Pathology_Robbins

Pathology_Robbins. dysentery. Amebic liver abscesses, which can exceed 10 cm in diameter, have a scant inflammatory reaction at their margins and a shaggy fibrin lining. The abscesses persist after the acute intestinal illness has passed and may rarely reach the lung and the heart by direct extension. Amebae may also spread to the kidneys and brain via the bloodstream.


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Pathology_Robbins. Individuals with amebiasis may present with abdominal pain, bloody diarrhea, or weight loss. Occasionally, acute necrotizing colitis and megacolon occur, and both are associated with significant mortality. Vibrio cholerae secretesapreformedtoxinthatcausesmassivechloridesecretion.Waterfollowstheresultingosmoticgradient,leadingtosecretorydiarrhea. Campylobacter jejuni isthemostcommonbacterialentericpathogenindevelopedcountriesandalsocausestraveler’sdiarrhea.Mostisolatesarenoninvasive.Salmonella andShigella spp.areinvasiveandassociatedwithexudativebloodydiarrhea(dysentery).Salmonella infectionisacommoncauseoffoodpoisoning.S. typhi cancausesystemicdisease(typhoidfever). PseudomembranouscolitisisoftentriggeredbyantibiotictherapythatdisruptsthenormalmicrobiotaandallowsC. difficile tocolonizeandgrow.Theorganismproducestoxinsthatdisruptepithelialfunction.Fecalmicrobialtransplantationisbecomingmorecommonasatherapeuticapproachinindividualswithrecurrentdisease.


Pathology_Robbins

Pathology_Robbins. Rotavirus isthemostcommoncauseofseverechildhooddiarrheaanddiarrhealmortalityworldwide.Thediarrheaissecondarytolossofmatureenterocytes,resultinginmalabsorptionaswellassecretion. Parasitic andprotozoal infectionsaffectoverhalfoftheworld’spopulationonachronicorrecurrentbasis. In general, diverticular disease refers to acquired pseudodiverticular outpouchings of the colonic mucosa and sub-mucosa. Such colonic diverticula are rare in individuals younger than 30 years of age, but the prevalence approaches 50% in Western adult populations older than 60 years of age. Diverticula generally are multiple, and the condition is referred to as diverticulosis. This disease is much less common in developing countries, probably because of dietary differences.


Pathology_Robbins

Pathology_Robbins. Colonic diverticula tend to develop under conditions of elevated intraluminal pressure in the sigmoid colon. This is facilitated by the unique structure of the colonic muscularis propria, where nerves, arterial vasa recta, and their connective tissue sheaths penetrate the inner circular muscle coat to create discontinuities in the muscle wall. In other parts of the intestine, these gaps are reinforced by the external longitudinal layer of the muscularis propria, but in the colon, this muscle layer is discontinuous, being gathered into three bands termed taeniae coli. High luminal pressures may be generated by exaggerated peristaltic contractions, with spasmodic sequestration of bowel segments that may be exacerbated by diets low in fiber, which reduce stool bulk. http://ebooksmedicine.net MORPHOLOGYAnatomically,colonicdiverticulaaresmall,flasklikeoutpouchings,usually0.5to1cmindiameter,thatoccurinaregulardistributioninbetweenthetaeniaecoli(


Pathology_Robbins


Pathology_Robbins

Pathology_Robbins. Most individuals with diverticular disease remain asymptomatic throughout their lives. About 20% of those affected Fig. 15.26 Distributionoflesionsininflammatoryboweldisease.ThedistinctionbetweenCrohndiseaseandulcerativecolitisisbasedprimarilyonmorphology. Fig. 15.25 Sigmoiddiverticulardisease.(A)Endoscopicviewoftwosigmoiddiverticulae.ComparetoB. (B)Grossexaminationofaresectedsigmoidcolonshowsregularlyspacedstool-filleddiverticulae.(C)Cross-sectionshowingtheoutpouchingofmucosabeneaththemuscularispropria.(D)Low-powerphotomicrographofasigmoiddiverticulumshowingprotrusionofthemucosaandsubmucosathroughthemuscularispropria.(Endoscopic image courtesy of Dr. Ira Hanan,The University of Chicago, Chicago, Illinois.)


Pathology_Robbins

Pathology_Robbins. Continuous colonic involvement, Skip lesions develop complaints including intermittent cramping, continuous lower abdominal discomfort, constipation, and diarrhea. Longitudinal studies have shown that while diverticula can regress early in their development they often become more numerous and larger over time. Whether a high-fiber diet prevents such progression or protects against diverticulitis is unclear. Even when diverticulitis occurs, it most often resolves spontaneously or after antibiotic treatment, and relatively few patients require surgical intervention.


Pathology_Robbins

Pathology_Robbins. Inflammatory bowel disease (IBD) is a chronic condition resulting from complex interactions between intestinal microbiota and host immunity in genetically predisposed individuals resulting an inappropriate mucosal immune activation. IBD encompasses two entities, Crohn disease and ulcerative colitis. The distinction between ulcerative colitis and Crohn disease is based, in large part, on the distribution of affected sites and the morphologic expression of disease at those sites ( Fig. 15.26 Table 15.5 ). Ulcerative colitis is limited to the colon and rectum and extends only into the mucosa and submucosa. By contrast, Crohn disease, also referred to as regional enteritis (because of frequent ileal involvement), may involve any area of the gastrointestinal tract and is frequently transmural.


Pathology_Robbins

Pathology_Robbins. Both Crohn disease and ulcerative colitis frequently present during adolescence or in young adults, although some studies suggest a second, smaller peak in the incidence of both diseases after the fifth decade. In Western http://ebooksmedicine.net Table 15.5 Features of Crohn Disease and Ulcerative Colitis Feature Crohn Disease Ulcerative Colitis submucosaPseudopolypsModerateMarkedUlcersDeep, knifelikeSuperficial, broad-basedLymphoid reactionMarkedModerateFibrosisMarkedMild to noneSerositisMarkedNoGranulomasYes (∼35%)NoFistulas/sinusesYesNo Perianal fistulaYes (in colonic Nodisease)Fat/vitamin YesNomalabsorptionMalignant potentialWith colonic YesinvolvementRecurrence after CommonNosurgeryToxic megacolonNoYesNOTE: Not all features may be present in a single case.


Pathology_Robbins

Pathology_Robbins. industrialized nations, IBD is most common among whites and, in the United States, occurs three to five times more often among eastern European (Ashkenazi) Jews. This predilection is at least partly due to genetic factors, as discussed below. The geographic distribution of IBD is highly variable, but it is most prevalent in North America, northern Europe, and Australia. The incidence of IBD worldwide is on the rise and it is becoming more common in regions in which the prevalence was historically low. The hygiene hypothesis, first applied to asthma, says that childhood and even prenatal exposure to environmental microbes resets the immune system in a way that prevents excessive reactions. Extrapolated to IBD, it suggests that a reduced frequency of enteric infections due to improved hygiene has resulted in inadequate development of regulatory processes that limit mucosal immune responses early in life. While attractive and commonly stated, firm evidence is lacking and hence the


Pathology_Robbins

Pathology_Robbins. hygiene has resulted in inadequate development of regulatory processes that limit mucosal immune responses early in life. While attractive and commonly stated, firm evidence is lacking and hence the increasing incidence of IBD remains mysterious.


Pathology_Robbins

Pathology_Robbins. Although precise causes are not yet defined, most investigators believe that IBD results from the combined effects of alterations in host interactions with intestinal microbiota, intestinal epithelial dysfunction, aberrant mucosal immune responses, and altered composition of the gut microbiome. This view is supported by epidemiologic, genetic, and clinical studies as well as data from laboratory models of IBD ( Fig. 15.27 Genetics. Risk for disease is increased when there is an affected family member, and in Crohn disease, the concordance rate for monozygotic twins is approximately 50%. By contrast, concordance of monozygotic twins for ulcerative colitis is only 16%, suggesting that genetic factors are less dominant in this form of IBD.


Pathology_Robbins

Pathology_Robbins. Molecular linkage analyses of affected families have identified NOD2 (nucleotide oligomerization binding domain 2) as a susceptibility gene in Crohn disease. NOD2 encodes a protein that binds to intracellular bacterial peptidoglycans and subsequently activates NF-κB. Some studies suggest that the disease-associated form of NOD-2 is ineffective at defending against intestinal bacteria. The result is that bacteria are able to enter through the epithelium into the wall of the intestine, where they trigger inflammatory reactions. It should, however, be recognized that disease develops in less than 10% of individuals carrying specific NOD2 polymorphisms, and these polymorphisms are uncommon in African and Asian patients with Crohn disease.


Pathology_Robbins

Pathology_Robbins. The search for IBD-associated genes using genome-wide association studies (GWAS) that assess single-nucleotide polymorphisms (SNPs) as well as high throughput sequencing and other approaches have yielded a rich harvest of over 200 genes associated with IBD. Among these, NOD2, discussed above, and two autophagy–related genes are of particular interest. They are ATG16L1 (autophagy-related 16–like-1) and IRGM (immunity-related GTPase M) Barrier defects lead to influxBacteria genes. Both are part of the autophagosome pathway and, like NOD-2, are involved in host cell responses to intracellular bacteria, supporting the hypothesis that inadequate defense against luminal bacteria may be important in the pathogenesis of IBD. None of these genes is associated with ulcerative colitis.


Pathology_Robbins

Pathology_Robbins. Mucosal immune responses. Although the mechanisms by which mucosal immunity contributes to the pathogenesis of ulcerative colitis and Crohn disease are still being deciphered, immunosuppressive and immunomodulatory agents remain mainstays of IBD therapy. Polarization of helper T cells to the TH1 type is well recognized in Crohn disease, and some data suggest that TH17 T cells also contribute to disease pathogenesis. Consistent with this, certain polymorphisms of the IL-23 receptor confer protection from Crohn disease and ulcerative colitis (IL-23 is involved in the development and maintenance of TH17 cells). However, agents that block IL-17 or its receptor have provided no benefit, whereas an antibody that inhibits both TH1-and TH17-inducing cytokines is effective, suggesting that the two T cell subsets may have a synergistic role in the disease. Some data suggest that mucosal production of the TH2-derived cytokine IL-13 is increased in ulcerative colitis, and, to a lesser degree,


Pathology_Robbins

Pathology_Robbins. two T cell subsets may have a synergistic role in the disease. Some data suggest that mucosal production of the TH2-derived cytokine IL-13 is increased in ulcerative colitis, and, to a lesser degree, Crohn disease.


Pathology_Robbins

Pathology_Robbins. Defects in regulatory T cells, especially the IL-10producing subset, are believed to underlie the inflammation especially in Crohn disease. Mutations in the IL-10 receptor are associated with severe, early-onset colitis. Thus, some combination of excessive immune activation by intestinal microbes and defective immune regulation likely is responsible for the chronic inflammation in both forms of IBD.


Pathology_Robbins

Pathology_Robbins. Epithelial defects. A variety of epithelial defects have been described in Crohn disease, ulcerative colitis, or both. For example, defects in intestinal epithelial tight junction barrier function occur in patients with Crohn disease and a subset of their healthy first-degree relatives. This barrier dysfunction cosegregates with specific disease-associated NOD2 polymorphisms, and experimental models demonstrate that barrier dysfunction can activate innate and adaptive mucosal immunity and sensitize subjects to disease. Interestingly, the Paneth cell granules, which contain anti-microbial peptides that can affect composition of the luminal microbiota, are abnormal in patients with Crohn disease carrying ATG16L1 mutations, thus providing one potential mechanism in which a defective feedback loop between the epithelium and microbiota could contribute to disease pathogenesis.


Pathology_Robbins

Pathology_Robbins. Microbiota. The quantity of microbial organisms in the gastrointestinal lumen is enormous, amounting to as many as 1012 organisms/mL of fecal material in the colon (50% of fecal mass). There is significant interindividual variation in the composition of this microbial population, which is modified by diet and disease. Microbial transfer studies are able to promote or reduce disease in animal models of IBD, and clinical trials suggest that probiotic (or beneficial) bacteria or even fecal microbial transplants from healthy individuals may benefit IBD patients. One model that unifies the roles of intestinal microbiota, epithelial function, and mucosal immunity suggests a cycle by which transepithelial flux of luminal bacterial compo nents activates innate and adaptive immune responses. In a genetically susceptible host, the subsequent release of


Pathology_Robbins

Pathology_Robbins. TNF and other immune signals directs epithelia to increase tight junction permeability, which further increases the flux of luminal material. These events may establish a self- sufficient to initiate IBD. With this background of pathogenesis we will discuss next the morphologic and clinical features of each of the two forms of IBD. MORPHOLOGYCrohndisease,alsoknownasregional enteritis, mayoccurinanyareaofthegastrointestinaltractbutthemostcommonsitesinvolvedatpresentationaretheterminal ileum, ileocecal valve, andcecum. Diseaseislimitedtothesmallintestinealoneinabout40%ofcases;thesmallintestineandthecolonbothareinvolvedin30%ofpatients;andtheremainderofcasesarecharacterizedbycolonicinvolvementonly.Infrequently,Crohndiseasemayinvolvetheesophagusorstomach.Thepresenceofmultiple,separate,sharplydelineatedareasofdisease,resultinginskip lesions, ischaracteristicofCrohndiseaseandmayhelpindifferentiationfromulcerativecolitis.Stricturesarecommon( Fig.15.28A


Pathology_Robbins

Pathology_Robbins. Fig.15.29B ),ahallmarkofCrohndisease,arefoundinapproximately35%ofcasesandmayariseinareasofactivediseaseoruninvolvedregionsinanylayeroftheintestinalwall( Fig. 15.29C ).Granulomasalsomaybefoundinmesentericlymphnodes.Cutaneousgranulomasformnodulesthatarereferredto(misleadingly)asmetastatic Crohn disease.The absence of granulomas does not preclude a diagnosis of Crohn disease. http://ebooksmedicine.net Fig. 15.28 GrosspathologyofCrohndisease.(A)Small-intestinalstricture.(B)Linearmucosalulcersandthickenedintestinalwall.(C)Creepingfat. Fig. 15.29 MicroscopicpathologyofCrohndisease.(A)HaphazardcryptUlcerativecolitisalwaysinvolvestherectumandextendsproxiorganizationresultsfromrepeatedinjuryandregeneration.(B)Noncaseatingmallyinacontinuousfashiontoinvolvepartortheentirecolongranuloma.(C)TransmuralCrohndiseasewithsubmucosalandserosal


Pathology_Robbins

Pathology_Robbins. The clinical manifestations of Crohn disease are extremely variable. In most patients, disease begins with intermittent attacks of relatively mild diarrhea, fever, and abdominal pain. Approximately 20% of patients present acutely with right lower-quadrant pain and fever, which may mimic acute appendicitis or bowel perforation. Patients with colonic involvement may present with bloody diarrhea and abdominal pain, creating a differential diagnosis with some colonic infections. Periods of disease activity typically are interrupted by asymptomatic intervals that last for weeks to many months. Disease reactivation can be associated with a variety of external triggers, including physical or emotional stress, specific dietary items, NSAID use, and cigarette smoking.


Pathology_Robbins

Pathology_Robbins. Iron-deficiency anemia may develop in individuals with colonic disease, while extensive small-bowel disease may result in serum protein loss and hypoalbuminemia, generalized nutrient malabsorption, or malabsorption of vitamin B12 and bile salts. Fibrosing strictures, particularly of the terminal ileum, are common and require surgical resection. Disease often recurs at the site of anastomosis, and as many as 40% of patients require additional resections within 10 years. Fistulas develop between loops of bowel and may also involve the urinary bladder, vagina, and abdominal or perianal skin. Perforations and peritoneal abscesses can also occur.


Pathology_Robbins

Pathology_Robbins. Extraintestinal manifestations of Crohn disease include uveitis, migratory polyarthritis, sacroiliitis, ankylosing spondylitis, erythema nodosum, and clubbing of the fingertips, any of which may develop before intestinal disease is recognized. Pericholangitis and primary sclerosing cholangitis may occur in Crohn disease but are more common in ulcerative colitis. As discussed later, the risk for development of colonic adenocarcinoma is increased in patients with long-standing colonic Crohn disease. Fig.15.30A ).Skiplesionsarenot granulomas(arrows). http://ebooksmedicine.net seen(althoughfocalappendicealorcecalinflammationoccasionallymaybepresentinthosewithleft-sideddisease).Diseaseoftheentirecolonistermedpancolitis ( Fig.15.30B ).Diseaselimitedtotherectumorrectosigmoidmaybereferredtodescriptivelyasulcerative proctitis orulcerative proctosigmoiditis. Thesmallintestineisnormal,althoughmildmucosalinflammationofthedistalileum,backwash ileitis, maybepresentinseverecasesofpancolitis.


Pathology_Robbins

Pathology_Robbins. Ongrossevaluation,involvedcolonicmucosamaybeslightlyredandgranular-appearingorexhibitextensivebroad-based ulcers. Thetransitionbetweendiseasedanduninvolvedcoloncanbeabrupt(see Fig.15.30C ).UlcersarealignedalongthelongaxisofthecolonbuttypicallydonotreplicatetheserpentineulcersofCrohndisease.Isolatedislandsofregeneratingmucosaoftenbulgeintothelumentocreatesmallelevations,termedpseudopolyps. Chronicdiseasemayleadtomucosal atrophy andaflat,smoothmucosalsurfacelackingnormalfolds.UnlikeinCrohndisease,mural thickening is absent, the serosal surface is normal, and strictures do not occur. However,inflammationandinflammatorymediatorscandamagethemuscularispropriaanddisturbneuromuscularfunctionleadingtocolonicdilationandtoxic megacolon, whichcarriesasignificantriskforperforation.


Pathology_Robbins

Pathology_Robbins. HistologicfeaturesofmucosaldiseaseinulcerativecolitisaresimilartothoseincolonicCrohndiseaseandincludeinflammatoryinfiltrates,cryptabscesses,cryptdistortion,andepithelialmetaplasia.However,skip lesions are absent, and inflammation generally is limited to the mucosa and superficial submucosa ( Fig.15.30D ).Thisdistinctionmaynotbedemonstratedbyendoscopicbiopsies,whichtypicallysamplethemucosaandlittleornosubmucosa.Inseverecases,mucosaldamagemaybeaccompaniedbyulcersthatextendmoredeeplyintothesubmucosa,butthemuscularispropriaisrarelyinvolved.Submucosalfibrosis,mucosalatrophy,anddistortedmucosalarchitectureremainasresiduaofhealeddisease,butthehistologicpatternalsomayreverttonearnormalafterprolongedremission.Granulomas are not present. SomeextraintestinalmanifestationsofulcerativecolitisoverlapwiththoseofCrohndisease,includingmigratorypolyarthritis,sacroiliitis,ankylosingspondylitis,uveitis,skinlesions,pericholangitis,andprimarysclerosingcholangitis.


Pathology_Robbins

Pathology_Robbins. Ulcerative colitis is a relapsing disorder characterized by attacks of bloody diarrhea with expulsion of stringy, mucoid material and lower abdominal pain and cramps that are temporarily relieved by defecation. These symptoms may persist for days, weeks, or months before they subside, and occasionally the initial attack may be severe enough to constitute a medical or surgical emergency. More than half of patients have mild disease, but almost all experience at least one relapse during a 10-year period. Colectomy cures intestinal disease, but extraintestinal manifestations may persist. The factors that trigger ulcerative colitis are not known; infectious enteritis precedes disease onset in some cases. The onset of symptoms can occur shortly after smoking cessation in some patients, and smoking may partially relieve symptoms. Unfortunately, studies of nicotine as a therapeutic agent have been disappointing.


Pathology_Robbins

Pathology_Robbins. One of the most feared long-term complications of ulcerative colitis and colonic Crohn disease is the development of neoplasia. This process begins as dysplasia, which, just as in Barrett esophagus and chronic gastritis, is a step along the road to full-blown carcinoma. The risk for development of dysplasia is related to several factors: Duration of disease. Risk increases beginning 8 to 10 years after disease initiation. Extent of involvement. Patients with pancolitis are at greater risk than those with only left-sided disease. Fig. 15.30 Pathologyofulcerativecolitis.(A)Endoscopicviewofsevereulcerativecolitiswithulcerationandadherentmucopurulentmaterial.(B)Totalcolectomywithpancolitisshowingactivedisease,withred,granularmucosainthececum(left) andsmooth,atrophicmucosadistally(right). (C)Sharpdemarcationbetweenactiveulcerativecolitis(bottom) andnormal(top). (D)Thisfull-thicknesshistologicsectionshowsthatdiseaseislimitedtothemucosa.Comparewith


Pathology_Robbins

Pathology_Robbins. Fig.15.29C .(Endoscopic image courtesy of Dr. Ira Hanan,The University of Chicago, Chicago, Illinois.) http://ebooksmedicine.net • Inflammation. Greater frequency and severity of active inflammation (characterized by the presence of neutrophils) may increase risk. This is another example of the enabling effect of inflammation on carcinogenesis (Chapter 6).


Pathology_Robbins

Pathology_Robbins. To facilitate early detection of neoplasia, patients typically are enrolled in surveillance programs approximately 8 years after diagnosis of IBD. An important exception to this approach is in patients with primary sclerosing cholangitis, who are at markedly greater risk for development of dysplasia and generally are enrolled for surveillance at the time of diagnosis. Surveillance requires regular and extensive mucosal biopsy, making it a costly practice. In many cases, dysplasia occurs in flat areas of mucosa that do not appear abnormal by eye. Thus, advanced endoscopic imaging techniques are being developed to try to enable the detection of early dysplastic changes. Inflammatoryboweldisease(IBD)isanumbrellatermforCrohndiseaseandulcerativecolitis. Crohndiseasemostcommonlyaffectstheterminalileumandcecum,butanysitewithinthegastrointestinaltractcanbeinvolved;skiplesionsandnoncaseatinggranulomasarecommon.


Pathology_Robbins


Pathology_Robbins

Pathology_Robbins. TheriskfordevelopmentofcolonicepithelialdysplasiaandadenocarcinomaisincreasedinpatientswhohavehadcolonicIBDformorethan8to10years. Polyps are most common in the colon but may occur in the esophagus, stomach, or small intestine. Those without stalks are referred to as sessile. As sessile polyps enlarge, proliferation of cells adjacent to the polyp and the effects of traction on the luminal protrusion may combine to create a stalk. Polyps with stalks are termed pedunculated. In general, intestinal polyps can be classified as nonneoplastic or neoplastic. The most common neoplastic polyp is the adenoma, which has the potential to progress to cancer. Nonneoplastic colonic polyps can be further classified as inflammatory, hamartomatous, or hyperplastic.


Pathology_Robbins

Pathology_Robbins. The solitary rectal ulcer syndrome is associated with a purely inflammatory polyp. Patients present with the clinical triad of rectal bleeding, mucus discharge, and an inflammatory lesion of the anterior rectal wall. The underlying cause is impaired relaxation of the anorectal sphincter, creating a sharp angle at the anterior rectal shelf. This leads to recurrent abrasion and ulceration of the overlying rectal mucosa. Chronic cycles of injury and healing produce a polypoid mass composed of inflamed and reactive mucosal tissue. Hamartomatous polyps occur sporadically and as components of various genetically determined or acquired syndromes (


Pathology_Robbins

Pathology_Robbins. Hamartomatous polyps occur sporadically and as components of various genetically determined or acquired syndromes ( Table 15.6 ). As described previously, hamartomas are disorganized, tumorlike growths composed of mature cell types normally present at the site at which the polyp develops. Hamartomatous polyposis syndromes are rare, but they are important to recognize because of associated intestinal and extraintestinal manifestations and the need to screen family members.


Pathology_Robbins

Pathology_Robbins. Juvenile polyps are the most common type of hamartomatous polyp. They may be sporadic or syndromic. Sporadic juvenile polyps are usually solitary, but the number varies from 3 to as many as 100 in individuals with the autosomal dominant syndrome of juvenile polyposis. In adults, the sporadic form is sometimes also referred to as an inflammatory polyp, particularly when dense inflammatory infiltrates are present. The vast majority of juvenile polyps occur in children younger than 5 years of age. Juvenile polyps characteristically are located in the rectum and most manifest with rectal bleeding. In some cases, prolapse occurs and the polyp protrudes through the anal sphincter. Dysplasia occurs in a small proportion of (mostly syndromeassociated) juvenile polyps, and the juvenile polyposis syndrome is associated with an increased risk for development of adenocarcinoma within the colon and at other sites (


Pathology_Robbins

Pathology_Robbins. Table 15.6 ). Colectomy may be required to limit the hemorrhage associated with polyp ulceration in juvenile polyposis. MORPHOLOGYIndividualsporadicandsyndromicjuvenilepolypsoftenareindistinguishable.Theytypicallyarepedunculated,smooth-surfaced,reddishlesionsthatarelessthan3cmindiameteranddisplaycharacteristiccysticspacesoncutsections.Microscopicexaminationshowsthespacestobedilatedglandsfilledwithmucinandinflammatorydebris( Fig.15.31A ).Somedatasuggestthatmucosalhyperplasiaistheinitiatingeventinpolypdevelopment,andthismechanismisconsistentwiththediscoverythatmutationsinpathwaysthatregulatecellulargrowth,suchastransforminggrowthfactor-β (TGF-β)signaling,areassociatedwithautosomaldominantjuvenilepolyposis. Peutz-Jeghers syndrome is a rare autosomal dominant disorder defined by the presence of multiple gastrointestinal hamartomatous polyps and mucocutaneous hyperpigmentation that carries an increased risk for http://ebooksmedicine.net


Pathology_Robbins

Pathology_Robbins. TuberoussclerosisInfancytoTSC1,TSC2 Hamartomatouspolyps(rectal)Facialangiofibroma,corticaladulthood tubers,renalangiomyolipoma development of several malignancies, including cancers of the colon, pancreas, breast, lung, ovaries, uterus, and testes, as well as other unusual neoplasms. Germ line loss-of-function mutations in the LKB1/STK11 gene are present in approximately half of the patients with the familial form of Peutz-Jeghers syndrome, as well as a subset of patients with the sporadic form. LKB1/STK11 encodes a tumor suppressive protein kinase that regulates cellular metabolism, yet another example of links between alterned metabolism, abnormal cell growth, and cancer risk. Intestinal polyps are most common in the small intestine, although they may also occur in the stomach and colon and, rarely, in the bladder and lungs. On gross evaluation, the polyps are large and pedunculated with a lobulated contour. Histologic examination demonstrates a characteristic arborizing network of


Pathology_Robbins

Pathology_Robbins. and, rarely, in the bladder and lungs. On gross evaluation, the polyps are large and pedunculated with a lobulated contour. Histologic examination demonstrates a characteristic arborizing network of connective tissue, smooth muscle, lamina propria, and glands lined by normal-appearing intestinal epithelium (


Pathology_Robbins

Pathology_Robbins. Fig. 15.31B Colonic hyperplastic polyps are common epithelial proliferations that typically are discovered in the sixth and seventh decades of life. The pathogenesis of hyperplastic polyps is incompletely understood, but formation of these lesions is thought to result from decreased epithelial cell turnover and delayed shedding of surface epithelial cells, leading to a “pileup” of goblet cells. Although these lesions have no malignant potential, they must be distinguished from sessile serrated adenomas, histologically similar lesions that have malignant potential, as described later.


Pathology_Robbins

Pathology_Robbins. MORPHOLOGYHyperplasticpolypsaremostcommonlyfoundintheleftcolonandtypicallyarelessthan5mmindiameter.Theyaresmooth,nodularprotrusionsofthemucosa,oftenonthecrestsofmucosalfolds.Theymayoccursinglybutmorefrequentlyaremultiple,particularlyinthesigmoidcolonandrectum.Histologically,hyperplasticpolypsarecomposedofmaturegobletandabsorptivecells.Thedelayedsheddingofthesecellsleadstocrowdingthatcreatestheserratedsurfacearchitecture,the morphologichallmarkoftheselesions(Fig.15.32 The most common and clinically important neoplastic polyps are colonic adenomas, benign polyps that give rise to a majority of colorectal adenocarcinomas. Most adenomas, however, do not progress to adenocarcinoma.


Pathology_Robbins

Pathology_Robbins. Colorectal adenomas are characterized by the presence of epithelial dysplasia. These growths range from small, often pedunculated polyps to large sessile lesions. There is no gender predilection, and they are present in nearly 50% of adults living in the Western world beginning at age 50. Because these polyps are precursors to colorectal cancer, current recommendations are that all adults in the United States undergo screening colonoscopy starting at 50 years of age. Because individuals with a family history are at risk for developing colon cancer earlier in life, they are typically screened at least 10 years before the youngest age at which a relative was diagnosed. While adenomas are less common in Asia, their frequency has risen (in parallel with an increasing incidence of colorectal adenocarcinoma) as Western diets and lifestyles become more common. http://ebooksmedicine.net


Pathology_Robbins

Pathology_Robbins. http://ebooksmedicine.net ABABFig. 15.31 Hamartomatouspolyps.(A)Juvenilepolyp.Notethesurfaceerosionandcysticallydilatedcryptsfilledwithmucus,neutrophils,anddebris.(B)Peutz-Jegherspolyp.ComplexglandulararchitectureandbundlesofsmoothmusclehelptodistinguishPeutz-Jegherspolypsfromjuvenilepolyps. MORPHOLOGYTypicaladenomasrangefrom0.3to10cmindiameterandcanbepedunculated ( Fig.15.33A )orsessile, withthesurfaceofbothtypeshavingatextureresemblingvelvet( Fig.15.33B )oraraspberry,duetotheabnormalepithelialgrowthpattern.Histologically,thecytologichallmarkofepithelial dysplasia ( Fig.15.34C )isnuclearhyperchromasia,elongation,andstratification.Thesechangesaremosteasilyappreciatedatthesurfaceoftheadenoma,becausetheepitheliumfailstomatureascellsmigrateoutofthecrypt.Pedunculatedadenomashaveslenderfibromuscularstalks(see Fig.15.33C )containingprominentbloodvesselsderivedfromthesubmucosa.Thestalkusuallyiscoveredbynonneoplasticepithelium,butdysplasticepitheliumissometimespresent.


Pathology_Robbins

Pathology_Robbins. Thehistologicfeaturesofsessile serrated adenomas, whicharealsoreferredtoassessileserratedpolyps,overlapwiththoseofhyperplasticpolypsandlacktypicalcytologicfeaturesofdysplasia( Fig.15.34D ).Nevertheless,sessileserratedadenomas,whicharemostcommonintherightcolon,haveamalignantpotentialsimilartothatofconventionaladenomas.Themostusefulhistologicfeaturethatdistinguishessessileserratedadenomasfromhyperplasticpolypsisthepresenceofserratedarchitecturethroughoutthefulllengthoftheglands,includingthecryptbase,associatedwithcryptdilationandlateralgrowth,intheformer( Fig.15.34D ).Bycontrast,serratedarchitecturetypicallyisconfinedtothesurfaceofhyperplasticpolyps. Althoughmostcolorectaladenomasbehaveinabenignfashion,asmallproportionharborinvasivecanceratthetimeofdetection.Size is the most important characteristic that correlates with risk for malignancy. Forexample,while


Pathology_Robbins

Pathology_Robbins. Fig. 15.32 Hyperplasticpolyp.(A)Polypsurfacewithirregulartuftingofepithelialcells.(B)Tuftingresultsfromepithelialovercrowding.(C)Epithelialcrowdingproducesaserratedarchitecturewhenglandsarecutincross-section. http://ebooksmedicine.net Fig. 15.33 Colonicadenomas.(A)Pedunculatedadenoma(endoscopicview).(B)Adenomawithavelvetysurface.(C)Low-magnificationphotomicrograph ofapedunculatedtubularadenoma.


Pathology_Robbins

Pathology_Robbins. Fig.15.32 cancerisextremelyrareinadenomaslessthan1cmindiameter,somestudiessuggestthatnearly40%oflesionslargerthan4cmindiametercontainfociofinvasivecancer.Inadditiontosize,high-gradedysplasiaisariskfactorforcancerinanindividualpolyp(butnototherpolypsinthesamepatient). Several syndromes associated with colonic polyps and increased rates of colon cancer have been described. The genetic basis of these disorders has been established and has greatly enhanced the current understanding of sporadic colon cancer ( Table 15.7 Familial adenomatous polyposis (FAP) is an autosomal dominant disorder marked by the appearance of numerous colorectal adenomas by the teenage years. It is caused by mutations of the adenomatous polyposis coli gene (APC). A count of at least 100 polyps is necessary for a diagnosis of classic FAP, and as many as several thousand may be present (


Pathology_Robbins

Pathology_Robbins. Fig. 15.35 ). Except for their remarkable numbers, these growths are morphologically indistinguishable from sporadic adenomas. Colorectal adenocarcinoma develops in 100% of patients with untreated FAP, often before 30 years of age. As a result, prophylactic colectomy is standard therapy for individuals carrying APC mutations. However, patients remain at risk for extraintestinal manifestations, including neoplasia at other sites. Specific APC mutations are also associated with the development of other manifestations of FAP and explain variants such as Gardner syndrome and Turcot syndrome. In addition to intestinal polyps, clinical features of Gardner syndrome, a variant of FAP, may include osteomas of the mandible, skull, and long bones; epidermal cysts; desmoid and thyroid tumors; and dental abnormalities, including unerupted and supernumerary teeth. Turcot syndrome is rarer and is characterized by intestinal adenomas and tumors of the central nervous system. Two-thirds of


Pathology_Robbins

Pathology_Robbins. and dental abnormalities, including unerupted and supernumerary teeth. Turcot syndrome is rarer and is characterized by intestinal adenomas and tumors of the central nervous system. Two-thirds of http://ebooksmedicine.net


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Pathology_Robbins. Table 15.7 Common Patterns of Sporadic and Familial Colorectal Neoplasia FamilialadenomatousAPC/WNTpathwayAPC AutosomaldominantNoneTubular,villous;typicalpolyposis(70%ofFAP) HereditarynonpolyposisDNAmismatchrepairMSH2, MLH1 AutosomaldominantRightsideSessileserratedadenoma;colorectalcancer patients with Turcot syndrome have APC gene mutations and develop medulloblastomas. The remaining one-third have mutations in one of several genes involved in DNA repair and develop glioblastomas. Some patients with hundreds of adenomas lack APC mutations but instead have mutations of the base excision repair gene MUTYH (also called MUTYH polyposis). The role of these genes in tumor development is discussed later. Hereditary nonpolyposis colorectal cancer (HNPCC), also known as Lynch syndrome, originally was described as familial clustering of cancers at several sites including the colorectum, endometrium, stomach, ovary, ureters, brain,


Pathology_Robbins

Pathology_Robbins. Fig. 15.35 Familialadenomatouspolyposis.(A)Hundredsofsmallcolonicpolypsarepresentalongwithadominantpolyp(right). (B)Threetubularadenomasarepresentinthissinglemicroscopicfield. small bowel, hepatobiliary tract, and skin. Colon cancers in patients with HNPCC tend to occur at younger ages than do sporadic colon cancers and often are located in the right colon ( Table 15.7 ). Adenomas are present in HNPCC, but excessive numbers (i.e., polyposis) is not. In many cases, sessile serrated adenomas are associated with HNPCC, and mucin production may be a prominent in the subsequent adenocarcinomas.


Pathology_Robbins

Pathology_Robbins. Just as identification of APC mutations in FAP has provided molecular insights into the pathogenesis of a majority of sporadic colon cancers, dissection of the defects in HNPCC has shed light on the mechanisms responsible for most of the remaining sporadic cases. HNPCC is caused by inherited germ line mutations in genes that encode proteins responsible for the detection, excision, and repair of errors that occur during DNA replication. At least five such mismatch repair genes have been recognized, but a majority of HNPCC cases involve either MSH2 or MLH1. Patients with HNPCC inherit one mutated DNA repair gene and one normal allele. When the second copy is lost through mutation or epigenetic silencing, defects in mismatch repair lead to the accumulation of mutations at rates up to 1000 times higher than normal, mostly in regions containing short repeating DNA sequences referred to as microsatellite DNA. The human genome contains approximately 50,000 to 100,000 microsatellites, which


Pathology_Robbins

Pathology_Robbins. higher than normal, mostly in regions containing short repeating DNA sequences referred to as microsatellite DNA. The human genome contains approximately 50,000 to 100,000 microsatellites, which are prone to undergo expansion during DNA replication and represent the most frequent sites of mutations in HNPCC. The consequences of mismatch repair defects and the resulting microsatellite instability are discussed next in the context of colonic adenocarcinoma.


Pathology_Robbins

Pathology_Robbins. Adenocarcinoma of the colon is the most common malignancy of the gastrointestinal tract and is a major contributor to morbidity and mortality worldwide. By contrast, the small intestine, which accounts for 75% of the overall length of the gastrointestinal tract, is an uncommon site for benign and malignant tumors. Among malignant small-intestinal tumors, adenocarcinomas and carcinoid (neuroendocrine) tumors have roughly equal rates of occurrence, followed by lymphomas and sarcomas.


Pathology_Robbins

Pathology_Robbins. Each year in the United States, there are more than 130,000 new cases and nearly 50,000 deaths from colorectal adenocarcinoma. This represents nearly 15% of all cancer-related deaths, second only to lung cancer. Colorectal cancer incidence peaks at 60 to 70 years of age; less than 20% of cases occur before 50 years of age. Males are affected slightly more often than females. Colorectal carcinoma is most prevalent in the United States, Canada, Australia, New Zealand, Denmark, Sweden, and other (so-called) developed countries that share lifestyles and diet. The incidence of this cancer is as much as 30-fold lower in India, South America, and Africa. In Japan, where incidence was previously very low, rates have now risen to intermediate levels (similar to those in the United Kingdom), presumably as a result of changes in lifestyle and diet. http://ebooksmedicine.net


Pathology_Robbins

Pathology_Robbins. http://ebooksmedicine.net The dietary factors most closely associated with increased colorectal cancer rates are low intake of unabsorbable vegetable fiber and high intake of refined carbohydrates and fat. In addition to dietary modification, pharmacologic chemoprevention has become an area of great interest. Several epidemiologic studies suggest that aspirin or other NSAIDs have a protective effect. This is consistent with studies showing that some NSAIDs cause polyp regression in patients with FAP in whom the rectum was left in place after colectomy. It is suspected that this effect is mediated by inhibition of the enzyme cyclooxygenase-2 (COX-2), which is highly expressed in 90% of colorectal carcinomas and 40% to 90% of adenomas and is known to promote epithelial proliferation, particularly in response to injury.


Pathology_Robbins

Pathology_Robbins. Studies of colorectal carcinogenesis have provided fundamental insights into the general mechanisms of cancer evolution. The combination of molecular events that lead to colonic adenocarcinoma is heterogeneous and includes genetic and epigenetic abnormalities. At least two distinct genetic pathways, the APC/β-catenin pathway and the microsatellite instability pathway, have been described. In simplest terms, mutations involving the APC/β-catenin pathway lead to increased WNT signaling, whereas those involving the microsatellite instability pathway are associated with defects in DNA mismatch repair (see Table 15.7). Both pathways involve the stepwise accumulation of multiple mutations, but the genes involved and the mechanisms by which the mutations accumulate differ. Epigenetic events, the most common of which is methylation-induced gene silencing, may enhance progression along both pathways.


Pathology_Robbins

Pathology_Robbins. • The APC/β-catenin pathway. The classic adenomacarcinoma sequence, which accounts for as much as 80% of sporadic colon tumors, typically involves mutation of the APC tumor suppressor early in the neoplastic process (


Pathology_Robbins

Pathology_Robbins. Fig. 15.36 ). For adenomas to develop, both copies of the APC gene must be functionally inactivated, either by mutation or epigenetic events. APC is a key negative regulator of β-catenin, a component of the WNT signaling pathway (Chapter 6). The APC protein normally binds to and promotes degradation of β-catenin. With loss of APC function, β-catenin accumulates and translocates to the nucleus, where it activates the transcription of genes, such as those encoding MYC and cyclin D1, that promote proliferation. This is followed by additional mutations, including activating mutations in KRAS, which also promote growth and prevent apoptosis. The conclusion that mutation of KRAS is a late event is supported by the observations that mutations are present in fewer than 10% of adenomas less than 1 cm in diameter, 50% of adenomas greater than 1 cm in diameter, and 50% of invasive adenocarcinomas. Neoplastic progression also is associated with mutations in other tumor suppressor genes such as


Pathology_Robbins

Pathology_Robbins. 1 cm in diameter, 50% of adenomas greater than 1 cm in diameter, and 50% of invasive adenocarcinomas. Neoplastic progression also is associated with mutations in other tumor suppressor genes such as SMAD2 and SMAD4, which encode effectors of TGF-β signaling. Because TGF-β signaling normally inhibits the cell cycle, loss of these genes may allow unrestrained cell growth.


Pathology_Robbins


Pathology_Robbins

Pathology_Robbins. http://ebooksmedicine.net The tumor suppressor gene TP53 is mutated in 70% to 80% of colon cancers but is uncommonly affected in adenomas, suggesting that TP53 mutations also occur at late stages of tumor progression. Loss of function of TP53 and other tumor suppressor genes is often caused by chromosomal deletions, highlighting chromosomal instability as a hallmark of the APC/β-catenin pathway. Alternatively, tumor suppressor genes may be silenced by methylation of CpG islands, a 5′ region of some genes that frequently includes the promoter and transcriptional start site. Expression of telomerase also increases as lesions become more advanced.


Pathology_Robbins

Pathology_Robbins. The microsatellite instability pathway. In patients with DNA mismatch repair deficiency (due to loss of mismatch repair genes, as discussed earlier), mutations accumulate in microsatellite repeats, a condition referred to as microsatellite instability. These mutations generally are silent, because microsatellites typically are located in noncoding regions, but other microsatellite sequences are located in the coding or promoter regions of genes involved in regulation of cell growth, such as those encoding the type II TGF-β receptor and the proapoptotic protein BAX (Fig. 15.37 ). Because TGF-β inhibits colonic epithelial cell proliferation, type II TGF-β receptor mutants can contribute to uncontrolled cell growth, while loss of BAX may enhance the survival of genetically abnormal clones.


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Pathology_Robbins. CpG island hyper methylation phenotype (CIMP). In a subset of colon cancers with microsatellite instability, there are no mutations in DNA mismatch repair enzymes. These tumors demonstrate the CpG island hypermethylation phenotype (CIMP). In these tumors, the MLH1 promoter region is typically hypermethylated, thereby reducing MLH1 expression and repair function. Activating mutations in the BRAF oncogene are common in these cancers. In contrast, KRAS and TP53 are not typically mutated. Thus, the combination of microsatellite instability, BRAF mutation, and methylation of specific targets, such as MLH1, is the signature of this pathway of carcinogenesis. Overall, adenocarcinomas are distributed approximately equally over the entire length of the colon. Tumors in the proximal colon often grow as polypoid, exophytic masses that extend along one wall of the large-caliber cecum and ascending colon; these tumors rarely cause obstruction (


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Pathology_Robbins. Fig. 15.38A ). By contrast, carcinomas in the distal colon tend to be annular lesions that produce “napkin ring” constrictions and luminal narrowing ( Fig. 15.38B ), sometimes to the point of obstruction. Both forms grow into the bowel wall over time and may be palpable as firm masses ( Fig. 15.38C ). The general microscopic characteristics of right- and left-sided colonic adenocarcinomas are similar. Most tumors are composed of tall columnar cells that resemble dysplastic epithelium found in adenomas ( Fig. 15.39A ). The invasive component of these tumors elicits a strong stromal desmoplastic response, which is responsible for their characteristic firm consistency. Some poorly differentiated tumors form few glands ( Fig. 15.39B). Others may produce abundant mucin that accumulates within the intestinal wall, and these carry a poor prognosis. Tumors also may be composed of signet ring cells similar to those in gastric cancer ( Fig. 15.39C


Pathology_Robbins

Pathology_Robbins. Fig. 15.39C The availability of endoscopic screening combined with the recognition that most carcinomas arise within adenomas presents a unique opportunity for cancer prevention. Unfortunately, colorectal cancers develop insidiously and may therefore go undetected for long periods. Cecal and other right-sided colon cancers most often are called to clinical attention by the appearance of fatigue and weakness due to iron-deficiency anemia.Thus, it is a clinical maxim that the underlying cause of iron-deficiency anemia in an older male or postmenopausal female is gastrointestinal cancer until proven otherwise. Left-sided colorectal adenocarcinomas may produce occult bleeding, changes in bowel habits, or cramping left lower-quadrant discomfort. Although poorly differentiated and mucinous histologic patterns are associated with poor prognosis, the two most important prognostic factors are depth of invasion and the MLH1, MSH2 (MSH6, PMS1, PMS2)


Pathology_Robbins

Pathology_Robbins. MLH1, MSH2 (MSH6, PMS1, PMS2) Microsatellite instability/ "mutator phenotype" Accumulated mutations in genes that regulate growth, differentiation, and/or apoptosis TGF RII, BAX, BRAF, TCF-4, IGF2R, others Fig. 15.37 Morphologic and molecular changes in the mismatch repair pathway of colon carcinogenesis. Defects in mismatch repair genes result in micro-satellite instability and permit accumulation of mutations in numerous genes. If these mutations affect genes involved in cell survival and proliferation, cancer may develop. LOH, Loss of heterozygosity.


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Pathology_Robbins. Fig. 15.38 Colorectalcarcinoma.(A)Endoscopicviewofulceratedascendingcolonadenocarcinoma.(B)Circumferential,ulceratedrectalcancer.Notetheanalmucosaatthebottomoftheimage.(C)Cancerofthesigmoidcolonthathasinvadedthroughthemuscularispropriaandispresentwithinsubserosaladiposetissue(left). Areasofchalkynecrosisarepresentwithinthecolonwall(arrow). (Endoscopic image courtesy of Dr. Ira Hanan,The University of Chicago, Chicago, Illinois.) presence or absence of lymph node metastases. These factors were originally recognized by Dukes and Kirklin and form the core of the TNM (tumor-node-metastasis) classification and staging system from the American Joint Committee on Cancer. Staging systems have become more complex with time, reflecting more nuanced treatment approaches and personalized therapeutic strategies. The most important distinctions are:


Pathology_Robbins

Pathology_Robbins. Depth of invasion. Tumors limited to the submucosa (i.e., those that do not cross the muscularis mucosae) have 5-year survival rates approaching 100%, while invasion into the submucosa or muscularis propria reduces 5-year survival to 95% and 70% to 90%, respectively (for tumors limited to the primary site). Invasion through the visceral serosal surface or into adjacent organs and tissues reduces survival further. The presence of lymph node metastases ( Fig. 15.40A ) further compromises survival. As a result, most cases with lymph node metastases receive radiation or chemotherapy. In some cases, these treatments may be administered prior to primary tumor resection, a process termed neoadjuvant therapy. Molecular characterization of the tumor can be helpful in guiding the specific therapeutic approach. • Distant metastases to lung ( Fig. 15.40B ), liver (


Pathology_Robbins

Pathology_Robbins. • Distant metastases to lung ( Fig. 15.40B ), liver ( Fig. 15.40C ), or other sites also limits survival, and only 15% or fewer of patients with tumors at this stage are alive 5 years after diagnosis. Because of the portal drainage, the liver is the most common site of metastatic lesions. However, the rectum does not drain by way of the portal circulation, and metastases from carcinomas of the anorectum region often circumvent the liver. Regardless of stage, however, some patients with small numbers of metastases do well for years after resection of distant tumor nodules. This is particularly true of metastases to liver or lung and emphasizes the clinical and molecular heterogeneity of colorectal carcinomas.


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Pathology_Robbins. Fig. 15.39 Histologicappearanceofcolorectalcarcinoma.(A)Well-differentiatedadenocarcinoma.Notetheelongated,hyperchromaticnuclei.Necroticdebris,presentintheglandlumen,istypical.(B)Poorlydifferentiatedadenocarcinomaformsafewglandsbutislargelycomposedofinfiltratingnestsoftumorcells.(C)Mucinousadenocarcinomawithsignetringcellsandextracellularmucinpools. http://ebooksmedicine.net Fig. 15.40 Metastaticcolorectalcarcinoma.(A)Lymphnodemetastasis.Notetheglandularstructureswithinthesubcapsularsinus.(B)Solitarysubpleuralnoduleofcolorectalcarcinomametastatictothelung.(C)Livercontainingtwolargeandmanysmallermetastases.Notethecentralnecrosiswithinmetastases. COLONICPOLYPS,ADENOMAS,ANDADENOCARCINOMAS Intestinal polyps canbeclassifiedasnonneoplastic orneoplastic. Thenonneoplasticpolypscanbefurtherdefinedasinflammatory, hamartomatous, orhyperplastic. Inflammatory polyps formasaresultofchroniccyclesofinjuryandhealing.


Pathology_Robbins

Pathology_Robbins. Inflammatory polyps formasaresultofchroniccyclesofinjuryandhealing. Hamartomatous polyps occursporadicallyorasapartofgeneticdiseases.Inthelattercase,theyoftenareassociatedwithincreasedriskformalignancy. Hyperplastic polyps arebenignepithelialproliferationsmostcommonlyfoundintheleftcolonandrectum.Theyarenotreactiveinorigin,incontrastwithgastrichyperplasticpolyps;havenomalignantpotential;andmustbedistinguishedfromsessileserratedadenomasorpolyps. Benign epithelial neoplastic polyps ofthecolonaretermedadeno-mas.Thehallmarkfeatureoftheselesions,whicharetheprecursorsofcolonicadenocarcinomas,iscytologicdysplasia. Incontrastwithtraditionaladenomas,sessile serrated adenomas,orpolyps,lackcytologicdysplasiaandsharesomemorphologicfeatureswithhyperplasticpolyps.


Pathology_Robbins

Pathology_Robbins. Incontrastwithtraditionaladenomas,sessile serrated adenomas,orpolyps,lackcytologicdysplasiaandsharesomemorphologicfeatureswithhyperplasticpolyps. Familial adenomatous polyposis (FAP) andhereditary nonpolyposis colorectal cancer (HNPCC) arethemostcommonformsoffamilialcoloncancer.FAPiscausedbyAPC mutations,andpatientstypicallyhaveover100adenomasanddevelopcoloncancerbefore30yearsofage. HNPCCiscausedbymutationsinDNAmismatchrepairgenes.PatientswithHNPCChavefarfewerpolypsanddevelopcanceratanolderagethanthattypicalforpatientswithFAPbutatayoungeragethaninpatientswithsporadiccoloncancer. Thevastmajorityofcoloniccancersareadenocarcinomas.TheyariseeitherbyAPC-β-cateninpathwayorthemicrosatelliteinstabilitypathway.Thetwomostimportantprognosticfactorsaredepthofinvasionandthepresenceorabsenceofmetastasestolymphnodesordistantorgans.


Pathology_Robbins

Pathology_Robbins. The appendix is a normal true diverticulum of the cecum. Like any diverticulum, it is prone to acute and chronic inflammation, and acute appendicitis is a relatively common entity. Other lesions, including tumors, can also occur in the appendix but are far less common. Acute appendicitis is most common in adolescents and young adults but may occur in any age group. The lifetime risk for appendicitis is 7%; males are affected slightly more often than females. Despite the prevalence of acute appendicitis, the diagnosis can be difficult to confirm preoperatively, and the condition may be confused with mesenteric lymphadenitis, acute salpingitis, ectopic pregnancy, mittelschmerz (pain associated with ovulation), and Meckel diverticulitis.


Pathology_Robbins

Pathology_Robbins. Acute appendicitis is thought to be initiated by progressive increase in intraluminal pressure that compromises venous outflow. In 50% to 80% of cases, acute appendicitis is associated with overt luminal obstruction, usually by a small, stone-like mass of stool, or fecalith, or, less commonly, a gallstone, tumor, or mass of worms. Ischemic injury and stasis of luminal contents, which favor bacterial proliferation, trigger inflammatory responses including tissue edema and neutrophilic infiltration of the lumen, muscular wall, and periappendiceal soft tissues.


Pathology_Robbins

Pathology_Robbins. Typically, early acute appendicitis produces periumbilical pain that ultimately localizes to the right lower quadrant, followed by nausea, vomiting, low-grade fever, and a mildly elevated peripheral white blood cell count. A classic physical finding is McBurney’s sign, deep tenderness noted at a location two-thirds of the distance from the umbilicus to the right anterior superior iliac spine (McBurney’s point). These signs and symptoms however, are often absent, creating difficulty in clinical diagnosis.


Pathology_Robbins

Pathology_Robbins. The most common tumor of the appendix is the carcinoid, or well-differentiated neuroendocrine tumor. It usually is discovered incidentally at the time of surgery or on examination of a resected appendix. This neoplasm most frequently involves the distal tip of the appendix, where it produces a solid bulbous swelling up to 2 to 3 cm in diameter. Although intramural and transmural extension may be evident, nodal metastases are very infrequent, and distant spread is exceptionally rare. Conventional adenomas or non–mucin-producing adenocarcinomas also occur in the appendix and may cause obstruction and enlargement that mimics the changes of acute appendicitis. Mucocele, a dilated appendix filled with mucin, may simply stem from an obstructed appendix containing inspissated mucin or may be a consequence of mucinous cystadenoma or mucinous cystadenocarcinoma. In the latter instance invasion through the appendiceal wall can lead to intraperitoneal seeding and spread. In women, the resulting


Pathology_Robbins

Pathology_Robbins. of mucinous cystadenoma or mucinous cystadenocarcinoma. In the latter instance invasion through the appendiceal wall can lead to intraperitoneal seeding and spread. In women, the resulting peritoneal implants may be mistaken for mucinous ovarian tumors. In the most advanced cases, the abdomen fills with tenacious, semisolid mucin, a condition called pseudomyxoma peritonei. This disseminated intraperitoneal disease may be held in check for years by repeated debulking, but ultimately is fatal in most instances.


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Pathology_Robbins. •Acuteappendicitisismostcommoninchildrenandadolescents.Itisthoughttobeinitiatedbyincreasedintraluminalpressureconsequenttoobstructionoftheappendiceallumen,whichcompromisesvenousoutflow. Themostcommontumoroftheappendix,thecarcinoid, orwell-differentiated neuroendocrine tumor, ismostoftendiscoveredincidentallyandisalmostalwaysbenign Theclinicalpresentationofappendicealadenocarcinomacanbeindistinguishablefromthatofacuteappendicitis,althoughtheformertendstopresentinolderpatients. Hennessey PT, Westra WH, Califano JA: Human papillomavirus and head and neck squamous cell carcinoma: recent evidence and clinical implications, J Dent Res 88:300, 2009. [A discussion of head and neck cancers associated with HPV.] Leemans CR, Braakhuis BJ, Brakenhoff RH: The molecular biology of head and neck cancer, Nat Rev Cancer 11:9, 2011. [A discussion of the molecular biology of head and neck cancer.]


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Pathology_Robbins. Leemans CR, Braakhuis BJ, Brakenhoff RH: The molecular biology of head and neck cancer, Nat Rev Cancer 11:9, 2011. [A discussion of the molecular biology of head and neck cancer.] Leivo I: Insights into a complex group of neoplastic disease: advances in histopathologic classification and molecular pathology of salivary gland cancer, Acta Oncol 45:662, 2006. [A good review of the histologic spectrum of salivary gland tumors.] Abonia JP, Rothenberg ME: Eosinophilic esophagitis: rapidly advancing insights, Annu Rev Med 63:421–434, 2012. [A comprehensive review of eosinophilic esophagitis.] Boeckxstaens GE, Zaninotto G, Richter JE: Achalasia, Lancet 383:83–93, 2014. [A clinically focused discussion of achalasia.] Clave P, Shaker R: Dysphagia: current reality and scope of the problem, Nat Rev Gastroenterol Hepatol 12:259–270, 2015. [A brief review of dysphagia management.]


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Pathology_Robbins. Clave P, Shaker R: Dysphagia: current reality and scope of the problem, Nat Rev Gastroenterol Hepatol 12:259–270, 2015. [A brief review of dysphagia management.] McDonald SAC, Graham TA, Lavery DL, et al: The Barrett’s gland in phenotype space, Cell Mol Gastroenterol Hepatol 1:41–54, 2015. [A detailed diiscussion of Barrett esophagus and metaplasia.] Spechler SJ, Souza RF: Barrett’s esophagus, N Engl J Med 371:836–845, 2014. [A clinically oriented review of Barrett esophagus.] Lin JT: Screening of gastric cancer: who, when, and how, Clin Gastroenterol Hepatol 12:135–138, 2014. [A discussion of gastric cancer screening indications and efficacy.] Shaib YH, Rugge M, Graham DY, et al: Management of gastric polyps: an endoscopy-based approach, Clin Gastroenterol Hepatol 11:1374– 1384, 2013. [A discussion of gastric polyps and their management.]


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Pathology_Robbins. Shaib YH, Rugge M, Graham DY, et al: Management of gastric polyps: an endoscopy-based approach, Clin Gastroenterol Hepatol 11:1374– 1384, 2013. [A discussion of gastric polyps and their management.] Wroblewski LE, Peek RM Jr: Helicobacter pylori in gastric carcinogenesis: mechanisms, Gastroenterol Clin North Am 42:285–298, 2013. [A comprehensive review of gastritis-associated gastric cancer.] Schappi MG, Staiano A, Milla PJ, et al: A practical guide for the diagnosis of primary enteric nervous system disorders, J Pediatr Gastroenterol Nutr 57:677–686, 2013. [A clinically oriented review of dysmotility.] Barzilay EJ, Schaad N, Magloire R, et al: Cholera surveillance during the Haiti epidemic—the first 2 years, N Engl J Med 368:599–609, 2013. [A review of the Haitian cholera epidemic.]


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Pathology_Robbins. Barzilay EJ, Schaad N, Magloire R, et al: Cholera surveillance during the Haiti epidemic—the first 2 years, N Engl J Med 368:599–609, 2013. [A review of the Haitian cholera epidemic.] Camilleri M: Intestinal secretory mechanisms in irritable bowel syndrome—diarrhea, Clin Gastroenterol Hepatol 13:1051–1057, quiz e61–e62, 2015. [A discussion of defects in secretion in patients with irritable bowel syndrome.] Ludvigsson JF, Green PH: The missing environmental factor in celiac disease, N Engl J Med 371:1341–1343, 2014. [A review of celiac disease pathogenesis.] http://ebooksmedicine.net van Nood E, Vrieze A, Nieuwdorp M, et al: Duodenal infusion of donor feces for recurrent Clostridium difficile, N Engl J Med 368: 407–415, 2013. [The first series showing efficacy of fecal microbial transplantation for recurrent C. difficile infection.]


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Pathology_Robbins. Mosadeghi S, Bhuket T, Stollman N: Diverticular disease: evolving concepts in classification, presentation, and management, Curr Opin Gastroenterol 31:50–55, 2015. [A review of diverticulitis and approaches to its treatment.] Jostins L, Ripke S, Weersma RK, et al: Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease, Nature 491:119–124, 2012. [A comprehensive review of polymorphisms linked to inflammatory bowel disease and their relationship to immune defense.] Rogler G: Chronic ulcerative colitis and colorectal cancer, Cancer Lett 345:235–241, 2014. [A review of colitis-associated cancer.] Brenner H, Kloor M, Pox CP: Colorectal cancer, Lancet 383:1490–1502, 2014. [A clinically oriented review of colorectal cancer.] Corley DA, Levin TR: Doubeni CA: Adenoma detection rate and risk of colorectal cancer and death, N Engl J Med 370:2541, 2014. [A study of adenoma detection and relationship to cancer risk.]


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Pathology_Robbins. Corley DA, Levin TR: Doubeni CA: Adenoma detection rate and risk of colorectal cancer and death, N Engl J Med 370:2541, 2014. [A study of adenoma detection and relationship to cancer risk.] Cartwright SL, Knudson MP: Evaluation of acute abdominal pain in adults, Am Fam Physician 77:971, 2008. [Clinically oriented approach to the acute abdomen.] Deschamps L, Couvelard A: Endocrine tumors of the appendix: a pathologic review, Arch Pathol Lab Med 134:871, 2010. [Pathologyfocused review of appendiceal carcinoid tumors.] http://ebooksmedicine.net studentconsult.com The Liver and Bile Ducts Mechanisms of Injury and Repair Bacterial, Parasitic, and Helminthic Infections Pathophysiology of Jaundice Impaired Blood Flow Into the Liver Impaired Blood Flow Through the Liver The Liver and Bile Ducts


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Pathology_Robbins. Bacterial, Parasitic, and Helminthic Infections Pathophysiology of Jaundice Impaired Blood Flow Into the Liver Impaired Blood Flow Through the Liver The Liver and Bile Ducts The normal adult liver weighs 1400 to 1600 gm. It has a dual blood supply, with the portal vein providing 60% to 70% of hepatic blood flow and the hepatic artery supplying the remaining 30% to 40%. The portal vein and the hepatic artery enter the inferior aspect of the liver through the hilum, or porta hepatis. Within the liver, the branches of the portal veins, hepatic arteries, and bile ducts travel in parallel within portal tracts, ramifying variably through 10 to 12 orders of branches. The most common terminology used to describe the hepatic microarchitecture is based on the lobular model (


Pathology_Robbins

Pathology_Robbins. The most common terminology used to describe the hepatic microarchitecture is based on the lobular model ( Fig. 16.1 ). This model divides the liver into lobules 1to 2-mm in diameter that are centered on a terminal tributary of the hepatic vein and demarcated by portal tracts at their periphery. These lobules are often drawn as hexagonal structures, though in humans the shapes are far more variable; nonetheless, it is a useful simplification. A second model divides the liver into triangular acini (see Fig. 16.1 ) based on the position of hepatocytes relative to their blood supply. The hepatocytes in the vicinity of the terminal hepatic vein are called centrilobular; those near the portal tract are periportal. Division of the lobular parenchyma into zones is an important concept because each zone differs with respect to its metabolic activities and susceptibility to certain forms of hepatic injury.


Pathology_Robbins

Pathology_Robbins. Within the lobule, hepatocytes are organized into anastomosing sheets or “plates” extending from portal tracts to the terminal hepatic veins. Between the trabecular plates of hepatocytes are vascular sinusoids. Blood traverses the sinusoids and exits into the terminal hepatic veins through numerous orifices in the vein wall. Hepatocytes are thus bathed by well-mixed portal venous blood on one side and hepatic arterial blood on the other. The sinusoids are lined by a fenestrated endothelium that overlies a perisinusoidal space (the space of Disse) into which abundant hepatocyte microvilli protrude. Attached to the luminal face of the sinusoids are scattered Kupffer cells, specialized long-lived tissue macrophages that arise early in embryogenesis. Another specialized cell type, the hepatic stellate cell, is found in the space of Disse and has a role in the storage of vitamin A. Between abutting hepatocytes are bile canaliculi, channels 1 to 2 µm in diameter that are formed by grooves


Pathology_Robbins

Pathology_Robbins. stellate cell, is found in the space of Disse and has a role in the storage of vitamin A. Between abutting hepatocytes are bile canaliculi, channels 1 to 2 µm in diameter that are formed by grooves in the plasma membranes of adjacent hepatocytes and are separated from the vascular space by tight junctions. These channels drain successively into the intralobular canals of Hering, periportal bile ductules, and finally into the terminal bile ducts within the portal tracts.


Pathology_Robbins

Pathology_Robbins. http://ebooksmedicine.net Fig. 16.1 Modelsofliveranatomy.Inthelobularmodel,theterminalhepaticveinisatthecenterofa“lobule,”whiletheportaltractsareattheperiphery.Pathologistsoftenrefertotheregionsoftheparenchymaas“periportalandcentrilobular.”Intheacinarmodel,onthebasisofbloodflow,threezonescanbedefined,zone1beingtheclosesttothebloodsupplyandzone3beingthefarthest.BD, Bileduct;CV, centralhepaticvein;HA, hepaticartery;PV, portaltracts. The major primary diseases of the liver are viral hepatitis, alcoholic liver disease, nonalcoholic fatty liver disease (NAFLD), and hepatocellular carcinoma (HCC). The liver also is frequently damaged secondarily in a variety of common disorders, such as cardiac disease, disseminated cancer, and extrahepatic infections. The functional reserve of the liver masks the clinical impact of mild liver damage, but severe diffuse liver disease often has life-threatening consequences.


Pathology_Robbins

Pathology_Robbins. With the rare exception of fulminant hepatic failure, liver disease is an insidious process in which the signs and symptoms of hepatic decompensation appear weeks, months, or even years after the onset of injury. The hepatic injury may be imperceptible to the patient and be manifest only by laboratory test abnormalities ( Table 16.1 ), and liver injury and healing also may be subclinical. Hence, individuals with hepatic abnormalities who are referred to hepatologists most frequently have chronic liver disease. Injured hepatocytes may show several potentially reversible changes, such as accumulation of fat and bilirubin (cholestasis); when injury is not reversible, hepatocytes die by necrosis or apoptosis. Necrosis ( Fig. 16.2 ) is commonly seen following hepatic injury caused by hypoxia and ischemia. Apoptotic cell death ( Fig. 16.3 ) predominates in viral, autoimmune, and drug-and toxin-induced hepatitides. Table 16.1 Laboratory Evaluation of Liver Disease


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Pathology_Robbins. Fig. 16.3 ) predominates in viral, autoimmune, and drug-and toxin-induced hepatitides. Table 16.1 Laboratory Evaluation of Liver Disease Total: unconjugatedplusconjugated Direct: conjugatedonly *Mostcommonlyusedtestsareinitalics;†anelevationsuggestsliverdisease;‡adecreasesuggestsliverdisease. Widespread death of hepatocytes may produce confluent necrosis. This may be seen in acute toxic or ischemic injuries or in severe chronic viral or autoimmune hepatitis. Confluent necrosis begins as a zone of hepatocyte dropout around the central vein. With increasing severity necrosis “bridges” central veins and portal tracts or adjacent portal tracts. Fig. 16.2 Hepatocytenecrosis.InthisPAS-D–stainedbiopsyfromapatientwithacutehepatitisB,clustersofpigmentedhepatocyteswitheosinophiliccytoplasmindicatefociofhepatocytesundergoingnecrosis.PAS-D, Periodicacid-Schiffstainafterdiastasedigestion. http://ebooksmedicine.net


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Pathology_Robbins. http://ebooksmedicine.net Fig. 16.3 Hepatocyteapoptosis.ThisbiopsyfromapatientwithlobularhepatitisduetochronichepatitisCshowsscatteredapoptotichepatocytes(“acidophilbodies”;single arrows)andapatchyinflammatoryinfiltrate(double arrows).


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Pathology_Robbins. Regeneration of lost hepatocytes takes place primarily by mitotic replication of hepatocytes adjacent to those that have died. In more severe forms of acute liver injury hepatic stem cells located in a niche near the canal of Hering may also begin to divide, but the contribution of stem cells to the replenishment of hepatocytes in the setting of acute liver damage remains uncertain. In longstanding chronic liver diseases, however, there is clear evidence that stem cell proliferation and differentiation make significant contributions to parenchymal restoration, probably following the replicative senescence of preexisting hepatocytes. The differentiating progeny of these tissue stem cells produce duct-like structures, called ductular reactions, a morphologic marker of stem cell–mediated liver regeneration.


Pathology_Robbins

Pathology_Robbins. Scar formation may follow very severe acute injury, but occurs more often as a reaction to chronic injury. The principal cell type involved in scar deposition is the perisinusoidal hepatic stellate cell. Following liver injury, stellate cells may become activated and convert into highly fibrogenic myofibroblasts, which produce the fibrous scar. Stellate cell activation involves complex interactions between Kupffer cells, hepatocytes, and inflammatory cells. When there is severe injury that causes death of large number of hepatocytes and the drop out of liver cells, there may be collapse of the underlying reticulin, precluding orderly regeneration of hepatocytes. In such cases, there is activation of stellate cells, and the areas of liver cell loss are replaced by fibrous septae. Eventually, these fibrous septa encircle surviving, regenerating hepatocytes in late-stage chronic liver disease, many forms of which are described as cirrhosis.


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Pathology_Robbins. Inflammation and immunologic reactions are involved in many forms of liver disease. Systemic inflammation alters the metabolic and biosynthetic activities of the liver, leading to increased secretion of acute-phase reactants such as C-reactive protein, serum amyloid A protein (a precursor of some forms of amyloid) and hepcidin, a key regulator of iron metabolism (Chapter 12). As we will discuss, adaptive immune cells play a critical role in viral hepatitis, with CD4+ and CD8+ T cells being particularly important in the eradication of virus-infected hepatocytes and, in chronic disease, liver injury. The most severe clinical consequence of liver disease is liver failure. It primarily occurs in three clinical scenarios: acute, chronic, and acute-on-chronic liver failure.


Pathology_Robbins

Pathology_Robbins. The most severe clinical consequence of liver disease is liver failure. It primarily occurs in three clinical scenarios: acute, chronic, and acute-on-chronic liver failure. Acute liver failure is defined as a liver disease that produces hepatic encephalopathy within 6 months of the initial diagnosis. The condition is known as fulminant liver failure when the encephalopathy develops within 2 weeks of the onset of jaundice, and as subfulminant liver failure when the encephalopathy develops within 3 months. In the United States, accidental or deliberate ingestion of acetaminophen accounts for almost 50% of cases of acute liver failure, while autoimmune hepatitis, other drugs and toxins, and acute hepatitis A and B infections account for the remainder of cases. In Asia, acute hepatitis B and E predominate as causes of acute liver failure.


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Pathology_Robbins. MORPHOLOGYTheclinicalsyndromeofacuteliverfailureisreflectedanatomicallyandhistologicallyasmassive hepatic necrosis. Theliverissmallandshrunkenduetolossofparenchyma( Fig.16.4A ).Microscopically,therearelargezonesofdestructionsurroundingoccasionalislandsofregeneratinghepatocytes( Fig.16.4B ).Scarismostlyabsentgiventheacutenatureoftheprocess.


Pathology_Robbins

Pathology_Robbins. Acute liver failure manifests with nausea, vomiting, jaundice, and fatigue, which are followed by the onset of life-threatening encephalopathy, coagulation defects, and portal hypertension associated with ascites. Typically, transaminase levels in the serum are elevated into the thousands. The liver is initially enlarged by swelling and edema related to inflammation, but then as parenchyma is destroyed the liver shrinks dramatically. Eventually, as hepatocytes are lost, serum transaminase values level off and then decline rapidly as their source disappears. Worsening jaundice, coagulopathy, and encephalopathy develop; with unabated progression, the end result is multiorgan failure and, without transplantation, death. Manifestations of acute liver failure include the following: • Jaundice and icterus (yellow discoloration of the skin and sclera, respectively) due to retention of bilirubin, and cholestasis due to systemic retention of not only bilirubin but also other solutes eliminated


Pathology_Robbins

Pathology_Robbins. icterus (yellow discoloration of the skin and sclera, respectively) due to retention of bilirubin, and cholestasis due to systemic retention of not only bilirubin but also other solutes eliminated in bile.


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Pathology_Robbins. http://ebooksmedicine.net Fig. 16.4 Massivelivernecrosis.(A)Theliverissmall(700g),bile-stained,soft,andcongested.(B)Hepatocellularnecrosiscausedbyacetaminophenoverdose.Confluentnecrosisisseenintheperivenularregion(zone3,arrow).Thereislittleinflammation.Residualnormaltissueisindicatedbytheasterisk. (Courtesy of Dr. Matthew Yeh,University of Washington,Seattle,Washington).


Pathology_Robbins

Pathology_Robbins. Hepatic encephalopathy encompasses a spectrum of disturbances in consciousness ranging from subtle behavioral abnormalities, to confusion and stupor, to coma and death. Encephalopathy may develop over days, weeks, or a few months after acute injury. Fluctuating neurologic signs, including rigidity, hyperreflexia, and asterixis, may develop. Asterixis refers to a nonrhythmic rapid extension-flexion movement of the head and extremities, best seen as “flapping” of the hands when the arms are held in extension with dorsiflexed wrists. Elevated ammonia levels in blood and the central nervous system correlate with impaired neuronal function and brain edema. Coagulopathy. The liver is the source of a number of coagulation factors that decline in the face of liver failure, leading to easy bruising and bleeding. Paradoxically, disseminated intravascular coagulation (Chapter 12) also may occur due to failure of the damaged liver to remove activated coagulation factors.


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Pathology_Robbins. Portal hypertension arises when there is diminished flow through the portal venous system, which may occur because of obstruction at the prehepatic, intrahepatic, or posthepatic level. While it can occur in acute live failure, portal hypertension is more commonly seen with chronic liver failure and is discussed later. In acute liver failure, the obstruction is usually intrahepatic and the major clinical consequences are ascites and hepatic encephalopathy. In chronic liver disease, portal hypertension develops over months to years, and its effects are more complex and widespread (see later).


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Pathology_Robbins. • Hepatorenal syndrome is a form of renal failure occurring in individuals with liver failure in whom there are no intrinsic morphologic or functional causes for kidney dysfunction. Sodium retention, impaired free-water excretion, and decreased renal perfusion and glomerular filtration rate are the main renal functional abnormalities. There is decreased renal perfusion pressure due to systemic vasodilation, activation of the renal sympathetic nervous system and vasoconstriction of the afferent renal arterioles, and increased activation of the renin-angiotensin axis, causing vasoconstriction that further decreases glomerular filtration. The syndrome’s onset begins with a decrease in urine output and rising blood urea nitrogen and creatinine levels. Cirrhosis is the morphologic change most often associated with chronic liver disease; it refers to the diffuse transformation of the liver into regenerative parenchymal nodules surrounded by fibrous bands (


Pathology_Robbins

Pathology_Robbins. Fig. 16.5 ). The leading causes of chronic liver failure worldwide include chronic hepatitis B, chronic hepatitis C, non-alcoholic fatty liver disease (NAFLD), and alcoholic liver disease. While cirrhosis is a common feature of a number of chronic liver diseases, it is not a specific entity, and it is important to recognize that not all chronic liver disease terminates in cirrhosis, and that not all cirrhosis leads to end-stage liver disease. For example, chronic biliary tract diseases often do not give rise to cirrhosis even at end stage, whereas patients with treated autoimmune hepatitis or cured hepatitis C may have adequate liver function in the face of cirrhosis. Even in diseases that are likely to give rise to cirrhosis, such as untreated viral hepatitis, alcoholic liver disease, NAFLD, and metabolic diseases, the morphology and pathophysiology of cirrhosis in each may be different.


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Pathology_Robbins. Fig. 16.5 Cirrhosisresultingfromchronicviralhepatitis.Notethebroadscarsseparatingbulgingregenerativenodulesovertheliversurface. http://ebooksmedicine.net MORPHOLOGYLiverfailureinchronic liverdiseaseismostoftenassociatedwithcirrhosis,whichismarkedbythediffusetransformationoftheentireliverintoregenerative parenchymal nodules surrounded by fibrous bands.Thenodularnatureoftheprocessisreadilyevidentbothgrossly( Fig.16.5 Fig.16.6,A ).Thesizeofthenodules,thepatternofscarring(linkingofportaltractstoeachothervs.linkingofportaltractstocentralveins),thedegreeofparenchymalloss,andthefrequencyofvascularthrombosis(particularlyoftheportalvein)allvarybetweendiseasesandeven,insomecases,betweenindividualswiththesamedisease.


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Pathology_Robbins. Asmentionedearlier,stemcellactivationanddifferentiationgivesrisetoduct-likestructures,thesocalledductularreactions.In chronic liver disease, ductular reactions increase with disease progression and are usually most prominent in cirrhosis. Ductularreactionsmayincitesomeofthescarringinchronicliverdiseaseandthusmayhaveanegativeeffectonprogressiveliverdisease. Regression of fibrosis andevenoffullyestablishedcirrhosismayfollowdiseaseremissionorcure.Scarsbecomethinner,moredenselycompacted,andeventuallystarttofragment(see Fig.16.6,B ).Asfibrousseptabreakapart,adjacentnodulesofregeneratingparenchymacoalesceintolargerislands.Allcirrhoticliversshowelementsofbothprogressionandregression,withthebalancebeingdictatedbytheseverityandpersistenceoftheunderlyingdisease.


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Pathology_Robbins. About 40% of individuals with cirrhosis are asymptomatic until the most advanced stages of the disease. Even at late stages, they present with nonspecific clinical manifestations, such as anorexia, weight loss, weakness, and, eventually signs and symptoms of liver failure discussed earlier. Jaundice, encephalopathy, and coagulopathy may result from chronic liver disease, much the same as in acute liver failure. However, there are some significant additional features: Chronic severe jaundice can lead to pruritus (itching), the intensity of which may be so profound that patients scratch their skin raw and risk repeated bouts of potentially life-threatening infection. In some patients, severe pruritus is the primary indication for liver transplantation. Pruritus also is frequently seen in other disorders associated with cholestasis, suggesting that it is somehow related to the build up of bile salts in the body, but its precise pathogenesis is unknown.


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Pathology_Robbins. Portal hypertension is more frequent and manifests in more complex ways in chronic liver failure than in acute liver failure ( Fig. 16.7 ). Portosystemic shunts develop when blood flow is reversed from the portal to systemic circulation. These shunts are principally produced by dilation of collateral vessels. Most notably, venous bypasses develop wherever the systemic and the portal circulations share common capillary beds, the most clinically important of which are esophagogastric varices, which appear in about 40% of individuals with advanced-stage liver disease. These often cause massive, frequently fatal hematemesis, particularly when there is compounding coagulopathy. Portal hypertension often occurs and may lead to congestive splenomegaly, which can lower the platelet count due to sequestration of these elements in the expanded red pulp.


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Pathology_Robbins. Hyperestrogenemia due to impaired estrogen metabolism in male patients with chronic liver failure can give rise to palmar erythema (a reflection of local vasodilatation) and spider angiomas of the skin. Such male hyperestrogenemia also leads to hypogonadism and gynecomastia. Hypogonadism also may occur in women from disruption of hypothalamic-pituitary axis functioning. Most chronic liver diseases predispose to development of hepatocellular carcinoma (HCC, discussed later). The course and severity of chronic liver disease with cirrhosis vary widely from patient to patient. Even in instances in which cirrhosis regresses following disease remission or cure, portal hypertension may persist due to the presence of irreversible shunts. The causes of death are


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Pathology_Robbins. Fig. 16.6 Alcoholiccirrhosisinanactivedrinker(A)andfollowinglong-termabstinence(B).A, Thickbandsofcollagenseparateroundedcirrhoticnodules.B, After1yearofabstinence,mostscarsaregone(Massontrichromestain).(Courtesy of Drs. Hongfa Zhu and Isabel Fiel, Mount Sinai School of Medicine, New York, New York.) http://ebooksmedicine.net Fig. 16.7 Major clinical consequences of portal hypertension in the setting of cirrhosis, shown for the male. In females, oligomenorrhea, amenorrhea, and sterility are frequent as a result of hypogonadism.


Pathology_Robbins

Pathology_Robbins. liver failure (as in acute liver disease) and HCC. Clinical and laboratory findings are the main criteria used to gauge prognosis and disease progression. It some centers, portal venous wedge pressures are measured to assess the degree of vascular obstruction. Liver biopsy findings correlate with the presence and severity of portal hypertension. For example, specimens with thin fibrous septa and large islands of regenerated parenchyma are unlikely to be associated with portal hypertension, whereas broad bands of fibrosis and loss of parenchyma portend the development of portal hypertension and end-stage liver disease.


Pathology_Robbins

Pathology_Robbins. Some individuals after years of stable, well-compensated, chronic disease suddenly develop signs of acute liver failure. In such patients, there is often established cirrhosis with extensive vascular shunting, or large volumes of functioning liver parenchyma with a borderline vascular supply, both of which leave the liver vulnerable to superimposed, potentially lethal insults. The short-term mortality of patients with this form of liver failure is around 50%.


Pathology_Robbins

Pathology_Robbins. Hepatic insults that cause sudden decompensation of patients with chronic liver disease include: hepatitis D superinfection in those with chronic hepatitis B; emergence of resistance to medical therapy in those with viral hepatitis; development of ascending bacterial cholangitis in patients with primary sclerosing cholangitis; or replacement of liver parenchyma by primary or metastatic carcinoma. In other instances the cause may be a systemic disorder, such as sepsis, acute cardiac failure or a superimposed toxic injury that tips a well-compensated cirrhotic patient into liver failure. Liver failure may follow acute injury or chronic injury, or itmay occur as an acute insult superimposed on otherwise well-compensated chronic liver disease. The mnemonic for causes of acute liver failure are as follows: A: acetaminophen, hepatitis A, autoimmune hepatitis B: hepatitis B F: fatty change of the microvesicular type (fatty liver ofpregnancy, valproate, tetracycline, Reye syndrome)


Pathology_Robbins

Pathology_Robbins. A: acetaminophen, hepatitis A, autoimmune hepatitis B: hepatitis B F: fatty change of the microvesicular type (fatty liver ofpregnancy, valproate, tetracycline, Reye syndrome) Potentially fatal sequelae of liver failure include coagulopathy, encephalopathy, portal hypertension and ascites, hepatorenalsyndrome, and portopulmonary hypertension. D: drugs/toxins, hepatitis D E: hepatitis E, esoteric causes (Wilson disease, Budd-Chiarisyndrome)


Pathology_Robbins

Pathology_Robbins. D: drugs/toxins, hepatitis D E: hepatitis E, esoteric causes (Wilson disease, Budd-Chiarisyndrome) The terminology for acute and chronic viral hepatitis can be confusing, because the same word, hepatitis, can be used to describe several different entities; careful attention to context can clarify its meaning in any situation. Firstly, hepatitis is the name applied to viruses (hepatitis A, B, C, D, and E virus) that are hepatotropic, that is, have a specific affinity for the liver. Secondly, hepatitis is applied to patterns of acute and chronic hepatic injuries that are produced not only by hepatotropic viruses, but also by damage produced by other viruses such as EBV, CMV , and yellow fever as well as autoimmune reactions, drugs, and toxins. In this section, we will focus on the main features of hepatotropic viruses, which are summarized in Table 16.2 , and we will then discuss the clinicopathologic characteristics of acute and chronic viral hepatitis.


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Pathology_Robbins. Table 16.2 , and we will then discuss the clinicopathologic characteristics of acute and chronic viral hepatitis. HAV usually is a benign self-limited infection that does not cause chronic hepatitis and rarely (in about 0.1% of cases) produces fulminant hepatitis. HAV has an incubation period of 3-6 weeks. It is typically cleared by the host immune response, so it does not establish a carrier state. The infection occurs throughout the world and is endemic in countries with poor hygiene and sanitation. Fig. 16.8 TemporalchangesinserologicmarkersinacutehepatitisAinfec-tion.HAV, HepatitisAvirus. Table 16.2 The Hepatitis Viruses ssRNA, Single-strandedRNA;dsDNA, double-strandedDNA;HBcAg, hepatitisBcoreantigen;HBsAg, hepatitisBsurfaceantigen;HDAg, hepatitisDantigen;ELISA, enzyme-linkedimmunosorbentassay.FromWashingtonK:Inflammatoryandinfectiousdiseasesoftheliver.InIacobuzio-DonahueCA,MontgomeryEA,editors:Gastrointestinal and liver pathology, Philadelphia,2005,ChurchillLivingstone.


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Pathology_Robbins. Acute HAV tends to cause a febrile illness associated with jaundice and nonspecific symptoms such as fatigue and loss of appetite. Overall, HAV accounts for about 25% of clinically evident acute hepatitis worldwide.


Pathology_Robbins

Pathology_Robbins. HAV is a small, nonenveloped, positive-strand RNA picornavirus that occupies its own genus, Hepatovirus. Ultrastructurally, HAV is an icosahedral capsid 27 nm in diameter. The receptor for HAV is HAVcr-1, a membrane glycoprotein that also may serve as a receptor for Ebola virus. HAV is spread by ingestion of contaminated water and food and is shed in the stool for 2 to 3 weeks before and 1 week after the onset of jaundice. Thus, close personal contact with an infected individual or fecal-oral contamination accounts for most cases and explains outbreaks in institutional settings such as schools and nurseries, as well as water-borne epidemics in places where people live in overcrowded, unsanitary conditions. HAV can also be detected in serum and saliva of infected individuals.


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Pathology_Robbins. In developed countries, sporadic infections may be contracted by the consumption of raw or steamed shellfish that have concentrated the virus from seawater contaminated with human sewage. Infected workers in the food industry are another source of outbreaks. HAV itself does not seem to be cytopathic. The cellular immune response, particularly that involving cytotoxic CD8+ T cells, plays a key role in HAV-mediated hepatocellular injury. Because HAV viremia is transient, blood-borne transmission is very rare; therefore, donated blood is not specifically screened for this virus. IgM antibody against HAV appears in blood at the onset of symptoms and is a reliable marker of acute infection (


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Pathology_Robbins. Fig. 16.8 ). Fecal shedding of the virus ends as the IgM titer rises. The IgM response usually declines in a few months followed by the appearance of IgG anti-HAV that persists for years, often conferring lifelong immunity. However, there are no routinely available tests for IgG anti-HAV; the presence of IgG anti-HAV is inferred from the difference between total and IgM anti-HAV. The HAV vaccine, available since 1992, is effective in preventing infection. The outcome of HBV infection varies widely, from (1) acute hepatitis with recovery and clearance of the virus; (2) nonprogressive chronic hepatitis; (3) progressive chronic disease ending in cirrhosis; (4) fulminant hepatitis with massive liver necrosis; and (5) an asymptomatic http://ebooksmedicine.net “healthy” carrier state. HBV-induced chronic liver disease is also an important precursor for the development of HCC. The approximate frequencies of various clinical outcomes of HBV infection are depicted in Fig. 16.9


Pathology_Robbins

Pathology_Robbins. Fig. 16.9 Liver disease due to HBV infection is an enormous global health problem. One-third of the world’s population (2 billion individuals) has been infected with HBV, and 400 million individuals have chronic infections. Seventy-five percent of chronic carriers live in Asia and the Western Pacific rim. The global prevalence of chronic hepatitis B infection varies from greater than 8% in parts of Africa to less than 2% in Western Europe, North America, and Australia.


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Pathology_Robbins. The mode of transmission of HBV also varies with the geographic locale. In high-prevalence regions of the world, perinatal transmission during childbirth accounts for 90% of cases. In areas with intermediate prevalence, horizontal transmission, especially in early childhood, dominates. Spread among children usually occurs through minor breaks in the skin or mucous membranes following physical contact with infected individuals. In low-prevalence areas, unprotected sex and intravenous drug abuse (sharing of needles and syringes) are the chief modes of spread. Transfusion-related spread has been reduced greatly by screening of donated blood for HBsAg and by cessation of the practice of paying blood donors. Vaccination induces a protective antibody response in 95% of infants, children, and adolescents. Universal vaccination has had notable success in Taiwan and Gambia, but has yet to be adopted worldwide.


Pathology_Robbins

Pathology_Robbins. HBV has a prolonged incubation period (2–26 weeks). Unlike HAV, HBV remains in the blood during active episodes of acute and chronic hepatitis. Approximately 70% of adults with newly acquired HBV have mild or no symptoms and do not develop jaundice. The remaining 30% have nonspecific constitutional symptoms such as anorexia, fever, jaundice, and right upper-quadrant pain. In most cases, the infection is self-limited and resolves without treatment, but chronic disease develops in 10% of infected individuals. Fulminant hepatitis is rare, occurring in approximately 0.1% to 0.5% of acutely infected individuals. HBV is a member of Hepadnaviridae, a family of DNA viruses that cause hepatitis in multiple animal species. The HBVgenomeisapartiallydouble-stranded,3200-nucleotide, circular DNA with four open reading frames, which encode the following proteins:


Pathology_Robbins

Pathology_Robbins. Nucleocapsid “core” protein (HBcAg, hepatitis B core antigen) and a longer polypeptide with a precore and core region, designated HBeAg (hepatitis B e antigen). The precore region directs the secretion of the HBeAg polypeptide into blood, whereas HBcAg remains in hepatocytes, where it participates in the assembly of virions. Envelope glycoproteins (HBsAg, hepatitis B surface antigen). Infected hepatocytes synthesize and secrete massive quantities of noninfective envelope glycoproteins (mainly small HBsAg). polymerase (Pol) with both DNA polymerase activity and reverse transcriptase activity, which enables genomic replication to occur through a unique DNA → RNA → DNA cycle via an intermediate RNA template. This unusual polymerase is the target of drugs used to treat hepatitis B infection (described later).


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Pathology_Robbins. HBx protein, which is required for virus replication and which may act as a transcriptional transactivator for viral genes and a wide variety of host genes. It has been implicated in the pathogenesis of HBV-associated liver cancer. The course of the disease can be followed clinically by monitoring certain serum markers ( Fig. 16.10 HBsAg appears before the onset of symptoms, peaks during symptomatic disease, and then usually declines to undetectable levels in 12 weeks (though it may occasionally persist as long as 24 weeks). http://ebooksmedicine.net 4–12 weeks Months to Years Fig. 16.10 TemporalchangesinserologicmarkersforhepatitisBviralinfection.(A)Acuteinfectionwithresolution.(B)progressiontochronicinfection.NoteinsomecasesofchronicHBVinfection,serumtransaminasesmaybecomenormal.


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Pathology_Robbins. Anti-HBs antibody appears after the acute disease is over and usually is not detected until a few weeks to several months after HBsAg disappears. Anti-HBs may persist for life and confers protection, which is the rationale for current vaccines containing HBsAg. HBeAg and HBV DNA appear in serum soon after HBsAg and signify ongoing viral replication. Persistence of HBeAg is an indicator of progression to chronic hepatitis. The appearance of anti-HBe antibodies implies that an acute infection has peaked and is on the wane. IgM anti-HBc becomes detectable in serum shortly before the onset of symptoms, concurrent with the onset of elevated serum aminotransferase levels (indicative of hepatocyte destruction). Over a period of months, the IgM anti-HBc antibody is replaced by IgG anti-HBc. As in the case of anti-HAV, there is no direct assay for IgG anti-HBc; its presence is inferred from decline of IgM anti-HBc in the face of rising total anti-HBc.


Pathology_Robbins

Pathology_Robbins. Occasionally, mutated strains of HBV emerge that do not produce HBeAg but are replication competent and express HBcAg. In such patients, the HBeAg may be low or undetectable despite the presence of serum HBV DNA. A second ominous development is the appearance of HBV mutants in vaccinated individuals that replicate in the presence of normally protective anti-HBs antibodies. The host immune response is the main determinant of the outcome of the infection. Innate immune mechanisms protect the host during initial phases of the infection, and a strong response by virus-specific CD4+ and CD8+ interferon γ–producing cells is associated with the resolution of acute infection. HBV generally is not directly hepatotoxic, and most hepatocyte injury is caused by CD8+ cytotoxic T cells attacking infected cells.


Pathology_Robbins

Pathology_Robbins. Patient age at the time of infection is the best predictor of chronicity. In general, the younger the age at the time of HBV infection, the higher the chance of chronic infection. Treatment of chronic hepatitis B with viral polymerase inhibitors and interferon can slow disease progression, reduce liver damage, and prevent liver cirrhosis or liver cancer but does not eliminate the infection. As a result, treatment sometimes fails due to emergence of viruses bearing mutations that lead to drug resistance.


Pathology_Robbins

Pathology_Robbins. HCV is a major cause of liver disease, with approximately 170 million individuals affected worldwide. Approximately 4.1 million Americans (1.6% of the population) have chronic HCV infection. Notably, there has been a decrease in the annual incidence of infection from a mid-1980s peak of over 230,000 new infections per year to 30,000 new infections per year currently, due primarily to a reduction in transfusion-associated cases as a result of effective screening procedures. Until recently, the number of patients with chronic infection appeared likely to continue to increase, but new therapies (discussed later) are changing the outlook for the better. According to data from the Centers for Disease Control and Prevention (CDC), the most common risk factors for HCV infection are as follows: Having had surgery within the last 6 months Multiple contacts with an HCV-infected individual Employment in the medical or dental field


Pathology_Robbins

Pathology_Robbins. Having had surgery within the last 6 months Multiple contacts with an HCV-infected individual Employment in the medical or dental field Currently, transmission of HCV by blood transfusion is close to zero in the United States; the risk for acquiring HCV by needle stick is about six times higher than that for HIV (1.8 vs. 0.3%). For children, the major route of infection is vertical perinatal transmission from the mother. Some patients have multiple risk factors, but one-third of http://ebooksmedicine.net individuals have no identifiable risk factors, an enduring mystery.