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Lec # 16 pathology 30/4/2014 Pancreas The first we are going to talk about is the congenital anomalies : Agenesis : absence of the pancreas ,which is a part of multiple congenital anomalies(associated with additional severe malformations ) ,the pt will be a newborn ,has multiple defects ,one of them is absence of the pancreas (not compatible with life). Pancreas divisum: is the most common clinically significant congenital pancreatic anomaly ,with an incidence of (3-4)%.Affect mainly the pancreatic duct ….which is very short and small ,drains only the head of pancreas (body +tail of pancreas are not reached by the main duct),The normal anatomy of the pancreas ,that we have the main duct and accessory ducts ,so in this problem the accessory duct will be function and make drainage to the majority of secretions and because they are narrow and small we might end with accumulation of the pancreatic enzymes in these ducts …cuzing inflammation…..chronic pancreatitis . Annular pancreas: again it is also a congenital anomalies ,the anatomy of the pancreas is abnormal ,it will form a ring around the duodenum the normal anatomy when the end of the pancreas makes like kissing structure with the duodenum ,finishing at the wall of duodenum annular :means ring…..surrounding the whole duodenum .this may be causing a problem in duodenum ,like obstruction ,so passing any material through the duodenum is controlled by the pancreas ,so any problem in the pancreas …….might ending with obstruction the duodenum passage (intestinal obstruction ))ectopic pancreas: abnormal site, pancreatic tissues are outside the pancreas , the pancreas is normal ,but we have extre-pancreatic tissues ;the most common sites for these tissues are :in the stomach, small intestine (especially the duodenum))the problem is ,we have pancreatic tissues in these sites ….pancreatic tissue secretes enzymes in abnormal sites.Normally ,these enzymes go through the duct to the gastric juice .but in this case ,these enzymes go to the other normal structures …………… so, the pts will have gastritis,(inflammation of the gastric tissues),duodenitis .In the ileum ,which is the last part of the last part of the small bowel ,we can see the ectopic pancreatic tissues which are called meckel diverticulum ,((the intestine has diverticulum + ectopic pancreatic tissues))The pt has :- inflammation - Recurrent pain in that site Pancreatitis : *which is an inflammation of the pancreas ,that is a very imp topic *we have two types: Acute pancreatitis Chronic pancreatitis *those both types are time-wise - acute pancreatitis: comes sharply ,rapid onset ,sever signs and symptoms,then resolve. -chronic pancreatitis: progressive ,longer time ,milder symptoms.Also we have another important feature in the pancreas…..which is the reversibility .Again the acute form :sometimes comes +stay longer period of time Chronic form : mild in undetectable exacerbation of symptoms(symptoms comes sharply then go mild). *the main imp cut between acute +chronic >>>is the irreversibility . *when the structure of the pancreas is return to the normal structure and function ..this is only acute ,when we have destruction ,loss of function +fibrosis …this is a chronic form. Pancreatitis is very common disease in the pancreas The most common cause in the west is the : alcohol drinking The 2nd most common cause is the billiary diseases (especially ;billiary stones),gallbladder stones can move and obstruct the canal …making obstruction in the pancreatic juice and stay within it making inflammation.Severity of the acute pancreatitis is variable ,can range from very mild to very sever to the life threatening ,can kill the pt sometimes ,the acute pancreatitis is a bad disease ,not easy ,it is a significant disease so under the microscope ,it can range from mild edema and focal fat necrosis …to a sever disease that kills the pt mainly through hemorrhage and shock .Causes of the acute pancreatitis :MetabolicMechanicalInfectionsVascularHereditary Idiopathic Metabolic causation :Alcohol is the most common cause In the pancreas ,it is important to know how the alcohol cause the pancreatitis ,what is the pathophysiology??-we have multiple theories and experiments ,each one has a prove, but in general we have multifactorial causes of the disease Mechanism of action of the alcohol:*alcohol is known to increase the conc of the pancreatic juice (concretions )-normally the pancreatic juice is fluid ,but the alcohol will dry this juice ..so it becomes more solid ,and their movement will be more difficult ..so the probability of inflammation will be higher *decrease the blood flow to the pancreas ..it makes a relative ischemia ,so any minor injury will be significant cause the blood cannot establish to correct the injury *free radicals …stimulates the inflammation *stimulating the enzymes (pancreatic enzymes) …pancreatic enzymes normally …will be inactive until reaching their sites ,they start their function and becoming active.-these enzymes are proteases ,like scissors ;they cut +destroy .-the alcohol ,activates these enzymes early before reaching the normal sites /locations, so it causes auto digestion ,destroying the pancreatic cells*those are the 4-main pathways for alcohol pancreatitis :Increase the concentration of pancreatic juice /concretions.Decrease the blood flow Free radicals Activate the enzymes early Less important causes metabolic ones :2-hypertriglyceride: not hypercholesttolemia ,if we have the TG that go beyond than 1000 then we will end with acute pancreatitis -normal # of TG is (150-170)…going beyond 1000 TG activate the lipase enzyme (this enzyme is founding in the pancreas ),it will metabolize the fats . so activates the lipase more than the normal ,the lipase makes destruction to the fats in the pancreas ..causing inflammation+ free fatty acids also give the free radicals causing inflammation .*sever increasing in the TG ..causing activating the pancreatic lipase enzyme more than normal …generating free radicals 3-hypercalcemia: Increasing the concentration of ca++ ,it activates the trypsinogen enzyme ..it destroys the proteins So hypercalcemia activates the trypsinogen + blocks enzymes secretions (they will stay inside pancreas ….causing the damage))So always we have activation the enzymes 4-drugs, we have a special drugs that have side effects …make pancreatitis *most famous one is the thaizid drug, diuretic drug which is used in hypertension pts .thaizid drug makes hypercacemia + hyperlipedemia ….pancreatitis *sulfonamides: they are antibiotics ,one of the side effect is the pancreatitis ,but this one is different …this is because of the hypersensitivity. Mechanical causes of acute pancreatitis: Stones: They obstruct the pancreatic duct ,so no more passage to the pancreatic juice and accumulation inside the ducts ….causing inflammation in the pancreas ,5 % of stones obstruct the common bile duct and cause pancreatitis . Trauma: Any kind of trauma like motor accidents .surgery So the trauma that hits the pancreas will cause pancreatitis Trauma in both ways :1)sharp ..like knife 2)blunt ..direct blow, like ,motor accidents .Trauma is the most common cause of pancreatitis in children. Tumors : Physical damage ,make obstruction multifactorial but mainly physical .Pancreatic tumor itself …makes pancreatitis Any tumor in the pancreas ..makes obstruction …pancreatitis …like billiary/duodenal / stomach tumors . Divisum : Short duct ,making at the end obstruction …physical damage …inflammation.In all cases ..the obstruction makes :- interstitial edema(makes relative ischemia ,then we will end with necrosis) - necrosis to pancreatic cells Infectious causes: Mumps virus: inflammation of the parotid glands It is action in systemic ways ,most important two organ that can be affected by this virus are : - testis - pancreas Testis: causing infertility in males Pancreas: pancreatitis (in both adult +children) Mycoplasma pneumonia : bacteria Makes atypical pneumonia (non-productive cough ;dry cough, no leukocytosis)It can go to systemic way …causing pancreatitis . Vascular causes: Shock: pt with shock …whatever kind of cause ;carcinogenic or septicemia …ischemia …pancreatitis . Thrombosis: arteries of pancreas with thrombosis ….necrosis…pancreatitis Vasculitis: inflammation in the arteries of pancreas …..necrosis…pancreatitis Hereditary causes: It is documented ,there are some people have recurrent episodes of pancreatitis without known cause of any one of the previous causation …so usually those person have abnormal genes that encode trypsin.So the trypsin gene is mutated …abnormal Note: any protein enzyme must have antagonist to stop its function after finishing its work .The mutated /abnormal trypsin will be resistant to the cleavage or proteolysis …so its action will be dominant ,it works more than what we want …causing inflammation to the pancreas (cause it makes auto-digestion to the pancreatic cells). Idiopathic causation: There is no unknown cause to the pancreas 10-20 % ..with unknown cause. Patho-biology: -different range of severity (variable)-main pathology in the ducts or in the acini (the place where the enzyme comes out )-alcohol makes :concretions +increase the pressure inside the ducts+ also affects the cells that synthesize the pancreatic enzymes. -1-microvascular leakage causing edema -2- injured acinar cells release lysosyme and pancreatic enzymes outside (auto-digestion) -3- necrosis of fat by lipases -4- an acute inflammatory reaction -5- proteolytic destruction of pancreatic parynchyma -6-destruction of blood vessels with hemorrhage . Morphology undermicroscope: Ranging from mild …..to sever We have two important features must be seen under microscope: Inflammatory cells: mainly neutrophiles in the acute pancreatitis form Fat necrosis : resulted from lipase enzyme *so any minor trauma ,will cause the lipase enzyme to act to digest the fats (normal fats structures in the pancreas ),so always we must see fat necrosis in the pancreatitis. *the degree of severity of necrosis + inflammation is different from one case to another .In the milder form : - we have interstitial edema +focal necrosis in the pancreatic substance + peri-pancreatic fat. In the sever form :- there is a wide area of necrotizing pancreatitis + hemorrhage ,fat necrosis that can reach the omentum (mesentry) or subcutaneous fat (lipase ..can go outside pancreas and digest the fat outside the pancreas …causing fat necrosis in the omentum or subcutaneous fat necrosis )Hemorrhage :is important one , it is the killing one .we have enzyme is called elastase enzyme ,it destroys the blood vessels and the pt will have hemorrhage . *we have on the right side a gross picture ,we can see on the upper left side of it a hemorrhage (severe one).in addition to the white –yellow fat.*microscopic picture: - on the right side of it we have fat necrosis (fat cells ..disturbed ,segmented to small pieces ,this is the fat necrosis ,not regular in shape). - in the middle we have inflammatory cells - normally ,we should see ducts + acini ..arranged perfectly ,but in this picture we cannot recognize a well-defined structure ,so all are filled with inflammatory cells. Clinical features: Pain in the pancreatitis is ver very sever same as the scale of pain in the billiary disease ((pain is intense and refer to the back)) *remember: billiary pain :epigastric pain and on the right side below the liver. Jaundice in case of having stone obstruction (billiary symptom + pancreatitis)) Leukocytosis Diagnosis the elevation serum amylase and lipase If they detected in the serum ,this means that they are go outside pancreas ,causing inflammation +destruction . Amylase has a problem ,it found in other structures than pancreas such as parotid gland .Lipase only found in the pancreas ,elevated serum lipase ..this means we have a pancreatitis. Hypocalemia : because of fat necrosis will bring with it ca++ causing hypocalcemia ((sabonification :fat with ca++)) Complications: Ranges from mild to a deadly disease .pancreatitis sometimes it kills the pt Trypsin is a proteolytic enzyme in the pancreas ,if it goes outside ,causes sever damage .it acts on the blood ,causing intense activating the clotting factors …making intense disseminated intravascular coagulation …microthrombiat the whole blood ,after that the body will respond to this situation by activating the anticoagulation factors…removing the thrombi…causing a bleeding + capillary Abs So those pts ..we give them blood transfusion or with clotting factors supplementation .-1- So pancreatitis causes DIC :disseminated intravascular coagulation . -2-if the trypsin reaches the lung ,it makes acute lung injury (diffuse alveolar damageon both sides)..this is due to dissemination of the trypsin outside the pancreas. -3- diffuse fat necrosis :the lipase that goes outside will make fat necrosis wherever the fat is present ,most famous sites in the mesentry (omentum)and in the more severe cases …it reaches to the subcutaneous fats (so we have severe pain +damage +hemorrhage under the skin).-4-shock:again ,it is one of the deadly complication ,it kills the pt .shock is the result of the interstitial edema .Pancreas is a retroperitoneal structure so the edema that is result from pancreas ,it can pulls the fluid from the blood itself due to inflammation in huge amount ..leading to shock .Shock can results from interstitial edema or third spacing (edema in the interstitial not in the cells or in the blood)…so the end result will be hypovolemia ,it kills the pt..cuz we don’t have effective amount of the blood.Shock can be converted to septic shock(bacteria comes from the small bowel and enter the blood causing septicemia ).-5-infection: usually ,it is a gram (-ve),from the gut causing local infection in the pancreas itself .not like septicemia (systemic)-6-pancreatic cysts…as a result of destruction with no complete repair in the pancreas ,so the end result will be a cyst that accumulates with fluid ,can be ruptured and makes again pancreatitis. Chronic pancreatitis: Loss of reversibility Permanent destruction of the pancreas with no repair It is a long standing inflammation +fibrosis + destruction of the exocrine pancreas. In the late stage ,the endocrine parynchyma destructed and lost The chronic pancreatitis can result from acute pancreatitis ,if the cause is persistent .like chronic alcohol abuse ,recurrent gallbladder stones ,tumors ,or hereditary causes . Distinguished from acute pancreatitis by its irreversibility of the function..loss of function.Most commonly the chronic pancreatitis occur in the middle age men. 40 % we don’t have identifiable cause. Patho-biology: Most famous one is the alcohol ,causing direct damage to the cells (we talked previously about the mechanism of alcohol in causing pancreatitis)Morphology: Is different from the acute :as we said in the acute pancreatitis ,we have two important morphology:1)inflammation 2)fat necrosis In chronic pancreatitis :Extensive fibrosis Different anatomy ..structure of the pancreas Dilatation of duct due to fibrosis will pull the duct outward Destruction to the acini ..because of fibrosis enlarge inrelation to the acini. Chronic inflammatory cells lefttopClinical pictures: *symptoms milder ,sometimes the pt asymptomatic The pt present with jaundice or vague indigestion (difficulty in digestion)Persistent or recurrent abdominal and back pain but milder than acute It may be entirely silent until pancreatic insufficiency +DM+malabsorption develop Attack can be precipitated by alcohol abuse +overeating +recurrent stones. Chronic pancreatitis not life threatening ,mortality occur at the end with ending of the complications.(with DM ,total failure of the pancreas ..at that time they might die from these complications).Pancreatic tumors: Tumors of the pancreas ,they are many types ,but we will talk about 3 major types:Cystic neoplasm: Tumors that have growth in the form of cysts ,they are not solid ,we have spaces in this tumor Constitutes less than 5 % of all pancreatic cancer (few percentage)They range from benign…to malignant tumprs. Cystic neoplasm: - serous cystadenoma - mucinous cystic neoplasmSerous cystadenoma: Serous from serum: clear part of the blood So this tumor will produce a serous fluid It is a cyst type ..so if we puncture it it will give a clear fluid It a totally benign tumor doesn’t transform to malignant one This cyst contains numerous small spaces ((proliferating cells that make small spaces ..at the end will form a big cyst))Content: clear serous fluid. This one is present in old-age group ,may cause symptoms like pancreatitis,but it doesn’t kills by itself . In this picture :gross section ,we have a multiple small spaces +under the microscope it is the same ,also we have small multiples spaces ,their epithelium is cuboidal epithelium. Mucinous cystic neoplasm: It is worser than the serous type Arises in women Remember: it looks like ovarian tumors ,so more common in women Found in the body and the tail of the pancreas ,the problem with these sites that any disesese stars their ..it will be silent,if the tumor reaches the duct it will start give the symptoms like pancreatitis .Multiple cysts with different morphology (lined by columnar epithelium and is associated with a very cellular stroma …opposite to the serous tumor; have no cellular stroma and they secrete the mucous. As we said the serous is totally benign , but the mucous is not , can start is brnign and continue to malignant. How to distinguish between the benign and the maliganant form of musinous type of tumor ??*if we have cells that look like each other + small nucleus + no atypia…benign *if we have atypia + no invasion….borderline mucinous neoplasm *atypia + invasion the tissue …..malignant neoplasm ((mucinous cyst adenocacinoma)) Benign mucinousBorderline mucinousMalignant mucinousAtypia -ve+ve +ve invasion-ve-ve+ve . Pancreatic carcinomas: The bulk of pancreatic tumors are represented by the pancreatic carcinoma It is the worst type of the pancreatic tumors It is the 4th cancer related cause of death in the US .Lung-breast-colon-pancreatic cancer They are rare ,but they are killers The worst type of human cancer ..highest mortality rate , doesn’t respond to any kind of treatement (if the pt reach to 6 month survival rate ..he is so lucky)5-survial rate < 5 % Old –age Arise in the head of pancreas…makes symptoms early but still bad Pathobiology: Accumulation of genetic mutations: they are progressive ,starting as few mutation making growth ,as we have more accumulation of tumor cells …we have more invasionBegins as small non-invasive lesions, called Pancreatic intraepithelial neoplasia “PanIN” in the small ducts to invasive onesRisk factors: smoking, chronic pancreatitis, diabetes Genetic mutations : K-ras mutations occur at early stages (one of the oncogenes that occur early))K-RAS mutations …we will have pancreatic intraepithelial neoplasia (only atypia without invasion)Invasion will start when we have a mutation to the p53 gene (most important gene to stop the cancer growth ..called also the big guard))Also mutations to the : SMAD4 + BRACA 2 occur in the late stages Morphology: Solid tumors + composed of glands ((arranged haphazardly)) + compressed +atypical Glands….secretes mucin Cells are atypical (pleomorphisim, highly mitosis , high N/C ratio,, dark nucleus))Glands are highly invasive into the nerves ,fat ,adjacent organs.Because the glands invades the nerves …they will destroy them ..will cause a very severe pain in the pt….so we will give them a local anesthesia in order to reduce this pain This cancer doesn’t respond to any kind of treatment The stroma around the cancer cells exhibits desmoplasia and lymphocyte Desmoplasia: composed of fibroblasts , they are not neoplasm but they are GF ,promotes the growth of cancer .Stroma normally ,very regular + arranged Dismoplasia: inflammation +lymphocytes +activation + shiny appearance Stroma something bad …cuz it promotes the growth of cancer *gross pict: we see a mass ,we can take CT/ultrasound radiograph ..to see cancer more clearly *under microscope: atypical glands +desmoplasia Clinical features: Remains silent until infiltrates other structuresPain is the main symptomObstructive jaundice can occurWeight loss, fatigue, anorexia develop with advancing diseaseOnly 20% of tumors are resectable …but 80 % surgery cannot do anything (treatement is ineffective). Done by: jumana alzoubi ................
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