Pathology_Robbins

Pathology_Robbins. MORPHOLOGYHCC may appear grossly as (1) a unifocal (usually large) mass ( Fig.16.37 );(2) multifocal,widely distributed nodules of variable size; or (3) a diffusely infiltrative cancer, permeatingwidelyandsometimesinvolvingtheentireliver.SometimesHCCsarisewithindysplasticnodules( Fig.16.37 ),eventuallyovergrowingtheseprecursorlesions.Intrahepaticmetastasesbyeithervascularinvasionordirectextensionbecomemorelikelyoncetumorsreach3cminsize.Thesemetastasesareusuallysmall,satellitetumornodulesaroundalargerprimarymass.Vascularinvasionisalsothemostlikelyrouteforextrahepaticmetastasis,especiallybythehepaticvenoussystem,usuallyonlyinadvancedcases.Occasionally,long,snakelikemassesoftumorinvadetheportalvein(causingportalhypertension)orinferiorvenacava;inthelatterinstance,thetumormayextendallthewayupintotherightventricle.Lymphnodemetastasesarelesscommon.


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Pathology_Robbins. HCCsrangefromwelldifferentiatedtohighlyanaplasticlesions.Well-differentiatedHCCsarecomposedofcellsthatlooklikenormalhepatocytesandgrowasthicktrabeculae(recapitulatinglivercellplates)orinpseudoglandularpatternsthatrecapitulatepoorlyformed,ectaticbilecanaliculi(see Fig.16.37 The clinical manifestations of HCC are varied and in Western populations are often masked by symptoms related to underlying cirrhosis or chronic hepatitis. In areas of high incidence, such as tropical Africa where aflatoxin exposure is common, patients usually have no clinical history of liver disease (although cirrhosis may be detected at autopsy). In both populations, most patients have ill-defined upper-abdominal pain, malaise, fatigue, weight loss, and sometimes awareness of an abdominal mass or abdominal fullness. Jaundice, fever, and gastrointestinal or esophageal variceal bleeding are inconstant findings. http://ebooksmedicine.net


Pathology_Robbins

Pathology_Robbins. http://ebooksmedicine.net Fig. 16.37 Hepatocellularcarcinoma.(A)Liverremovedatautopsyshowingaunifocal,massiveneoplasmreplacingmostoftherighthepaticlobeinanoncirrhoticliver.(B)Malignanthepatocytesgrowingindistortedversionsofnormalarchitecture:largepseudoacinarspaces,essentiallymalformed,dilatedbilecanaliculi,andthickenedhepatocytetrabeculae. Laboratory studies may provide clues but are rarely conclusive. Elevated serum levels of α-fetoprotein are found in 50% of individuals with advanced HCC, but this is neither a sensitive nor specific marker for premalignant or early well-differentiated cancers. Better tests for detection of small tumors are imaging studies, such as ultrasonography, computed tomography, and magnetic resonance imaging. Increasing arterialization during the development and progression of HCC can be identified by imaging and is so characteristic that its detection can be diagnostic, precluding the need for tissue biopsy.


Pathology_Robbins

Pathology_Robbins. The natural history of HCC involves the progressive enlargement of the primary mass until it disturbs hepatic function or metastasizes, most commonly to the lungs. Death usually occurs from (1) cachexia, (2) gastrointestinal or esophageal variceal bleeding, (3) liver failure with hepatic coma, or rarely (4) rupture of the tumor with fatal hemorrhage. The 5-year survival of large tumors is dismal, and the majority of patients die within 2 years of diagnosis.


Pathology_Robbins

Pathology_Robbins. With implementation of screening procedures and advances in imaging, the detection of HCCs less than 2 cm in diameter has increased in countries where such facilities are available. These small tumors can be removed surgically or ablated (e.g., through embolization, microwave radiation, or freezing) with good outcomes. If relatively small HCCs arise in the setting of advanced stage (cirrhotic) chronic liver disease, liver transplantation is a better option and may be curative. Radiofrequency ablation and chemoembolization are used for local control of unresectable tumors. The kinase inhibitor sorafenib can prolong the life of individuals with advanced-stage HCC.


Pathology_Robbins

Pathology_Robbins. Cholangiocarcinoma (CCA), the second most common primary malignant tumor of the liver after HCC, arises from intrahepatic and extrahepatic bile ducts. It accounts for 3% of gastrointestinal cancers in the United States, where there are approximately 2000 to 3000 new cases each year. However, in some regions of southeast Asia such as northeastern Thailand, Laos, and Cambodia where infestation with liver flukes is endemic, cholangiocarcinoma is much more common, occurring at rates 30 to 40 times higher than in areas of Asia without liver fluke infestation.


Pathology_Robbins

Pathology_Robbins. All risk factors for cholangiocarcinoma cause chronic inflammation and cholestasis, which presumably promote occurrence of somatic mutations or epigenetic alterations in cholangiocytes. The risk factors include infestation by liver flukes (particularly Opisthorchis and Clonorchis species), chronic inflammatory disease of the large bile ducts (such as primary sclerosing cholangitis), hepatolithiasis, and fibropolycystic liver disease. As with HCC, rates of cholangiocarcinoma also are elevated in patients with hepatitis B and C and NAFLD. lesionsatthetimeofdiagnosis,astheycauseobstructionofthe biliarytractearlyintheircourse.Mosttumorsappearasfirm, infiltrative,whileothersarepapillaryorpolypoid.Intrahepatic Fig.16.38A produceasinglemassivetumor. cinomas.Mostarewelltomoderatelydifferentiated,growingas Fig.16.38B ).Theytypicallyincitemarkeddesmoplasia.Lym metastases. http://ebooksmedicine.net


Pathology_Robbins

Pathology_Robbins. Fig.16.38A produceasinglemassivetumor. cinomas.Mostarewelltomoderatelydifferentiated,growingas Fig.16.38B ).Theytypicallyincitemarkeddesmoplasia.Lym metastases. http://ebooksmedicine.net Fig. 16.38 Cholangiocarcinoma.(A)MultifocalcholangiocarcinomainaliverfromapatientwithinfestationbytheliverflukeClonorchis sinensis (flukesnotvisible)(B)Invasivemalignantglandsinareactive,scleroticstroma.(A, Courtesy of Dr.Wilson M.S.Tsui, Caritas Medical Centre, Hong Kong.) Theliveristhemostcommonsiteofmetastaticcancersfromprimarytumorsofthecolon,lung,andbreast. Hepatocellular adenomas arebenigntumorsofhepatocytes.Mostcanbesubclassifiedonthebasisofmolecularchangeswithvaryingdegreesofmalignantpotential.Theyareassociatedwithuseoforalcontraceptivesandandrogens. Thetwomaintypesofmalignanttumorsarehepatocellular carcinomas and cholangiocarcinomas;HCCsaremuchmorecommon. HCCisacommontumorinregionsofAsiaandAfrica,anditsincidenceisincreasingintheUnitedStates.


Pathology_Robbins


Pathology_Robbins

Pathology_Robbins. Cholangiocarcinomaisatumorofintrahepaticorextrahepaticbileductsthatisrelativelycommoninareaswhereliverflukes,suchasOpisthorchis andClonorchis species,areendemic. Gallstones afflict 10% to 20% of adults residing in Western countries in the Northern Hemisphere, 20% to 40% in Latin American countries, and only 3% to 4% in Asian countries. In the United States, about 1 million new cases of gallstones are diagnosed annually, and two-thirds of individuals so affected undergo surgery, resulting in the removal of as much as 25 to 50 million tons of stones per year! There are two main types of gallstones: cholesterol stones, containing crystalline cholesterol monohydrate (80% of stones in Western countries), and pigment stones, made of bilirubin calcium salts.


Pathology_Robbins

Pathology_Robbins. Bile formation is the only significant pathway for elimination of excess cholesterol from the body, either as free cholesterol or as bile salts. Cholesterol is rendered water-soluble by aggregation with bile salts and lecithins. When cholesterol concentrations exceed the solubilizing capacity of bile (supersaturation), cholesterol can no longer remain dispersed and crystallizes out of solution. Cholesterol gallstone formation is enhanced by hypomobility of the gallbladder (stasis), which promotes nucleation, and by mucus hypersecretion, with consequent trapping of the crystals, thereby enhancing their aggregation into stones. Pigment stones form when the bile contains a high concentration of unconjugated bilirubin in the biliary tree, as may occur in patients with chronic extravascular red cell hemolysis or with certain infections of the biliary tract, such as liver flukes. The precipitates are primarily insoluble calcium bilirubinate salts.


Pathology_Robbins

Pathology_Robbins. The major risk factors for gallstones are listed in Table 16.6 . In up to 80% of individuals with gallstones, the only identifiable risk factors are age and gender. Some elaboration on these risk factors follows: • Age and gender. The prevalence of gallstones increases throughout life. In the United States, less than 5% to 6% of the population younger than 40 years of age has stones, in contrast with 25% to 30% of those older than http://ebooksmedicine.net Table 16.6 Risk Factors for Gallstones Demography:NorthernEuropeans,NorthandSouthAmericans,Native Americans,MexicanAmericansAdvancingageFemalesexhormones Demography:AsianmorethanWestern,ruralmorethanurbanChronichemolysis(e.g.,sicklecellanemia,hereditaryspherocytosis)BiliaryinfectionGastrointestinaldisorders:ilealdisease(e.g.,Crohndisease),ileal resectionorbypass,cysticfibrosiswithpancreaticinsufficiency 80 years of age. The prevalence in women of all ages is about twice as high as in men.


Pathology_Robbins

Pathology_Robbins. Ethnic and geographic. Cholesterol gallstone prevalence approaches 50% to 75% in certain Native American populations (Pima, Hopi, and Navajo), whereas pigment stones are rare. The high prevalence in these populations seems to be related to biliary cholesterol hypersecretion. Heredity. In addition to ethnicity, a positive family history imparts increased risk, as do a variety of inborn errors of metabolism, such as those associated with impaired bile salt synthesis and secretion. Environment. Estrogens increase hepatic cholesterol uptake and synthesis, leading to excess biliary secretion of cholesterol. These effects explain the increased risk for gallstone disease with oral contraceptive use and with pregnancy. Obesity, rapid weight loss, and treatment with the hypocholesterolemic agent clofibrate also are strongly associated with increased biliary cholesterol secretion and risk for gallstone disease.


Pathology_Robbins

Pathology_Robbins. Acquired disorders. Any condition in which gallbladder motility is reduced predisposes to gallstones, such as pregnancy, rapid weight loss, and spinal cord injury. In most cases, however, gallbladder hypomotility is present without obvious cause. MORPHOLOGYCholesterol stones ariseexclusivelyinthegallbladderandconsistof50%to100%cholesterol.Purecholesterolstonesarepaleyellow;increasingproportionsofcalciumcarbonate,phos phates,andbilirubinimpartgray-whitetoblackdiscoloration(Fig. 16.39 ).Theyareovoidandfirm;theycanoccursingly,butmostoftenthereareseveral,withfacetedsurfacesresultingfromtheirapposition.Mostcholesterolstonesareradiolucent,althoughasmanyas20%maycontainsufficientcalciumcarbonatetoberadiopaque. Pigment stones mayariseanywhereinthebiliarytreeandareclassifiedintoblackandbrownstones.Ingeneral,blackpigmentstonesarefoundinsterilegallbladderbile,whilebrownstonesarefoundininfectedintrahepaticorextrahepaticducts.


Pathology_Robbins

Pathology_Robbins. Gallstones may be present for decades without causing any symptoms, and 70% to 80% of individuals with gallstones remain asymptomatic throughout life. In an unfortunate minority, however, the symptoms are striking. There is usually right upper-quadrant or epigastric pain, often excruciating, which may be constant or, less commonly, spasmodic. Such “biliary” pain is caused by gallbladder or biliary tree obstruction or by inflammation of the gallbladder itself. More severe complications include empyema, perforation, fistulas, inflammation of the biliary tree, obstructive cholestasis and pancreatitis. The larger the stone, the less likely it is to enter the cystic or common ducts to produce obstruction; thus, the very small stones, or “gravel,” are dangerous. Occasionally a large stone may erode directly into an adjacent loop of small bowel, generating intestinal obstruction


Pathology_Robbins

Pathology_Robbins. Fig. 16.40 Pigmentgallstones.Severalfacetedblackgallstonesarepresentinthisotherwiseunremarkablegallbladderfromapatientwithamechanicalmitralvalveprosthesis,leadingtochronicintravascularhemolysis. http://ebooksmedicine.net (gallstone ileus). Inflammation of the gallbladder may be acute, chronic, or acute superimposed on chronic, and almost always occurs in association with gallstones. In the United States, cholecystitis is one of the most common indications for abdominal surgery. Its epidemiologic distribution closely parallels that of gallstones.


Pathology_Robbins

Pathology_Robbins. Acute inflammation of a gallbladder that contains stones is termed acute calculous cholecystitis and is precipitated in 90% of cases by obstruction of the gallbladder neck or cystic duct. It is the most common major complication of gallstones and the most frequent indication for emergency cholecystectomy. Manifestations of obstruction may appear with remarkable suddenness and constitute a surgical emergency. In some cases, however, symptoms may be mild and resolve without intervention.


Pathology_Robbins

Pathology_Robbins. Acute calculous cholecystitis initially results from chemical irritation and inflammation of the gallbladder wall due to obstruction of bile outflow. Gallbladder injury in the setting of bile obstruction stems from several sources, including: phospholipases derived from the mucosa hydrolyze biliary lecithin to lysolecithin, which is toxic to the mucosa; the normally protective glycoprotein mucous layer is disrupted, exposing the mucosal epithelium to the detergent action of bile salts.; prostaglandins released within the wall of the distended gallbladder enhance mucosal and mural inflammation; and distention and increased intraluminal pressure may compromise blood flow to the mucosa. All of these effects occur in the absence of bacterial infection, which may be superimposed later. Between 5% and 12% of gallbladders removed for acute cholecystitis contain no gallstones. Most cases occur in seriously ill patients. Some of the most common predisposing insults are as follows:


Pathology_Robbins

Pathology_Robbins. Between 5% and 12% of gallbladders removed for acute cholecystitis contain no gallstones. Most cases occur in seriously ill patients. Some of the most common predisposing insults are as follows: Severe trauma (e.g., from motor vehicle crashes) Other contributing factors include dehydration, gallbladder stasis and sludging, vascular compromise, and bacterial contamination.


Pathology_Robbins

Pathology_Robbins. Chronic cholecystitis may be the sequel to repeated bouts of acute cholecystitis, but in most instances it develops without any antecedent history of acute attacks. Like acute cholecystitis, it is almost always associated with gallstones. However, gallstones do not seem to be an essential part of the initiation of inflammation or the development of pain, because chronic acalculous cholecystitis causes symptoms and morphologic alterations similar to those seen in the calculous form. Rather, supersaturation of bile appears to predispose to both chronic inflammation and, in most instances, stone formation. Microorganisms, usually E. coli and enterococci, can be cultured from the bile in only about one-third of cases. Unlike acute calculous cholecystitis, obstruction of gallbladder outflow by stones is not requisite in chronic cholecystitis. Most gallbladders removed at elective surgery for gallstones show features of chronic cholecystitis, making it likely that biliary symptoms emerge


Pathology_Robbins

Pathology_Robbins. by stones is not requisite in chronic cholecystitis. Most gallbladders removed at elective surgery for gallstones show features of chronic cholecystitis, making it likely that biliary symptoms emerge after long-term coexistence of gallstones and low-grade inflammation.


Pathology_Robbins

Pathology_Robbins. Fig.16.41A ).Outpouchingsofmucosalepitheliumthroughthewallofthegallbladder(Rokitansky-Aschoffsinuses)maybequiteprominent(see Fig.16.41B Acute calculous cholecystitis presents with biliary pain that lasts for more than 6 hours. The pain is severe, usually steady, upper abdominal in location, and often radiates to the right shoulder. Fever, nausea, leukocytosis, and prostration are classic; the presence of conjugated hyperbilirubinemia suggests obstruction of the common bile duct. The right subcostal region is markedly tender and rigid as a result of spasm of the abdominal muscles; occasionally a http://ebooksmedicine.net Fig. 16.41 Chroniccholecystitis.(A)Thegallbladdermucosaisinfiltratedbychronicinflammatorycells.(B)ARokitansky-Aschoffsinuscontaininga fragmentedbilepigmentstone.


Pathology_Robbins

Pathology_Robbins. Fig. 16.41 Chroniccholecystitis.(A)Thegallbladdermucosaisinfiltratedbychronicinflammatorycells.(B)ARokitansky-Aschoffsinuscontaininga fragmentedbilepigmentstone. tender, distended gallbladder can be palpated. Mild attacks usually subside spontaneously over 1 to 10 days; however, recurrence is common. Approximately 25% of symptomatic patients are sufficiently ill to require surgical intervention. The diagnosis of acute cholecystitis usually is based on the detection of gallstones by ultrasonography, typically accompanied by evidence of a thickened gallbladder wall. Attention to this disorder is important because of the potential for the following serious complications: Bacterial superinfection leading to cholangitis or sepsis Gallbladder rupture leading to diffuse peritonitis Biliary enteric (cholecystenteric) fistula, with drainage of bile into adjacent organs, entry of air and bacteria into the biliary tree, and potentially gallstone-induced intestinal obstruction (ileus)


Pathology_Robbins

Pathology_Robbins. Aggravation of preexisting medical illness, with cardiac, pulmonary, renal, or liver decompensation Symptoms arising from acute acalculous cholecystitis usually are obscured by another serious medical or surgical condition, which sets the stage for the development of cholecystitis. The diagnosis therefore rests on a high index of suspicion. Chronic cholecystitis lacks the striking manifestations of the acute forms and is usually characterized by recurrent attacks of steady epigastric or right upper-quadrant pain. Nausea, vomiting, and intolerance for fatty foods are frequent accompaniments. Chronic cholecystitis is a pathologic diagnosis based on the examination of the resected gallbladder. Beyond signs and symptoms mentioned above, its principal importance may lie in the association of gallstones and chronic inflammation with carcinoma of the gallbladder (discussed next).


Pathology_Robbins

Pathology_Robbins. Carcinoma of the gallbladder is the most common malignancy of the extrahepatic biliary tract. It is slightly more common in women and occurs most frequently in the seventh decade of life. The incidence in the United States is 1 in 50,000. Only rarely is it discovered at a resectable stage, and the mean 5-year survival rate has remained unchanged at about 5% to 12% over the past many years. The most important risk factor associated with gallbladder carcinoma is gallstones (cholelithiasis), which are present in 95% of cases. Presumably, gallbladders containing stones or infectious agents develop cancer as a result of chronic inflammation, a known enabler of malignancy in several organs (Chapter 6). Carcinogenic derivatives of bile acids also are suspected to play a role. Primary sclerosing cholangitis is also a risk factor.


Pathology_Robbins

Pathology_Robbins. MORPHOLOGYCarcinomasofthegallbladdershowtwopatternsofgrowth:infiltrating andexophytic. Theinfiltratingpatternismorecommonandusuallyappearsasapoorlydefinedareaofdiffusewallthickeningandinduration.Theexophyticpatterngrowsintothelumenasanirregular,cauliflowermass,butatthesametimeinvadestheunderlyingwall( Fig.16.42 ).Mostcarcinomasofthegallbladderareadenocarcinomas.About5%aresquamouscellcarcinomasorhaveadenosquamousdifferentiation. Preoperative diagnosis of carcinoma of the gallbladder is the exception rather than the rule, occurring in fewer than 20% of patients. Presenting symptoms are insidious and typically indistinguishable from those associated with cholelithiasis: abdominal pain, jaundice, anorexia, nausea and vomiting. There is no satisfactory treatment of gall bladder cancer due to the advanced stage at the time of diagnosis. Only 10% are diagnosed at a stage that is early enough to attempt curative surgery.


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Pathology_Robbins. Acutecalculouscholecystitisisthemostcommonreasonforemergencycholecystectomy. Gallbladdercancerisalmostalwaysassociatedwithgallstones.Becauseoftheadvancedstageatdiagnosis,ithasaverypoorprognosis. Mechanisms of Liver Injury and Repair Gouw ASW, Clouston AD, Theise ND: Ductular reactions in human livers: diversity at the interface, Hepatology 54:2011, 1853. [A review of ductular reactions, the stem cell response of human livers in all liver diseases, that are related to mechanisms of regeneration, fibrogenesis, and neoplasia.] Kocabayoglu P, Friedman SL: Cellular basis of hepatic fibrosis and its role in inflammation and cancer, Front Biosci (Schol Ed) 5:217, 2013. [Interweaves what is known about hepatic stellate cells and other myofibroblastic cells of the liver with inflammatory, fibrosing, and neoplastic disease processes.] Acute, Chronic, and Acute-on-Chronic Liver Failure Bernal W, Wendon J: Acute liver failure, New Engl J Med 369:2525, 2013. [An excellent clinical review.]


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Pathology_Robbins. Acute, Chronic, and Acute-on-Chronic Liver Failure Bernal W, Wendon J: Acute liver failure, New Engl J Med 369:2525, 2013. [An excellent clinical review.] Berzigotti A, Seijo S, Reverter E, et al: Assessing portal hypertension in liver diseases, Expert Rev Gastroenterol Hepatol 7:141, 2013. [Evolving definitions and methodologies for evaluating portal hypertension.] Khungar V, Poordad F: Hepatic encephalopathy, Clin Liver Dis 16:301, 2012. [A good overview of the one of the most ominous sequelae of all forms of liver failure.] Quaglia A, Alves VA, Balabaud C, et al: Role of aetiology in the progression, regression, and parenchymal remodelling of liver disease: implications for liver biopsy interpretation, Histopathology 68:953, 2016. [A general review comparing and contrasting clinical and pathologic variants of advanced stages different acute and chronic liver diseases.].


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Pathology_Robbins. Yoon E, Babar A, Choudhary M, et al: Acetaminophen-induced hepatotoxicity: a comprehensive update, J Clin Transl Hepatol 4:131, 2016. Chung RT, Baumert TF: Curing chronic hepatitis C—the arc of medical triumph, New Engl J Med 370:1576, 2014. [An excellent perspective on why and how hepatitis C can be cured.] Trepo C, Chan HLY, Lok A: Hepatitis B infection, Lancet 384:2053, 2014. [A thorough look at the continually evolving nature of hepatitis B and our attempts to prevent and treat it.] Ward JW, Lok AS, Thomas DL: Report on a single-topic conference on “Chronic viral hepatitis—strategies to improve effectiveness of screening and treatment,” Hepatology 55:307, 2012. [An overview of all aspects of chronic viral hepatitis and the relationship of pathology to disease course and management.] Carey EJ, Ali AH, Lindor KD: Primary biliary cirrhosis, Lancet 386:1565, 2015. [A classic liver disease whose origins remain obscure—the latest in what is understood or hypothesized.]


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Pathology_Robbins. Carey EJ, Ali AH, Lindor KD: Primary biliary cirrhosis, Lancet 386:1565, 2015. [A classic liver disease whose origins remain obscure—the latest in what is understood or hypothesized.] Lazaridis KN, LaRusso NF: Primary sclerosing cholangitis, N Eng J Med 375:1161, 2016. [A comprehensive review of all aspects of this disease.] Manns MP, Lohse AW, Vergani D: Autoimmune hepatitis—update 2015, J Hepatol 62:S100, 2015. [A review of pathogenesis, diagnosis, and treatment approaches.] Crawford JM: Histologic findings in alcoholic liver disease, Clin Liver Dis 16:699, 2012. [A thorough look at the morphologic changes in alcoholic liver disease and the underlying mechanisms that produce them.] Kleiner DE: The pathology of drug-induced liver injury, Semin Liver Dis 29:364, 2009. Louvet A, Mathurin P: Alcoholic liver disease: mechanisms of injury and targeted treatment, Nat Rev Gastroenterol Hepatol 12:231, 2015. [A discussion of pathways of disease progression and possible interventions.]


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Pathology_Robbins. Hardy T, Oakley F, Anstee QM, et al: Nonalcoholic fatty liver disease: Pathogenesis and disease spectrum, Annu Rev Pathol 11:451, 2016. [A comprehensive discussion of NAFLD pathogenesis.] Pietrangelo A: Hereditary hemochromatosis: pathogenesis, diagnosis, and treatment, Gastroenterology 139:393, 2010. [A comprehensive review.] http://ebooksmedicine.net Rosencrantz R, Schilsky M: Wilson disease: pathogenesis and clinical considerations in diagnosis and treatment, Semin Liver Dis 31:245, 2011. [A still current review of basic and translational features of the disease.] Beuers U, Gershwin ME, Gish RG, et al: Changing nomenclature for PBC: From “cirrhosis” to “cholangitis”, Hepatology 62:1620, 2015. [A change in nomenclature by liver disease experts made in response to the needs of patients and their advocates.]


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Pathology_Robbins. Hirschfield GM, Heathcote EJ, Gershwin ME: Pathogenesis of cholestatic liver disease and therapeutic approaches, Gastroenterology 139:1481, 2010. [A thorough overview of the most common features of liver disease.] Paumgartner G: Biliary physiology and disease: reflections of a physician-scientist, Hepatology 51:1095, 2010. [How bench top work comes to exert an impact on clinical medicine, sometimes, slowly, over decades.] Bioulac-Sage P, Cubel G, Balabaud C: Revisiting the pathology of resected benign hepatocellular nodules using new immunohistochemical markers, Semin Liver Dis 31:91, 2011. [From the team largely responsible for the new molecular subclassifications of hepatocellular adenomas.] Bosman F, Carneiro F, Hruban R, editors: WHO Classification of Tumours of the Digestive System, ed 4, Geneva, Switzerland, 2010, WHO Press. [The current bible for tumors of the liver and biliary tree and the rest of the digestive tract.]


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Pathology_Robbins. Forner A, Llovet JM, Bruix J: Hepatocellular carcinoma, Lancet 379:1245, 2012. [Clinical, radiologic, pathologic, and oncologic perspectives all woven together.] Razumilava N, Gores GJ: Cholangiocarcinoma, Lancet 383:2168, 2014. [Update on pathogenesis and clinical features.] Shibata T, Aburatani H: Exploration of liver cancer genomes, Nat Rev Gastroenterol Hepatol 11:340, 2014. [A review hepatocellular carcinoma pathogenesis seen through the prism of analysis of cancer genomes.] http://ebooksmedicine.net studentconsult.com The pancreas is a transversely oriented retroperitoneal organ extending from the so-called “C loop” of the duodenum to the hilum of the spleen. Although the pancreas does not have well-defined anatomic subdivisions, adjacent vessels and ligaments serve to demarcate the organ into a head, body, and tail.


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Pathology_Robbins. The pancreas is really two organs packaged into one. The islets of Langerhans scattered in the pancreas serve critical endocrine functions, and the exocrine portion that makes up the bulk of this organ is a major source of enzymes that are essential for digestion. Diseases affecting the pancreas can be the source of significant morbidity and mortality. Unfortunately, the retroperitoneal location of the pancreas and the generally vague nature of signs and symptoms associated with its injury or with dysfunction of the exocrine portion allow many pancreatic diseases to progress undiagnosed for extended periods of time; thus, recognition of pancreatic disorders requires a high degree of suspicion.


Pathology_Robbins

Pathology_Robbins. The pancreas gets its name from the Greek pankreas, meaning “all flesh,” and is a complex lobulated organ. The endocrine portion constitutes only 1% to 2% of the pancreas and is composed of about 1 million cell clusters, the islets of Langerhans; these cells secrete insulin, glucagon, and somatostatin. The most significant disorders of the endocrine pancreas are diabetes mellitus and neoplasms; these are discussed in detail in Chapter 20 and are not discussed further here. The exocrine pancreas is composed of acinar cells and the ductules and ducts that convey their secretions to the duodenum. The acinar cells are responsible for the synthesis of digestive enzymes, which are mostly made as inactive pro-enzymes that are stored in zymogen granules. When The contributions of those who authored this chapter in previous editions of this book are gratefully acknowledged.


Pathology_Robbins

Pathology_Robbins. The contributions of those who authored this chapter in previous editions of this book are gratefully acknowledged. acinar cells are stimulated to secrete, the granules fuse with the apical plasma membrane and release their contents into the central acinar lumen. These secretions are transported to the duodenum through a series of anastomosing ducts. The epithelial cells lining the ducts also are active participants in pancreatic secretion: The cuboidal cells that line the smaller ductules secrete bicarbonate-rich fluid, while the columnar cells lining the larger ducts produce mucin. The epithelial cells of the ducts also express the cystic fibrosis transmembrane conductance regulator (CFTR); aberrant function of this membrane protein affects the biochemical content and viscosity of pancreatic secretions. CFTR has a fundamental role in the pathophysiology of pancreatic disease in individuals with cystic fibrosis (Chapter 7).


Pathology_Robbins

Pathology_Robbins. As discussed later, autodigestion of the pancreas (e.g., in pancreatitis) can be a catastrophic event. A number of “fail-safe” mechanisms have evolved to minimize the risk for occurrence of this phenomenon: A majority of pancreatic enzymes are synthesized as inactive pro-enzymes and sequestered in membrane-bound zymogen granules, as mentioned earlier. Activation of pro-enzymes requires conversion of trypsinogen to trypsin by duodenal enteropeptidase (also called enterokinase). Trypsin inhibitors (e.g., SPINK1, also known as pancreatic secretory trypsin inhibitor) also are secreted by acinar and ductal cells. Trypsin cleaves and inactivates itself, a negative feedback mechanism that normally puts a limit on local levels of activated trypsin. Acinar cells are remarkably resistant to the action of activated enzymes such as trypsin, chymotrypsin, and phospholipase A2.


Pathology_Robbins

Pathology_Robbins. Acinar cells are remarkably resistant to the action of activated enzymes such as trypsin, chymotrypsin, and phospholipase A2. Diseases of the exocrine pancreas include cystic fibrosis, congenital anomalies, acute and chronic pancreatitis, and neoplasms. Cystic fibrosis is discussed in detail in Chapter 7; the other pathologic processes are discussed in this chapter. http://ebooksmedicine.net Pancreatic development is a complex process involving fusion of dorsal and ventral primordia; subtle deviations in this process frequently give rise to congenital variations in pancreatic anatomy. While most of these do not cause clinical disease, variants (especially in ductal anatomy) can present challenges to the endoscopist and the surgeon. For example, failure to recognize idiosyncratic anatomy could result in inadvertent severing of a pancreatic duct during surgery, resulting in pancreatitis.


Pathology_Robbins

Pathology_Robbins. Very rarely, the pancreas may be totally absent, a condition usually (but not invariably) associated with additional severe malformations that are incompatible with life. Pancreatic duodenal homeobox 1 (PDX1) is a homeodomain transcription factor critical for normal pancreatic development, and germline mutations of this gene have been associated with pancreatic agenesis.


Pathology_Robbins

Pathology_Robbins. Pancreas divisum is the most common congenital anomaly of the pancreas, with an incidence of 3% to 10%. In most individuals, the main pancreatic duct (the duct of Wirsung) joins the common bile duct just proximal to the papilla of Vater, and the accessory pancreatic duct (the duct of Santorini) drains into the duodenum through a separate minor papilla. Pancreas divisum is caused by a failure of fusion of the fetal duct systems of the dorsal and ventral pancreatic primordia. As a result, the bulk of the pancreas (formed by the dorsal pancreatic primordium) drains into the duodenum through the small-caliber minor papilla. The duct of Wirsung in individuals with divisum drains only a small portion of the head of the gland through the papilla of Vater. More than 95% of individuals are asymptomatic. The remaining 5% develop acute or chronic pancreatitis, possibly related to inadequate drainage of pancreatic secretions through the minor papilla.


Pathology_Robbins

Pathology_Robbins. Annular pancreas is a relatively uncommon variant of pancreatic fusion in which a ring of pancreatic tissue completely encircles the duodenum. It can manifest with signs and symptoms of duodenal obstruction such as gastric distention and vomiting. Aberrantly situated, or ectopic, pancreatic tissue occurs in about 2% of the population; favored sites are the stomach and duodenum, followed by the jejunum, Meckel diverticulum, and ileum. These embryologic rests typically are small (ranging from millimeters to centimeters in diameter) and are located in the submucosa; they are composed of normal pancreatic acini with occasional islets. Though usually incidental and asymptomatic, ectopic pancreas may become inflamed, leading to pain, or—rarely—can cause mucosal bleeding. Approximately 2% of pancreatic neuroendocrine tumors (Chapter 20) arise in ectopic pancreatic tissue.


Pathology_Robbins

Pathology_Robbins. Congenital cysts result from anomalous development of the pancreatic ducts. In polycystic disease, the kidneys, liver, and pancreas may all contain cysts (Chapter 14). Congenital cysts generally are unilocular and range from microscopic to 5 cm in diameter. They are lined by either uniform cuboidal or flattened epithelium and are enclosed in a thin, fibrous capsule. These benign cysts contain clear serous fluid—an important point of distinction from pancreatic cystic neoplasms, which often are mucinous (discussed later). Inflammatory disorders of the pancreas are divided into acute and chronic forms. In acute pancreatitis, function can return to normal if the underlying cause of inflammation is removed. By contrast, chronic pancreatitis causes irreversible destruction of exocrine pancreas.


Pathology_Robbins

Pathology_Robbins. Acute pancreatitis is a reversible inflammatory disorder that varies in severity, from focal edema and fat necrosis to widespread hemorrhagic necrosis. This is a relatively common condition, with an annual incidence of 10 to 20 per 100,000 people in the Western world. The most common cause of acute pancreatitis in the United States is the impaction of gallstones within the common bile duct, impeding the flow of pancreatic enzymes through the ampulla of Vater (“gallstone pancreatitis”); this is closely followed by pancreatitis secondary to excessive alcohol intake. Overall, gallstones and alcoholism account for greater than 80% of acute pancreatitis cases, with the remaining caused by a multitude of factors ( Table 17.1 ). These include the following: Non–gallstone-related obstruction of the pancreatic ducts (e.g., due to pancreatic cancer or other periampullary neoplasms, pancreas divisum, biliary “sludge,” or parasites, particularly Ascaris lumbricoides and Clonorchis sinensis)


Pathology_Robbins

Pathology_Robbins. Medications including anti-convulsants, cancer chemotherapeutic agents, thiazide diuretics, estrogens, and more than 85 others in clinical use Infections with mumps virus or coxsackievirus, which can directly infect pancreatic exocrine cells Metabolic disorders, including hypertriglyceridemia, hyperparathyroidism, and other hypercalcemic states http://ebooksmedicine.net Table 17.1 Etiologic Factors in Acute Pancreatitis HyperlipoproteinemiaHypercalcemiaDrugs(e.g.,azathioprine) *MostcommoncausesintheUnitedStates. Ischemia due to vascular thrombosis, embolism, vasculitis, or shock Trauma, both blunt force and iatrogenic during surgery or endoscopy


Pathology_Robbins

Pathology_Robbins. Germline mutations involving genes encoding pancreatic enzymes or their inhibitors. For example, hereditary pancreatitis is a rare autosomal dominant disease with 80% penetrance that is characterized by recurrent attacks of severe pancreatitis, usually beginning in childhood. It is caused by mutations in the PRSS1 gene, which encodes trypsinogen, the proenzyme of pancreatic trypsin. The pathogenic mutations alter the site through which trypsin cleaves and inactivates itself, abrogating an important negative feedback mechanism. This defect leads not only to the hyperactivation of trypsin, but also to the hyperactivation of many other digestive enzymes that require trypsin cleavage for their activation. As a result of this unbridled protease activity, the pancreas is prone to autodigestion and injury. Loss-of-function mutations in genes that encode protease inhibitors such as SPINK1 are less commonly associated with hereditary pancreatitis.


Pathology_Robbins

Pathology_Robbins. Of note, 10% to 20% of cases of acute pancreatitis have no identifiable cause (idiopathic pancreatitis), although a growing body of evidence suggests that many may have an underlying genetic basis. For example, a subset of these so-called idiopathic pancreatitis patients has underlying germ line mutations of the CFTR gene with symptoms predominantly restricted to the pancreas (Chapter 7).


Pathology_Robbins

Pathology_Robbins. Acute pancreatitis appears to be caused by autodigestion of the pancreas by inappropriately activated pancreatic enzymes. As discussed earlier, once activated trypsin is capable of converting other zymogen forms of pancreatic enzymes to their active forms. Premature activation of trypsin within the substance of the pancreas can unleash these proenzymes (e.g., phospholipases and elastases), leading to tissue injury and inflammation. Trypsin also converts prekallikrein to its activated form, thus sparking the kinin system, and, by activation of factor XII (Hageman factor), also sets in motion the clotting and complement systems (Chapter 4). Three pathways can incite the initial enzyme activation that may lead to acute pancreatitis ( Fig. 17.1


Pathology_Robbins

Pathology_Robbins. Fig. 17.1 Pancreatic duct obstruction. Impaction of a gallstone or biliary sludge, or extrinsic compression of the ductal system by a mass blocks ductal flow, increases intraductal pressure, and allows accumulation of an enzyme-rich interstitial fluid. Since lipase is secreted in an active form, local fat necrosis may result. Injured tissues, periacinar myofibroblasts, and leukocytes then release pro-inflammatory cytokines that promote local inflammation and interstitial edema through a leaky microvasculature. Edema further compromises local blood flow, causing vascular insufficiency and ischemic injury to acinar cells. Primary acinar cell injury. This pathogenic mechanism comes into play in acute pancreatitis caused by ischemia, viral infections (e.g., mumps), drugs, and direct trauma to the pancreas.


Pathology_Robbins

Pathology_Robbins. Primary acinar cell injury. This pathogenic mechanism comes into play in acute pancreatitis caused by ischemia, viral infections (e.g., mumps), drugs, and direct trauma to the pancreas. Defective intracellular transport of proenzymes within acinar cells. In normal acinar cells, digestive enzymes intended for zymogen granules (and eventually extracellular release) and hydrolytic enzymes destined for lysosomes are transported in discrete pathways after synthesis in the endoplasmic reticulum. However, at least in some animal models of metabolic injury, pancreatic proenzymes and lysosomal hydrolases become packaged together. This results in proenzyme activation, lysosomal rupture (action of phospholipases), and local release of activated enzymes. The role of this mechanism in human acute pancreatitis is not clear.


Pathology_Robbins

Pathology_Robbins. Alcohol consumption may cause pancreatitis by several mechanisms. Alcohol transiently increases pancreatic exocrine secretion and contraction of the sphincter of Oddi (the muscle regulating the flow of pancreatic juice through papilla of Vater). Alcohol also has direct toxic effects on acinar cells, including induction of oxidative stress in acinar cells, which leads to membrane damage (discussed later). Finally, chronic alcohol ingestion results in the secretion of protein-rich pancreatic fluid, which leads to the deposition of inspissated protein plugs and obstruction of small pancreatic ducts. lar leakage causing edema, (2) necrosis of fat by lipases, (3) an acute inflammatory reaction, (4) proteolytic destruction of pancreatic parenchyma, and (5) destruction of blood vessels leading to interstitial hemorrhage. http://ebooksmedicine.net CAUSES: DUCT OBSTRUCTION ACINAR CELL INJURY DEFECTIVE INTRACELLULAR TRANSPORT MECHANISMS: LESIONS:


Pathology_Robbins

Pathology_Robbins. http://ebooksmedicine.net CAUSES: DUCT OBSTRUCTION ACINAR CELL INJURY DEFECTIVE INTRACELLULAR TRANSPORT MECHANISMS: LESIONS: Release of intracellular proenzymes and lysosomal hydrolases Activation of enzymes (intracellular or extracellular) (proteases) (lipase, phospholipase) Delivery of proenzymes to lysosomal compartment Intracellular activation of enzymes Fig.17.1 Proposedpathogenesisofacutepancreatitis. Inmildforms,thereisinterstitialedemaandfocalareasoffat necrosisinthepancreasandperipancreaticfat( Fig.17.2A ).Fat necrosis results from enzymatic destruction of fat cells; the releasedfattyacidscombinewithcalciumtoforminsolublesalts thatprecipitateinsitu. Inmoresevereforms,suchasacute necrotizing pancreatitis,thedamagealsoinvolvesacinarandductalcells,theislets ofLangerhans,andbloodvessels.Macroscopically,thepancreas exhibits red-blackhemorrhagic areasinterspersedwith foci of yellow-white,chalkyfat necrosis(


Pathology_Robbins

Pathology_Robbins. Fig.17.2B ).Fatnecrosisalso canoccurinextrapancreaticfat,includingtheomentumandbowel mesentery,andevenoutsidetheabdominalcavity(e.g.,insubcutaneousfat).Inmostcases,theperitoneumcontainsaserous, slightlyturbid,brown-tingedfluidwithglobulesoffat(derivedfrom enzymaticallydigestedadiposetissue).Inthemostsevereform, hemorrhagic pancreatitis, extensive parenchymal necrosis isaccompaniedbydiffusehemorrhagewithinthesubstanceof thegland. Abdominal pain is the cardinal manifestation of acute pancreatitis.Its severity varies from mild and uncomfortable to severe and incapacitating. Acute pancreatitis is diagnosed primarily by the presence of elevated plasma levels of amylase and lipase and the exclusion of other causes of abdominal pain. In 80% of cases, acute pancreatitis is mild and self-limiting; the remaining 20% develop severe disease.


Pathology_Robbins

Pathology_Robbins. Full-blown acute pancreatitis is a medical emergency of the first order.Affected individuals usually experience the sudden calamitous onset of an “acute abdomen” with pain, guarding, and the ominous absence of bowel sounds. Characteristically, the pain is constant, intense and referred to the upper back; it must be differentiated from pain of other causes such as perforated peptic ulcer, biliary colic, acute cholecystitis with rupture, and occlusion of mesenteric vessels with infarction of the bowel. The manifestations of severe acute pancreatitis are attributable to systemic release of digestive enzymes and Fig. 17.2 Acutepancreatitis.(A)Themicroscopicfieldshowsaregionoffatnecrosis(right) andfocalpancreaticparenchymalnecrosis(center). (B)Thepancreashasbeensectionedlongitudinallytorevealdarkareasofhemorrhageinthepancreaticsubstanceandafocalareaofpalefatnecrosisintheperipancreaticfat(upper left).


Pathology_Robbins

Pathology_Robbins. explosive activation of the inflammatory response. The initial clinical evaluation may reveal leukocytosis, disseminated intravascular coagulation (Chapter 12), acute respiratory distress syndrome (due to diffuse alveolar damage) (Chapter 13), and diffuse fat necrosis. Peripheral vascular collapse (shock) can rapidly ensue as a result of increased microvascular permeability and resultant hypovolemia, compounded by endotoxemia (from breakdown of the barriers between gastrointestinal flora and the bloodstream), and renal failure due to acute tubular necrosis (Chapter 14). Laboratory findings include markedly elevated serum amylase during the first 24 hours, followed (within 72–96 hours) by rising serum lipase levels. Hypocalcemia can result from precipitation of calcium in areas of fat necrosis; if persistent, it is a poor prognostic sign. The enlarged inflamed pancreas can be visualized by computed tomography (CT) or magnetic resonance imaging (MRI).


Pathology_Robbins

Pathology_Robbins. The crux of the management of acute pancreatitis is supportive therapy (e.g., maintaining blood pressure and alleviating pain) and “resting” the pancreas by total restriction of oral food and fluids. In 40% to 60% of cases of acute necrotizing pancreatitis, the necrotic debris becomes infected, usually by gram-negative organisms from the alimentary tract, further complicating the clinical course. Although most individuals with acute pancreatitis eventually recover, some 5% die from shock during the first week of illness; acute respiratory distress syndrome and acute renal failure are ominous complications. In surviving patients, sequelae include sterile or infected pancreatic “abscesses” or pancreatic pseudocysts.


Pathology_Robbins

Pathology_Robbins. A common sequela of acute pancreatitis (and in particular, alcoholic pancreatitis) is a pancreatic pseudocyst. Liquefied areas of necrotic pancreatic tissue become walled off by fibrous tissue to form a cystic space, lacking an epithelial lining (hence the designation pseudo). The cyst contents are rich in pancreatic enzymes, and a laboratory assessment of the cyst aspirate can be diagnostic. Pseudocysts account for approximately 75% of all pancreatic cysts. While many pseudocysts spontaneously resolve, they can become secondarily infected, and larger pseudocysts can compress or even perforate into adjacent structures. Fig.17.3A ).Theycanrangeindiameterfrom2cmto30cm.Sincepseudocystsformbywallingoffareasofhemorrhagicfatnecrosis,theytypicallyarecomposedofnecroticdebrisencasedbywallsofgranulationtissueandfibroblastslackinganepitheliallining(see Fig.17.3B ).Iftheygetinfected,apancreaticabscessisformed.


Pathology_Robbins

Pathology_Robbins. Fig.17.3B ).Iftheygetinfected,apancreaticabscessisformed. Chronic pancreatitis is characterized by long-standing inflammation that leads to irreversible destruction of the exocrine pancreas, followed eventually by loss of the islets of Langerhans. Of note, recurrent bouts of acute pancreatitis regardless of etiology can evolve over time into chronic pancreatitis. The prevalence of chronic pancreatitis is difficult to determine but probably ranges between 0.04% and 5% of the U.S. population. By far the most common cause of chronic pancreatitis is long-term alcohol abuse. Middle-aged men constitute the bulk of patients in this etiologic group. Less common causes of chronic pancreatitis include the following: Duct Obstruction. Long-standing obstruction of pancreatic duct e.g., by pseudocysts, calculi, neoplasms, or pancreas divisum. Tropical pancreatitis, a poorly characterized heterogeneous disorder seen in Africa and Asia, with a subset of cases having a hereditary basis.


Pathology_Robbins

Pathology_Robbins. Tropical pancreatitis, a poorly characterized heterogeneous disorder seen in Africa and Asia, with a subset of cases having a hereditary basis. Hereditary pancreatitis due to mutations in the pancreatic trypsinogen gene (PRRS1), or the SPINK1 gene encoding a trypsin inhibitor (see Table 17.1 Chronic pancreatitis associated with CFTR mutations. The pathophysiology of chronic pancreatitis in cystic fibrosis is discussed in detail in Chapter 7. Autoimmune pancreatitis is a pathogenically distinct form of chronic pancreatitis that is associated with the http://ebooksmedicine.net Fig. 17.3 Pancreaticpseudocyst.(A)Cross-sectionrevealingapoorlydefinedcystwithanecroticbrownishwall.(B)Histologically,thecystlacksanepithelialliningandinsteadislinedbyfibrinandgranulationtissue,withtypicalchangesofchronicinflammation.


Pathology_Robbins

Pathology_Robbins. presence of IgG4-secreting plasma cells in the pancreas. Autoimmune pancreatitis is one manifestation of IgGrelated disease (Chapter 5), which may involve multiple tissues. It is important to recognize because it responds to steroid therapy. As many as 40% of individuals with chronic pancreatitis have no recognizable predisposing factors. As with acute pancreatitis, however, a growing number of these “idiopathic” cases are associated with inherited mutations in genes, such as CFTR, that are important for normal pancreatic exocrine function. Recent studies have also identified polymorphisms in genes encoding exocrine pancreatic enzymes, including carboxypeptidase A1 (CPA1) and lipase (CEL), that may confer increased susceptibility to chronic pancreatitis. Although the pathogenesis of chronic pancreatitis is not well defined, several hypotheses are proposed:


Pathology_Robbins

Pathology_Robbins. Although the pathogenesis of chronic pancreatitis is not well defined, several hypotheses are proposed: Ductal obstruction by concretions. Many of the inciting agents in chronic pancreatitis (e.g., alcohol) increase the protein concentration of pancreatic secretions, and these proteins can form ductal plugs. Toxic-metabolic. Toxins, including alcohol and its metabolites, can exert a direct toxic effect on acinar cells, leading to lipid accumulation, acinar cell loss, and eventually parenchymal fibrosis. Oxidative stress. Alcohol-induced oxidative stress may generate free radicals in acinar cells, leading to membrane damage (Chapter 2), and subsequent expression of chemokines like interleukin-8 (IL-8), which recruits inflammatory cells. Oxidative stress also promotes the fusion of lysosomes and zymogen granules with resulting acinar cell necrosis, inflammation, and fibrosis. Inappropriate activation of pancreatic enzymes due to mutations affecting genes mentioned earlier.


Pathology_Robbins

Pathology_Robbins. Inappropriate activation of pancreatic enzymes due to mutations affecting genes mentioned earlier. In contrast to acute pancreatitis, a variety of profibrogenic cytokines, such as transforming growth factor-β (TGF-β), connective tissue growth factor, and platelet-derived growth factor, are secreted in chronic pancreatitis by infiltrating immune cells such as macrophages. These cytokines induce the activation and proliferation of periacinar myofibroblasts (“pancreatic stellate cells”), which deposit collagen and give rise to fibrosis. MORPHOLOGYChronicpancreatitisischaracterizedbyparenchymal fibrosis, reduced number and size of acini, and variable dilation of the pancreatic ducts; thereisarelativesparingoftheisletsofLangerhansinitially( Fig.17.4A ).Acinar loss isaconstantfeature,usuallywithachronicinflammatoryinfiltratearoundremaininglobulesandducts.Theductalepitheliummaybeatrophiedorhyperplasticorexhibitsquamousmetaplasia,andductalconcretionsmaybenoted(


Pathology_Robbins

Pathology_Robbins. Fig.17.4B ).TheremainingisletsofLangerhansbecomeembeddedinthesclerotictissueandmayfuseandappearenlarged;eventuallytheyalsodisappear.Ongrossevaluation,theglandishard,sometimeswithextremelydilatedductsandvisiblecalcifiedconcretions. Autoimmunepancreatitis(AIP)isadistinctformofchronicpancreatitisthatischaracterizedbystrikinginfiltrationofthepancreasbylymphocytesandplasmacells,manyofwhicharepositiveforIgG4,accompaniedbya“swirling”fibrosisandvenulitis(lymphoplasmacytic sclerosing pancreatitis). Chronic pancreatitis manifests as repeated bouts of jaundice, vague indigestion, or persistent or recurrent abdominal and back pain, or it may be entirely silent until pancreatic insufficiency and diabetes mellitus develop (the latter as a consequence of islet destruction). Attacks can be precipitated by alcohol abuse, overeating (which increases demand on pancreatic secretions), or opiates or other drugs that increase the muscle tone of the sphincter of Oddi. http://ebooksmedicine.net


Pathology_Robbins

Pathology_Robbins. http://ebooksmedicine.net Fig. 17.4 Chronicpancreatitis.(A)Extensivefibrosisandatrophyhaveleftonlyresidualislets(left) andducts(right), withasprinklingofchronicinflammatorycellsandacinartissue.(B)Ahigher-powerviewdemonstratingdilatedductswithinspissatedeosinophilicconcretionsinapatientwithalcoholicchronicpancreatitis. The diagnosis of chronic pancreatitis requires a high degree of clinical suspicion. During an attack of abdominal pain, there may be mild fever and modest elevations of serum amylase. In end-stage disease, however, acinar destruction may be so advanced that enzyme elevations are absent. Gallstone-induced obstruction may manifest as jaundice or elevated levels of serum alkaline phosphatase. A very helpful finding is visualization of calcifications within the pancreas by CT or ultrasonography. Weight loss and hypoalbuminemic edema from malabsorption caused by pancreatic exocrine insufficiency can also point to the disease.


Pathology_Robbins

Pathology_Robbins. Although chronic pancreatitis is usually not acutely life-threatening, the long-term outlook is poor, with a 50% mortality rate over 20 to 25 years. The most common longterm sequelae of chronic pancreatitis is insufficiency of pancreatic exocrine enzymes, with consequent malabsorption and deficiency of fat-soluble vitamins (Chapter 8). Exocrine insufficiency typically predates endocrine dysfunction, and patients with severe loss of islets can develop diabetes mellitus (Chapter 20). In other patients, severe chronic pain may dominate the clinical picture. Pancreatic pseudocysts (discussed earlier) develop in about 10% of patients. The most feared long-term complication of chronic pancreatitis is pancreatic cancer. The risk for malignant transformation in adult-onset disease is modest, with no more than 5% of patients developing cancer at 20 years. In contrast, chronic pancreatitis that begins in childhood, such as hereditary pancreatitis secondary to PRSS1 mutations, confers a 40% to


Pathology_Robbins

Pathology_Robbins. no more than 5% of patients developing cancer at 20 years. In contrast, chronic pancreatitis that begins in childhood, such as hereditary pancreatitis secondary to PRSS1 mutations, confers a 40% to 55% lifetime risk for pancreatic cancer. It is not unusual for patients with PRSS1 mutations to undergo prophylactic pancreatectomy.


Pathology_Robbins

Pathology_Robbins. •Acute pancreatitis ischaracterizedbyinflammationandreversibleparenchymaldamagethatrangesfromfocaledemaandfatnecrosistowidespreadparenchymalnecrosisandhemorrhage;theclinicalpresentationvarieswidely,frommildabdominalpaintorapidlyfatalvascularcollapse. Chronic pancreatitis ischaracterizedbyirreversibleparenchymaldamageandscarformation;clinicalpresentationsincludechronicmalabsorption(duetopancreaticexocrineinsufficiency)anddiabetesmellitus(duetoisletcellloss). Bothentitiessharesimilarpathogenicmechanisms,andindeedrecurrentacutepancreatitiscanresultinchronicpancreatitis.Ductal obstruction andlong-term alcohol abuse arethemostcommoncausesinbothforms.Inappropriateactivationofpancreaticdigestiveenzymes(duetomutationsingenesencodingtrypsinogenortrypsininhibitors)andprimaryacinarinjury(duetotoxins,infections,ischemia,ortrauma)alsocausepancreatitis. Pancreatic exocrine neoplasms can be cystic or solid. Some tumors are benign, while others are among the most lethal of all malignancies.


Pathology_Robbins

Pathology_Robbins. Pancreatic exocrine neoplasms can be cystic or solid. Some tumors are benign, while others are among the most lethal of all malignancies. Cystic neoplasms are diverse tumors that range from harmless benign cysts to invasive, potentially lethal, cancers. Approximately 5% to 15% of all pancreatic cysts are neoplastic; these constitute less than 5% of all pancreatic neoplasms. Some of these are almost always benign (e.g., serous cystadenoma); others, such as mucinous cystic neoplasms, can be benign or malignant. Serous cystadenomas account for approximately 25% of all pancreatic cystic neoplasms; they are composed of glycogen-rich cuboidal cells surrounding small cysts containing clear, straw-colored fluid (


Pathology_Robbins

Pathology_Robbins. Fig. 17.5 ). The tumors typically manifest in the seventh decade of life with nonspecific symptoms such as abdominal pain; the female-to-male ratio is 2:1. These tumors are almost uniformly benign, and surgical resection is curative in the vast majority of patients. Most serous cystadenomas carry somatic loss of function mutations of the von Hippel-Lindau (VHL) tumor suppressor gene, which you will recall is a negative regulator of hypoxia-inducible factor 1 alpha (HIF-1-alpha) (Chapter 6). http://ebooksmedicine.net Fig. 17.5 Serouscystadenoma.(A)Cross-sectionthroughaserouscystad-enoma.Onlyathinrimofnormalpancreaticparenchymaremains.Thecystsarerelativelysmallandcontainclear,straw-coloredfluid.(B)Thecystsarelinedbycuboidalepitheliumwithoutatypia.


Pathology_Robbins

Pathology_Robbins. In contrast to serous cystic tumors, close to 95% of mucinous cystic neoplasms arise in women, usually in the body or tail of the pancreas, and manifest as painless, slow-growing masses. The cystic spaces are filled with thick, tenacious mucin, and the cysts are lined by a columnar mucinous epithelium with an associated densely cellular stroma resembling that of the ovary ( Fig. 17.6 ). Based on the degree of cytologic and architectural atypia in the epithelial lining, noninvasive mucinous cystic neoplasms are classified as harboring low-grade, moderate, or severe dysplasia. Up to one-third of these cysts can be associated with an invasive adenocarcinoma, another important difference from the serous tumors. Distal pancreatectomy for noninvasive mucinous cysts typically is curative, even in the setting of severe dysplasia.


Pathology_Robbins

Pathology_Robbins. In contrast with mucinous cystic neoplasms, intraductal papillary mucinous neoplasms (IPMNs) occur more frequently in men than in women and more frequently involve the head of the pancreas. IPMNs arise in the main pancre-atic ducts, or one of its major branch ducts, and lack the cellular stroma seen in mucinous cystic neoplasms ( Fig.


Pathology_Robbins

Pathology_Robbins. Fig. 17.7 ). As with mucinous cystic neoplasms, the epithelia of noninvasive IPMNs harbor various grades of dysplasia, and a subset of lesions is associated with invasive adenocarcinoma. In particular, “colloid” carcinomas of the pancreas, which are adenocarcinomas associated with abundant extracellular mucin production, nearly always represent malignant transformation of an IPMN. Up to two-thirds of IPMNs harbor oncogenic mutations of GNAS on chromosome 20q13, which encodes the alpha subunit of a stimulatory G-protein, Gs (Chapter 20). Constitutive activation of this G-protein is predicted to result in an intracellular cascade that promotes cell proliferation. Fig. 17.6 Mucinouscysticneoplasm.(A)Cross-sectionthroughamucinousmultiloculatedcystinthetailofthepancreas.Thecystsarelargeandfilledwithtenaciousmucin.(B)Thecystsarelinedbycolumnarmucinousepithe-lium,withadenselycellular“ovarian”stroma.


Pathology_Robbins

Pathology_Robbins. Infiltrating ductal adenocarcinoma of the pancreas (more commonly referred to as pancreatic cancer) is the third leading cause of cancer deaths in the United States, preceded only by lung and colon cancers. Although it is substantially less common than the other two malignancies, pancreatic carcinoma is near the top of the list of killers because it carries one of the highest mortality rates. Close to 49,000 Americans were diagnosed with pancreatic cancer in 2015, and virtually all will die in a short period after diagnosis; the 5-year survival rate is a dismal 8%. http://ebooksmedicine.net Like all cancers, pancreatic cancer arises as a consequence of inherited and acquired mutations in cancer-associated


Pathology_Robbins

Pathology_Robbins. http://ebooksmedicine.net Like all cancers, pancreatic cancer arises as a consequence of inherited and acquired mutations in cancer-associated Fig. 17.7 Intraductal papillary mucinous neoplasm. (A) Cross-section through the head of the pancreas showing a prominent papillary neoplasm distending the main pancreatic duct. (B) The papillary mucinous neoplasm involves the main pancreatic duct (left) and is extending down into the smaller ducts and ductules (right). genes. In a pattern analogous to that seen in the multi-step progression of colon cancer (Chapter 6), there is a progressive accumulation of genetic changes in pancreatic epithelium as it proceeds from nonneoplastic, to noninvasive precursor lesions, to invasive carcinoma (


Pathology_Robbins

Pathology_Robbins. Fig. 17.8 ). While both intraductal papillary mucinous neoplasms and mucinous cystic neoplasms can progress to invasive adenocarcinoma, the most common antecedent lesions of pancreatic cancer arise in small ducts and ductules, and are called pancreatic intraepithelial neoplasias (PanINs). Evidence in favor of the precursor relationship of PanINs to frank malignancy includes the observations that these microscopic lesions often are found adjacent to infiltrating carcinomas and the two share a number of genetic alterations. Moreover, the epithelial cells in PanINs show dramatic telomere shortening, potentially predisposing these lesions to pathogenic chromosomal abnormalities that may contribute to acquisition of the full spectrum of cancer hallmarks. The recent sequencing of the pancreatic cancer genome has confirmed that four genes are most commonly affected by somatic mutations in this neoplasm: KRAS, CDKN2A/ p16, SMAD4,andTP53:


Pathology_Robbins

Pathology_Robbins. The recent sequencing of the pancreatic cancer genome has confirmed that four genes are most commonly affected by somatic mutations in this neoplasm: KRAS, CDKN2A/ p16, SMAD4,andTP53: KRAS is the most frequently altered oncogene in pancreatic cancer; it is activated by a point mutation in greater than 90% of cases. These mutations impair the intrinsic GTPase activity of the KRAS protein so that it is constitutively active. In turn, KRAS activates a number of intracellular signaling pathways that promote carcinogenesis (Chapter 6). The p16 (CDKN2A) gene is the most frequently inactivated tumor suppressor gene in pancreatic cancer, being turned off in 95% of cases. The p16 protein has a critical role in cell-cycle control; inactivation removes an important checkpoint.


Pathology_Robbins

Pathology_Robbins. The SMAD4 tumor suppressor gene is inactivated in 55% of pancreatic cancers and only rarely in other tumors; it codes for a protein that plays an important role in signal transduction downstream of the transforming growth factor-β receptor. Inactivation of the TP53 tumor suppressor gene occurs in 50% to 70% of pancreatic cancers. Its gene


Pathology_Robbins

Pathology_Robbins. Fig. 17.8 Progression model for the development of pancreatic cancer. It is postulated that telomere shortening and mutations of the KRAS oncogene occur at early stages, inactivation of the p16 tumor suppressor gene occurs at intermediate stages, and inactivation of the TP53, SMAD4, and BRCA2 tumor suppressor genes occurs at late stages. Note that while there is a general temporal sequence of changes, the accumulation of multiple mutations is more important than their occurrence in a specific order. PanIN, Pancreatic intraepithelial neoplasm. The numbers following the labels on the top refer to stages in the development of PanINs. (Modified from Maitra A, Hruban RH: Pancreatic cancer, Annu Rev Pathol Mech Dis 3:157, 2008.) product, p53, acts both to enforce cell-cycle checkpoints and as an inducer of apoptosis or senescence (Chapter 6). BRCA2 is also mutated late in a subset of pancreatic cancers.


Pathology_Robbins

Pathology_Robbins. Pancreatic cancer is primarily a disease of older adults, with 80% of cases occurring between 60 and 80 years of age. The strongest environmental influence is smoking, which doubles the risk. Long-standing chronic pancreatitis and diabetes mellitus are also associated with a modestly increased risk for pancreatic cancer. These two entities have a bidirectional link with pancreatic cancer. Thus, for example, tumors arising in the head of the pancreas often cause chronic pancreatitis in the distal parenchyma, while diabetes caused by duct obstruction and subsequent pancreatitis may be the manifestation of an underlying neoplasm. In fact, approximately 1% of the older adult population with new-onset diabetes harbor an unsuspected pancreatic cancer. Familial clustering of pancreatic cancer has been reported, and a growing number of inherited genetic defects are now recognized that increase pancreatic cancer risk. For example, germ line mutations of the familial breast/ ovarian cancer gene


Pathology_Robbins

Pathology_Robbins. been reported, and a growing number of inherited genetic defects are now recognized that increase pancreatic cancer risk. For example, germ line mutations of the familial breast/ ovarian cancer gene BRCA2 are seen in approximately 10% of cases arising in individuals of Ashkenazi Jewish heritage.


Pathology_Robbins

Pathology_Robbins. Approximately 60% of pancreatic cancers arise in the head of the gland, 15% in the body, and 5% in the tail; in the remaining 20%, the neoplasm diffusely involves the entire organ. Carcinomasofthepancreasusuallyarehard,gray-white,stellate,poorlydefinedmasses( Fig.17.9A Twofeaturesarecharacteristicofpancreaticcancer:Itishighlyinvasive(even“early”invasivepancreaticcancersinvadeperipancreatictissuesextensively),anditelicitsanintensehostreactionintheformofdensefibrosis(desmoplastic response).


Pathology_Robbins

Pathology_Robbins. Most carcinomas of the head of the pancreas obstruct the distal common bile duct asitcoursesthroughtheheadofthepancreas.In50%ofsuchcases,thereismarkeddistentionofthebiliarytree,andpatientstypicallyexhibitjaundice.Incontrast,carcinomasofthebodyandtailofthepancreasdonotimpingeonthebiliarytract.Pancreaticcancersoftenextendthroughtheretroperitonealspace,entrappingadjacentnerves(thus,accountingforthepain),andoccasionallyinvadethespleen,adrenalglands,vertebralcolumn,transversecolon,andstomach.Peripancreatic,gastric,mesenteric,omental,andportahepaticlymphnodesfrequentlyareinvolved,andtheliveroftenisenlargedwithmetastaticdeposits.Distantmetastasesmayoccur,principallytothelungsandbones. Onmicroscopicexamination,pancreaticcarcinomausuallyisamoderately to poorly differentiated adenocarcinoma formingabortiveglandswithmucinsecretionorcellclustersandexhibitinganaggressive,deeplyinfiltrativegrowthpattern(see


Pathology_Robbins


Pathology_Robbins

Pathology_Robbins. Carcinomas of the pancreas typically remain silent until their extension impinges on some other structure. Pain usually is the first symptom, but by that point these cancers are often beyond cure. Obstructive jaundice can be associated with carcinoma in the head of the pancreas, but it rarely draws attention to the cancer soon enough for timely intervention. Weight loss, anorexia, and generalized malaise and weakness are manifestations of advanced disease. Migratory thrombophlebitis (Trousseau syndrome) occurs in about 10% of patients and is attributable to the elaboration of platelet-aggregating factors and pro-coagulants from the tumor or its necrotic products (Chapter 6). As previously stated, new-onset diabetes is the first manifestation of pancreatic cancer in some patients. http://ebooksmedicine.net


Pathology_Robbins

Pathology_Robbins. http://ebooksmedicine.net The clinical course of pancreatic carcinoma is rapidly progressive and often distressingly brief. Less than 20% of pancreatic cancers are resectable at the time of diagnosis. It has long been recognized that there is a profound need for biomarkers capable of detecting early, potentially curable, pancreatic cancers. Although serum levels of many enzymes and antigens (e.g., carcinoembryonic and CA19-9 antigens) are elevated, these markers are neither specific nor sensitive enough to be useful for screening. Several imaging techniques, such as endoscopic ultrasonography and high-resolution CT scans, are helpful for investigation in cases of suspected cancer but are not practical screening tests. Pancreaticcancerprobablyarisesfromnoninvasiveprecursorlesions(mostcommonly,PanINs),developingbyprogressiveaccumulationofmutationsofoncogenes(e.g.,KRAS)andtumorsuppressorgenes(e.g.,CDKN2A/p16,TP53, andSMAD4).


Pathology_Robbins

Pathology_Robbins. Typically,theseneoplasmsareductaladenocarcinomasthatproduceanintensedesmoplasticresponse. Mostpancreaticcancersarediagnosedatanadvancedstage,accountingforthehighmortalityrate. Obstructivejaundiceisafeatureofcarcinomaoftheheadofthepancreas;manypatientsalsoexperiencedebilitatingpain. Carcinomasofthetailofthepancreasareoftennotdetecteduntillateintheircourse. Andersen DK, Andren-Sandberg Å, Duell EJ, et al: Pancreatitisdiabetes-pancreatic cancer: summary of an NIDDK-NCI workshop, Pancreas 42:1227–1237, 2013. [A white paper that summarizes the current state of evidence regarding the bidirectional and complex relationship between chronic pancreatitis or diabetes and pancreatic cancer. The recently described entity of pancreatogenic diabetes is also discussed.]


Pathology_Robbins

Pathology_Robbins. Bailey P, Chang DK, Nones K, et al: Genomic analyses identify molecular subtypes of pancreatic cancer, Nature 531:47–52, 2016. [A comprehensive genomic profiling of pancreatic cancer by the International Cancer Genome Consortium.]. Dellinger EP, Forsmark CE, Layer P, et al: Determinant-based classification of acute pancreatitis severity: an international multidisciplinary consultation, Ann Surg 256:875–880, 2012. [An international classification system for the clinical severity of acute pancreatitis, which represents the consensus of opinions from physicians spanning 49 countries.] Hart PA, Zen Y, Chari ST: Recent advances in autoimmune pancreatitis, Gastroenterology 149:39–51, 2015. [An up-to-date review on the etiopathogenesis and clinical subtypes of autoimmune pancreatitis from one of the foremost expert groups on this subject.]


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Pathology_Robbins. Knudson ES, O’Reilly EM, Brody JR, et al: Genetic diversity of pancreatic ductal adenocarcinoma and opportunities for precision medicine, Gastroenterology 150:48–63, 2016. [An up-to-date description of the molecular abnormalities in cancer of the pancreas revealed by next-generation sequencing and possible drug targets.] Ryan DP, Hong TS, Bardeesy N: Pancreatic adenocarcinoma, N Engl J Med 371:1039–1049, 2014. [An outstanding clinically oriented update on pancreatic cancer, including newly emerging molecular targets for therapy.] Shelton CA, Whitcomb DC: Genetics and treatment options for recurrent acute and chronic pancreatitis, Curr Treat Options Gastroenterol 12:359–371, 2014. [A comprehensive review on germ line mutations that result in recurrent pancreatitis, as well as recently identified polymorphisms that enhance the risk for pancreatitis.]


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Pathology_Robbins. Tanaka M, et al: International consensus guidelines 2012 for the management of IPMN and MCN of the pancreas, Pancreatology 12:183– 197, 2012. [An update to the 2006 consensus guidelines on how to identify the presence of malignancy within cystic precursor lesions of pancreatic cancer using imaging and other diagnostic criteria. Although not definitive, these guidelines are widely used for deciding which cyst patients require surgery versus observation.] http://ebooksmedicine.net studentconsult.com Scrotum,Testis,andEpididymis Ureter,Bladder,andUrethra


Pathology_Robbins

Pathology_Robbins. Scrotum,Testis,andEpididymis Ureter,Bladder,andUrethra Among the most common malformations of the penis are those in which the distal urethral orifice is abnormally located. In hypospadias, the abnormal urethral opening is found on the ventral aspect of the penis anywhere along the shaft. This anomalous orifice is sometimes constricted, resulting in urinary tract obstruction and an increased risk for urinary tract infections. Hypospadias occurs in 1 in 300 live male births and may be associated with other congenital anomalies, such as inguinal hernia and undescended testis. In epispadias, which is less common, the abnormal urethral orifice is on the dorsal aspect of the penis.


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Pathology_Robbins. Balanitis and balanoposthitis refer to local inflammation of the glans penis and of the overlying prepuce, respectively. Among the more common agents are Candida albicans, anaerobic bacteria, Gardnerella, and pyogenic bacteria. Most cases occur as a consequence of poor hygiene in uncircumcised males, leading to the accumulation of desquamated epithelial cells, sweat, and debris, termed smegma, which acts as a local irritant. Phimosis is a condition in which the prepuce cannot be retracted easily over the glans penis. Phimosis may be a congenital anomaly, but most cases stem from scarring of the prepuce caused by balanoposthitis.


Pathology_Robbins

Pathology_Robbins. More than 95% of penile neoplasms arise on squamous epithelium. In the United States, squamous cell carcinomas of the penis are relatively uncommon, accounting for about 0.4% of all cancers in males. In developing countries, however, penile carcinoma occurs at much higher rates. Most cases occur in uncircumcised patients older than 40 years of age. Several factors have been implicated in the pathogenesis of penile squamous cell carcinoma, including poor hygiene (with resultant exposure to potential carcinogens in smegma), smoking, and infection with human papillomavirus (HPV), particularly types 16 and 18. Squamous cell carcinoma in situ of the penis (Bowen disease) occurs in older uncircumcised males and appears grossly as a solitary plaque on the shaft of the penis. Histologic examination reveals dysplastic cells throughout the epidermis with no invasion of the underlying stroma ( Fig. 18.1 ). It gives rise to invasive squamous cell carcinoma in approximately 10% of patients.


Pathology_Robbins

Pathology_Robbins. Fig. 18.1 ). It gives rise to invasive squamous cell carcinoma in approximately 10% of patients. Invasive squamous cell carcinoma of the penis appears as a gray, crusted, papular lesion, most commonly on the glans penis or prepuce. In many cases, infiltration of the underlying connective tissue produces an indurated, ulcerated lesion with irregular margins ( Fig. 18.2 ). Histologically, the tumor is most often a typical keratinizing squamous cell carcinoma. The prognosis is related to the stage of the tumor. With localized lesions, the 5-year survival rate is 66%, whereas metastasis to inguinal lymph nodes carries a grim 27% 5-year survival rate. Verrucous carcinoma is a non-HPV–related variant of squamous cell carcinoma characterized by papillary architecture, virtually no cytologic atypia, and rounded, pushing deep margins. Verrucous carcinomas are locally invasive but do not metastasize. http://ebooksmedicine.net


Pathology_Robbins

Pathology_Robbins. Several inflammatory processes may affect the skin of the scrotum, including local fungal infections and systemic dermatoses, such as psoriasis (Chapter 24). Neoplasms of the scrotal sac are unusual. Squamous cell carcinoma, the most common of these, is of historical interest in that it represents the first human malignancy associated with environmental exposures, dating from Sir Percival Pott’s observation of a high incidence of the disease in chimney sweeps. The subsequent edict by the Chimney Sweeps Guild that its members must bathe daily remains one of the most successful public health measures for cancer prevention. Several disorders unrelated to the testes and epididymis may present as scrotal enlargement. Hydrocele, the most common cause of scrotal swelling, is caused by an accumulation of serous fluid within the tunica vaginalis. It may be idiopathic or arise in response to neighboring infections or tumors. The clear fluid of a hydrocele allows light to pass through


Pathology_Robbins

Pathology_Robbins. an accumulation of serous fluid within the tunica vaginalis. It may be idiopathic or arise in response to neighboring infections or tumors. The clear fluid of a hydrocele allows light to pass through (transluminescence), distinguishing it from collections of blood, pus, or lymph, all of which are cloudy or opaque. Accumulation of blood or lymphatic fluid within the tunica vaginalis, termed hematocele and chylocele, respectively, also may cause scrotal enlargement. In extreme cases of lymphatic obstruction, caused, for example, by filariasis, the scrotum and the lower extremities may enlarge to grotesque sizes—a condition termed elephantiasis.


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Pathology_Robbins. Cryptorchidism is a failure of testicular descent into the scrotum. Normally, the testes descend from the abdominal cavity into the pelvis by the third month of gestation and then through the inguinal canals into the scrotum during the last 2 months of intrauterine life. The diagnosis of cryptorchidism is only established with certainty after 1 year of age, particularly in premature infants, because testicular descent into the scrotum is not always complete at birth. Cryptorchidism affects 1% of the male population. In the vast majority of cases, the cause is unknown. The condition is bilateral in approximately 10% of affected patients, a small percentage of whom have chromosomal aberrations and other developmental abnormalities. Because undescended testes become atrophic, bilateral cryptorchidism results in sterility. For unclear reasons, even unilateral cryptorchidism may be associated with atrophy of the contralateral descended gonad.


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Pathology_Robbins. In addition to infertility, failure of testicular descent is associated with a 3to 5-fold increased risk for testicular cancer. Patients with unilateral cryptorchidism also are at increased risk for the development of cancer in the contralateral, normally descended testis, suggesting that some intrinsic abnormality, rather than simple failure of descent, underlies the increased cancer risk. Surgical placement of the undescended testis into the scrotum (orchiopexy) is recommended by 18 months of age to decrease the likelihood of testicular atrophy, infertility, and testicular cancer.


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Pathology_Robbins. The cryptorchid testis may be of normal size early in life, but some degree of atrophy usually is evident by the onset of puberty. Microscopically, tubular atrophy begins to appear by 5 to 6 years of age, and is usually advanced by the time of puberty. Germ cell neoplasia in-situ (discussed later) may be present in cryptorchid testes and is a likely precursor of subsequent germ cell tumors. Atrophic changes similar to those in cryptorchid testes may be caused by other insults, including chronic ischemia, trauma, irradiation, and anti-neoplastic chemotherapy, as well as conditions associated with chronically elevated estrogen levels (e.g., cirrhosis). http://ebooksmedicine.net Cryptorchidism referstoincompletedescentofthetestisfromtheabdomentothescrotumandispresentinabout1%of1-year-oldmaleinfants. Bilateralor,insomecases,evenunilateralcryptorchidismisassociatedwithtubularatrophyandsterility.


Pathology_Robbins

Pathology_Robbins. Inflammatory lesions of the testis are more common in the epididymis than in the testis proper. Sexually transmitted infectious disorders are discussed later in the chapter. Other causes of testicular inflammation include nonspecific epididymitis and orchitis, mumps, and tuberculosis. Nonspecific epididymitis and orchitis usually begin as a primary urinary tract infection that spreads to the testis through the vas deferens or the lymphatics of the spermatic cord. The involved testis is swollen and tender, and histologic examination reveals numerous neutrophils. Mumps infection involving the testes is rare in male children but occurs in roughly 20% of infected adults. Affected testes are edematous and congested, and contain a lymphoplasmacytic inflammatory infiltrate. Severe mumps orchitis may lead to extensive necrosis, loss of seminiferous epithelium, tubular atrophy, fibrosis, and sterility. Several conditions, including infections and autoimmune injury, may elicit granulomatous


Pathology_Robbins

Pathology_Robbins. may lead to extensive necrosis, loss of seminiferous epithelium, tubular atrophy, fibrosis, and sterility. Several conditions, including infections and autoimmune injury, may elicit granulomatous inflammation in the testis. Of these, tuberculosis is the most common. Testicular tuberculosis generally begins as an epididymitis, with secondary involvement of the testis. Histologically, there is granulomatous inflammation and caseous necrosis identical to that seen in active tuberculosis in other sites.


Pathology_Robbins

Pathology_Robbins. Torsion, or twisting of the spermatic cord, typically results in obstruction of testicular venous drainage while leaving the thick-walled and more resilient arteries patent. This leads to intense vascular engorgement and infarction unless the torsion is relieved. There are two types of testicular torsion. Neonatal torsion occurs either in utero or shortly after birth. There is no associated anatomic defect to account for its occurrence. Adult torsion typically is seen in adolescence and manifests with the sudden onset of testicular pain. In contrast with neonatal torsion, adult torsion results from a bilateral congenital anomaly whereby the testis is abnormally anchored in the scrotal sac giving rise to increased mobility (bell clapper abnormality). It often occurs without any inciting injury; sudden pain heralding the torsion may even awaken the patient from sleep.


Pathology_Robbins

Pathology_Robbins. Torsion constitutes one of the few urologic emergencies. If the testis is explored surgically and the cord is manually untwisted within approximately 6 hours, the testis will likely remain viable. To prevent the catastrophic occurrence of torsion in the contralateral testis, the unaffected testis typically is surgically fixed within the scrotum (orchiopexy). Testicular neoplasms occur in roughly 6 per 100,000 males. In the 15to 34-year-old age group, when these neoplasms peak in incidence, they are the most common tumors in men. Neoplasms of the testis are heterogeneous and include germ cell tumors and sex cord–stromal tumors. In postpubertal males, 95% of testicular tumors arise from germ cells, and almost all are malignant. By contrast, sex cord-stromal tumors derived from Sertoli or Leydig cells are uncommon and usually benign. The focus of the remainder of this discussion is on testicular germ cell tumors.


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Pathology_Robbins. The cause of testicular neoplasms is poorly understood. Testicular tumors are more common in whites than in blacks, and the incidence has increased in white populations over recent decades. As discussed earlier, cryptorchidism is associated with a 3to 5-fold increase in the risk for cancer in the undescended testis, as well as an increased risk for cancer in the contralateral descended testis. A history of cryptorchidism is present in approximately 10% of cases of testicular cancer. Intersex syndromes, including androgen insensitivity syndrome and gonadal dysgenesis, also are associated with an increased frequency of testicular cancer. Family history is important, as brothers of males with germ cell tumors have an 8to 10-fold increased risk, presumably owing to inherited factors. The development of cancer in one testis also is associated with a markedly increased risk for neoplasia in the contralateral testis. Extra copies of the short arm of chromosome 12, usually due to the presence


Pathology_Robbins

Pathology_Robbins. of cancer in one testis also is associated with a markedly increased risk for neoplasia in the contralateral testis. Extra copies of the short arm of chromosome 12, usually due to the presence of an isochromosome 12 [i(12p)], are found in virtually all germ cell tumors. Of note, point mutations that create oncogenes are relatively rare in germ cell tumors, occurring at the lowest frequency of any solid tumor in adults. Among these are oncogenic mutations in KIT which are found in up to 25% of tumors.


Pathology_Robbins

Pathology_Robbins. Most testicular tumors in postpubertal males arise from germ cell neoplasia in situ. This precursor lesion is present in conditions associated with a high risk for developing germ cell tumors (e.g., cryptorchidism, dysgenetic gonads) and exhibits the same abnormality of chromosome 12 that is characteristic of fully developed germ cell tumors. As might be expected, germ cell neoplasia in situ often is found in “normal” testis adjacent to full-blown germ cell tumors. Testicular germ cell tumors are subclassified into seminomas and nonseminomatous germ cell tumors ( 18.1 ). Seminomas are most common, accounting for about http://ebooksmedicine.net Table 18.1 Summary of Testicular Tumors Spermatocytic50-60Small,medium,andlargepolygonalcells;noNegativetumor


Pathology_Robbins

Pathology_Robbins. Table 18.1 Summary of Testicular Tumors Spermatocytic50-60Small,medium,andlargepolygonalcells;noNegativetumor Yolksactumor3Poorlydifferentiatedendothelium-like,cuboidal,90%ofpatientshaveelevatedAFPorcolumnarcells 50% of testicular germ cell neoplasms. They are histologically identical to tumors called dysgerminomas, which occur in the ovary, and germinomas, which occur in the central nervous system and other extragonadal sites. MORPHOLOGYGermcelltumorsmaybe“pure”(i.e.,composedofasinglehistologictype)ormixed(seenin40%ofcases).Seminoma presentsasasoft,well-demarcated,gray-whitetumorthatbulgesfromthecutsurfaceoftheaffectedtestis( Fig.18.3 ).Largetumorsmaycontainfociofcoagulativenecrosis,usuallywithouthemorrhage.Seminomasarecomposedoflarge, uniform cells with distinct cell borders, clear, glycogen-rich cytoplasm, round nuclei, and conspicuous nucleoli (


Pathology_Robbins


Pathology_Robbins

Pathology_Robbins. Embryonal carcinoma presentsasill-defined,invasivemassescontainingfociofhemorrhageandnecrosis( Fig.18.5 ).Theprimarylesionsmaybesmall,eveninpatientswithsystemicmetastases.The tumor cells are large and have basophilic cytoplasm, indistinct cell borders, large nuclei, and prominent nucleoli. Theneoplasticcellsmaybearrayedinundifferentiated,solidsheetsormayformprimitiveglandularstructuresandirregularpapillae( Fig.18.6 ).Inmostcases,cellscharacteristicofothergermcelltumors(e.g.,yolksactumor,teratoma,choriocarcinoma)areadmixedwiththeembryonalareas.Pureembryonalcarcinomasaccountforonly2%to3%ofalltesticulargermcelltumors. Fig. 18.3 Seminomaofthetestisappearingasawell-circumscribed,pale,fleshy,homogeneousmass. Fig. 18.4 Seminomaofthetestis.Microscopicexaminationrevealslargecellswithdistinctcellborders,palenuclei,prominentnucleoli,andasparselymphocyticinfiltrate. http://ebooksmedicine.net Fig. 18.5 Embryonalcarcinoma.Incontrastwiththeseminomain Fig.18.3 ,thistumorishemorrhagic.


Pathology_Robbins

Pathology_Robbins. http://ebooksmedicine.net Fig. 18.5 Embryonalcarcinoma.Incontrastwiththeseminomain Fig.18.3 ,thistumorishemorrhagic. Yolk sac tumor isthemostcommonprimarytesticularneoplasminchildrenyoungerthan3yearsofage;inthisagegroup,ithasaverygoodprognosis.Inadults,yolksactumorsmostoftenareseenadmixedwithembryonalcarcinoma.Thesetumorsoftenarelargeandmaybewelldemarcated.Theyarecomposedoflowcuboidaltocolumnarepithelialcellsthatformmicrocysts,lacelike(reticular)patterns,sheets,glands,andpapillae( Fig.18.7 ).Adistinctivefeatureisthepresence Fig. 18.6 Embryonalcarcinoma.Notethesheetsofundifferentiatedcellsandprimitiveglandlikestructures.Thenucleiarelargeandhyperchromatic. ofstructuresresemblingprimitiveglomeruli,theso-calledSchiller-Duval bodies. Thesetumorsoftenhaveeosinophilichyalineglobulescontainingα1-anti-trypsinandalphafetoprotein(AFP),whichcanbedemonstratedbyimmunohistochemicaltechniques.


Pathology_Robbins

Pathology_Robbins. Choriocarcinoma isatumorinwhichthepluripotentialneoplasticgermcellsdifferentiateintocellsresemblingplacentaltrophoblasts. Theprimarytumorsoftenaresmallandnonpalpable,eveninpatientswithextensivemetastaticdisease.Thetumoriscomposedofsheetsofsmallcuboidalcytotrophoblast like cells thatareirregularlyintermingledwithorcappedbylarge,eosinophilicsyncytiotrophoblast like cells containingmultipledark,pleomorphicnuclei( Fig.18.8 ).HCGcanbeidentifiedinthesyncytiotrophoblasticcellsbyimmunohistochemicalstaining. differentiatealongmultiplesomaticcelllineages.Thesetumors Fig. 18.7 Yolksactumordemonstratingareasoflooselytextured,micro-cystictissueandpapillarystructuresresemblingadevelopingglomerulus(Schiller-Duvalbodies). Fig. 18.8 Choriocarcinoma.Bothcytotrophoblasticcellswithsinglecentralnuclei(arrowhead, upper-right) andsyncytiotrophoblasticcellswithmultipledarknucleiembeddedineosinophiliccytoplasm(arrow, middle) arepresent.Hemorrhageandnecrosisareprominent.


Pathology_Robbins

Pathology_Robbins. http://ebooksmedicine.net ofcartilage.Theymayoccuratanyagefrominfancytoadultlife.Pureformsofteratomaarefairlycommonininfantsandchildren,beingsecondinfrequencyonlytoyolksactumors.Inadults,pureteratomasarerare,constituting2%to3%ofgermcelltumors,andtheremainingtumorsareseenincombinationwithotherhistologictypes.Teratomasarecomposedofaheterogeneous,helter-skeltercollectionofdifferentiatedcellsororganoidstructures,suchasneuraltissue,musclebundles,islandsofcartilage,clustersofsquamousepithelium,structuresreminiscentofthyroidgland,bronchialepithelium,andbitsofintestinalwallorbrainsubstance,allembeddedinafibrousormyxoidstroma (Fig. 18.9 ).Elementsmaybemature(resemblingvarioustissueswithintheadult)orimmature(sharinghistologicfeatureswithfetalorembryonaltissues).In prepubertal males, teratomas are benign, whereas the majority of teratomas in postpubertal males are malignant, being capable of metastasis regardless of whether they are composed of mature or immature elements.


Pathology_Robbins

Pathology_Robbins. Rarely,non–germcelltumorsmayariseinteratoma—aphenomenonreferredtoasteratoma with malignant transformation. Examplesofsuchneoplasmsincludesquamouscellcarcinoma,adenocarcinoma,andvarioussarcomas.Thesenon–germcellmalignanciesdonotrespondtotherapiesthatareeffectiveagainstmetastaticgermcelltumors(discussedlater);thus,theonlyhopeforcureinsuchcasesresidesinsurgicalresection. Patients with testicular germ cell neoplasms present most frequently with a painless testicular mass that (unlike enlargements caused by hydroceles) is nontranslucent. Biopsy of a testicular neoplasm is associated with a risk for tumor spillage, which would necessitate excision of the scrotal skin in addition to orchiectomy. Consequently, the standard management of a solid testicular mass is radical orchiectomy, based on the presumption of malignancy. Some tumors, especially nonseminomatous germ cell neoplasms, may have metastasized widely by the time of diagnosis in the absence of a palpable testicular lesion.


Pathology_Robbins

Pathology_Robbins. Seminomas and nonseminomatous tumors differ in their behavior and clinical course. Seminomas often remain confined to the testis for long periods and may reach considerable size before diagnosis. Metastases most commonly are encountered in the iliac and paraaortic lymph nodes, particularly in the upper lumbar region. Hematogenous metastases occur late in the course of the disease. Nonseminomatous germ cell neoplasms tend to metastasize earlier, by lymphatic as well as hematogenous routes. Hematogenous metastases are most common in the liver and lungs. Metastatic lesions may be identical to the primary testicular tumor or may contain elements of other germ cell tumors. Fig. 18.9 Teratoma.Testicularteratomascontainmaturecellsfromendodermal,mesodermal,andectodermallines.(AtoD)Fourdifferentfieldsfromthesametumorspecimencontainneural(ectodermal)(A),glandular(endodermal)(B),cartilaginous(mesodermal)(C),andsquamousepithelial(D)elements.


Pathology_Robbins

Pathology_Robbins. Assay of tumor markers secreted by germ cell tumors is important in two ways; these markers (summarized in Table 18.1 , along with salient clinical and morphologic features) are helpful diagnostically and very valuable in following the response of tumors to therapy after the diagnosis is established. HCG is always elevated in patients with choriocarcinoma and, as noted, may be minimally elevated in individuals with other germ cell tumors containing syncytiotrophoblastic cells. Increased AFP in the setting of a testicular neoplasm indicates a yolk sac tumor component. The levels of lactate dehydrogenase (LDH) correlate with the tumor burden.


Pathology_Robbins

Pathology_Robbins. The treatment of testicular germ cell neoplasms is a remarkable clinical success story. Although roughly 8000 new cases of testicular cancer occur in the United States yearly, fewer than 400 men are expected to die of the disease. Seminoma, which is extremely radiosensitive and tends to remain localized for long periods, has the best prognosis. More than 95% of patients with early-stage disease can be cured. Among nonseminomatous germ cell tumors, the histologic subtype does not influence the therapy. Approximately 90% of patients achieve complete remission with aggressive chemotherapy, and most are cured. The exception is choriocarcinoma, which is associated with a poorer prognosis. With all testicular tumors, recurrences, typically in the form of distant metastases, usually occur within the first 2 years after treatment.


Pathology_Robbins

Pathology_Robbins. HCGisproducedbysyncytiotrophoblastsandisalwayselevatedinpatientswithchoriocarcinomasandthosewithseminomascontainingsyncytiotrophoblasts.AFPiselevatedwhenthereisayolksactumorcomponent. The prostate can be divided into biologically distinct regions, the most important of which are the peripheral and transition zones (


Pathology_Robbins

Pathology_Robbins. The prostate can be divided into biologically distinct regions, the most important of which are the peripheral and transition zones ( Fig. 18.10 ). The types of proliferative lesions are different in each region. For example, most hyperplastic lesions arise in the inner transition zone, while most carcinomas (70%–80%) arise in the peripheral zones. As a result, carcinomas are often detected by rectal exammination, whereas hyperplasias are more likely to cause urinary obstruction. The normal prostate contains glands with two cell layers, a flat basal cell layer and an overlying columnar secretory cell layer. Surrounding prostatic stroma contains a mixture of smooth muscle and fibrous tissue. The prostate is involved by infectious, inflammatory, hyperplastic, and neoplastic disorders, of which prostate cancer is by far the most important clinically.


Pathology_Robbins

Pathology_Robbins. Fig. 18.10 Adultprostate.Thenormalprostatecontainsseveraldistinctregions,includingacentralzone(CZ),aperipheralzone(PZ),atransitionalzone(TZ),andaperiurethralzone.Mostcarcinomasarisefromtheperiph-eralglandsoftheorgan,whereasnodularhyperplasiaarisesfrommorecentrallysituatedglands.BladderProximal urethra Anterior fibromuscular stroma Periurethral zone Distal urethra CZTZTZPZCZSeminal vesicle Ejaculatory duct Rectum Prostatitis is divided into three categories: (1) acute bacterial prostatitis (2%–5% of cases), caused by the same organisms associated with other acute urinary tract infections; (2) chronic bacterial prostatitis (2%–5% of cases), also caused by common uropathogens; and (3) chronic pelvic pain syndrome (90%–95% of cases). The latter can be subdivided into inflammatory cases, which are associated with leukocytes in prostatic secretions, and noninflammatory cases, in which leukocytes are absent.


Pathology_Robbins

Pathology_Robbins. The diagnosis of prostatitis is not typically based on biopsy, as the histologic findings are nonspecific and biopsy of an infected prostatitis can result in sepsis. The exception is granulomatous prostatitis, which may produce prostatic induration, leading to biopsy to rule out prostate cancer. In the United States, the most common cause of granulomatous prostatitis is instillation of Bacille Calmette-Guérin (BCG) within the bladder for treatment of superficial bladder cancer. BCG is an attenuated tuberculosis strain that produces a granulomatous immune reaction that is histologically indistinguishable from tuberculosis. Prostatic tuberculosis also occurs but is rare in the Western world. Fungal granulomatous prostatitis is typically seen only in immunocompromised hosts. Nonspecific granulomatous prostatitis is relatively common and stems from a foreign-body reaction to fluids that leak into tissue from ruptured prostatic ducts and acini. Postsurgical prostatic granulomas also may be


Pathology_Robbins

Pathology_Robbins. prostatitis is relatively common and stems from a foreign-body reaction to fluids that leak into tissue from ruptured prostatic ducts and acini. Postsurgical prostatic granulomas also may be seen.


Pathology_Robbins

Pathology_Robbins. http://ebooksmedicine.net


Pathology_Robbins

Pathology_Robbins. Acute bacterial prostatitis presents with sudden onset of fever, chills, dysuria, perineal pain, and bladder outlet obstruction; it may be complicated by sepsis. If acute prostatitis is suspected, digital rectal examination is contraindicated, as pressure on the boggy, exquisitely tender prostate can cause bacteremia. Chronic bacterial prostatitis usually is associated with recurrent urinary tract infections bracketed by asymptomatic periods. Presenting manifestations include low back pain, dysuria, and perineal and suprapubic discomfort. Both acute and chronic bacterial prostatitis is treated with antibiotics. Chronic pelvic pain syndrome is characterized by chronic pain localized to the perineum, suprapubic area, and penis. Pain during or after ejaculation is a prominent finding. The etiology is uncertain, and it is a diagnosis of exclusion; indeed, it is not even clear if the pain is related to an abnormality of the prostate. Therapy for chronic pelvic pain syndrome is empirical


Pathology_Robbins

Pathology_Robbins. etiology is uncertain, and it is a diagnosis of exclusion; indeed, it is not even clear if the pain is related to an abnormality of the prostate. Therapy for chronic pelvic pain syndrome is empirical and depends on the nature of the symptoms.