 40x 1Follicles depleted of colloid 2Lymphocytic infiltrate Æ Papillary formations 1 1 2 j0305257 Basedow 100x 04 Thyroid hyperplasia 1. Follicles depleted of colloid 2. Lymphocytic infiltrate Æ Papillary formations 1 1 2 j0305257 Nontoxic goitre û Iodine defficiency, goitrogenes etc. → impaired synthesis of thyroid hormones → activation of hypothalamus-pituitary-thyroidal axis - ↑TSH û û Irregular activation, hyperplastic phase, colloid involution, reactive and regressive changes û û Nodular transformation – multinodular goitre û û Mostly euthyroid or low-level of hypothyroidism j0305257 Multinodular goitre û Gross: ð irregular nodules, granular, yellow-brown (colloid goitre) ð common regressive changes – haemorrhage, cysts, fibrosis, calcification ð û Micro: ð dilated follicles filled with colloid, sparse resorptive vacuoles, flat epithelial cells j0305257 thyr-multinod-ma Multinodular goitre copy j0305257 Multinodular goitre struma 20x 1Follicles Æ Fibrous septa 1 1 1 j0305257 Thyroid tumors û Adenomas with variable structure ð follicular, oncocytic, etc. û Carcinomas ð papillary, follicular, medullary – parafollicular C-cells, anaplastic ð û Malignant lymphomas, secondary tu, etc. j0305257 Follicular adenoma û Mostly solitary û Encapsulated û Pressure atrophy of adjacent parenchyma û Diff. dg. x follicular carcinoma ð similar histologic structure, transcapsular invasion into surrounding thyroid tissue and/or angioinvasion necessary for ca diagnosis û Diagnosis possible only with complete biopsy û Cytology – well differentiated follicular neoplasia j0305257 Follicular adenoma FolikAd-20HE 1Thyroid parenchyma with follicles 2Adenoma ÆFibrotic capsule (adenoma demarcation) 1 1 2 j0305257 Follicular adenoma FolikAd-100HE Æ microfollicular adenoma j0305257 Papillary adenocarcinoma û Most common thyroid malignancy û F 25-50 yrs, M less common, possible in children, adolescent û ↑ incidence (better diagnostics) û Solitary / multifocal û Subtypes according histological structure ð papillary, follicular, diffuse sclerosing, etc. û Diagnosis based on cytologic morphology j0305257 Papillary adenocarcinoma û Gross: ð pale focus ð û Micro: ð ground-glass nuclei • clear nuclei, grooved nuclei, excentric nucleolus („Orphan Annie“), nuclear superposition ð papillary formations with disp. microcalcification j0305257 Papillary adenocarcinoma û Microcarcinoma ð incidental finding, < 1 cm, very good prognosis ð û Worse prognosis in males, older people, ca with extrathyroidal extension û û Metastases into regional LN, lungs û û j0305257 Papillary adenocarcinoma thyr-papca-ma j0305257 Papillary adenocarcinoma papilární ca ŠŽ 20x 1 fibrotic capsule 2normal thyroid parenchyma 3adenocarcinoma Æpapillary formations 1 1 2 3 j0305257 Papillary adenocarcinoma papilární ca ŠŽ 100x Æpsammoma body è papillary formation 1 j0305257 Papillary adenocarcinoma papilární ca ŠŽ 400x Æground-glass nuclei j0305257 Pathology of adrenals û Adrenal medulla pathology ð Hyperplasia ( MEN sy) ðTumors • Neuroblastoma • Ganglioneuroma • Pheochromocytoma j0305257 Pheochromocytoma û Chromaffin cells of adrenal medulla (paraganglioma), extraadrenal site possible û Catecholamines synthesis û Hypertension (incl. paroxysmal), tachycardia, sweating, tremor, headache û Risk of brain haemorrhage û More common 4.-5. decade, possible in children û 90% benign behaviour j0305257 Pheochromocytoma û Gross: ð demarcated paler lesion of variable size (g-kg), possible regressive changes (haemorrhage, necrosis) ð ûMicro: ð fine capillarized stroma ð trabeculae, solid alveoli ð large cells, granulated cytoplasm, neurosecretory granules ð nuclear atypias are not a sign of malignancy ð û Definitive diagnosis of malignancy based exclusively on finding of metastases j0305257 Pheochromocytoma feochromocytom 200x 1 solid alveoli Æcapillarized stroma 1 1 1 j0305257 Pheochromocytoma feochromocytom 400x Æ large cells with granulated cytoplasm