Liver Pathology: Cirrhosis, Hepatitis, and Primary Liver Tumors. … · 2019. 4. 30. · Cirrhosis,...

SHORT COURSE

Liver Pathology:Cirrhosis, Hepatitis, and Primary Liver Tumors.Update and Diagnostic ProblemsLinda Ferrell, M.D.

Department of Anatomic Pathology, University of California–San Francisco, San Francisco, California

DIAGNOSTIC PROBLEMS: CIRRHOSIS

Making the histologic diagnosis of cirrhosis andhepatitis is usually an easy task, but not always.Many times, the cause of a fibrotic or inflammatoryprocess in the liver can be difficult to recognizebecause the liver responds to a wide range of inju-ries in only a limited number of ways. However,certain patterns of injury and other microscopicfeatures when applied in the appropriate clinicalsetting can help differentiate various causes of suchprocesses.

“Hard to Diagnose” CirrhosisThe first thing to look for when considering a

diagnosis of cirrhosis is loss of normal architec-ture—that is, loss of normal central–portal relation-ships (1). For this observation to be made, the spec-imen must be large enough to contain several intactportal and central areas. A specimen that is frag-mented into small pieces of hepatic parenchymacontaining scant connective tissue, no normal por-tal tracts, and perhaps an irregular pattern of cen-tral veins may suggest a cirrhotic process, especiallyif regenerative cell plates (“twin plates,” two cellsthick) are present or if the fragments have roundededges, suggestive of nodularity. When a biopsy of acirrhotic liver is taken with a cutting core needle,the biopsied tissue may fragment because althoughthe cirrhotic nodules are easily extracted from theliver, the connective tissue component that joinsthe nodules remains in situ. The rounded frag-ments that are removed may still contain someconnective tissue around their edges, which can bevisualized more readily on trichrome or reticulinstains. The reticulin stain also enhances areas of

regeneration by better demonstrating the presenceof double cell plates. The atypical enlargement ofnuclei with little if any corresponding increase innuclear:cytoplasmic ratio, known as “large cellchange” (or previously as “large cell dysplasia”), isvery common in cirrhotic livers, but this cytologicaberration should be used only as an adjunct to thediagnostic clues of regeneration and architecturalabnormalities for identifying cirrhosis (see Table 1).

In another rare type of cirrhosis, called incom-plete septal cirrhosis, extremely thin bands of colla-gen partially or totally separate hepatocytic nodules(1, 2). Some disorganized cell plates or zones re-sembling foci of nodular regenerative hyperplasiacan be seen (see section below on partial nodulartransformation). The main complication of thisvariant of macronodular cirrhosis is portal hyper-tension; liver function is usually well preserved.Connective tissue is extremely difficult to identifyon needle biopsies, and a possible diagnosis of cir-rhosis could be missed if areas of regeneration orrounded fragments are not noted by the patholo-gist.

Wedge biopsies can pose special diagnostic prob-lems because the subcapsular connective tissue canbe more prominent (especially on specimens ob-tained from the sharp anterior border of the liver)and extend into the portal triads within 1 cm of thecapsule. In addition, if a fragment or zone of fibroustissue contains a large artery and large duct, it mayrepresent a normal portal tract rather than scartissue. Finally, if regeneration without fibrosis ispresent in a clinical setting of portal hypertension,nodular regenerative hyperplasia might be consid-ered in the differential diagnosis of cirrhosis (asdiscussed below with partial nodular transforma-tion).

For all biopsies, though, if the tissue is scant or ifthe degree of fibrosis is difficult to determine (i.e., ifdiffuse disease with portal–portal, central–portal, orcentral– central bridging fibrosis is not definitivelypresent), then a diagnosis of “probable cirrhosis,”“possible cirrhosis,” or “cannot exclude cirrhosis”should be made, depending on the degree of sus-

Copyright © 2000 by The United States and Canadian Academy ofPathology, Inc.VOL. 13, NO. 6, P. 679, 2000 Printed in the U.S.A.Date of acceptance: November 30, 1999.The author is fully responsible for all materials enclosed. No financialaffiliation with any organization is applicable to this material.Address reprint requests to: Linda Ferrell, M.D., Department of AnatomicPathology, M590, Box 0102, University of California–San Francisco, SanFrancisco, CA 94143-0102; e-mail: [email protected]; fax: 415-502-4128.

679

picion. The term early cirrhosis probably should beused only when the duration of a cirrhotic state orprogression of fibrosis has been documented clin-ically or histologically, rather than for describingfocal bridging fibrosis. Likewise, to describe an ex-tensive fibrosis with minimal residual parenchyma,the term end-stage cirrhosis is the appropriate termrather than severe cirrhosis. (See section “ChronicHepatitis and Cirrhosis” for other terminology.)

Case 1A 45-year-old woman with cirrhosis was referred

to the University of California–San Francisco(UCSF) for liver transplantation. The micronodularpattern of injury with loss of central veins is typicalof alcohol (Fig. 1). The degree of inflammation isscant, as is often seen with alcoholic disease.Diagnosis: alcoholic cirrhosis

Discussion: Central-Based Fibrotic Lesions

Alcoholic fibrosis and cirrhosisWhen present concurrently, micronodular cir-

rhosis, Mallory bodies, and fatty change are highlyindicative of alcoholic injury (3). Fatty change andMallory bodies, however, can resolve over time (2 to4 weeks and 6 to 12 weeks, respectively), and alco-holic injury can induce a cirrhosis with larger nod-ules, probably caused by periodic abstinence from

alcohol intake, during which time more regenera-tion of the hepatocytes probably can occur. Thereare, however, other patterns of injury that also sug-gest an alcoholic cause (Table 2). Probably the mostreliable of these is perivenular, pericellular fibrosisnoted as partial or complete obliteration of thecentral vein. These sclerotic central regions canbest be differentiated from portal regions by theabsence of arterioles in the central zone. The pres-ence of ductular structures without an arterioleshould not be used as a criterion for identifyingformer portal tracts because ductular structures canoccur outside the portal zones in cirrhotic livers.Ischemia or other toxic injuries can also cause cen-trilobular fibrosis, so this finding is not pathogno-monic; however, when hepatocytes are individuallysurrounded by collagenous stroma in the centri-lobular region, the process is more likely due toalcohol. This pattern of pericellular fibrosis (or“chicken-wire” fibrosis because of its appearanceon trichrome or van Gieson stains) can extendthroughout the entire lobule. This finding shouldnot be confused with a variant of normal vein struc-ture consisting of a uniform, dense, thick, centralvein wall. The centrilobular injury leads to moreprominent central zone– central zone and centralzone–portal zone bridging than in cirrhosis causedby biliary disease and most forms of chronic hepa-titis. In addition, relatively few inflammatory cellsof mononuclear or neutrophilic type are present,unless there is a superimposed viral or alcoholichepatitis, respectively.

Differential diagnosis. It is important to notethat other conditions besides alcoholism can in-duce fatty change with fibrosis and mimic alcoholichepatitis (with Mallory bodies, fat, and neutrophilicinfiltrates) or cirrhosis, including obesity, diabetesmellitus, Weber-Christian disease, and drugs suchas perhexiline maleate, glucocorticoids, syntheticestrogens, amiodarone, and nifedipine (4 – 6). Somesurgical procedures, such as jejunoileal bypass andextensive small bowel resection, may also inducemimics of alcoholic cirrhosis. Such lesions, whichcan progress to cirrhosis, are categorized as nonal-coholic steatohepatitis. The swollen hepatocytes inthese cases may contain Mallory bodies or eosino-

TABLE 1. Features of “Hard to Diagnose” Cirrhosis

Fragmented specimen with “rounded” edgesReticulin fibers at edge of fragmentsPortal tracts absentIrregular pattern of central veinsTwin platesEnlarged nuclei (large cell change)Caution with capsule on wedge biopsies

From Ferrell LD. Liver. In Weidner N, Cote R, Suster S, Weiss L, editors.Modern surgical pathology. Philadelphia: W.B. Saunders; in press. Re-printed with permission.

FIGURE 1. Trichrome stain of alcoholic cirrhosis with centrilobularsclerosis. Note the absence of artery and interlobular bile duct in thescarred region (center), which represents the sclerosed central vein(Trichrome, 333).

TABLE 2. Features of Alcoholic Cirrhosis

Often seen in a micronodular patternMallory hyaline, especially centrilobularFatty changeCentrilobular sclerosisPericellular, perivenular fibrosis (“chicken-wire” pattern)Fairly uniform, diffuse processPaucity of inflammationCentral–central, central–portal bridging prominent

From Ferrell LD. Liver and gallbladder pathology. In: Weidner N,editor. The difficult diagnosis in surgical pathology. Philadelphia: W.B.Saunders; 1996. p. 285. Reprinted with permission.

680 Modern Pathology

philic material highly suggestive of Mallory bodiesbut are not overtly diagnostic. In this entity in con-trast to alcoholic injury, an inflammatory compo-nent of mononuclears (including plasma cells) canbe more prominent.

Cardiac fibrosis (sclerosis), ischemia, and venousoutflow obstruction

Cardiac disease associated with chronic heartfailure can induce a centrilobular sclerosis similarto that seen with alcoholic injury (Table 3); how-ever, with cardiac injury, the sinusoids are oftendilated and filled with erythrocytes, which can com-press liver cell plates (7). Hemosiderin andlipochrome-laden macrophages, resulting from thebreakdown of erythrocytes in the sinusoids andhepatocytic necrosis, and inflammatory cells, re-spectively, can be present. Cholestasis at the edgeof the fibrotic zone also can occur. Periodic acid-Schiff–positive globules, which, by light micro-scopic analysis are morphologically similar to a-1-antitrypsin (AAT) globules, have been reported inischemic central zones (8). Cardiac sclerosis (orcirrhosis) rarely involves portal tracts significantlyuntil late in the course. Overall, cardiac sclerosisrarely progresses to a fully developed cirrhosis.

If an acute ischemic process has occurred with orwithout an underlying chronic ischemic process,then coagulative hepatocyte necrosis can occuraround the central vein. This type of necrosis is notseen with alcohol toxicity.

A distinctive but somewhat uncommon centri-lobular lesion associated with ischemic necrosisand congestion consists of loss of hepatocyteswithin the cell plates and replacement by erythro-cytes, the mirror image of that seen in chronicpassive congestion, in which the hepatocytes areintact and the sinusoids are congested (9).

Venous outflow obstruction can also cause anischemic injury and so must be considered in thedifferential diagnosis in the appropriate clinicalcontext. A common form of venous outflow ob-struction of the liver is the Budd-Chiari syndrome,

a lesion characterized by occlusion of the largehepatic vein(s) or its entrance into the inferior venacava (10). This occlusion is usually caused by athrombus; thus, it is commonly associated withdisorders of blood coagulation as seen in polycy-themia vera, in myeloproliferative disorders, andwith oral contraceptive use. Other associated le-sions include neoplasia (especially renal carcinomawith invasion of the inferior vena cava) and suppu-rative infections of the liver and/or hepatic veins.Characteristic clinical findings in the Budd-Chiarisyndrome include gross ascites as well as abdomi-nal pain, mild jaundice, and/or hepatomegaly. Theliver lesions are central and may have an acute orchronic appearance. Acute changes often includesevere sinusoidal congestion with necrosis of thecentrilobular hepatocytes. In the chronic lesions,fibrosis develops in the centrilobular zone, but pe-riportal regeneration can be prominent, reminis-cent of nodular regenerative hyperplasia, causingnodule formation.

Another form of venous outflow obstruction isveno-occlusive disease (VOD) secondary to radio-and chemotherapy during bone marrow transplan-tation (10, 11). VOD usually develops within 1 to 3weeks after transplantation, often presenting ashepatomegaly, ascites, and jaundice similar toBudd-Chiari syndrome. During the first few days oftherapy, congestion of sinusoids and hemorrhagicnecrosis of the central zonal hepatocytes occur.Later, thin strands of loosely aggregated collagenfibers as well as hemosiderin macrophages andfragmented red blood cells can be noted within thecentral vein. The trichrome stain can help differen-tiate the dense, somewhat wavy collagen remnantsof the original central vein from the newly aggre-gated, thinner strands of wispy collagen present inearly VOD. Over time, these centrilobular collagendeposits become more concentric, resulting in se-vere congestion. A minimal degree of fibrosis canbe found in portal zones as well, and they may showdilated lymphatics and venules.

Differential diagnosis. Cardiac fibrosis, isch-emia, and VOD can be virtually indistinguishablefrom one another as the basic pathophysiology ofischemia and central fibrosis are key to all; how-ever, the presence of intravascular occlusivechanges with preservation of the original vascularwall is more likely present in VOD and Budd-Chiarisyndrome than in cardiac sclerosis. Correlation ofthe histologic findings with a history of cardiacdisease, bone marrow transplantation with com-bined therapy, or thrombotic disorders is usuallynecessary to confirm the diagnosis. As discussed inthe previous section, alcohol toxicity is a more com-mon cause of central fibrosis, usually has a morepericellular pattern of fibrosis, and lacks the con-

TABLE 3. Central Sclerosis

C or I Alcoholic

Sinusoidal dilation 11C 2Compressed liver plates 1C 2Cholestasis at edge of lesion 1C,I 6Pigmented macrophages 11C.I 6Centrilobular hepatocyte necrosis 111I 6Erythrocytes in cell plates 11C..I 2Ballooned hepatocytes 1I 111

C, cardiac; I, ischemia; 1, present to a 11 degree; 11, present to a 21degree; 111, present to a 31 degree; 2, not present; 6, minimal degreeof involvement.


Cirrhosis, Hepatitis, and Liver Tumors (L. Ferrell) 681

gestion and the compression of the cell plates thatare often seen in vascular outflow lesions.

Case 2This is a 55-year-old woman with chronic liver

disease. The diagnostic feature is the near-total lossof interlobular bile ducts (the ducts that coursealongside the hepatic artery) (Fig. 2). However, bileductules derived from the periportal hepatocytesare present. In addition, no granulomas are presentand chronic inflammatory infiltrates are somewhatless than might be expected, a feature that can bemore typical of late-stage disease.Diagnosis: primary biliary cirrhosis

Case 3A 58-year-old woman with chronic cholestasis of

long duration was referred to UCSF for liver trans-plantation. The liver showed a biliary pattern ofcirrhosis, with more irregularly shaped and sizednodules than often seen in viral hepatitis. Theseirregularly shaped nodules have been described asthe “jigsaw” pattern of fibrosis and are a result ofthe portal–portal nature of the fibrosis. The large- tomedium-sized ducts in this case showed focal fi-brous obliteration, increased periductal fibrosis(Fig. 3A), focal dilation, and ulceration with acuteinflammatory changes. The more peripheral portaltracts showed similar interlobular duct loss, densefibrous obliteration of ducts, and periductal fibro-sis. Copper can be seen in the periportal hepato-cytes as a sign of chronic cholestasis (Fig. 3B).Diagnosis: primary sclerosing cholangitis

Discussion: Portal-Based Fibrotic Lesions

Chronic hepatitis and cirrhosisThe findings that are pertinent to the diagnosis of

cirrhosis caused by chronic hepatitis are discussed

in detail in the section “Chronic Hepatitis” andoutlined in Tables 4– 6.

Differential diagnosis. Focal necrosis and somedegree of inflammation can be found in many cir-rhotic processes and are signs of ongoing degener-ation. Thus, an isolated necrotic cell would notnecessarily support a diagnosis of chronic viral hep-atitis and cirrhosis in instances when the cause ofthe cirrhosis is unclear. A process would be consid-ered consistent with a cause of chronic hepatitis(e.g., a viral infection, autoimmune hepatitis) whena mononuclear inflammatory component is presentand the clinical situation including history ofchronic hepatitis and appropriate serum markerssupports the diagnosis.

Biliary tract diseaseCirrhoses resulting from biliary tract disorders

such as primary biliary cirrhosis (PBC), sclerosingcholangitis (primary or secondary), inflammatorychanges associated with idiopathic inflammatorybowel disease, and duct obstruction (localizedsmaller duct versus large duct obstruction) show aspectrum of common histologic findings in theirearly stages. These changes, together with the clin-ical and laboratory findings (especially dispropor-tionately elevated levels of alkaline phosphatase),are used to differentiate these lesions from chronichepatitis (Tables 4 and 5). Because biliary diseaseprimarily damages the portal tracts, the cirrhosisfrequently appears to have a jigsaw-like pattern.That is, the portal–portal bridging fibrosis at low-power light microscopy separates anastomosingbands of hepatocytes. Distinctive, isolated, roundedcirrhotic nodules are not typical, and regenerationwith rosette formation or numerous double cellplates is often not prominent. The central veinseither are not involved in the fibrotic process orbecome involved late in the course of the disease,so central–portal relationships are minimally dis-torted. In the chronic cholestatic disorders, seques-tration of copper can occur in the periportal hepa-tocytes, which can be visualized with copper stains.The orcein stain also can be used effectively. Itprobably does not stain the copper itself but ratherreacts with the copper-associated protein by stain-ing these protein deposits black. Periportal Mallorybody formation occurs in chronic, severe choles-tatic disorders and may be related to the copperdeposition. Bile duct damage of any kind can resultin cholangiole proliferation, portal tract inflamma-tion with neutrophils around the cholangioles, dis-ruption of the terminal plate by mononuclear in-flammatory cells, and “piecemeal necrosis,”sometimes referred to as “biliary piecemeal necro-sis” and now referred to as interface hepatitis.

Differential diagnosis. A common difficulty forpathologists lies in distinguishing early biliary dis-

FIGURE 2. Primary biliary cirrhosis. This portal zone shows amoderate degree of inflammatory (lymphocytic) infiltrate. The hepaticartery is present, but the corresponding interlobular bile duct is absent(103).


ease from mild chronic hepatitis. The inflammationin the periportal zones seen in biliary disease canmimic the disruption of the limiting plate and thepiecemeal necrosis (interface hepatitis) of chronichepatitis of mild to moderate inflammatory activity.Biliary piecemeal necrosis usually differs from thepiecemeal necrosis (interface hepatitis) of chronichepatitis in that although the periportal hepato-

cytes are surrounded by inflammatory cells, theyare normal histologically, especially in less choles-tatic states, and generally display no significantswelling, necrosis, or rosette formation. In addition,the mononuclear cells in biliary piecemeal necrosisdo not seem to cuff or encircle the hepatocytes andthe fibrosis does not tend to form thin, holly-leaf–like extensions into the nodule as is often seen inchronic hepatitis. Neutrophils around bile ductulescan be important indicators of a ductal lesion in theappropriate clinical setting or as an isolated finding,but in the context of hepatitis with cholangiolar

TABLE 4. BTD Versus CH

BTD CH

Disruption of terminal plate (“piecemeal”) 11 11Cholangiolar proliferation 111 1Periportal copper deposition 11 2Periportal hepatocyte rosettes 6 11Pericellular mononuclear cuffing 6 11Holly-leaf pattern of fibrosis 6 11Cholestasis with bile plugs DO 2Bile infarcts, bile lakes LBDO 2

BTD, biliary tract disease; CH, chronic hepatitis; DO, duct obstruction;LBDO, large bile duct obstruction; 1, present to a 11 degree; 11, presentto a 21 degree; 111, present to a 31 degree; 2, not present; 6, minimaldegree of involvement.


TABLE 5. PBC Versus CH

PBC CH

Granulomas, portal 11 2Loss of interlobular ducts 111 2Inflammation of ducts 111 1 (HCV, AIH)Increased sinusoidal mononuclears 111 6 (11HCV)Lymphoid aggregates 11 1 (11HCV)Plasma cells 11 1 (11AIH)Cholestasis (bile plugs) rare* rare,

periportal*Mallory bodies rare,

periportal*2

PBC, primary biliary cirrhosis; CH, chronic hepatitis; HCV, hepatitis C;AIH, autoimmune hepatitis; 1, present to a 11 degree; 11, present to a21 degree; 111, present to a 31 degree; 2, not present; 6, minimaldegree of involvement; *, not present until late stage.


TABLE 6. PBC and PSC

SimilaritiesDisappearing bile ductsChronic inflammatory infiltrationInterface hepatitis (“biliary piecemeal”)Periportal Mallory bodies and copper

PBC PSC

HistologyGranulomas, bile duct 111 6Granulomas, parenchymal 111 6Lymphoid aggregates 111 1Sinusoidal infiltrate 111 6Scarring at bile duct 1 11Concentric fibrosis 6 11Portal tracts without ducts 111 1Lesions of LBDO No Yes

Lab/clinicalHx of UC/Crohn’s 2 11AMA 111 6ANA, DSDNA, SMAb 1 61IgM 111 21Alkaline phosphatase 11 11ERCP findings 1 111Long indolent course 1 111

PBC, primary biliary cirrhosis; PSC, primary sclerosing cholangitis;LBDO, large bile duct obstruction; UC, ulcerative colitis; AMA, antimito-chondrial antibody; ANA, antinuclear antibody; DSDNA, double-strandedDNA; SMAb, smooth muscle antibody; ERCP, endoscopic retrogradecholangiopancreatography; 1, present to a 11 degree; 11, present to a21 degree; 111, present to a 31 degree; 2, not present; 6, minimaldegree of involvement.


FIGURE 3. Primary sclerosing cholangitis, medium-sized portal zone. A, the left panel shows an interlobular bile duct with periductal, concentricfibrosis (333). The right panel shows a well-formed scar at the site of the missing bile duct (253). B, primary sclerosing cholangitis. Orcein stainshows periportal copper deposition as evidenced by black granules in the periportal hepatocytes. The portal zone is lower right, hepatocytes upperleft (803).


proliferation, such neutrophils become a nonspe-cific reaction. Immunologic markers such as theantimitochondrial antibody (AMA), which is posi-tive in at least 95% of patients who have PBC, andantinuclear antibodies or other autoimmune anti-bodies to smooth muscle, liver-kidney-microsomal,or soluble liver antigen, which may indicate anautoimmune chronic hepatitis, should be corre-lated with the biopsy findings.

Other significant problems arise when attempt-ing to differentiate one type of biliary disorder fromanother. Although many of these disorders shareseveral common pathologic features, many othersdisplay unique features that can be used to distin-guish one from another. Sepsis (so-called “cholan-gitis lenta”) produces proliferations of dilatedcholangioles containing bile at the periphery of theportal tract in the periportal zone (12). Features thatare more unique to bile duct obstruction are bilelakes and infarcts. Bile plugs in canaliculi are afeature of duct obstruction, including large ductobstruction in primary sclerosing cholangitis (PSC),but it is generally not a feature of PBC until late inthe course of the disease. Loss of interlobular bileducts (those located in the small portal tracts adja-cent to the arteriole) is a feature of both PBC andPSC. Increased numbers of mononuclear cells inthe sinusoids and hepatocyte necrosis with ahepatitis-like appearance, portal-based granulo-mas, and, sometimes, granulomas in the paren-chyma are typical features of PBC (Table 6), espe-cially in the earlier stages (13). In contrast, PSC isusually associated with periductal fibrosis aroundsmall and large ducts, with eventual loss of ductsand replacement by a hyalinized scar (14). Thus, aperipheral core biopsy of PSC can show a combi-nation of findings, including decreased numbers ofducts, scarring around small ducts, and/or evi-dence of large bile duct obstruction such as bilelakes or infarcts, cholestasis, and/or bile ductularproliferation with pericholangitis. In addition, PSCmay be a predisposing factor for the developmentof adenocarcinoma in the liver hilum or elsewherein the biliary tree, which can result in findings thatare consistent with large duct obstruction on pe-ripheral core biopsy (15). The large hilar ducts inPSC can also be involved with an active inflamma-tory process, ulceration, exudation, bile inspissa-tion, and a xanthomatous reaction or can be asso-ciated with intrahepatic cholangiectases (16).Laboratory and clinical data can help differentiatePBC from PSC (Table 6). A newly described entitythat is similar to PBC is autoimmune cholangiopa-thy, or autoimmune cholangitis (17–20). This dis-ease may affect women more than men, clinicallypresents with pruritus, and is associated with otherautoimmune manifestations such as arthralgias,sicca syndrome, and Raynaud’s phenomenon. In

addition, as with autoimmune chronic hepatitis,the antinuclear antibody (ANA) is positive and theAMA is negative. Histopathologic aberrations in-clude ductopenia with bile duct damage similar tothat seen in PBC, mild chronic active hepatitis-likeportal changes, and bile ductular proliferation.Some descriptions have noted the absence of gran-ulomas and its similarity to autoimmune hepatitis,but others have reported the presence of granulo-mas and suggest that the entity might more likelybe a variant of AMA-negative PBC.

Some investigators have recently suggested thatthe nomenclature for PBC, autoimmune cholangi-opathy, and other overlap syndromes be changedto autoimmune cholangiopathy, with type I asAMA-positive type (PBC), type II as ANA-positivetype, and so forth, so some changes in this area mayoccur in the near future.

Other lesions that can cause obliteration of bileducts and lead to subsequent cirrhosis include bil-iary atresia in infants, histiocytosis X, liver trans-plant rejection, sarcoidosis, longstanding obstruc-tion or cholangitis, severe suppurative cholangitis,and cholestatic drug reactions with ductopenia. Insarcoidosis, the granulomas can coalesce, leadingto considerable scarring and the production of awell-developed reticulin network, suggestive of achronic, organizing process. Nodules of scar can beseen at sites of “healed” granulomas. There is noobvious centering of the granulomas around theducts as in PBC, and other types of inflammatorycells are usually few in number. With longstandingobstruction or cholangitis, periductal fibrosis oreven the rare disappearance of small ducts canoccur, mimicking the small duct lesions of PSC. Insuppurative cholangitis, the larger ducts are de-stroyed and replaced by fibrous scars or atreticducts, again mimicking PSC in late stages. Choles-tatic drug reactions can also lead to ductopenia andprobable cirrhosis. These drug-related lesions canoccur as soon as 1 week after beginning the therapyand can persist long after the drug is withdrawn.Entities that cause bile duct damage but that prob-ably do not lead to biliary cirrhosis include graft-versus-host disease and hepatitis C.

DIAGNOSTIC PROBLEMS: HEPATITIS

Case 4An 80-year-old man with clinical liver failure,

status-post diagnosis of prostatic adenocarcinoma(Gleason score 8, Stage C1), was treated with radi-ation and the chemotherapeutic agent flutamide(21). He was admitted 3 months after beginningflutamide therapy with a 1-week history of jaun-dice. At that time, he also complained of a 1-monthduration of weakness, anorexia, and right upper-


quadrant pain. His total bilirubin was 24 mg/dL,aspartate aminotransferase was 843 U/L, alanineaminotransferase was 759 U/L, and alkaline phos-phatase was 520 U/L. Hepatitis panels for A, B, andC were negative, and cultures for herpes simplexvirus and cytomegalovirus were negative. No viralinclusions were noted microscopically, and noother causes of hepatitis were identified. Thus, thehepatitis was thought most likely to be due to flu-tamide. The focal inflammatory infiltrates support ahepatitis rather than a toxic injury but may not beas prominent as expected because the drug hadbeen withdrawn 2 weeks before death (Fig. 4A). Themarked regenerative changes without completecollapse of the reticulin framework also fit the timecourse for exposure to this drug (Fig. 4B). Thetrichrome stain shows some staining in the necroticzones that is more likely representative of collaps-ing framework rather than new fibrosis (Fig. 4C).Hemorrhage is often present in the septa at thisstage of injury (Fig. 4A, C).Diagnosis: submassive to massive hepatic necrosis,in late regenerative stage (early cirrhotic stage),probably due to an idiosyncratic reaction to flut-amide

Discussion: Differential Diagnosis of AcuteHepatitis

Because acute hepatitis is not often seen on bi-opsies, features that can help to differentiate acutefrom chronic hepatitis are not well known to manypathologists. Most biopsies are done to confirm thepresence of chronic hepatitis and grade its level ofactivity. However, the pathologist must be able todifferentiate acute from chronic hepatitis, mustknow when the sample is insufficient or nondiag-nostic, and must be able to differentiate hepatitisfrom other lesions that can mimic it.

Hepatitis can be classified in two main ways: bycausative agent and/or by clinical syndromes. Be-cause the morphologic appearances of the variousforms of hepatitis are similar for many causativeagents (Tables 7 and 8), the pathologist usuallyneeds the clinical history and specific laboratorystudies to identify a likely cause. Thus, it probablymakes more sense for the pathologist initially toapproach the classifications of hepatitis in the set-ting of clinical syndromes and then apply the nec-essary marker information to determine a definitivecause when this information is available.

Patterns of Injury According to ClinicalSyndromes

Acute hepatitisThe term acute hepatitis typically is used to de-

scribe lesions with a clinical duration of less than 6

months. For the purpose of this review, this designa-tion is maintained. Acute hepatitis generally showsmore spotty parenchymal inflammation and damagethan the typical chronic hepatitis but may show sim-ilar degrees of portal inflammatory changes and ne-crosis. The diagnosis of typical acute hepatitis withspotty necrosis usually is a straightforward matter.Lesions predominantly contain diffuse sinusoidal andportal mononuclear infiltrates (lymphocytes, plasma

FIGURE 4. Submassive necrosis in regenerative stage of acutehepatitis. A, note the hemorrhage within the stroma and regenerativechanges in the surviving hepatocytes (253). B, the trichrome stainshows the hemorrhage as well but also shows in the necrotic areasstaining that likely represents residual framework rather than scar(253). C, the reticulin stain shows preservation of the framework at thisstage, but it is compressed in the necrotic zones (center) (503).


cells, Kupffer cells), swollen hepatocytes, and/or ne-crotic hepatocytes (also called apoptotic, acidophilic,or Councilman bodies) (22). There can be cholestasis,as evidenced by canalicular bile plugs, but this usuallyis not prominent except in the acute cholestatic vari-eties of hepatitis (see the section “Acute CholestaticHepatitis”). Generally, low-power light microscopyreveals lobular disarray and increased cellularity. Cellplates and sinusoids may be indistinct in more severecases as a result of hepatocyte swelling, filling of si-nusoids by mononuclear inflammatory cells, and re-generation of hepatocytes. Some interface hepatitis asseen in chronic hepatitis may occur. More severecases can also show prominent hepatocellular necro-sis around the central vein (Zone 3).

Differential diagnosis. Making the diagnosis ofacute hepatitis usually is not a problem for thepathologist because the typical clinical syndrome ofacute hepatitis usually will not indicate the need forliver biopsy. However, individuals who have milddisease, especially anicteric cases, may need tohave a biopsy to differentiate acute hepatitis fromchronic hepatitis of unknown duration, the latteroften due to hepatitis C. Hepatitis C infection at anystage can have a prominent lobular component ofmononuclear cells and acidophilic bodies, but it

will also almost always have aggregates of lympho-cytes in portal zones, a finding that usually is notprominent in acute hepatitis. Serum viral markersfor hepatitis A, B, or C often are necessary to dis-tinguish among these entities. A drug-related hep-atitis should always be in the differential diagnosiswhen applicable clinically.

Resolving hepatitisAlthough making the diagnosis of typical acute

hepatitis is relatively straightforward, resolvinghepatitis can be more problematic. This lesion maypresent clinically as a late stage of acute hepatitisand so usually is not biopsied. Occasionally, how-ever, a mild hepatitis will be noticed on a biopsyfrom a patient with a subclinical infection of un-known duration; hence, a differential diagnosisconsisting of acute, chronic, or resolving hepatitisarises. Also, because the residual histologic effectsof a resolving hepatitis occasionally can persist formore than 6 months, it can be confused withchronic hepatitis. Thus, clinical follow-up with re-biopsy may be necessary if symptoms persist or thepathologic findings are not clear cut.

Differential diagnosis. Prolonged resolving acutehepatitis can be very difficult to distinguish histo-logically from mild chronic hepatitis (Table 9). In

TABLE 7. Hepatotropic Hepatitis Viruses

Type Old Name Clinical Presentation Specific Histology Diagnostic Tests

A Infectious hepatitis agent AH, ACH, SN, MN, NH, no chronic Plasma cells, periportal damage,cholestasis 6

Anti-HAV IgM or IgG

B Serum hepatitis agent AH, SN, MN, NH, chronic hepatitis,cirrhosis, HCC

In chronic hepatitis, ground glass cells,HBsAg1 & HBcAg1 on section

HBsAg, HBsAb,HBcAg, HBcAb,PCR

C Transfusion-associatedNANB hepatitis virus

AH, chronic hepatitis, cirrhosis, HCC(?SN, MN, NH)

Fatty change, prominent lymphoidnodules, bile duct inflammatoryinfiltrate

Anti-HCV IgG, PCR

D d agent AH, SN, MN, chronic hepatitis, cirrhosis Sometimes microvesicular fat Anti-d antigen IgGE Enteric NANB hepatitis

virusAH, ACH, others? no chronic Cholestasis and PMNs, possible fat Electron microscopy

on tissue

AH, acute hepatitis; ACH, acute cholestatic hepatitis; SN, submassive necrosis; MN, massive necrosis; NH, neonatal hepatitis; HCC, hepatocellularcarcinoma; PCR, polymerase chain reaction; NANB, non-A non-B.

TABLE 8. Nonviral Causes of Hepatitis

Type Clinical Presentation Histology

Drug reaction Acute or chronichepatitis

Similar to hepatotropic viruses

Autoimmune Chronic hepatitis;can be rapidlyprogressive


Wilson’sdisease

Acute, includingfulminant;chronic hepatitis

Similar to hepatotropicviruses; copper deposits

a-1-antitrypsindeficiency

Chronic hepatitis Similar to hepatotropicviruses; a-1-antitrypsinglobules

?Alcoholism Chronic hepatitis(may be due to B,C, non-B non-C)



TABLE 9. MCHa Versus RAH

MCH RAH

Portal inflammation 111 1Lobular inflammation 1 1Hepatocyte dropout, lobular 11 1Hepatocyte dropout, periportal 6 6PASD 1 Kupffer cells 6 111Fe 1 Kupffer cells 6 11Persistent centrilobular lesion 2 11

MCH, mild chronic hepatitis; RAH, resolving acute hepatitis; PASD,periodic acid-Schiff stain with amylase digestion; Fe, iron; 1, present to a11 degree; 11, present to a 21 degree; 111, present to a 31 degree; 2,not present; 6, rare.

a MCH refers to chronic persistent hepatitis or mild chronic activehepatitis in the old terminology.

From Ferrell LD. Liver. In: Weidner N, Cote R, Suster S, Weiss L,editors. Modern surgical pathology. Philadelphia: W.B. Saunders; in press.Reprinted with permission.


resolving hepatitis, Kupffer cells forming focal mi-crogranulomas (or Kupffer cell nodules) usually areprominent within the sinusoids near central veinsbut also can be scattered throughout the liver pa-renchyma. These Kupffer cells may contain iron orlipochrome and are best demonstrated by the pe-riodic acid-Schiff digest technique. Portal tract in-flammation may not be as prominent, and earlychanges of fibrosis usually are not present as inchronic hepatitis, but both lesions may contain fociof spotty lobular necrosis. Also, residual centrilobu-lar necrosis and inflammation are more prevalentin resolving hepatitis. Cases of severe chronic hep-atitis can have centrilobular necrosis, but thesecases usually are not a diagnostic problem becausethey also display significant portal-based inflam-matory changes, interface hepatitis, and fibrosis,indicating that the lesion is still active and chronicrather than resolving.

Acute cholestatic hepatitisAn unusual form of acute hepatitis is the acute

cholestatic variant. This lesion is rarely seen, butwhen it is, it often is due to the hepatitis A virus(HAV) (22) or, in endemic areas, hepatitis E. Thispattern of injury mimics obstructive jaundice withbile ductular proliferation, pericholangitis (neutro-phils around ducts), and cholestasis. Hepatocyteswelling(ballooning)canbeprominent,and“pseudo-glands” (hepatocytic acini) can form around bileplugs.

Differential diagnosis. Acute cholestatic hepati-tis can be differentiated histologically from obstruc-tion by the presence of necrotic hepatocytes, whichare not present in obstruction. The patient’s HAVstatus, results of biliary imaging studies to excludeobstruction, and cholestatic drug reactions alsowould be important factors to consider in the diag-nosis.

Submassive or massive necrosisAcute hepatitis can present with submassive or

massive necrosis (Case 4) in which confluent ne-crosis extends from portal to portal zones or portalto central zones (bridging necrosis), usually with aninflammatory reaction similar to typical acute hep-atitis when due to a hepatotropic virus or an idio-syncratic drug reaction. Submassive cases predom-inantly involve centrilobular zones (Zone 3 of theliver acinus) but can involve the midzone regions(Zone 2 of the liver acinus). The pattern of injuryseen depends on when during the disease coursethe biopsy is obtained. In early stages, hepatocytenecrosis with replacement by Kupffer cells and fi-brin is seen, but the underlying reticulin frameworkremains intact. Later in the course, regenerationoccurs in the zones with preserved hepatocytes(usually the better oxygenated zones such as the

periportal Zone 1 of the liver acinus), leading to theformation of nodules that compress the residualreticular framework; this stage should not be con-fused with cirrhosis. Bile ductular transformationtypically is prominent in the necrotic zones in thelater stages. Histologic evaluation of trichrome-stained sections will reveal the lack of significant,dense, collagen deposition in early stages, and thedensity of the collagen generally will appear to beless than the original portal tract collagen in the latestages. A reticulin stain will show the collapse of thereticulin framework in these necrotic zones, and anorcein stain should show the absence of elastic fiberdeposition in the collapsed zones. Subsequently,normal regeneration of hepatocytes along the col-lapsed cell plates may be inhibited, probably as aresult of compression of the original residualframework and early scar formation. These laterregenerative changes often are called subacute he-patic necrosis. Many investigators believe thatthese lesions predispose to postnecrotic cirrhosis orhepatic failure.

Acute hepatitis with massive necrosis usually ex-hibits extensive necrosis in all zones, with the pos-sible exception of some of the periportal regions(Zone 1). The surviving cells in Zone 1 may attemptto proliferate, often in the form of ductules or pseudo-glands (or hepatocytic acini). The remaining paren-chyma is filled with necrotic hepatocytes and/orKupffer cells, the latter containing lipochrome andcell debris. In early stages, the reticulin frameworkis intact, but it may partially collapse in later stagesif the patient survives long enough. In livers re-moved at time of transplantation from patientswith fulminant hepatic failure, large nodular zonesof regeneration can be present, confirming that theextent of necrosis may vary from region to region.Thus, any given liver biopsy sample may not rep-resent the organ’s overall functional state and, con-sequently, may not be predictive of outcome.

Differential diagnosis. The major diagnosticproblem in differentiating among these hepatitidesis in the determination of the causative agent, be-cause toxic/drug reactions and viral causes can ap-pear histologically identical. The nonhepatotropicviruses such as herpes simplex virus should be ex-cluded as a possible cause as it would be likely torecur soon after transplantation.

Neonatal hepatitisNeonatal hepatitis is a unique form of acute hep-

atitis. Its morphologic features include cholestasis;the presence of giant hepatocytes (usually mostprominent around the central vein in Zone 3); he-patocyte ballooning and necrosis; and sinusoidaland portal-based, predominantly mononuclear, in-flammatory infiltrates (23). Portal fibrosis with


some ductular proliferation as well as extramedul-lary hematopoiesis also can occur. The giant hepa-tocytes can persist for up to 6 months after thehepatitis has resolved (personal observation). Viralagents associated with neonatal hepatitis includethe hepatotropic viruses as well as viruses such ascytomegalovirus, herpes simplex virus, varicella, ru-bella, coxsackie, and echo. In addition, toxoplasmo-sis and treponema have been thought to cause thisgiant cell hepatitis (23).

Differential diagnosis. This lesion can pose di-agnostic problems because there also are severalnonviral causes of giant cell transformation. Theneonatal liver is somewhat unique in its capacity toform giant cells in response to any hepatocyte in-jury. The exact reason for their formation is un-known; perhaps infection or some other injury in-hibits cell division. Regardless, giant cells are notspecific for infectious causes of liver injury and canbe seen frequently in metabolic or cholestatic dis-orders of the liver, especially in children who areyounger than 1 year. Metabolic disorders associatedwith a neonatal hepatitis-like morphology includeAAT deficiency, fructose intolerance, and cortisoldeficiency (24, 25). The extrahepatic biliary atresiasalso can induce significant proliferations of giantcells as a result of cholestasis, but there should bemore portal-based fibrosis, proliferations of bileductules, and ductular cholestasis without evidenceof significant loss of hepatocytes compared withviral hepatitis.

A hepatitis with giant cells has recently been de-scribed in association with infection by paramyxo-virus (so-called “syncytial giant cell hepatitis”) (26);however, this possible cause for giant cell hepatitishas been questioned. It is known that giant cellformation is not pathognomonic for a specific typeof hepatitis but may be somewhat more common incases of autoimmune hepatitis (27, 28).

Case 5A 54-year-old man with cirrhosis was referred for

liver transplantation. The prominent lymphoid ag-gregates are typical of HCV hepatitis (Fig. 5A). Thefollowing diagnosis is based on the new nomencla-ture recommended by the World Congresses ofGastroenterology Working Group (29) and Ludwig’sgrading and staging system.Diagnosis: cirrhosis due to hepatitis C viral infec-tion, Grade 2 inflammatory change (mild piecemealactivity), Stage 4 (cirrhosis) (Fig. 5B)

Discussion: Differential Diagnosis of ChronicHepatitis, with Emphasis on New Nomenclatureand Grading System

Chronic hepatitisIn the past, the term chronic active hepatitis

(CAH) had been used only for patients who hadknown liver disease for more than 6 months withthe classic histologic findings of portal-based in-flammation, fibrosis, disruption of the terminalplate, and piecemeal necrosis (30, 31). This lesion isnow called chronic hepatitis with piecemeal (peri-portal) necrosis (or interface hepatitis), with or with-out fibrosis (29). The periportal hepatocytic damagein this form of hepatitis probably stimulates regen-eration, resulting in periportal hepatocyte rosettes,or clusters of hepatocytes arranged in a circularmanner. Ballooned hepatocytes and acidophilicbodies can also be seen in a periportal location.Many times, the mononuclear cells seem to formrings or “cuffs” around the swollen hepatocytes. Anoccasional necrotic hepatocyte (acidophilic body)often can be seen within the lobule. Collagen dep-osition occurs in the periportal zone, forming septathat extend into the lobule in a holly-leaf pattern(Table 4). Ductular proliferation may occur butusually is not prominent except in the more severe,aggressive lesions. When ductular proliferation is

FIGURE 5. Hepatitis C with cirrhosis. A, note the lymphoid aggregate typical of hepatitis C and the rounded nodules of the cirrhosis (253). B,interface hepatitis at the edge of a nodule for a Grade 2 on a scale of 4 for necroinflammatory activity (503).


present, neutrophils may be present in the periductalinflammatory infiltrate. The lesions with interfacehepatitis (piecemeal necrosis) have been thought tobe more likely to progress to cirrhosis, especially if theprocess shows bridging or confluent necrosis be-tween the central vein and the portal zone (32, 33).

Chronic persistent hepatitis (CPH) has been usedto describe lesions of chronic hepatitis with no sig-nificant periportal necrosis or regeneration butthat, nonetheless, had a fairly dense mononuclearportal infiltrate. This lesion is now referred to aschronic hepatitis without piecemeal necrosis (or in-terface hepatitis) (29). Frequently, acidophilic bod-ies could be seen within the lobule.

Chronic lobular hepatitis was a term that hadbeen infrequently used to describe a form of mildchronic hepatitis that consisted of persistent paren-chymal focal hepatocyte necrosis (apoptosis) withmononuclear sinusoidal infiltrates. This lesion isnow called chronic hepatitis without piecemeal ne-crosis (or interface hepatitis) (29). Chronic lobularhepatitis mimics mild acute hepatitis in its degreeof cell necrosis, but the condition persists for longerthan 6 months. No bridging necrosis or periportalinterface hepatitis is present. Because this nomen-clature was not readily in use, such lesions hadbeen referred to in the past as CPH with prominentlobular activity.

As noted above, the classifications for the twomajor types of chronic hepatitis, chronic active andchronic persistent hepatitis, as well the less popularterm of chronic lobular hepatitis, have fallen intodisfavor. After the establishment of the old nomen-clature, new discoveries were made about the abil-ity of HBV and HCV to wax and wane in such amanner that an initial diagnosis of CPH might ac-tually develop into end-stage cirrhosis despite afavorable histologic diagnosis. Sampling errors alsocan contribute to misclassification as foci of necro-sis can vary from portal zone to portal zone and anyone biopsy may contain more or less necrosis thanthe remaining unbiopsied liver tissue. Thus, to basea diagnosis on a single biopsy sample can lead to amisjudgment of the patient’s prognosis. Also, thechronic hepatitis of HCV often is very mild. Fre-quently, even after evaluation of multiple sections,only limited piecemeal necrosis (interface hepatitis)can be seen, so it is very difficult to classify theselesions as either CPH or mild CAH. Yet with theadvent of antiviral therapies for these diseases,more detailed analysis of the severity of the lesionsby the pathologist may be needed to justify or fol-low the clinical and histologic response to antiviraltherapy. For these reasons, it has been recom-mended by the World Congresses of Gastroenterol-ogy (29) that the CAH/CPH nomenclature be re-placed by the more simple terminology of “chronichepatitis” including the causative agent or cause, if

known (see Table 7, 8, and 10) with the addition ofa grading of activity of the hepatitis based on thedegree of inflammation, piecemeal or bridging ne-crosis (interface hepatitis), and the stage of fibrosis.Several grading systems (34 –38) that use a variety ofscores have been proposed, but the one listed be-low is one of the simplest and the one we use atUCSF when numerical scoring is needed (37). It isworth noting that this new scheme not only in-cludes chronic viral and autoimmune hepatitis butalso may be applied to chronic hepatitis of drug-related or unknown causes; biliary lesions such asPBC, PSC, and autoimmune cholangiopathy thatare similar histologically to chronic hepatitis; Wil-son’s hepatitis; and AAT deficiency. In addition,when scoring for portal and lobular inflammatoryactivity, if the scores are not the same, the moresevere score should be used. Scoring by numericalmeans is not mandatory, and descriptive grading ofthe lesions usually should suffice for routine use.

Differential diagnosis. Unfortunately, the vari-ous morphologic appearances of the chronic hep-atitides (Tables 7 and 8) can be difficult to distin-guish individually (39 – 43). It is, therefore, veryimportant to correlate clinical information with thepathologic findings. Obviously, the serologic datanow available on HAV, HBV, HCV, and HDV can beused to identify the viral infections, and autoim-mune antibody assays can be used to identify au-toimmune hepatitis (see below). Other clinical testscan be done to determine the presence of Wilson’sdisease or AAT deficiency. Drug histories also couldbe investigated, but a true drug-related chronichepatitis would be very unusual.

Although the histologic patterns of the varioushepatitides overlap significantly, some histologicfeatures can help to delineate or suggest a specific

TABLE 10. Simple Scoring System for Chronic Hepatitis

Portal and Lobular Inflammatory Activity

Grade Pathology

0 None or minimal portal inflammation1 Portal inflammation without necrosis and/or lobular

inflammation without evidence of necrosis2 Mild limiting plate necrosis (or mild interface hepatitis) and/

or focal lobular necrosis3 Moderate limiting plate necrosis (or moderate interface

hepatitis) and/or severe focal cell necrosis (confluentnecrosis)

4 Severe limiting plate necrosis (or severe interface hepatitis)and/or bridging necrosis

Fibrosis

Stage Pathology

0 No fibrosis1 Confined to enlarged portal zones2 Periportal or portal–portal septa, with intact architecture3 Architectural distortion (septal fibrosis, bridging), without obvious

cirrhosis4 Probable or definite cirrhosis


diagnosis. For example, in acute HAV, Zone 1 (pe-riportal) hepatocytes are more susceptible to injurythan those of Zone 3, and prominent portal andperiportal inflammation with numerous plasmacells can occur (42). The lack of fibrosis can help todifferentiate this form of acute hepatitis fromchronic hepatitis with moderate to severe activity.

In HBV infections, ground glass cells, which con-tain hepatitis B surface antigen (HBsAg), may beseen in many cases on hematoxylin and eosin–stained sections, and the presence of HBsAg can beconfirmed by a positive immunoperoxidase or or-cein stain. HBV also can be identified by immuno-histochemical staining for the hepatitis B core an-tigen (HBcAg) (44). The staining reaction can vary,depending on sample size and stage of disease. Forexample, in acute hepatitis, surface antigen stainingusually is negative as the infected cells are effec-tively cleared from the liver. The positive staining ismore often seen in chronic hepatitis in which theviral proliferation outstrips the immune clearance.Likewise, in late-stage chronic hepatitis or in long-term healthy carriers, HBsAg can be present but notHBcAg. This probably is because the viral genomeis incorporated into nuclear DNA so that HBsAg iscoded for but viral DNA is not. HBcAg is oftenpositive in immunocompromised patients, and thepresence of HBcAg in the cytoplasm of hepatocytesmay suggest replication of HBV.

HCV (Case 5) is thought to induce a milder formof disease and to produce more bile duct damage,lymphocyte infiltration of the parenchyma, and re-active changes in the duct epithelium than does HBV.The duct damage is not thought to be severe enoughto cause duct loss or cirrhosis. In addition, lympho-cytic aggregates in the portal zones and fatty changeof hepatocytes are more frequent than with HBV.Immunoperoxidase techniques for staining paraffin-embedded tissues for HCV are commercially availablebut difficult to utilize successfully.

Delta hepatitis can be superimposed on hepatitisB (45– 47) as either acute or chronic clinical exac-erbations of disease. Submassive or massive he-patic necrosis can occur; thus, delta hepatitisshould be suspected in any patient who has chronichepatitis B that suddenly flares up significantly.With HDV, the necroinflammatory activity of theprocess is often more pronounced than that seenwith HCV or HBV.

Autoimmune hepatitis (AIH) (no longer called“lupoid hepatitis” or used with the term “chronic”)has been clinically subclassified into three formscharacterized by differences in their clinical presen-tations or the antibodies found (48 –50). Most pa-tients respond favorably to immunosuppressivetherapy, with a resultant decrease in the activity ofthe disease, so their distinction from viral hepatitisor chronic hepatitis due to other causes is impor-

tant. Classical type 1 AIH presents the typical pro-file of a predominantly female disease. Patientsrange in age from 10 to 15 and 45 to 70 years andhave positive ANA titers and some association (inapproximately 10% of cases) with other autoim-mune disorders such as arthralgias and thyroid dis-ease. Type 2 AIH seems to present more in childrenand frequently is associated with other autoim-mune disorders (approximately 17%) as well. Theanti–liver-kidney-microsomal antibody (LKM1) ispresent in these patients, who often present withthe clinical picture of acute or fulminant hepatitis.The most recently described variant, type 3 AIH,also occurs mostly in women but with a later onset(mean age, 37). Approximately 25% of these pa-tients will display the antisoluble liver antigen only.These patients are seronegative for ANA and liver-kidney-microsomal antibody, but 75% will have an-ti–smooth muscle antibody or liver membrane an-tibody. In contrast to types 1 and 2, systemicautoimmune manifestations are not typical.

AIH often displays the prominent lymphoid ag-gregates and duct damage seen with HCV hepatitis;however, patients who have AIH seem to have morediffuse and severe interface hepatitis, an increasedincidence of bridging and confluent necrosis, andmore rapid progression to cirrhosis (51). In addi-tion, infiltration of mononuclear inflammatory cellstends to be diffuse with AIH and focal with chronicHCV. Plasma cells usually are more prominent inAIH than in HCV.

Other types of chronic hepatitis can have charac-teristic but not necessarily diagnostic features. Thefinding of copper deposits is necessary to make adiagnosis of Wilson’s disease, but because thesedeposits may be focal, a liver core biopsy may notsample them. AAT disease should have eosinophilicglobules in periportal zones. Periodic acid-Schiffdigest and AAT immunoperoxidase stains are goodfor confirming the nature of the globules. Largenumbers of AAT globules also have been noted inalcohol-associated disease and with other disor-ders, so phenotyping is necessary for definitive di-agnosis. Alcohol may or may not produce a CAH-like picture (52, 53). Recent studies of alcoholicshave shown that a large percentage of these pa-tients (possibly 30%) also have HCV antibodies andare positive for HCV by the polymerase chain reac-tion. Because typical alcoholic injury involves min-imal inflammatory activity, the presence of consid-erable mononuclear inflammation and the absenceof diagnostic evidence of alcohol damage may in-dicate that a viral infection is the cause of the injury(54 –56).

CAH can also be difficult to distinguish from PBC(see section “Biliary Tract Disease” and Tables 4and 5) and resolving acute hepatitis (see section“Acute Hepatitis” and Table 9).


Exacerbations, or sporadic rises in the quantitiesof liver enzymes, are commonly seen in patientswho have chronic hepatitis (57–59). These exacer-bations have been associated with increased hepa-tocyte necrosis on biopsy, and usually, the presenceof portal-based fibrosis is the most reliable histo-logic feature to identify an exacerbation of achronic disease. The clinical history and/or serummarkers may be needed, however, to distinguishthis lesion from a de novo acute hepatitis. It hasbeen well documented that HBV and HCV can bothwax and wane; thus, a diagnosis of mild chronichepatitis (or CPH) may not assure the patient of afavorable outcome. Some exacerbations in type Binfections can be due to the delta agent (see Table7). Other exacerbations of chronic hepatitis possi-bly could be due to mixed infection of HBV andHCV or by HAV or cytomegalovirus superimposedon chronic HBV or HCV. However, more recentstudies have shown that mixed infections of HBVand HCV may tend to behave clinically as HBVinfection alone.

Other virusesThe GBV-C virus (recently known as hepatitis G

virus) is a recently described RNA virus that belongsto the same family of viruses as HCV (Flaviviridae)(60, 61). The agent was discovered at the Centers forDisease Control and Prevention in the process ofstudying a possible variant of HCV. They found thevirus in patients who had acute and chronic typesof hepatitis (62) and suggested that this agent ac-counted for approximately 10% of non-A-E hepati-tis. They also identified the virus in 1.5% of blooddonors who had normal alanine aminotransferaselevels. The virus can be spread by transfusion, andrisk factors seem to include those for HBV and HCV,such as intravenous drug abuse and multiple sexualpartners. HBV and HCV coinfections also have beenidentified in as many as 10% and 20%, respectively(63, 64). Numerous studies of histopathologicchanges and clinical outcome strongly suggest thatHGV may not be a significant cause of hepatitis byitself and does not seem to alter the clinical out-come of patients who are coinfected with eitherHBV or HCV. Instead, the virus may simply be a“passenger” virus that is present but does not causesignificant pathology (62, 65– 67).

Another recently described virus is the TT virus,a DNA virus seen associated with hepatitis in Ja-pan, but questions still remain as to its significance(68, 69).

DIAGNOSTIC PROBLEMS: TUMORS AND

TUMOR-LIKE LESIONS

Making the diagnosis of benign or malignant livertumors usually is not a major problem for pathol-

ogists, especially when the diagnosis is made on aresection specimen. However, difficulties may arisewhen the biopsy samples are small as with core orfine needle aspiration (FNA) biopsies or when it isnecessary to distinguish between reactive processesand benign or malignant tumors of the same celltype. In these situations, it is important to know themost definitive criteria for making a diagnosis andto understand the pitfalls inherent in core or FNAbiopsies so that the most appropriate diagnosticsample can be obtained.

Case 6A 65-year-old man with longstanding cirrhosis of

undetermined cause was referred for evaluation forpossible liver transplantation. The workup revealeda possible liver mass, and a CT-guided FNA biopsywas performed. The presence of intact reticulin inthe pigmented zones is consistent with cirrhosisdue to hemochromatosis (Fig. 6A, B). The nonpig-mented areas that lack reticulin framework repre-sent the fragments of well-differentiated hepatocel-lular carcinoma (HCC), clear cell type (Fig. 6A, B).Iron stain showed 41/41 positivity in the cirrhoticliver and no iron in the tumor (Fig. 6C).Diagnosis: clear-cell, well-differentiated HCC aris-ing in hemochromatosis

Case 7A 29-year-old woman with cirrhosis was referred

for liver transplantation for autoimmune hepatitis.Her explanted liver contained six well-circumscribedtan nodules that were significantly larger than theremainder of the background cirrhotic nodules, mea-suring 1.4 to 2.3 cm in greatest diameter. There wasno evidence of carcinoma. The background cirrhosisshowed minimal inflammatory activity, so the diag-nosis of autoimmune hepatitis in an active stagecould not be confirmed histologically. The noduleseach had cytologic and architectural features (with anintact reticulin framework) of a benign nodule (Fig. 7).Diagnosis: macroregenerative nodules

Case 8A 58-year-old man with a history of alcohol abuse

and cirrhosis was referred for liver transplantation.His explanted liver contained two greenish nodulesin the left lobe, measuring 1.2 and 2.8 cm in greatestdiameter. The illustration represents findings fromone of the nodules (Fig. 8A, B). The other nodulewas also well-differentiated HCC with a more tra-becular architecture and more small cell change.Follow-up over a 2-year period has shown no re-currence of carcinoma.Diagnosis: small, well-differentiated HCC


Discussion: Hepatocellular TumorsDiagnostic problems usually arise when attempt-

ing to differentiate benign proliferative processesfrom well-differentiated, primary, malignant le-sions. To do this, it is first necessary to be aware ofthe usual differential diagnosis for lesions in cir-

rhotic livers versus noncirrhotic livers (70) (Table11); thus, reliable information about the back-ground liver is crucial. This information is best ob-tained by tissue biopsy, as radiographic findingsand even a surgeon’s impression of the gross ap-pearance of the liver can be in error. Without suchdefinitive information, it may be wise to exercisecaution when making a diagnosis.

Large cell and small cell changeAs the name implies, in small cell change (also

known as small cell dysplasia), the hepatocytes areconsiderably smaller than normal liver cells andappear as a zone of nuclear crowding or increasednuclear density. The cytoplasm may be more baso-philic than in normal hepatocytes, but there is nosignificant nuclear atypia or enlargement. Thesesmaller cells should be present in clusters ratherthan as isolated, single cells. Small cell change maybe indicative of a preneoplastic or neoplastic pro-cess but can also be seen in regeneration and atro-phy.

Large cell change (also known as large cell dys-plasia), in comparison, consists of scattered fociwithin a cirrhotic liver of enlarged hepatocytes withlarge, often irregularly shaped nuclei and nucleolibut with a normal nuclear:cytoplasmic ratio. Itspreneoplastic nature has been implicated but pos-sibly not completely proved, and some investiga-tors believe that it may represent a form of degen-erative or reactive change (71). However, whenclusters of cells with large cell change are seen, thefindings could be more compatible with a preneo-plastic or neoplastic focus.

A problem arises in the nomenclature for largeand small cell change (dysplasia) because of thenew World Congresses’ recommendations to usethe term dysplasia for nodules or foci of atypia thatare thought to be preneoplastic (72) (see section“Hepatocellular Tumors in the Cirrhotic Liver”).

FIGURE 6. Clear cell type of hepatocellular carcinoma arising inhemochromatosis with cirrhosis. A, routine staining shows two types oftissues on the sample. The left panel shows brown pigment in thecirrhotic liver, the right lacks pigment and the hepatocytes have palecytoplasm (663). B, reticulin stain reveals that the pigmented areashave intact framework (left panel) consistent with cirrhosis, but thepale cells lack distinct cell plate architecture (right panel) consistentwith hepatocellular carcinoma (403). C, iron stain shows 41 iron in thecirrhotic liver but no iron in the hepatocellular carcinoma (503).

FIGURE 7. Macroregenerative nodule. The reticulin stain shows anintact cell plate architecture similar to that expected in normal liver ora cirrhotic nodule (503).


Obviously, the use of the same term for differententities in the same organ can be confusing, so therecommendation is to use large and small cellchange instead of large and small cell dysplasia todescribe the cytologic (cellular) changes present inthe liver and to reserve the term dysplastic for nod-ules or foci that are thought to be preneoplastic innature.

Hepatocellular tumors in the cirrhotic liverIn cirrhotic livers, a mass most likely would rep-

resent either a macroregenerative (or dysplastic)nodule (with or without fatty change) or HCC (Ta-bles 11 and 12). Metastatic tumors rarely involvecirrhotic livers. Large nodules with atypical fea-tures, such as being a different color from the back-ground cirrhotic nodules (greener, paler, more yel-low, etc.), being irregular as opposed to havinguniformly rounded borders, or having a tendency toexpand or bulge when the initial cut is madethrough it, should raise suspicions of an early HCC.In addition, any nodule that is larger than 3 cm

most likely represents a true neoplasm; however, acaveat is that radiographically or by gross inspec-tion, multiple regenerative nodules may appear as asingle large mass.

Macroregenerative nodules (MRN) or low-gradedysplastic nodules (Case 7) (Table 12), formerly re-ferred to as a form of adenomatous hyperplasia(73), ordinary adenomatous hyperplasia (74), type IMRN (75), simple MRN (76), or large regenerativenodule (72), measure more than 0.8 cm in diameterand presumably represent regenerative foci ofhepatocytes within a cirrhotic liver versus an abnor-mal clone. (When the lesion is thought to representa neoplastic clone rather than a regenerative nod-ule, the term low-grade dysplastic nodule (72) maybe used for this lesion, see section on borderlinenodules.) On light microscopic examination, MRNsmaintain the cell plate architecture and reticulinframework of the typical, smaller regenerative nod-ules, and the hepatocyte morphology is unremark-able or shows only mild cytologic atypia. MRNsusually contain portal tracts and central veins, andbecause they are so large, a core biopsy may notreveal the fibrous bands that separate them fromthe rest of the cirrhotic liver; thus, a biopsy samplecan resemble normal liver. A reticulin stain, how-ever, may reveal double-layered cell plates and lay-ers of reticulin fibers at the edge of the specimenfragments, both of which are features of cirrhoticnodules (76). MRNs also can contain increased ironstores, bile, and Mallory bodies, and they may un-dergo fatty change (73, 77, 78). MRNs are not asso-ciated with significant elevations of seruma-fetoprotein (AFP) (79).

(Histologically similar nodules also occur in non-cirrhotic livers with chronic vascular disease suchas Budd-Chiari syndrome or portal vein thrombosisor as a sequelae of acute necrosis. Nomenclaturefor these nodules according to the World Con-gresses of Gastroenterology is multiacinar regener-

FIGURE 8. Hepatocellular carcinoma, solid type. A, the tumor has a typical hepatocytic appearance with eosinophilic cytoplasm and round, fairlyuniform nuclei (663). B, reticulin stain shows absence of cell plate architecture (663).

TABLE 11. Differential Diagnosis: Lesion in Liver

Hepatocellular Type

With cirrhosisMacroregenerative nodule (low-grade dysplastic nodule)Borderline (high-grade dysplastic) noduleHCC

Without cirrhosisMultiacinar regenerative noduleAdenomaFocal nodular hyperplasiaFibrolamellar HCCHCC (nonfibrolamellar)

Mimics cirrhosis clinicallyNodular regenerative hyperplasiaPartial nodular transformation

In children without cirrhosisHepatoblastomaMesenchymal hamartoma

HCC, hepatocellular carcinoma.From Ferrell LD. Liver and gallbladder pathology. In: Weidner N,

editor. The difficult diagnosis in surgical pathology. Philadelphia: W.B.Saunders; 1996. p. 298. Reprinted with permission.


ative nodule, formerly called adenomatous hyper-plasia [72].)

MRNs with borderline or overt malignantchanges have been much studied in Japan, where itis believed that the lesions can be preneoplastic orneoplastic, especially when associated with cyto-logic atypia such as small cell change, or dysplasia(see above), fat, clear cell change, or clusters ofMallory hyaline bodies. Of these atypical features,small cell change seems to be a much greater riskfactor than large cell change (dysplasia) for progres-sion to HCC (Table 13).

Borderline nodules (Table 12), or high-grade dys-plastic nodules (formerly known as atypical adeno-matous hyperplasia [74, 80], type II MRN [75], andatypical MRN [76]), have atypical features that arenot overtly diagnostic of malignancy but that are ofuncertain malignant potential (72). These nodulesmay have foci of fat, Mallory bodies, bile, iron, orclear cell change (76). There may be foci of smallcell change, which can give the appearance of in-

creased nuclear density in the involved zone. Inborderline lesions, the nuclear density can be up totwice what is normal without there being a significantconcern for HCC (76). Such nodules also can showmore significant focal decreases in the reticulinframework, and liver cell plates may be up to threecells thick but should not be arranged in uniformgroups of trabeculae. The edges of the nodules mayprotrude irregularly, and isolated gland-like struc-tures (pseudoglands) may be present.

The World Congresses of Gastroenterology haveproposed two grades of dysplastic nodules, low andhigh grade (72). The low-grade dysplastic nodulesare thought to represent a clonal proliferation andare characterized by mild atypia. The hepatocytesmay be enlarged with eosinophilic cytoplasm; thenuclear:cytoplasmic ratio may be low, normal, orslightly increased (small or large cell change); nu-clear atypia is minimal; and mitoses are absent.Mallory bodies may be seen, and iron content maybe greater or less than that of the surrounding liver.

TABLE 12. Histologic Features of Hepatocellular Nodules in Cirrhotic Livers

MorphologyLow-grade dysplastic nodule(macroregenerative nodule)

High-grade dysplastic nodule(borderline nodule)

HCC

Large cell change Can be present Can be present CommonNuclear density . 23 normal (small cell

change)No significant small cell

changeOccasional small foci in

borderline lesionsCommon, large foci

Cell plates, zone $ 3 cells thick (trabecular) None Rare in borderline lesions,no zones of trabeculae

Common pattern

Decrease or loss of reticulin Reticulin intact May see focal decrease orloss

Common, extensive

Fibrous septa separating thick plates None None Occasional patternIrregular, infiltrative edge Not present Sometimes present OccasionalPseudoglands Not present Rare Occasional patternPresence of portal zones Usually present Usually present NoneIncreased iron stores Occasional Occasional Almost always absentFatty change Can be present Can be present Can be presentBile production Can be present Can be present Can be presentMallory hyaline Can be present Can be present Can be present

(clusters)

HCC, hepatocellular carcinoma.From Ferrell LD. Liver and gallbladder pathology. In: Weidner N, editor. The difficult diagnosis in surgical pathology. Philadelphia: W.B. Saunders;

1996. p. 299. Reprinted with permission.

TABLE 13. Differential Diagnosis of Hepatocellular Lesions in Noncirrhotic Livers

MorphologyFocal Nodular

HyperplasiaAdenoma

Nodular RegenerativeHyperplasia

Fibrolamellar HCC

Hepatocellular morphology(large versus small cells)

Normal, no small orlarge cell change

Normal or slightlylarger or smallercells, may have fatand/or glycogen

Normal or slightlycompressed,suggesting foci ofsmall cell change

Larger-than-normal polygonal tospindle shapes, pale bodies,enlarged nuclei, abundanteosinophilic granular cytoplasm

Bile ducts Present in scar Not present Present in portal zones Not presentLarge vessels Present Present Not present Not typical, variableConnective tissue Scar May be present Not present Lamellar fibrosisMitoses None None None RareReticulin stain Normal pattern;

sinusoidalstaining; mayshow double cellplates

Normal or slightlydecreasedsinusoidal staining;may show doublecell plates

Normal withregenerative foci(thicker cell plates)compressing singlecell plates

Not used for diagnosis, variablepattern

HCC, hepatocellular carcinoma.From Ferrell LD. Liver and gallbladder pathology. In: Weidner N, editor. The difficult diagnosis in surgical pathology. Philadelphia: W.B. Saunders;

1996. p. 302. Reprinted with permission.


The width of the cell plates is similar to that ofMRN, and the overall atypia is such that manywould consider these lesions to fall within the lightmicroscopic realm of MRN as described above. Thehigh-grade dysplastic nodule has the same diagnos-tic criteria as the borderline nodule.

In addition, some nodules may contain smalldysplastic foci as small as 1 mm in diameter. Thesefoci can consist of clusters of small or large cellchange and are especially common in AAT defi-ciency, tyrosinemia, and chronic hepatitis B. Theseatypical foci often result in a microscopic “nodule-in-nodule” pattern of histology in the cirrhotic liver.

Recently, vascular studies of cirrhotic and dys-plastic nodules as well as of HCC (81) have shownmore unpaired arteries and sinusoidal capillariza-tion (as identified by CD34 staining) in dysplasticnodules and HCC as compared with the cirrhoticnodules, with the most extensive changes in HCC.These findings confirm an element of neoangiogen-esis and support the concept that the dysplasticnodule represents a step toward neoplastic trans-formation.

In well-differentiated HCC (Table 12) (Cases 6and 8), cytologic atypia (small or large cell type) canbe seen as well as significant architectural abnor-malities such as numerous trabeculae at least threecells thick that form zones of irregular cell plates(82). If there are significant degrees of small cellchange present on hematoxylin and eosin stain or agreater than twofold increase in nuclear density,then a reticulin stain should be used to examine forabnormal cell plate architecture. Because benignnodules should have a well-developed reticulinframework, the lack of such strongly supports adiagnosis of carcinoma. Angioinvasion also may bediagnostic for HCC, but this may not be evident onsmall samples or present in small lesions. A varietyof distinct subpopulations of cell differentiationmay be present, including clear cell change, Mal-lory body formation, eosinophilic change or inclu-sions, fatty change, or presence of bile (83– 85). Inaddition, the presence of numerous pseudoglandsis another feature that usually is indicative of car-cinoma (86). However, the most important diag-nostic markers of HCC are the architectural featuresof irregular and thickened cell plates and loss ofreticulin. Fully developed malignant changes evenin a microfocus less than 1 mm in diameter warrantsa diagnosis of HCC in a setting of a cirrhotic liver.

In some cases of well-differentiated HCC, fibroussepta separating the trabecular cell plates may bepresent. This has been referred to as the scirrhousvariant of HCC. These septa can stain strongly pos-itive with reticulin, but the cell plates are usuallygreater than two cells thick as in the more typicaltrabecular-type lesions without fibrosis.

Differential diagnosis. Distinguishing cases ofwell-differentiated HCC from a regenerative nodulecan pose diagnostic problems for the pathologist,especially on FNA biopsies. The literature on thissubject deals mostly with lesions of moderate topoor differentiation, which are relatively straight-forward (87, 88). The main problems arise when thepathologist attempts to make the diagnosis on FNAbiopsy material of a well-differentiated hepatocel-lular lesion without making and examining a cellbutton preparation, which would allow for archi-tectural evaluation by hematoxylin and eosin andreticulin stains (89 –92). On smears, architecturalabnormalities such as abnormally thick trabeculaelined by endothelial cells can be easily disrupted orbe difficult to distinguish from regenerative cellplates. Also, it may be impossible to determinewhether the hepatocytes sampled represent smallcell change, because there may be no normal cellssampled with which to compare them, and, further-more, the smeared cells may be affected by shrink-ing, drying, or crowding artifacts. Thus, an in-creased nuclear:cytoplasmic ratio or increasednuclear density, which often occurs in HCC, caneasily be missed. Large cell change within a cir-rhotic liver can look very similar to a well-differentiated HCC arising in a cirrhotic liver onFNA biopsy smears as both lesions may have only afew atypical cells against a background of morenormal-appearing hepatocytes. Small lesions lessthan 2 cm are particularly vulnerable to poor sam-pling. If the lesion is small, the surrounding cir-rhotic liver is likely to have been sampled, resultingin the presence of ductal epithelium or lipochrome-laden hepatocytes from the adjacent liver on thesmear, and the tumor cells may be missed. Thepresence of bile, fat, or Mallory bodies is not aspecific diagnostic criterion as these can be foundin both MRNs and HCCs. Hence, smears alone of-ten are insufficient for rendering a diagnosis, and acell button should be obtained to evaluate architec-ture. Furthermore, if an FNA biopsy sample doesnot reveal obvious HCC, then a core biopsy wouldbe appropriate to evaluate architecture further.

So far, special stains and immunoperoxidase stud-ies have not been much help in differentiating benignhepatocellular proliferations from malignant ones;however, these stains can differentiate HCC frommetastatic adenocarcinomas or cholangiocarcinoma.Mucicarminophilic material is present in many ade-nocarcinomas (including cholangiocarcinomas) andmixed hepatocellular-cholangiocarcinomas. AFP canbe focally positive in HCC, but many (50 to 80%)HCCs will not stain (93) and the small HCCs arealmost always negative. Keratin stain AE1/AE3 (kera-tin cocktail) is usually negative in HCC (some cellsmay stain) but is diffusely positive in adenocarci-noma; CAM 5.2 keratin reacts with most HCCs and


adenocarcinoma in a diffuse pattern (94). Cytokeratin7 (CK7) may be commonly positive in a focal patternin HCC, and this does not indicate cholangiolar dif-ferentiation. CK19 and 20 tend to be diffusely negativein HCC (70 to 80%) (95, 96), with various combina-tions positive in other types of adenocarcinomas (97).For example, colorectal adenocarcinomas tend to beCK7 negative, CK20 positive; pancreatic carcinomasCK7 positive, CK20 positive; and cholangiocarcino-mas CK7 positive, CK20 negative, CK19 positive.Staining of the bile canaliculi with polyclonal carci-noembryonic antigen (CEA) is specific for HCC (98),whereas cytoplasmic staining with polyclonal CEA andcytoplasmic and membranous monoclonal CEA is typ-ical of adenocarcinomas (99) but not of HCC. Othermarkers for adenocarcinoma, such as Leu-M1 andB-72.3, probably are not as specific but tend to be morepositive in adenocarcinoma than in HCC (93). Variousneuroendocrine stains, such as Grimelius, andimmunoperoxidase stains, such as neuron-specific enolase, chromogranin-A, and neuroten-sin, have been reported to be positive in hepatocel-lular malignancies, including fibrolamellarcarcinoma and hepatoblastoma (100, 101). Thus, atumor that arises in a cirrhotic liver and that mor-phologically appears as a typical HCC but has afocal positive staining pattern with one of theseneuroendocrine markers likely should be viewed asan HCC with neuroendocrine differentiation. In situhybridization for albumin messenger RNA may alsoprove to be useful in demonstrating hepatocellulardifferentiation (102).

Hepatocellular tumors in noncirrhotic liversIn a noncirrhotic liver in an older patient, a tu-

mor mass more likely would be a metastatic carci-noma than a primary liver process (Table 13), but ina younger patient, the lesion more likely may rep-resent focal nodular hyperplasia (FNH), partialnodular transformation, adenoma, or the fibrola-mellar variant of HCC (the last two are more com-monly seen in young women). Primary HCC of thenonfibrolamellar type also can occur in the noncir-rhotic liver generally in older patients, although it ismuch more frequently associated with cirrhosis.Diagnostic possibilities in children include hepato-blastoma versus other rare tumors, such as mesen-chymal hamartoma, if the lesion is hepatocellularin nature.

The pathology of metastatic lesions is not con-sidered in this course. These lesions, however, ac-count for the majority of all liver tumors, and it isimportant to obtain a complete patient history thatwould indicate any previous neoplasms. Metastasesshould be considered if a tumor shows cytologicfeatures not typical of a primary liver lesion. Immu-noperoxidase or other special stains as describedabove should be used, if necessary.

Focal nodular hyperplasiaFNH is thought to be a non-neoplastic tumor that

may arise as part of a vascular malformation/hamartoma; hemangioma; or reaction to a previ-ous, localized insult, such as ischemia (103–105).FNH was originally called focal cirrhosis because ofits resemblance to cirrhosis microscopically. It typ-ically contains large bands of fibrous tissue, whichmay be most prominent in the center of the lesion,the so-called stellate scar, but this gross feature isnot always present. Variable numbers of bile ductsor ductules are present in the fibrous tissue. Large,muscular vessels are present in the larger fibrousbands, but no large bile ducts are associated withthem, supporting the concept that these vessels areabnormal and the lesion is more likely a hamar-tomatous one.

Differential diagnosis. Because FNH maypresent as multiple nodules within the same liver,differentiating it from multiple adenomas or meta-static lesions may be difficult by gross examination.A microscopic examination should quickly elimi-nate metastases from the differential diagnosis, butdistinguishing it from adenoma may be difficult onsmall core or FNA biopsies. Thus, adequate sam-pling is the key to identifying the necessary ductularstructures in the fibrous stroma present in FNH butnot in adenoma.

Partial nodular transformationPartial nodular transformation is a perihilar le-

sion composed of regenerative hepatocytes withoutfibrosis. This lesion is likely to be a focal variant ofnodular regenerative hyperplasia (NRH), a diffuseprocess involving the entire liver, and both canresult in portal hypertension. The nodules in bothlesions contain regenerating liver cells with thick-ened cell plates that compress adjacent nonregen-erating single cell plates. These regenerative andcompressive hepatocytic changes can be observedreadily with the reticulin stain. Portal tracts arepresent and essentially normal. NRH, also known asnodular or micronodular transformation, has beenfound in association with a variety of disease states,including immune complex diseases, lymphoprolif-erative or myeloproliferative disorders, massive he-patic metastases, immunosuppressive drug ther-apy, PBC, organic cardiac disease, lesions withright-sided cardiac hypertrophy such as pulmonaryhypertension, and systemic amyloidosis (106 –111).The cause of both lesions is unknown, but a reac-tive hyperplasia after an ischemic injury or irregularblood flow to the liver has been implicated as apossible factor.

Differential diagnosis. Clinically and grossly,NRH is often mistaken for cirrhosis because of clin-ical evidence of portal hypertension or gross nodu-larity of the liver. However, liver function tests are


usually minimally abnormal, and, of course, thebiopsy shows no significant fibrosis. This lesion canbe especially difficult to diagnose on needle biopsyand only somewhat easier to diagnose on a deepwedge biopsy. A reticulin stain revealing thick re-generating cell plates compressing the interveningones can at least suggest the diagnosis of NRH. Onediagnostic problem is to differentiate NRH frommacronodular cirrhosis when the biopsy lacks thecharacteristic fibrous bands of the latter. Anotherdiagnostic consideration is the MRN, in which nor-mal portal zones are also commonplace. Neithermacronodular cirrhosis nor MRN, however, wouldbe expected to show the variable pattern of regen-eration and compression of hepatocytes that NRHshows.

For partial nodular transformation, the clinicalimpression is more likely to be that of a tumorwithin a noncirrhotic liver, and adequate samplingagain is needed to distinguish it from an adenomaor an FNH. In contrast to partial nodular transfor-mation, adenoma would lack portal zones (see be-low) and FNH would have abnormal portal-likezones with bile duct proliferation and fibrosis (seeabove).

Hepatic adenomaHepatic adenoma is the benign lesion that is

most likely associated with a history of oral contra-ceptive use and is very rare in childhood, mostlyoccurring in young women of child-bearing age(112, 113). It can appear singly or as multiple nod-ules (usually the former). It may or may not beencapsulated and is usually fairly round, withsmooth borders. On light microscopy, the cellplates mimic normal liver but can be two to threecells thick. Reticulin formation is present but maybe less than that seen in normal (or regenerative)liver. No bile ductules or portal triads are present inthe lesion, but central vein-like vessels are present.In addition, large muscular vessels (arteries and/orveins) typically are present. The cytology of thetumor cells is very similar to normal liver, althoughthe hepatocytes may be slightly larger or smallerthan normal. Usually, nuclei are relatively small,round, and uniform and have small nucleoli. Fibro-sis, hemorrhage, necrosis, bile production, pseudo-gland (acinar) formation, and fatty change can oc-cur, and glycogen deposits, lipochrome pigment,and Mallory bodies can be present. Mitoses andvascular invasion are not seen. Rarely, an HCC hasarisen in a lesion histologically and clinically anadenoma (113, 114). Adenomas may also arise inthe setting of glycogen storage disorder (115).

Differential diagnosis. Adenoma, partial nodulartransformation, FNH, and even normal liver can bevirtually impossible to diagnosis on an FNA biopsysample because their cytologic and architectural

features are so similar. A core biopsy is a bettermethod for obtaining a diagnostic sample, but thecore must be long enough (1.5 to 2 cm) to obtainmaterial with distinctive architectural features suchas the absence of portal zones in adenoma or afocal cirrhosis–like picture in FNH. The presence ofabnormally large muscular arteries (or vessels)without a corresponding large duct would be typi-cal of FNH or adenoma but not of normal liver;however, it may be necessary to do a wedge orexcisional open biopsy to clearly differentiate thelesions as described above.

Fibrolamellar variant of HCCThe fibrolamellar variant of HCC also arises in

noncirrhotic liver but usually occurs in youngerindividuals than those with cirrhosis and HCC, andserum AFP usually is not elevated. This tumor, asoriginally described (116, 117), has abundant,dense, fibrous, stromal bands that separate thenests and clusters of tumor cells. The malignanthepatocytes vary in shape, but for the most part, thecells are large and have polygonal, eosinophilic,and granular cytoplasm.

Differential diagnosis. Because this tumor oc-curs in noncirrhotic livers of younger individuals, itmust be differentiated from the benign lesions (seeabove) that occur in a similar clinical setting. Thecytologic pleomorphism of the tumor is the key tothe diagnosis, as normal livers and those with be-nign hepatocytic tumors lack this feature. Unfortu-nately, the fibrous component in our experience isnot sampled readily by FNA biopsy because thecutting needle probably preferentially extracts thetumor cells rather than the dense stroma. Thus, thediagnosis may not be completely definitive on FNAbiopsy samples. Because the diagnosis of fibrola-mellar HCC implies a favorable prognosis as com-pared with other HCCs, one should be strict in theapplication of the criteria when making the diagno-sis. The scirrhous variant of HCC that usually occursin the cirrhotic liver also contains considerable fi-brous tissue, but it does not have the distinctivelamellar fibrosis and pleomorphic cytologic fea-tures seen in the fibrolamellar type. Another fibro-sing tumor of the liver, so-called sclerosing hepaticcarcinoma, which is associated with hypercalcemia,also has been described (118). This type of carci-noma has extensive fibrosis, can be of hepatocellu-lar or cholangiolar type, and occurs in cirrhotic andnoncirrhotic livers; but, again, such lesions do nothave the typical hepatocellular cytologic features offibrolamellar carcinoma. Thus, because a diagnosisof fibrolamellar HCC implies a favorable prognosiscompared with other HCCs or cholangiolar carci-noma, adherence to these diagnostic criteria shouldbe applied when making the diagnosis.


Hepatocellular tumors in childrenIn children, the differential diagnosis of hepato-

cellular tumors is considerably different than it is inadults. Cases of HCC are very rare, but when seen,they are essentially always in the setting of cirrhosisor a metabolic disorder such as tyrosinemia. HCCin children has the same architectural and cytologicfeatures seen in adults (119).

Hepatoblastoma is the most common hepatocel-lular tumor of children. The most common histo-logic subtypes are the epithelial or epithelial-mesenchymal types, followed by the small cellundifferentiated (anaplastic) type, and macrotrabe-cular type (120). The epithelial subtype differenti-ates into two patterns: the fetal and the embryonal.The fetal differentiation consists of polygonal tu-mor cells with round, medium-sized nuclei andmoderate amounts of eosinophilic cytoplasm. Thetumor cells are smaller than normal liver cells andresemble fetal hepatocytes. They are arranged incords and often contain glycogen or fat, which ap-pears as an alternating pink and white cytoplasmicpattern on low-power light microscopy. There is amarked diminution of the reticulin framework inmost zones. The embryonal pattern is made up ofsmaller, darker staining cells with meager, morebasophilic cytoplasm. The cells often are arrangedin an acinar or tubular pattern. Some studies indi-cate a better prognosis for patients who have tu-mors of predominantly fetal differentiation (.75%of the tumor) (121).

The small cell undifferentiated (anaplastic) typeis composed of a fairly uniform population of cellsthat lack evidence of epithelial or stromal differen-tiation and could be mistaken for neuroblastoma,lymphoma, or rhabdomyosarcoma. This subtype isalso often associated with the fetal-epithelial sub-type and seems to have a poorer prognosis whenpresent.

The architectural features of the macrotrabeculartype of hepatoblastoma are similar to those of thetrabecular variant of HCC, but the presence of thispattern probably does not worsen the overall prog-nosis. The trabeculae should be at least 10 cellsthick and present in a repetitive pattern. Cytologicatypia may be present, but the cells usually aresmaller than normal rather than larger as in manyHCCs. According to Haas et al. (122), this variant isalways associated with the fetal-epithelial subtype,so it can be distinguished from HCC by thorough

microscopic examination of the resected tumorspecimen for the fetal pattern.

Mesenchymal elements, including osteoid, carti-lage, and fibrous tissue, can show varying degreesof differentiation. The presence of stromal elementsprobably does not influence prognosis. Extramed-ullary hematopoiesis often can be present.

Differential diagnosis. Diagnostic problems arisewhen attempting to differentiate the various formsof hepatoblastoma from other tumor types, such asa hepatic adenoma, HCC, embryonal carcinomas,neuroblastoma, lymphoma, or rhabdomyosar-coma, on sparse biopsy material. For example, apure fetal type of differentiation should not be con-fused with hepatic adenoma, which is extremelyrare in children who are younger than 10 years. Thefetal component of hepatoblastoma should containsmaller-than-normal liver cells with increased nu-clear density (increased nuclear:cytoplasmic ratio)and most likely a “light and dark” cytoplasmicchange because of the deposition of glycogen andfat as described above (Table 14). Polyclonal CEAwill be positive in the fetal zones (123). The macro-trabecular type of hepatoblastoma usually does nothave the variation in cell size or cellular enlarge-ment seen in many HCCs, which only rarely occursin children with noncirrhotic livers. But this form ofhepatoblastoma could still be impossible to differ-entiate from HCC by histologic means; thus, furthersampling or resection may be helpful. The small cellvariant can be differentiated from lymphoma byleukocyte common antigen and/or B- and T-celllymphocyte immunohistochemical markers (as theAFP may be negative [124]), but differentiationfrom neuroendocrine tumors is more problematicbecause hepatoblastomas can demonstrate neu-roendocrine differentiation (101). One might alsosuspect that focal rhabdomyoblastic differentiationcould be present. Again, thorough examination ofthe biopsy or resection specimen should showother patterns of differentiation in hepatoblastoma.Another point to note is that the tumors may “dif-ferentiate” after chemotherapy (125).

In hepatoblastoma, as in HCC, AFP levels may beelevated; however, in the former, the patients usu-ally are younger (younger than 2 years comparedwith older than 5 years for HCC), and there usuallyis no background cirrhosis or underlying metabolicdisorder. AFP also may be elevated in embryonalmalignancies such as yolk sac tumor, so this is not

TABLE 14. Differentiating Features: Hepatoblastoma Versus Adenoma

Patient Age AFP Cell SizeReticulin

StainLight/Dark

CellsNodularity

HB, fetal type usually ,2–3 y often 1 , nl focally absent 1 1Adenoma usually .10 y 2 nl or . mostly intact 2 6

HB, hepatoblastoma; AFP, serum a-fetoprotein levels; nl, normal; 1, present; 2, not present; 6, minimal degree of involvement.


specific for HCC or hepatoblastoma. AFP shouldnot be significantly elevated in benign hepatocellu-lar lesions such as adenoma or FNH.

Mesenchymal hamartomaAnother rare tumor in children is mesenchymal

hamartoma, previously known as cavernous lym-phangioadenomatoid tumor, cystic hamartoma, orbenign mesenchymoma (126). This benign tumorcan be large and contains clusters of normal-appearing hepatocytes arranged in cell plates ad-mixed with an abundant myxoid stroma that con-tains numerous branched bile ducts. Many cysticspaces lined by flattened cells also are present,filled with a translucent fluid or gelatinous material.The stroma often contains smaller lymphatic-likechannels.

Differential diagnosis. When cystic spaces arethe most prominent components of the tumor,mesenchymal hamartoma can grossly resemblepolycystic disease of the liver. However, the mes-enchymal hamartoma is a single nodule rather thana multifocal lesion, and the stroma (which containsductules between the cysts) is more prominent andmyxoid than that seen between the cysts of poly-cystic disease. Infantile hemangioendotheliomaalso may contain many ducts separating the vascu-lar slits and stroma throughout the tumor, but thistumor has more prominent vasculature, often withsolid areas of endothelial proliferation, than seenwith mesenchymal hamartoma.

VASCULAR AND STROMAL NEOPLASMS

In the liver, the main problem in diagnosing vas-cular and stromal tumors is recognizing their mes-enchymal natures. This can be especially difficulton small core or FNA biopsy samples. Even com-mon lesions such as cavernous hemangiomas,which pose no diagnostic problem in resected liv-

ers, may be unrecognizable on FNA biopsy samplesbecause they contain very few cells and yield highlybloody biopsy specimens. Likewise, Kaposi’s sar-coma in the liver is usually not a clinical diagnosticproblem in a patient who has a history of AIDS andKaposi’s sarcoma at other sites, but again, it can bedifficult or impossible to diagnose with FNA. He-mangioendothelioma in children, epithelioid he-mangioendothelioma, and angiosarcoma all are un-common, and a diagnosis of one of these tumors isbest made on a core or wedge biopsy specimen orresected tissue to examine sufficiently the cytologicand architectural features.

Case 9A 25-year-old woman who had history of “vascu-

lar mass” of the liver was referred to UCSF forresection. At the time of surgery, two lesions mea-suring 2.7 and 3 cm were noted. The tumor wascomposed of epithelioid to spindle cells, some witha signet ring–like configuration, which were em-bedded in a myxoid to fibrous stroma (Fig. 9A). Thetumor grew around portal tracts (Fig. 9A) andtended to grow into veins (Fig. 9B). Residual factorVIII and CD34 immunohistochemical stains werepositive on the tumor cells, confirming the vascularrather than hepatocellular or cholangiolar nature ofthe tumor.Diagnosis: epithelioid hemangioendothelioma

Discussion: Vascular NeoplasmsEpithelioid hemangioendothelioma is a rare pri-

mary vascular tumor with many histologic appear-ances (127). The tumor cells can be spindled ordendritic with branching processes, polygonal withepithelioid features, and/or signet ring–like withintracytoplasmic spaces or lumina. The tumorcharacteristically grows into the venous channels as

FIGURE 9. Epithelioid hemangioendothelioma. A, the tumor shows spindle to epithelioid cells embedded in a myxoid to fibrous stroma. Somecells have a signet ring–like configuration. A normal portal zone has been preserved (bottom center). B, elastochrome stain shows a central vein thathas been completely occluded by tumor cells (203).


either solid tufts of epithelial cells or as myxoid/fibrous stroma containing the irregularly shapedcells described above. The lesion spreads in such anirregular manner that it can spare some zones ofresidual liver even in the center of the tumor. Inaddition, the stroma can become densely collag-enized over time and can even calcify and appearradiopaque. Most of the tumor cells (.60%) stainfor factor VIII, Ulex europaeus, or CD31 or 34 withimmunoperoxidase techniques. This lesion can bemultifocal and will behave in a low-grade malig-nant fashion; overall, it is a much less aggressivetumor than angiosarcoma.

Differential diagnosis. This is the vascular neo-plasm most likely to be misdiagnosed because itspeculiar pattern of spread within the sinusoids,variable cell shape, and the accompanying myxoid/fibrous reaction can mislead the unwary into mak-ing a diagnosis of adenocarcinoma, HCC, or evenan unusual scar reaction or venous thrombosis. Thepolygonal tumor cells can resemble entrappedhepatocytes or duct cells, and the individual vacu-olated cells entrapped in the stroma may mimic thesignet ring cells of adenocarcinoma, but mucin andkeratin stains of the tumor cells should be negative.Other immunoperoxidase stains also can easily dif-ferentiate the neoplastic processes: many of thepolygonal and epithelioid cells should be factor VIIIpositive in epithelioid hemangioendothelioma,whereas AFP, monoclonal CEA, polyclonal CEA,and keratin stains can be used to identify HCCs oradenocarcinomas as described previously. Keratinstains can stain liver or bile duct cells entrappedwithin an epithelioid hemangioendothelioma aswell as the epithelioid tumor cells in rare cases (byreport [128]), so care must be taken when interpret-ing such findings.

AngiosarcomaAngiosarcoma usually is multicentric and has a

variety of histologic appearances. It is similar to

epithelioid hemangioendothelioma in that it has apredilection to spread along sinusoids and veins;however, the myxoid/fibrous stroma seen in thelatter is either not prominent or absent. The tumorcells are usually spindled or polygonal and have atendency to line the sinusoids adjacent to survivinghepatocytes in a scaffold-like pattern, dissecting thecell plates into smaller fragments or expanding thesinusoidal space between cell plates. The tumorcells can also grow in solid sheets and form smalland large, irregular vascular spaces or pelioticchannels. These larger spaces may contain papil-lary projections of tumor cells. Extramedullary he-matopoiesis often is present. Endothelial markersshould be focally positive, but the solid, spindleareas may not stain. Angiosarcoma has a rapidlyprogressive course with a much poorer prognosisthan epithelioid hemangioendothelioma. Angiosar-coma can occur in children as well as in adults(129).

Differential diagnosis. In children, angiosar-coma may be difficult to distinguish from undiffer-entiated (embryonal) sarcoma, which can containsimilar-appearing spindled areas. Embryonal sar-coma, however, more closely resembles malignantfibrous histiocytoma than does angiosarcoma. Em-bryonal sarcoma can be distinguished by the pres-ence of large, multinucleated tumor cells and hya-line periodic acid-Schiff digest–positive globuleswithin the cytoplasm of the tumor cells or in thetumor stroma. These globules are negative for AFPand AAT, and their exact nature is unknown (130 –132).

Case 10A 37-year-old woman had a pedunculated liver

mass of the right lobe, measuring 11 cm in greatestdiameter, that was discovered incidentally during aroutine gynecologic examination. The tumor wasresected successfully, and the pathology was re-

FIGURE 10. Angiomyolipoma, epithelioid variant. A, the tumor cells are large, with abundant eosinophilic cytoplasm that tends to retract from thecytoplasmic border, causing a halo-like effect. The nuclei are round, often with prominent nucleoli (503). B, smooth muscle actinimmunohistoperoxidase stain shows strong staining of the tumor cells (663).


ferred to UCSF for consultation and special studies.The routine light microscopy revealed a tumor thathad large eosinophilic cells with large, round nuclei(Fig. 10A). The differential diagnosis was HCC, an-giomyolipoma, or adenoma with atypical features.Reticulin stain showed poorly formed, trabecular-like structures, mimicking HCC. Immunohisto-chemical stains for keratin (CAM5.2, AE1/3) andAFP stains were negative, and HMB-45 and smoothmuscle actin were positive (Fig. 10B), diagnostic forangiomyolipoma.Diagnosis: angiomyolipoma

Discussion: Stromal Neoplasm-AngiomyolipomaPrimary stromal neoplasms such as lipoma, fi-

brosarcoma, and malignant fibrous histiocytomahave been described as rare occurrences in theliver. These tumors are morphologically identical tothe soft tissue primaries and so pose no significantdiagnostic dilemma. However, one lesion that canpose difficult diagnostic problems in the liver isangiomyolipoma. This benign lesion typically con-sists of a triad of well-formed vessels, fat, and spin-dle cells, the last representing the muscle compo-nent. Foam cells (histiocytes) and hematopoieticelements also can be present. Mitotic figures arenot seen.

Differential diagnosisUnfortunately, angiomyolipomas often can vary

from the typical picture. They can demonstrate avery prominent spindle-cell or epithelioid type ofdifferentiation, have little or no fat, and lack theprominent vasculature often seen in renal lesions(133, 134). Trabecular patterns, which simulate thatof HCC, also have been described, and oncocytic

cytoplasmic changes reminiscent of fibrolamellarHCC also may be prominent (133, 134). These le-sions can become very large and have significantnecrosis. When these atypical patterns are present,immunohistochemical stains may help differentiatethese lesions from malignant processes. The char-acteristic immunohistochemical profile includespositivity for HMB-45 and smooth muscle actin(133, 135, 136). Desmin and S-100 staining is vari-able, and cytokeratin, carcinoembryonic antigen,AFP, and chromogranin are negative. Factor VIIIantigen stains only the walls of identifiable vesselswithin the tumor (Table 15).

REFERENCES

1. Millward-Sadler GH. Cirrhosis. In: MacSween RNM, An-thony PP, Scheuer PJ, Burt AD, Portmann BC, editors. Pa-thology of the liver. 3rd ed. London: Churchill Livingstone;1994. p. 397– 424.

2. Nevens F, Staessen D, Sciot R, Van Damme B, Desmet V,Fevery J, et al. Clinical aspects of incomplete septal cirrho-sis in comparison with macronodular cirrhosis. Gastroen-terology 1994;106:459 – 63.

3. Baptista A, Bianchi L, De Groote J, Desmet V, Gedigk P,Korb G, et al. Alcoholic liver disease: morphological mani-festations. Lancet 1981;1:707–11.

4. Lewis J, Mullick F, Ishak K, Ranard R, Ragsdale B, Perse R,et al. Histopathologic analysis of suspected amiodaronehepatotoxicity. Hum Pathol 1990;21:59 – 67.

5. Babany G, Uzzan F, Larrey D, Degott C, Bourgeois P, ReneE, et al. Alcoholic-like liver lesions induced by nifedipine.J Hepatol 1989;9:252–5.

6. Snover D. The liver in systemic disease. In: Biopsy diagnosisof liver disease. 1st ed. Baltimore: Williams & Wilkins; 1992.p. 192– 4.

7. Arcidi J, Moore G, Hutchins G. Hepatic morphology incardiac dysfunction: a clinico-pathologic study of 1000 sub-jects at autopsy. Am J Pathol 1981;104:159 – 66.

8. Klatt E, Koss M, Young T, Macauley L, Martin S. Hepatichyaline globules associated with passive congestion. ArchPathol Lab Med 1988;112:510 –3.

9. Kanel G, Ucci A, Kaplan M, Wolfe H. A distinctive perive-nular hepatic lesion associated with heart failure. Am J ClinPathol 1980;73:235–9.

10. Wanless I. Vascular disorders. In: MacSween R, Anthony P,Scheuer P, Burt A, Portmann B, editors. Pathology of theliver. 3rd ed. London: Churchill Livingstone; 1994. p. 535–62.

11. Shulman H, McDonald G. Liver disease after marrow trans-plantation. In: Sale G, Shulman H, editors. The pathology ofbone marrow transplantation. New York: Masson Publish-ing; 1984. p. 104 –35.

12. Lefkowitch J. Bile ductular cholestasis: an ominous his-topathologic sign related to sepsis and cholangitis lenta.Hum Pathol 1982;13:19 –24.

13. Nakanuma Y. Necroinflammatory changes in hepatic lob-ules in primary biliary cirrhosis with less well-defined cho-lestatic changes. Hum Pathol 1993;24:378 – 83.

14. Harrison R, Hubscher S. The spectrum of bile duct lesionsin end-stage primary sclerosing cholangitis. Histopathology1991;19:321–7.

15. Wee A, Ludwig J, Coffey R, LaRusso N, Wiesner R. Hepato-biliary carcinoma associated with primary sclerosingcholangitis and chronic ulcerative colitis. Hum Pathol 1985;16:719 –26.

TABLE 15. Differential Diagnosis: AML, Adenoma, and

Well-Differentiated HCC

Pathology AML Adenoma HCC

Cytoplasmic featuresEpithelioid features 1 1 1Spindle cells 1 2 2Intense eosinophilia 1 2 1Smaller-than-normal hepatocytes 6 2 6

Nuclear featuresNucleoli 1 1 1Variable nuclear shapes 1 2 2Round, regular nuclei 2 1 1Mitotic figures 2 2 6

Architectural featuresTrabeculae 6 2 1Solid zones 1 2 1Absent reticulin 1 2 1

Immunohistochemical featuresHMB-45 1 2 2SMA 1 2 2AFP 2 2 6

AML, angiomyolipoma; HCC, hepatocellular carcinoma; SMA, smoothmuscle actin; AFP, a-fetoprotein; 1, present; 2, not present; 6, minimaldegree of involvement.


16. Ludwig J, MacCarty R, LaRusso N, Krom R, Wiesner R.Intrahepatic cholangiectases and large-duct obliteration inprimary sclerosing cholangitis. Hepatology 1986;6:560 – 8.

17. Ben-Ari Z, Dhillon A, Sherlock S. Autoimmune cholangi-opathy: part of the spectrum of autoimmune chronic activehepatitis. Hepatology 1993;18:10 –5.

18. Goodman Z, McNally P, Davis D, Ishak K. Autoimmunecholangitis—a variant of primary biliary cirrhosis. Hepatol-ogy 1993;18:109A.

19. Taylor S, Dean P, Riely C. Primary autoimmune cholangitis:an alternative to antimitochondrial antibody-negative pri-mary biliary cirrhosis. Am J Surg Pathol 1994;18:91–9.

20. Colombato L, Alvarez F, Cote J, Huet P. Autoimmunecholangiopathy: the result of consecutive primary biliarycirrhosis and autoimmune hepatitis? Gastroenterology1994;107:1839 – 43.

21. Dourakis S, Alexopoulou A, Hadziyannis S. Fulminant hep-atitis after flutamide treatment. J Hepatol 1994;20:350 –3.

22. Scheuer P. Viral hepatitis. In: MacSween R, Anthony P,Scheuer P, Burt A, Portmann B, editors. Pathology of theliver. 3rd ed. London: Churchill Livingstone; 1994. p. 243–67.

23. Ishak K, Sharp H. Developmental abnormalities and liverdiseases in childhood. In: MacSween R, Anthony P, ScheuerP, Burt A, Portmann B, editors. Pathology of the liver. 3rded. London: Churchill Livingstone; 1994. p. 83–122.

24. Hadchouel M, Gautier M. Histopathologic study of the liverin the early cholestatic phase of alpha-1-antitrypsin defi-ciency. J Pediatr 1976;89:211–5.

25. Leblanc A, Odievre M, Hadchouel M, Gendrel D, ChaussainJ, Rappaport R. Neonatal cholestasis and hypoglycemia:possible role of cortisol deficiency. J Pediatr 1981;99:577–80.

26. Phillips M, Blendis L, Poucell S, Offterson J, Petric M, Rob-erts E, et al. Syncytial giant cell hepatitis: sporadic hepatitiswith distinctive pathological features, a severe clinicalcourse, and paramyxoviral features. N Engl J Med 1991;324:455– 60.

27. Pappo O, Yunis E, Jordan J, Jaffe R, Mateo R, Fung J, et al.Recurrent and de novo giant cell hepatitis after orthotopicliver transplantation. Am J Surg Pathol 1994;18:804 –13.

28. Devaney K, Goodman Z, Ishak K. Postinfantile giant-celltransformation in hepatitis. Hepatology 1992;16:327–33.

29. Gastroenterology IWPotWCo. Terminology of chronic hep-atitis, hepatic allograft rejection, and nodular lesions of theliver: summary of recommendations developed by an In-ternational Working Party, supported by the World Con-gresses of Gastroenterology, Los Angeles, 1994. Am J Gas-troenterol 1994;89:S177– 81.

30. Popper H, Shaffner F. The vocabulary of chronic hepatitis.N Engl J Med 1971;284:1154 – 6.

31. Acute and chronic hepatitis revisited. Review by an inter-national group. Lancet 1977;2:914 –9.

32. Cooksley W, Bradbear R, Robinson W, Harrison M, HallidayJW, Powell LW, et al. The prognosis of chronic active hep-atitis without cirrhosis in relation to bridging necrosis.Hepatology 1986;6:345– 8.

33. Popper H. Changing concepts of the evolution of chronichepatitis and the role of piecemeal necrosis. Hepatology1983;3:759 – 62.

34. Knodell R, Ishak K, Black W, Chen T, Craig R, Kaplowitz N,et al. Formulation and application of a numerical scoringsystem for assessing histological activity in asymptomaticchronic active hepatitis. Hepatology 1981;1:431–5.

35. Ishak K, Baptista A, Bianchi L, Callea F, DeGroote J, GudatF, et al. Histological grading and staging of chronic hepa-titis. J Hepatol 1995;22:696 –9.

36. Batts KP, Ludwig J. Chronic hepatitis—an update on termi-nology and reporting. Am J Surg Pathol 1995;19(12):1409–17.

37. Tsui W. New classification of chronic hepatitis and more.Adv Anat Pathol 1996;3:64 –70.

38. Bedossa P, Bioulac-Sage P, Callard P, Chevallier M, DegottC, Deugnier Y, et al. Intraobserver and interobserver vari-ations in liver biopsy interpretation in patients with chronichepatitis C. Hepatology 1994;20:15–20.

39. Scheuer P, Ashrafzadeh P, Sherlock S, Brown D, DusheikoG. The pathology of hepatitis C. Hepatology 1992;15:567–71.

40. Gerber M, Krawczynski K, Alter M, Sampliner R, MargolisH. Histopathology of community acquired chronic hepati-tis C. Mod Pathol 1992;5:483– 6.

41. Ulich T, Anders K, Layfield L, Cheng L, Lewin K. Chronicactive hepatitis of hepatitis B and non-A, non-B etiology.Arch Pathol Lab Med 1985;109:403–7.

42. Teixeira M, Weller I, Murray A, Bamber M, Thomas H,Sherlock S, et al. The pathology of hepatitis A in man. Liver1982;2:52– 60.

43. Kryger P, Christoffersen P. Liver histopathology of the hep-atitis A virus infection: a comparison with hepatitis type Band non-A, non-B. J Clin Pathol 1983;36:650 – 4.

44. Gerber M, Thung S. The diagnostic value of immunohisto-chemical demonstration of hepatitis viral antigens in theliver. Hum Pathol 1987;18:771– 4.

45. Govindarajan S, Valinluck B. Serum hepatitis B virus-DNAin chronic hepatitis B and delta infection. Arch Pathol LabMed 1985;109:398 –9.

46. Govindarajan S, DeCock K, Peters R. Morphologic and im-munohistochemical features of fulminant delta hepatitis.Hum Pathol 1985;16:262–7.

47. Govindarajan S, DeCock K, Redeker A. Natural course ofdelta superinfection in chronic hepatitis B virus-infectedpatients: histopathologic study with multiple liver biopsies.Hepatology 1986;6:640 – 4.

48. Johnson P, McFarlane I, Feddleston A. The natural courseand heterogeneity of autoimmune-type chronic active hep-atitis. Semin Liver Dis 1991;11:187–96.

49. Johnson P, McFarlane I. Meeting report: International Au-toimmune Hepatitis Group. Hepatology 1993;18:998 –1005.

50. Manns M. Cytoplasmic autoantigens in autoimmune hep-atitis: molecular analysis and clinical relevance. SeminLiver Dis 1991;11:205–14.

51. Bach N, Thung S, Schaffner F. The histological features ofchronic hepatitis C and autoimmune chronic hepatitis: acomparative analysis. Hepatology 1992;15:572–7.

52. Ferrell L, Steinkirchner T, Sterneck M, Lake J, Roberts J,Ascher N. Alpha-1-antitrypsin (AAT) globules in cirrhoticlivers. Mod Pathol 1993;6:110A.

53. Pariente E, Degott C, Martin J, Feldmann G, Potet F, Ben-hamou J. Hepatocytic PAS-positive diastase-resistant inclu-sions in the absence of alpha-1-antitrypsin deficiency: highprevalence in alcoholic cirrhosis. Am J Clin Pathol 1981;76:299 –302.

54. Sterneck M, Ferrell L, Wright T, Read A, Roberts J, Ascher N,et al. Viral co-factors in patients with alcoholic cirrhosisundergoing liver transplantation. Gastroenterology 1991;100(Suppl):A800.

55. Takase S, Takada N, Enomoto N, Yasuhara M, Takada A.Different types of chronic hepatitis in alcoholic patients:does chronic hepatitis induced by alcohol exist? Hepatol-ogy 1991;13:876 – 81.

56. Brillanti S, Masci C, Siringo S, DiFebo G, Miglioli M, Bar-bara L. Serological and histological aspects of hepatitis Cvirus infection in alcoholic patients. J Hepatol 1991;13:347–50.

57. Davis G, Hoofnagle J, Waggoner J. Spontaneous reactiva-tion of chronic hepatitis B virus infection. Gastroenterology1984;86:230 –5.

58. Liaw Y, Chen J, Chen T. Acute exacerbation in patients with


liver cirrhosis: a clinicopathological study. Liver 1990;10:177– 84.

59. Fattovich G, Brollo L, Alberti A, Realdi G, Pontisso P, Gius-tina G, et al. Spontaneous reactivation of hepatitis B virusinfection in patients with chronic type B hepatitis. Liver1990;10:141– 6.

60. Linnen J, Wages J, Zhang-Keck Z, Fry K, Kwawczynski K,Alter H, et al. Molecular cloning and disease association ofhepatitis G virus: a transfusion-transmissible agent. Sci-ence 1996;271:505– 8.

61. Mphahlele M, Lau G, Carman W. HGV: the identification,biology and prevalence of an orphan virus. Liver 1998;18:143–55.

62. Cheung RC, Keeffe EB, Greenberg HB. Hepatitis G virus: isit a hepatitis virus? [see comments]. West J Med 1997;167(1):23–33.

63. Martinot M, Marcellin P, Boyer N, Detmer J, Pouteau M,Castelnau C, et al. Influence of hepatitis G virus infectionon the severity of liver disease. Ann Intern Med1997;126(11):874 – 81.

64. Fried MW, Khudyakov YE, Smallwood GA, Cong M, Nichols B,Diaz E, et al. Hepatitis G virus co-infection in liver transplan-tation recipients with chronic hepatitis C and nonviralchronic liver disease. Hepatology 1997;25(5):1271–5.

65. Pessoa MG, Terrault NA, Ferrell LD, Kim JP, Kolberg J,Detmer J, et al. Hepatitis G virus in patients with cryptogenicliver disease undergoing. Hepatology 1997;25(5):1266–70.

66. Haydon GH, Jarvis LM, Simpson KJ, Hayes PC, SimmondsP. The clinical significance of the detection of hepatitisGBV-C RNA in the serum of patients with fulminant, pre-sumed viral, hepatitis. J Viral Hepatol 1997;4(1):45–9.

67. Sarrazin C, Herrmann G, Roth WK, Lee JH, Marx S, ZeuzemS. Prevalence and clinical and histological manifestation ofhepatitis G/GBV-C infections in patients with elevated ami-notransferases of unknown etiology. J Hepatol 1997;27(2):276 – 83.

68. Matsumoto A, Yeo A, Shih W, Tanaka E, Kiyosawa K, AlterH. Transfusion-associated TT virus infection and its rela-tionship to liver disease. Hepatology 1999;30:283– 8.

69. Kanda T, Yokosuka O, Ikeuchi T, Seta T, Kawai S, Imazeki F,et al. The role of TT virus infection in acute viral hepatitis.Hepatology 1999;29:1905– 8.

70. Melato M, Laurino L, Mucli E, Valente M, Okuda K. Rela-tionship between cirrhosis, liver cancer, and hepatic me-tastases: an autopsy study. Cancer 1989;64:455–9.

71. Crawford J. Pathologic assessment of liver cell dysplasiaand benign liver tumors: differentiation from malignanttumors. Semin Diagn Pathol 1990;7:115–28.

72. Wanless I, Callea F, Craig J, Crawford J, Desmet VJ, FarberE, et al. Terminology of nodular lesions of the liver. Hepa-tology 1995;25:983–93.

73. Terada T, Hoso M, Nakanuma Y. Mallory body clustering inadenomatous hyperplasia in human cirrhotic livers: reportof four cases. Hum Pathol 1989;20:886 –90.

74. Nakanuma Y, Terada T, Ueda K, Terasaki S, Nonomura A,Matsui O. Adenomatous hyperplasia of the liver as a pre-cancerous lesion. Liver 1993;13:1–9.

75. Furuya K, Nakamura M, Yamamoto Y, Togei K, Otsuka H.Macroregenerative nodule of the liver: a clinicopathologicstudy of 345 autopsy cases of chronic liver disease. Cancer1988;61:99 –105.

76. Ferrell L, Wright T, Lake J, Roberts J, Ascher N. Incidenceand diagnostic features of macroregenerative nodules vs.small hepatocellular carcinoma in cirrhotic livers. Hepatol-ogy 1992;16:1372– 81.

77. Terada T, Kadoya M, Nakanuma Y, Matsui O. Iron-accumulating adenomatous hyperplastic nodule with ma-lignant foci in the cirrhotic liver. Cancer 1990;65:1994 –2000.

78. Terada T, Nakanuma Y, Hoso M, Saito K, Sasaki M, Nono-mura A. Fatty macroregenerative nodule in non-steatoticliver cirrhosis: a morphologic study. Virchows Arch APathol Anat Histopathol 1989;415:131– 6.

79. Theise N, Fiel I, Hytiroglou P, Ferrell L, Schwartz M, MillerC, et al. Macroregenerative nodules in cirrhosis are notassociated with elevated serum or stainable tissue alpha-fetoprotein. Liver 1995;15:30 – 4.

80. Nakanuma Y, Terada T, Terasaki S, Ueda K, Nonomura A,Kawahara E, et al. Atypical adenomatous hyperplasia inliver cirrhosis: low-grade hepatocellular carcinoma or bor-derline lesion. Histopathology 1990;17:27–35.

81. Park Y, Yang C-T, Fernandez G, Cubukcku O, Thung S,Theise N. Neoangiogenesis and sinusoidal “capillarization”in dysplastic nodules of the liver. Am J Surg Pathol 1998;22:656 – 62.

82. Ferrell L, Crawford J, Dhillon A, Scheuer P, Nakanuma Y.Proposal for standardized criteria for the diagnosis of be-nign, borderline, and malignant hepatocellular lesions aris-ing in chronic advanced liver disease. Am J Surg Pathol1993;17:1113–23.

83. Nakanuma Y, Ohta G. Small hepatocellular carcinoma con-taining many Mallory bodies. Liver 1984;4:128 –33.

84. Nakanuma Y, Ohta G. Is Mallory body formation a preneo-plastic change? A study of 181 cases of liver bearing hepa-tocellular carcinoma and 82 cases of cirrhosis. Cancer 1985;55:2400 – 4.

85. Nakanuma Y, Ohta G. Expression of Mallory bodies inhepatocellular carcinoma in man and its significance. Can-cer 1986;57:81– 6.

86. Kondo Y, Nakajima T. Pseudoglandular hepatocellular car-cinoma: a morphogenetic study. Cancer 1987;60:1032–7.

87. Bottles K, Cohen M, Holly E, Chui S, Abele J, Cello J, et al.A step-wise logistic regression analysis of hepatocellularcarcinoma. Cancer 1988;62:558 – 63.

88. Cohen M, Haber M, Holly E, Ahn D, Bottles K, Stoloff A.Cytologic criteria to distinguish hepatocellular carcinomafrom nonneoplastic liver. Am J Clin Pathol 1991;95:125–30.

89. Cochand-Priollet B, Chagnon S, Ferrand J, Blery M, HoangC, Galian A. Comparison of cytologic examination ofsmears and histologic examination of tissue cores obtainedby fine needle aspiration biopsy of the liver. Acta Cytol1987;31:476 – 80.

90. Sangalli G, Livraghi T, Giordano F. Fine needle biopsy ofhepatocellular carcinoma: improvement in diagnosis bymicrohistology. Gastroenterology 1989;96:524 – 6.

91. Kung I, Chan S, Fung K. Fine-needle aspiration in hepato-cellular carcinoma: combined cytologic and histologic ap-proach. Cancer 1991;67:673– 80.

92. Ljung B, Ferrell L. Fine needle aspiration biopsy of the liver:diagnostic problems. In: Ferrell L, editor. Diagnostic prob-lems in liver pathology. Philadelphia: Hanley & Belfus;1994. p. 161– 84. (Pathology: State of the Art Reviews; vol 3).

93. Fucich L, Cheles M, Thung S, Gerber M, Marrogi A. Primaryversus metastatic hepatic carcinoma: an immunohisto-chemical study of 34 cases. Arch Pathol Lab Med 1994;118:927–30.

94. Johnson D, Herndier B, Medieros L, Warnke R, Rouse R.The diagnostic utility of the keratin profiles of hepatocel-lular carcinoma and cholangiocarcinoma. Am J Surg Pathol1988;12:187–97.

95. Maeda T, Kajiyama K, Adachi E, Takenaka K, Sugimachi K,Tsuneyoshi M. The expression of cytokeratins 7, 19, 20 inprimary and metastatic carcinomas of the liver. Mod Pathol1996;9:901–9.

96. Maeda T, Adachi E, Kajiyama K, Sugimachi K, TsuneyoshiM. Combined hepatocellular and cholangiocarcinoma:proposed criteria according to cytokeratin expression and


analysis of clinicopathologic features. Hum Pathol 1995;26(9):956 – 64.

97. Wang N, Zee S, Zarbo R, Bacchi C, Gown A. Coordinateexpression of cytokeratins 7 and 20 defines unique subsetsof carcinomas. Appl Immunohistochem 1995;3:99 –107.

98. Carrozza M, Calafati S, Edmonds P. Immunocytochemicallocalization of polyclonal carcinoembryonic antigen inhepatocellular carcinomas. Acta Cytol 1991;35:221– 4.

99. Hurlimann J, Gardiol D. Immunohistochemistry in the dif-ferential diagnosis of liver carcinomas. Am J Surg Pathol1991;15:280 – 8.

100. Garcia de Davila M, Gonzalez-Crussi F, Mangkornkanok M.Fibrolamellar carcinoma of the liver in a child: ultrastruc-tural and immunohistologic aspects. Pediatr Pathol 1987;7:319 –31.

101. Ruck P, Harms D, Kaiserling E. Neuroendocrine differenti-ation in hepatoblastoma: an immunohistochemical inves-tigation. Am J Surg Pathol 1990;14:847–55.

102. Krishna M, Lloyd R, Batts K. Detection of albumin messen-ger RNA in hepatic and extrahepatic neoplasms—a markerof hepatocellular differentiation. Am J Surg Pathol 1997;21:147–52.

103. Wanless I, Mawdsley C, Adams R. On the pathogenesis offocal nodular hyperplasia of the liver. Hepatology 1985;5:1194 –200.

104. Mathieu D, Zafrani E, Anglade M, Dhumeaux D. Associa-tion of focal nodular hyperplasia and hepatic hemangioma.Gastroenterology 1989;97:154 –7.

105. Ndimbie O, Goodman Z, Chase R, Ma C, Lee M. Hemangi-omas with localized nodular proliferation of the liver: asuggestion on the pathogenesis of focal nodular hyperpla-sia. Am J Surg Pathol 1990;14:142–50.

106. Stromeyer F, Ishak K. Nodular transformation (nodular re-generative hyperplasia) of the liver: a clinicopathologicstudy of 30 cases. Hum Pathol 1981;12:660 –71.

107. Nakanuma Y, Ohta G. Nodular hyperplasia of the liver inprimary biliary cirrhosis of early histological stages. Am JGastroenterol 1987;82:8 –10.

108. Nakanuma Y. Nodular regenerative hyperplasia of the liver:retrospective survey in autopsy series. J Clin Gastroenterol1990;12:460 –5.

109. Wanless I. Micronodular transformation (nodular regener-ative hyperplasia) of the liver: a report of 64 cases among2500 autopsies and a new classification of benign hepato-cellular nodules. Hepatology 1990;11:787–97.

110. Yutani C, Imakita M, H I-u, Okubo S, Naito M, Kunieda T.Nodular regenerative hyperplasia of the liver associatedwith primary pulmonary hypertension. Hum Pathol 1988;19:726 –31.

111. Nakanuma Y, Ohta G, Sasaki K. Nodular regenerative hy-perplasia of the liver associated with polyarteritis nodosa.Arch Pathol Lab Med 1984;108:133–5.

112. Chandra R, Kapur S, Kelleher J, Luban N, Patterson K.Benign hepatocellular tumors in the young: a clinicopath-ologic spectrum. Arch Pathol Lab Med 1984;108:168 –71.

113. Tao L. Oral contraceptive-associated liver cell adenomaand hepatocellular carcinoma: cytomorphology and mech-anism of malignant transformation. Cancer 1991;68:341–7.

114. Ferrell L. Hepatocellular carcinoma arising in a focus ofmultilobular adenoma. Am J Surg Pathol 1993;17:525–9.

115. Poe R, Snover D. Adenomas in glycogen storage diseasetype 1: two cases with unusual histologic features.Am J Surg Pathol 1988;12:477– 83.

116. Craig J, Peters R, Edmondson H, Omata M. Fibrolamellarcarcinoma of the liver: a tumor of adolescents and young

adults with distinctive clinico-pathologic features. Cancer1980;46:372–9.

117. Berman M, Sheahan D. Fibrolamellar carcinoma of theliver: an immunohistochemical study of nineteen cases anda review of the literature. Hum Pathol 1988;19:784 –94.

118. Omata M, Peters R, Tatters D. Sclerosing hepatic carci-noma: relationship to hypercalcemia. Liver 1981;1:33– 49.

119. Weinberg A, Finegold M. Primary hepatic tumors of child-hood. Hum Pathol 1983;14:512–37.

120. Stocker J. Hepatoblastoma. Semin Diagn Pathol 1994;11:136 – 43.

121. Conran R, Hitchcock C, Waclawiw M, Stocker J, Ishak K.Hepatoblastoma: the prognostic significance of histologictype. Pediatr Pathol 1992;12:167– 83.

122. Haas J, Muczynski K, Krailo M, Ablin A, Land V, Vietti T, etal. Histopathology, and prognosis in childhood hepatoblas-toma and hepatocarcinoma. Cancer 1989;64:1082–95.

123. Fasano M, Theise N, Nalesnik M, Goswami S, Garcia de DavilaMT, Finegold MJ, et al. Immunohistochemical evaluationof hepatoblastomas with use of the hepatocyte-specificmarker, hepatocyte paraffin 1, and the polyclonal anti-carcino-embryonic antigen. Mod Pathol 1998;11:934–8.

124. Abenoza P, Manivel C, Wick M, Hagen K, Dehner L. Hepa-toblastoma: an immunohistochemical and ultrastructuralstudy. Hum Pathol 1987;18:1025–35.

125. Saxena R, Leake J, Shafford E, Davenport M, Mowat A,Pritchard J, et al. Chemotherapy effects on hepatoblastoma:a histological study. Am J Surg Pathol 1993;17:1266 –71.

126. Stocker J, Ishak K. Mesenchymal hamartoma of the liver:report of 30 cases and review of the literature. PediatrPathol 1983;1:245– 67.

127. Ishak K, Sesterhenn I, Goodman Z, Rabin L, Stromeyer F.Epithelioid hemangioendothelioma of the liver: a clinico-pathologic and follow-up study of 32 cases. Hum Pathol1984;15:839 –52.

128. Gray M, Rosenberg A, Dickersin G, Bhan A. Cytokeratinexpression in epithelioid vascular neoplasms. Hum Pathol1990;21:212–7.

129. Selby D, Stocker J, Ishak K. Angiosarcoma of the liver inchildhood: a clinicopathologic and follow-up study of 10cases. Pediatr Pathol 1992;12:485–98.

130. Stocker J, Ishak K. Undifferentiated (embryonal) sarcoma ofthe liver: report of 31 cases. Cancer 1978;42:336 – 48.

131. Aoyama C, Hachitanda Y, Sato J, Said J, Shimada H. Undif-ferentiated (embryonal) sarcoma of the liver: a tumor ofuncertain histogenesis showing divergent differentiation.Am J Surg Pathol 1991;15:615–24.

132. Lack E, Schloo B, Azumi N, Travis W, Grier H, Kozakewich H.Undifferentiated (embryonal) sarcoma of the liver: clinicaland pathologic study of 16 cases with emphasis on immuno-histochemical features. Am J Surg Pathol 1991;15:1–16.

133. Tsui W, Colombari R, Bonetti F, Portmann BC, Thung SN,Ferrell LD, et al. Hepatic angiomyolipoma: delineation ofunusual morphological variants. Am J Surg Pathol 1999;23:34 – 48.

134. Tsui W, Yuen A, Ma K, Tse C. Hepatic angiomyolipomaswith a deceptive trabecular pattern and HMB-45 reactivity.Histopathology 1992;21:569 –73.

135. Linton P, Ahn W, Schwartz M, Ciller C, Thung S. Angiomyo-lipoma of the liver: immunohistochemical study of a case.Liver 1991;11:158 – 61.

136. Chan J, Tsang W, Pau M, Tang M, Pang S, Fletcher C.Lymphangiomyomatosis and angiomyolipoma: closely re-lated entities characterized by hamartomatous prolifera-tion of HMB-45-positive smooth muscle. Histopathology1993;22:445–55.


Liver Pathology: Cirrhosis, Hepatitis, and Primary Liver Tumors. … · 2019. 4. 30. · Cirrhosis,...

Documents

Transcript of Liver Pathology: Cirrhosis, Hepatitis, and Primary Liver Tumors. … · 2019. 4. 30. · Cirrhosis,...