Research Article Focal Nodular Hyperplasia and Hepatocellular...

Hindawi Publishing CorporationInternational Journal of HepatologyVolume 2013 Article ID 268625 12 pageshttpdxdoiorg1011552013268625

Research ArticleFocal Nodular Hyperplasia and Hepatocellular Adenoma aroundthe World Viewed through the Scope of theImmunopathological Classification

Charles Balabaud1 Wesal R Al-Rabih2 Pei-Jer Chen34 Kimberley Evason5 Linda Ferrell5

Juan C Hernandez-Prera6 Shiu-Feng Huang3 Thomas Longerich7 Young Nyun Park8

Alberto Quaglia2 Peter Schirmacher7 Christine Sempoux9 Swan N Thung6

Michael Torbenson10 Aileen Wee11 Matthew M Yeh12 Shiou-Hwei Yeh3

Brigitte Le Bail113 Jessica Zucman-Rossi1415 and Paulette Bioulac-Sage113

1 Inserm U1053 Universite Bordeaux Segalen 33076 Bordeaux Cedex France2 Institute of Liver Studies Kingrsquos College Hospital London UK3National Taiwan University College of Medicine Taipei Taiwan4National Taiwan University Hospital Taipei Taiwan5Department of Pathology University of California San Francisco CA 94143-0102 USA6Department of Pathology Mount Sinai School of Medicine New York NY 10029 USA7 Institute of Pathology University Hospital 69120 Heidelberg Germany8Department of Pathology Yonsei University College of Medicine PO Box 8044 Seoul Republic of Korea9 Service drsquoAnatomie Pathologique Cliniques Universitaires Saint Luc Universite Catholique de Louvain 1200 Brussels Belgium10Department of Pathology Johns Hopkins University School of Medicine Baltimore MD USA11Department of Pathology Yong Loo Lin School of Medicine National University of Singapore National University HospitalNational University Health System Singapore 119074

12Department of Pathology University of Washington School of Medicine Seattle WA USA13Pathology Department Hopital Pellegrin CHU Bordeaux 33076 Bordeaux Cedex France14Inserm UMR-674 Genomique Fonctionnelle des Tumeurs Solides IUH 75010 Paris France15Universite Paris Descartes Labex Immunooncology Sorbonne Paris Cite Faculte de Medecine 75005 Paris France

Correspondence should be addressed to Charles Balabaud charlesbalabaudu-bordeaux2fr

Received 5 November 2012 Accepted 25 December 2012

Academic Editor Charissa Chang

Copyright copy 2013 Charles Balabaud et al This is an open access article distributed under the Creative Commons AttributionLicense which permits unrestricted use distribution and reproduction in any medium provided the original work is properlycited

Focal nodular hyperplasia (FNH) and hepatocellular adenoma (HCA) are benign hepatocellular tumors The risk of bleeding andmalignant transformation of HCA are strong arguments to differentiate HCA from FNH Despite great progress that has beenmade in the differential radiological diagnosis of the 2 types of nodules liver biopsy is sometimes necessary to separate the 2entities Identification of HCA subtypes using immunohistochemical techniques namely HNF1A-inactivated HCA (35ndash40)inflammatory HCA (IHCA) and beta-catenin-mutated inflammatory HCA (b-IHCA) (50ndash55) beta-catenin-activated HCA (5ndash10) and unclassifiedHCA (10) has greatly improved the diagnostic accuracy of benign hepatocellular nodules IfHCAmalignanttransformation occurs in all HCA subgroups the risk is by far the highest in the 120573-catenin-mutated subgroups (b-HCA b-IHCA)In the coming decade the management of HCA will be more dependent on the identification of HCA subtypes particularly forsmaller nodules (lt5 cm) in terms of imaging follow-up and resection

2 International Journal of Hepatology

1 Introduction

The knowledge of benign hepatocellular tumors that is focalnodular hyperplasia (FNH) and hepatocellular adenoma(HCA) has considerably progressed in the last 10 yearsthanks tomolecular biology followed by immunohistochem-ical applications Following these advances new classificationis now largely used first in France andmore recently in otherEuropean American and East countries

2 A Brief Overview of Focal NodularHyperplasia and Hepatocellular Adenoma

21 Focal Nodular Hyperplasia It is the secondmost frequentbenign liver nodule (after hemangioma) occurring in 08of an adult autopsy population and has been reported in06ndash3 of the general population In 80ndash90 of cases FNHis discovered in women in their third or fourth decade Incountries (ie China) where OC use has been less prevalentFNH tends to be a lesion of adult men or children of eithergender

FNH is solitary in 23 of cases Most lesions are asymp-tomatic and are therefore discovered as incidental findingsduring surgery autopsy or imaging procedures for unrelatedsymptoms Large lesions can present with abdominal painor compression of adjacent organs Reports of hemorrhageor malignant transformation probably do not exist or areexceptional and require confirmation FNH lesions mayregresswith age as shownbydisappearance of presumedFNHlesions on serial imaging studies

The background liver is usually normal FNH is associ-ated with hepatic hemangioma in 20 of cases Coexistencewith HCA is not rare Associated lesions outside the liverhave been reported such as hemihypertrophy hemangiomaof cervix vascular malformations of brain and meningioma

211 Typical FNH Morphological Features

(1) Gross Findings On cut section classical FNH is a palefirm mass measuring from a few millimeters to more than10 centimeters in diameter The margin is well delimitedand the mass is lobulated and non encapsulated The lesionis composed of nodules each measuring 2-3mm separatedby zones of atrophy that give the lesion a multinodularappearance The lesion characteristically has a central oreccentric stellate fibrous scar with radiating extensions thatpartially surround some component nodules

(2)Microscopic Findings FNH lesions are composed of nod-ules of benign-appearing hepatocytes arranged in plates notmore than 2 cells in thickness Steatosis may occur usuallyfocal The central scar is often edematous or congested andcontains one or more large dystrophic vessels accompaniedby numerous small arteriolesThe large vessels have irregularfibrous thickening of the intima with focal thinning of themedia The internal elastic lamina is poorly formed andreduplicated The portal vein is absent The central fibrous

region has radiating branches composed of portal tract-like structures that contain an artery unaccompanied byportal veins or ducts When fibrous septation is prominentthe appearance may be indistinguishable from cirrhosisespecially in biopsy specimens A lymphocytic or mixedinflammatory infiltrate is frequent in fibrous regions At theinterface between fibrous regions and nodules there are oftenfeatures of cholate stasis including feathery degeneration ofhepatocytes Mallory-Denk bodies and a ductular reactionthat may be highlighted with CK7 and CK19 immunos-taining Sinusoids adjacent to arterial sources are lined byCD34-positive endothelium Glutamine synthetase is a veryuseful immunostain showing a characteristic broadband ofexpression in hepatocytes often near the hepatic veins

212 Atypical FNH Incomplete or early forms may lacka central scar they have an incompletion (or absence) ofmultinodular organization and sometimes exhibit more orless prominent regions of congestion

213 Molecular Features Clonal analysis using theHUMARA test demonstrated the reactive polyclonal natureof liver cells in FNH in 50ndash100 of the cases [2 7] MessengerRNA (mRNA) expression levels of the angiopoietin genes(ANGPT1 and ANGPT2) involved in vessel maturation arealtered with the ANGPT1ANGPT2 ratio increased com-pared with normal liver cirrhosis and other liver tumorsThese data support the importance of vascular alterations inthe pathogenesis of FNH The beta-catenin pathway is acti-vated including the downstream target glutamine synthetase[9] This activation explains the expansion of hepatocytesexpressing glutamine synthetase that is so useful for histo-logic diagnosis The molecular mechanisms of this activationare uncertain but do not involve demonstrable mutations inbeta-catenin or Axin1

The pathogenesis of FNH is not fully established Theassociation with conditions having local or systemic vascularanomalies and the presence of unusually large vessels withinthe lesions has led to the belief that FNH is a nonspecificresponse to focally increased blood flow

22 Hepatocellular Adenoma It is a rare benign liver neo-plasm composed of hepatocytes The incidence is around 3-4100 000 in Europe and North America and is lower in Asia85 of cases occur in young women HCA is rare in childrenmen and the elderly

The major risk factor for development of HCA is theexposure to estrogenic or androgenic steroids In youngwomen 80have been users of oral contraceptives (OC)Therisk increases with the duration and type of OC usage Theprevalence appears to be declining as low-estrogen prepa-rations have become more widely used The lesions usuallydecrease in size after stopping OC or after menopause Theclinical presentation of HCA may include abdominal painabdominal mass intraperitoneal hemorrhage abnormal livertests or space occupying lesion found incidentally on animaging study HCA can be single or multiple When 10 or

International Journal of Hepatology 3

more adenomas occur the condition is known as adenomato-sis Clinically significant hemorrhage is observed in 20ndash25of cases the risk is highest when the tumors are larger than5 cm Malignant transformation to hepatocellular carcinoma(HCC) is rare but well documented occurring in up to7 of cases as reported from referral centers The risk oftransformation varies with the HCA subtype (see below) andwith the clinical association being higher in patients withglycogenosis or androgenic-anabolic steroid use

221 General Morphological Data

(1) Gross Findings Hepatocellular adenomas are typicallylarge globular tumors with prominent vessels in the overlyinghepatic capsule On cut section the tumor parenchyma issoft and relatively uniform although areas of congestionnecrosis hemorrhage or fibrosis are frequent The marginsof the lesion are ill-defined both grossly and microscopicallywith little or no fibrous capsule Lesions vary in size frommicroscopic up to 20 cm in diameter In livers with adeno-matosis there may be hundreds of lesions visible as minuteill-defined nodules visible grossly or only microscopicallyHCA may be similar in color and texture to the backgroundliver but are more easily seen when there is lesional steatosismajor congestion and hemorrhage or degenerative changesThe background liver is usually normal though there may bepallor fibrosis or brown pigmentation related respectively tofatty liver disease glycogen storage disease iron overload orother diseases(2) Microscopic Findings HCA is typically composed ofbenign hepatocytes arranged in regular liver cell plates thatare usually one or at most two cells in width A pseudoglan-dular growth pattern may be seen focally Tumor hepatocyteshave cytoplasm that may be normal clear (glycogen-rich)steatotic or contain pigment in lysosomes Nuclear atypiaand mitoses are unusual The tumor parenchyma is suppliedby isolated arteries unaccompanied by bile ducts Variationsin this typical pattern are frequently seen in some of thesubtypes as described below

222 Molecular Features The reader is referred to the paperby Nault et al in this issue

Briefly

(1) HNF1120572-Inactivated HCA (H-HCA) The HNF1A geneencodes the hepatocyte nuclear factor 1 (HNF1120572) a tran-scription factor that is involved in hepatocyte differentiationBi-allelic inactivating mutations of this gene is found inapproximately 35ndash40 of HCA 90 of HNF1A mutationsare somatic in 10 they are constitutional (germline) Het-erozygous germline mutations in HNF1A are responsible foran autosomal dominant form of diabetes MODY3 (maturityonset diabetes of the young type 3) In patients with MODY3 and HCA there is an additional somatic mutation of thesecond allele in the tumor

(2) Beta-Catenin Activated HCA (b-HCA) An activating 120573-catenin mutation is found in 10ndash15 of HCA cases Glul a

target gene of 120573-catenin coding for the protein glutaminesynthetase (GS) is also upregulated

(3) Inflammatory HCA Inflammatory HCA (IHCA) repre-sent more than half of HCA cases They are characterizedby increased expression of inflammation-associated proteinssuch as serum amyloid A (SAA) and C-reactive protein(CRP) at both the mRNA and protein levels 60 of theseadenomas harbor mutations in gp130 Mutant gp130 activatesSTAT3 in the absence of its ligand which is IL-6 Beta-cateninmutationsmay coexist with gp130mutations in 10 of IHCA

(4) Unclassified HCAHCA without distinguishing histologi-cal features and without knownmutations represent less than10 of all cases

23 Diagnosis of FNH and HCA An accurate diagnosis canbe made using imaging techniques in 90 of cases in experi-enced centers Contrast enhanced ultrasonography (CEUS)is the first modality of choice for FNH MRI is the firstmodality of choice for HCA In less than 10 of casesthe differential diagnosis of FNH HCA and hepatocellularcarcinoma (HCC) cannot be solved by imaging alone Abiopsy interpreted by an experienced liver pathologist canresolve most of these problem cases with standard andorimmunohistochemical stainings If the biopsy is not defini-tive surgery may be advocated

The first task is to be certain that the biopsy includesthe lesion Therefore it is recommended that a biopsy beaccompanied by a sample of non-lesional liver

24 Differential Diagnosis HCA is the most frequent lesionto be distinguished from FNH The histologic diagnosis ofFNH requires two main criteria The lesion must be com-posed of benign-appearing hepatocytes andmust be suppliedby altered portal tracts Adenomas are supplied by isolatedarteries not portal tracts A source of difficulty in this regardis the presence of CK7CK19-positive ductular elements inHCA of the inflammatory type The key feature is thatglutamine synthetase expression shows a distinctivemap-likedistribution adjacent to hepatic veins in FNH while expres-sion is diffusely positive in beta-catenin-activated HCA andmostly negative in other types of HCA (see the following)

Macroregenerative noduleFNH-like in cirrhotic patientsand patients with vascular alterations may be difficult todifferentiate from FNH or HCA These nodules share somesimilarities with FNH but differ in some ways the beta-catenin pathway is not activated in cirrhotic FNH-like nod-ules [9] the ANGPT1ANGPT2 ratio is not increased GS isabsent or mildly expressed inflammatory proteins such asCRP may occasionally be expressed The presence of focalhepatic vein obstruction and the association with Budd-Chiari syndrome suggest a role of outflow obstruction

HCC may mimic FNH including focal scarring arterial-ized sinusoids and residual portal tract remnants Warningsigns of malignancy include nuclear pleomorphism highNC ratio wide plates and mitotic figures in the lesion andoften cirrhosis in the background liver


The differential diagnosis between HCA and well-dif-ferentiated HCC remains difficult

3 HCAFNH throughout the World

The aims of this study are (1) tomake a brief general overviewof these 2 entities [2ndash8] (2) to report results of a surveythrough different academic centers in France and through-out the world (3) to report applications of the molecu-larimmunohistochemical data and of the new HCA classi-fication in practice through the Bordeaux experience

At the end of the last century it was thought that HCAwill disappear with the use of OC of the third generationThis was not the case There are several reasons for that thewider use of modern imaging techniques the better iden-tification of HCA among hepatocellular tumors and theemergence of new etiological factors such as obesity [10 11]HCA still remains a challenge for clinicians radiologistsand pathologists The number of publications is still rising(a pubmed search using hepatocellular adenoma as criterionin 1980ndash1984 1990ndash1994 2000ndash2004 and 2005ndash2009 gave28 30 69 and 87 publications resp) Surgery (or any othermethod to eliminate the HCA) is still necessary to preventthe risk of hemorrhage which can be lethal and the HCCtransformation These risks being absent in FNH surgery isnot recommended surgery is however still performedThereare several reasons for that surrounding organ compressioncompression of liver vessels and biliary tree pain and per-haps more importantly doubt about the nature of the tumorFrom a brief survey performed in some academic centers(Table 1) as well as from other publications reported in thisissue or elsewhere it is obvious that surgery and biopsiesare still performed in France Europe and the US for FNHand HCA The percentage of the different HCA subtypesare in the range previously published (Table 1) The greatdifference concerns Asia whereHCA is extremely rare [12 13]probably because of other means of contraception than oralcontraceptives

Today the use of the HCA immunohistochemical classifi-cation [1 14ndash19] is spreading Several centers have publishedtheir own data [20ndash24]

4 The Diagnosis of HCA Subtypes in RoutinePractice The Bordeaux Experience

Thepathological diagnosis of benign liver tumors should takeinto account the clinical biological [25] and radiological data[26ndash35] including etiology

Main informations are summarized in Box 1 The grossanatomy (nodule and nontumoral liver) remains an essentialpart of the diagnosis and is essential for the sampling Werecommend to take pictures of the sampled areas and tosample all areas that look different In the non tumoralliver it is recommended to sample even tiny areas that lookabnormal To facilitate IHC interpretation we sample areas atthe junction of tumor and nontumoral tissueThe histologicalfeatures are recorded to classify HCA (Box 2) The IHC dataobserved in benign liver nodules are summarized in Table 2

to reach a diagnosis not all IHC techniques are usedMarkersare used according to the algorithm in Figure 1

Briefly H-HCA represents a homogeneous group oftumors with lobulated contours showing typically markedand diffuse steatosis absence of significant inflammation ornuclear atypia FABP1 coding for L-FABP (liver fatty acidbinding protein) is a gene positively regulated by HNF1Aexpressed in normal liver tissue and clearly downregulatedin this HCA subtype By immunohistochemistry there isa nearly complete absence of LFABP staining contrastingwith the nontumoral surrounding liver which appearedhomogeneously stained (even though faintly)Therefore lackof LFABP expression is a very good diagnostic argument forHNF1-alpha-inactivated HCA specific of this subtype sincethere is a very good concordance between this immunophe-notype and HNF1A mutations Furthermore the downreg-ulation of LFABP may contribute to the fatty phenotypethrough impaired fatty acid trafficking HNF1A-mutatedHCA occurs almost exclusively in women Nodules can besolitary ormultipleMost of adenomatosis isHNF1AmutatedConstitutional mutations can affect both sexes and can bediscovered in children sometimes as a familial form orassociated with MODY 3

B-HCA This HCA subtype is often associated with specificconditions (ie glycogenosis male hormone administration)and male gender The lesions are usually solitary (exceptin glycogenosis) and have an increased risk of malignanttransformation compared to the other subtypes Steatosisand inflammation are usually absent Nuclear atypia and apseudoglandular growth pattern are frequent in this subtypeso that distinction fromwell-differentiated HCCmay be verydifficult By immunohistochemistry glutamine synthetase isusually strongly expressed in a diffuse pattern associatedwithaberrant cytoplasmic and nuclear expression of beta-cateninWhen glutamine synthetase staining is heterogeneous andbeta-catenin nonconclusive molecular biology remains themethod of choice for identifying beta-catenin mutation

IHCA Most patients with IHCA are women Obesity andfatty liver diseases are frequent In 50 of cases there areelevated serum levels of CRP and increased erythrocytesedimentation rate rarely in association with fever andanemia features which can regress after HCA resectionNodules can be solitary or multiple Micronodules can alsobe detected by SAA and CRP immunostaining in the liverparenchyma outside the main tumors Histologically IHCAtypically exhibits focal or diffuse inflammation sinusoidaldilatation congestion and peliotic areas and numerous andthick-walled arteries often associated with ductular reactionlying in small amount of connective tissues Steatosis may beseen mainly focally Immunohistochemistry demonstratesstrong expression of SAA and CRP restricted to tumoralhepatocytes There is a risk of malignant transformationparticularly for IHCA which is also beta-catenin mutated

Reasons for classifying HCA are summarized in Box 3Major advances brought by the classification are (a)

individualization of FNH from HCA and FNH from FNH-like (b) identification of MODY3 and patients at high


Table 1 Diagnosis of FNH and HCA performed in different academic centers

HCA FNH No final diagnosis

Surgery Biopsy Surgery Biopsy Surgery BiopsyFrench (from 2008 to 2011)

(1) Besancon 4 (4) 10 13 3 0 0(2) Bordeaux 49 (44) 16 27 29 0 2(3) Caen 22 (20) 6 19 6 0 0

(4) Creteil 14 (13)2 with HCC

193 with HCC 19 13 0 0

(5) Grenoble 19 (18) 18 3 12 0 1

(6) Lille 31 (26)1 with HCC 30 25 39 2 6

(7) Lyon (1) 49 (41)4 with HCC 13 17 16 4 7

(1 with HCC)

(8) Lyon (2) 16 (13)1 with HCC 25 14 22 0 4

(9) Montpellier 32 (31)1 with HCC 28 15 25 3 1

(10) Nice 32 (31)1 with HCC 28 3 25 3 1

(11) Paris (St Antoine) 11 (9)1 with HCC 13 20 14 0 2

(1 with HCC)(12) Villejuif (Gustave Roussy) 1 (1) 3 5 (4) 6 0 4

International

(1) Baltimore (from 1984 to 2012) 63 (61)7 with HCC 6 79 54 4 8

(2) Brussels(Cliniques universitairesSaint-Luc-UCL)(1992ndash2012)lowast

37 (33) 21 IHCA10H-HCA 1 with IHCA +H-HCA 3 120573-HCA (2 with

HCC) 2UHCA

14 22 14

(3) Heidelberg (2007ndash2011) 11 (11) 9 IHCA 1H-HCA1 with IHCA + H-HCA 34

(4) London Kings (1998ndash2011)35 (30) 18 IHCA7H-HCA 1 120573-HCA

9UHCA

(5) NY (Mt Sinai) (2007ndash2011)lowast 27 9H-HCA 11 I-HCA7UHCA 15

(6) San Francisco(selected cases)

12 (10) 2 IHCA 3H-HCA(1 with HCC 1 borderline)3 120573-HCA (2 with HCC 1borderline) 4UHCA (1

with HCC)

(7) Seattle (2008ndash2011) 9 (7) 3 IHCA 3H-HCA 1120573-HCA 2UHCA 1 1

(8) Seoul (2008ndash2011) 2 (1) 1 120573-IHCA 1 120573-HCA(1 with HCC) 4 (3)

(9) Singapore (selected cases) 2 (2) 1 120573-IHCA (withHCC) 1H-HCA

(10) Taiwan 12 (5) 3 IHCA 2 120573-HCA1H-HCA 6UHCA

lowastSee papers in this issue for additional information


Age sexMode of discovery emergency pain behavior after stopping (or not) OCNumber of nodules max size locationRadiological diagnosis FNH HCA HCC MRN cannot differentiateWoman oral contraception (age beginning stop) duration type

Number of children (age)Drugs including all types of hormones particularly male antiepilepticHabit alcohol tobaccoDiseases

BMI metabolic syndrome NASHDiabetes MODY3 (family history)Glycogenosis deficit OTCMc Cune AlbrightFAPVascular diseases

Congenital malformations BCS HPSBiliary diseases CHF polycystic kidney diseasesPOCSBrain tumor

Family history of liver tumorsPathological diagnosis

Biopsy surgical specimen (safety margin)Biopsy qualityHCA H-HCA IHCA 120573-HCA 120573-IHCA UHCAHCCHCA borderline lesion HCA with dysplasia HCC fociFNHFNHUHCAFNHMRNFNH-likeAssociation of different types of nodulesNontumoral liver

Normal steatosis NASH glycogenosis vascular liver diseases biliary disease and so forth

Box 1 Clinical and pathological information useful to manage the patient

risk of malignant transformation (c) demonstration thatadenomatosis was not per se a specific HCA subtype butan entity defined by an arbitrary number of nodules gt tendetected by imaging techniques (the high number linkedprobably to a specific susceptibility) and (d) correction oferrors (the so-called telangiectatic FNH being IHCA)

Practical guidelines for the diagnosis ofHCA subtypes aresummarized in Figure 2

The HCA classification has changed the way we considerHCA and FNH in our centerThe diagnosis accuracy of FNHand HCA has completely changed at the end of the first 2000decadeThere are probably in the literaturemany unavoidablediagnostic errors concerning benign hepatocellular nodulesparticularly in the field of hemorrhagic FNH malignanttransformation of FNH identification of difficult nodulesand so forth

41 Practical Guidelines for the Management of HCA Subtypes[25 36ndash56] For practical reasons once the diagnosis ofliver tumors is made the patient is often referred to asurgeon In spite of the vast literature in various domainsimaging pathology surgery complications and so forththere is no guidelines for the diagnosis and treatment of

HCANevertheless themajor contribution of some Europeancenters (see Supplemental Table 1 in Supplementary Materialavailable online at httpdxdoiorg1011552013268625) is agood starting point to obtain valuable information

There is a global consensus among liver surgeons thatadenoma gt5 cm should be resected if they have not regressedafter stopping oral contraceptives Some surgeons prefer thatall HCA should be removed particularly if they are easilyaccessible laparoscopicaly Indeed the clinical presentationin terms of age sex oral contraceptives and other majoretiology number of nodules (from single to several and upto myriads) and size (2 to 20 cm) mode of discovery and soforth therefore it is extremely difficult to define acceptableguidelines based on solid arguments Most of the seriespublished are very small and it is difficult tomake a judgmenton case report

This is the reason why we believe that to make progresswe need to collect prospective data from different countriesand continents The identification of subtypes is one of thekey factors among others that need to be collected (Box 1)The ideal situation would be to follow strictly well- identified(MRIbiopsy) HCA particularly those at a high risk ofmalignant transformation (120573-HCA and 120573-IHCA)


Gross anatomy location size color hemorrhagenecrosis softhardFirst step HampE trichrome CK7 CD34

Areas of necrosis hemorrhage congestion peliosisFibrosis (bands) constitutional versus remodeling scar ductular reactionSteatosis (distribution) sinusoidal dilatation (degree and location) arteriesthickness of thewallpseudoportal tractsinflammationCytological abnormalitiesNontumoral liver steatosis underlying liver disease micronodules etc

Second step (see Figure 1) GS then (if necessary) other IHC markersAt the end should be able toDifferentiate FNH from HCA(i) FNH typical typical (GS) but lacking key features or with unusual findings (massive steatosissinusoidal dilation involution)(ii) MRNFNH-like (cirrhosis vascular disorders)(iii) HCASubtype HCAIdentify premalignantmalignant HCA lesion (focal or spread)

HampE rosettes small cellsReticulin disarray lossGS abnormal staining strongmildweak diffusefocalfew cellsCD34 normal patterndiffuse120573-cat nuclear staining (many some rare)Additional markers GPC3 HSP70 clathrin etc may be useful

HCA with extensive necrosishemorrhage or remodeling may not be identified with certaintyWhen the diagnosis (FNH versus HCA and HCA subtypes) is not clear on regular stainings and IHCmolecular biology is the next step (techniques on paraffin sections should becomeavailable in the near future this is particularly important concerning 120573-catenin-mutatedHCA)

Box 2 Pathological record

Clinical researchTo investigate the natural history of subtypes (relevant for the follow-up)To identify MODY patients (genetic counseling)To convince patients with IHCA in the context of overweightobesitymetabolic syndrome to be medically followedTo discover nodules with a high risk of malignancyTo find correlation between etiology and subtypeTo retrospectively correct diagnostic errors (FNH versus HCA in cirrhosis FNH versus MRNFNH-like)Translational researchCorrelation between IHC markers and mutationsNew IHC markers to identify new mutationsResearch toolIdentification of new mutations (UHCA)Prognostic factors among patients at risk for malignant transformation according to subtypesUse the terms of the IHC classification to avoid misnomers (telangiectatic HCA steatotic HCA mixed form FNHHCA etc)

Box 3 Reasons to classify hepatocellular nodules using IHC methods

In the absence of accepted guidelines our proposition forthe management of HCA subtypes lt5 cm is summarized inFigure 3

42 Future Developments It is clear that we have entered anew era in the study of benign hepatocellular tumors andperhaps more importantly in the field of HCC developingin nonfibrotic liver One may still consider that this breach

has not yet dramatically changed our strategiesmdashdiagnosticand therapeutic [38] This is only partly true (see above)because it will take time before the classification brings itsfull potential It is true that our knowledge is still limitedFuture development will be based on imaging techniques[35] molecular data including chromosomal abnormalities[57] on the ability to combine molecular radiological andclinical data and first of all on the reinterpretation of the


120573-catc

Standardhistology Certain Certain

Certain

Probable Probable Doubtful

Doubtful

Doubtful

GS

GS(pivotal role)

Abnormal

Diffuseheterogeneous (strongmoderate)Difficult to interpret

See Figure 1b

T+NTminus TminusNTminus

CRPSAAT+NTminus

CRPSAATminusNTminus

CRPSAAT+NTminus

CRPSAATminusNTminus

120573-IHCA 120573-HCA120573-IHCA 120573-HCA

Stop Stop

Stop

Stop Stop

ALLminusT+NTminus

LFABBTminusNT+

H-HCA IHCA UHCA

Stop Stop Stop

StoplowastlowastStoplowast

(120573-HCA)

IHCHCA subtyping

HCA FNH

Normala

CRPSAAb

(a)

Difficult to interpret(faintfocal)

120573-cat mutations(IHCMB)

All markers

+ + minusminus minus120573-cat mutations

All markers

LFABPminus CRP+

120573-HHCA 120573-IHCA 120573-HCA

LFABPminus

H-HCA

CRP+

IHCA

Allmarkers-

Allmarkers-

UHCAd

(b)

Figure 1 Adapted from Bioulac-Sage et al [1] Algorithm for immunohistochemical (IHC) diagnosis of benign hepatocellular nodulesfocal nodular hyperplasia (FNH) and hepatocellular adenoma (HCA) Glutamine synthetase (GS) is not always mandatory for the diagnosisof lowastFNH or lowastlowastHCA in routine practice IHC is mandatory for HCA subtyping markers are presented in grey square with their resultspositive (+) or negative (minus) in tumor (T) and nontumoral liver (NT) LFABP liver fatty acid binding protein CRP C-reactive-proteinFinal diagnosis of HCA subtypes is HNF1a inactivated (H-HCA) inflammatory (IHCA) B-catenin activated (B-HCA) B-catenin activatedinflammatory (B-IHCA) or unclassified (UHCA) a GS negativity or positivity limited at the periphery andor around some veins withinHCA b serum amyloid A staining is usually less sensitive and specific than CRP c aberrant B-catenin nuclear staining needs molecularbiology confirmation d can be difficult to differentiate from FNH


Imaging (USCEUS and MRI)Diagnosis

FNH HCA HCC

Consider biopsy (TNT)

Repeat imaging Consider biopsy (TNT)

Take into account etiology clinicalbiological data

H-HCA IHCA

gt5 cm lt5 cm

(no formal evidence for either diagnosisor

Clinicalbiological data

doubt between FNHHCA HCAHCC etc)

Destruction(Sample tissue T and NT before destruction)

Figure 2 Practical guidelines for the identification of HCA subtypes (outside the emergency context)

Then every 2 years

Then every 5 years

Every 10 years

If stable for 2 years



If size decreases time interval can be increasedIf size increases

Follow-up as indicated H-HCA

Patients overweightobesewith metabolic syndrome (the majority with IHCA) should be followed

Genetic counseling (MODY3)

Strict follow-uplowast

- Destruction independently of the size in menlowastlowast- Perform a biopsy particularly in patients at risk of malignant transformation young womanmetabolic

or vascular disorders if GS is abnormal consider destruction independently of the size

120573-HCA120573-IHCAUHCA

CEUSMRI

H-HCA IHCA Other

Stop oral contraceptives and male hormone administration

US Follow-up MRI MRI 2 options Biopsy

Every year (every 6 months gt4 cm)

lowastDestruction should be considered for nodules lt5 cm (in the 3-4 cm range)lowastlowastIn men destruction is planned well before the size of the nodule reached 5 cm

In presence of multiple HCA nodules generally all nodules are of the same subtype (ie H-HCA IHCA) Among IHCA some may be120573-catenin mutated others not Association of H-HCA and IHCA has been rarely observed in a same liver In glycogenosis di

types of nodules may exist (120573-HCA IHCA 120573-IHCA and UHCA) Th e destruction (resection radio frequency) of nodules depends on thesize on the presence of 120573-catenin mutation and on the disease background OLT is exceptional and should not be considered just

fferent

on thenumber criteria

- Destruction if ge5 cmlowast

Figure 3 Management of HCA subtypes lt5 cm

routine histopathologic and IHC data considering the newmolecular data (work in progress)

Because HCA is rare it is necessary to combine data fromdifferent centers The main task is to better define patients atrisk of malignant transformation [58 59] to understand the

susceptibility of some individuals compared to controls todevelop nodules either onewhile others developmyriads thesusceptibility of some nodules to grow while others remainundetectable to transform while others remain quiescentand to regress or not Other main objectives are to study on a


Table 2 IHC in benign liver nodules

(a) LFABP

T NTH-HCA minus (a) + (b)120573-HCA IHCA 120573-IHCA UHCA + +FNH + +MNRMNR-FNH-like (cirrhosis) + +(a) Some hepatocytes may be positive at the periphery of the nodule as wellas in between 2 coalescent nodules(b) When the expression is weak reading may be difficult

(b) CRP

T NTIHCA 120573-IHCA + (a) minus (b)H-HCA 120573-HCA UHCA minus minus (b)FNH minus (b1015840) minus (b)MRNMRN-HNF-like (cirrhosis) (c) (d)(a) Staining can be heterogeneous(b) Can be positive (in case of hemorrhagenecrosis inflammatory syn-drome portal branch embolization etc)(b1015840) Can be positive if (b) is positive(c) Often positive (weakmild)(d) Negative to positive (weak to mild) heterogeneous from nodule tonodule

(c) GS

T NTFNH + (a) (b)MRNMRN FNH-like (cirrhosis) (c) (d)120573-HCA 120573-IHCA + (e) (b)H-HCA IHCA UHCA minus (b)(a) Map-like pattern(b) Normal positivity around central veins (1ndash3 rows)(c) From absence to positivity (limited to veins andor border of fibrousaxis)(d) Negative occasional faint staining(e) Strong and diffuse or heterogeneous

large scale HCA in various etiological conditions particularlyin vascular diseases and in different liver diseases withdifferent pathological backgrounds particularly NASH andcirrhosis [60]

Deciphering the molecular pathways leading to noduleformation one can imagine that the medical treatment ofHCA is not out of hand

5 Conclusion

The diagnosis and prognosis of benign hepatocellular nod-ules have changed in the recent yearsThiswill have an impacton the management of these nodules including surveillance

Acknowledgments

The authors wish to thank all French liver pathologists whosent their numerical data about FNH and HCA B Bancel

C Bazille J Calderaro A Cazorla M Fabre E LeteurtreJ Ramos M C Saint Paul J Y Scoazec N Sturm DWendum as well as the Taiwan Liver Cancer Network andthe Bordeaux team including surgeons (Professors J SaricC Laurent L Chiche) hepatologist (Professor J F Blanc)radiologists (Professor H Trillaud and Drs H Laumonierand N Frulio) and clinical research assistant (L Possenti)This study was supported by Association pour la Recherchesur le Cancer (ARC) Grant no 3194

References

[1] P Bioulac-Sage G Cubel S Taouji et al ldquoImmunohistochem-ical markers on needle biopsies are helpful for the diagnosisof focal nodular hyperplasia and hepatocellular adenoma sub-typesrdquoAmerican Journal of Surgical Pathology vol 36 no 11 pp1691ndash1699 2012

[2] S Rebouissou P Bioulac-Sage and J Zucman-Rossi ldquoMolecu-lar pathogenesis of focal nodular hyperplasia and hepatocellularadenomardquo Journal of Hepatology vol 48 no 1 pp 163ndash1702008

[3] J Zucman-Rossi E Jeannot J T Van Nhieu et al ldquoGenotype-phenotype correlation in hepatocellular adenoma new classifi-cation and relationship with HCCrdquo Hepatology vol 43 no 3pp 515ndash524 2006

[4] A K Shanbhogue S R Prasad N Takahashi R Vikram andD V Sahani ldquoRecent advances in cytogenetics and molecularbiology of adult hepatocellular tumors implications for imagingand managementrdquo Radiology vol 258 no 3 pp 673ndash693 2011

[5] P Bioulac-Sage C Balabaud P Bedossa et al ldquoPathologicaldiagnosis of liver cell adenoma and focal nodular hyperplasiaBordeaux updaterdquo Journal of Hepatology vol 46 no 3 pp 521ndash527 2007

[6] V Paradis A Benzekri D Dargere et al ldquoTelangiectatic focalnodular hyperplasia a variant of hepatocellular adenomardquoGastroenterology vol 126 no 5 pp 1323ndash1329 2004

[7] V Paradis A Laurent J F Flejou M Vidaud and P BedossaldquoEvidence for the polyclonal nature of focal nodular hyperplasiaof the liver by the study of X-chromosome inactivationrdquoHepatology vol 26 no 4 pp 891ndash895 1997

[8] P Bioulac-Sage S Rebouissou A Sa Cunha et al ldquoClinicalmorphologic and molecular features defining so-called telang-iectatic focal nodular hyperplasias of the liverrdquo Gastroenterol-ogy vol 128 no 5 pp 1211ndash1218 2005

[9] S Rebouissou G Couchy L Libbrecht et al ldquoThe 120573-cateninpathway is activated in focal nodular hyperplasia but not incirrhotic FNH-like nodulesrdquo Journal of Hepatology vol 49 no1 pp 61ndash71 2008

[10] P Bioulac-Sage S Taouji L Possenti and C Balabaud ldquoHep-atocellular adenoma subtypes the impact of overweight andobesityrdquo Liver International vol 32 no 8 pp 1217ndash1221 2012

[11] V Paradis A Champault M Ronot et al ldquoTelangiectaticadenoma an entity associated with increased body mass indexand inflammationrdquoHepatology vol 46 no 1 pp 140ndash146 2007

[12] M Sasaki and Y Nakanuma ldquoOverview of hepatocellular ade-noma in Japanrdquo International Journal of Hepatology vol 2012Article ID 648131 6 pages 2012

[13] H Lin J Van Den Esschert C Liu and T M Van Gulik ldquoSys-tematic review of hepatocellular adenoma in China and otherregionsrdquo Journal of Gastroenterology andHepatology vol 26 no1 pp 28ndash35 2011


[14] P Bioulac-Sage H Laumonier and C Balabaud ldquoBenign hep-atocellular tumorsrdquo in Practical Hepatic Pathology R SaxenaEd pp 473ndash488 Elsevier Saunders Philadelphia Pa USA2010

[15] P Bioulac-Sage C Balabaud and I Wanless ldquoFocal nodularhyperplasia and hepatocellular adenomardquo in Tumors of theDigestive Tract World Health Organization F Bosman FCarneiro RHruban andNDTheise Eds pp 198ndash204 IARCLyon France 2nd edition 2010

[16] P Bioulac-Sage G Cubel C Balabaud and J Zucman-RossildquoRevisiting the pathology of resected benign hepatocellularnodules using new immunohistochemical markersrdquo Seminarsin Liver Disease vol 31 no 1 pp 91ndash103 2011

[17] P Bioulac-Sage G Cubel and C Balabaud ldquoPathological diag-nosis of hepatocellular adenoma in clinical practicerdquoDiagnosticHistopathology vol 17 no 12 pp 521ndash529 2011

[18] P Bioulac-Sage S RebouissouCThomas et al ldquoHepatocellularadenoma subtype classification using molecular markers andimmunohistochemistryrdquoHepatology vol 46 no 3 pp 740ndash7482007

[19] P Bioulac-Sage H Laumonier A Rullier et al ldquoOver-ex-pression of glutamine synthetase in focal nodular hyperplasiaa novel easy diagnostic tool in surgical pathologyrdquo Liver Inter-national vol 29 no 3 pp 459ndash465 2009

[20] S Van Der Borght L Libbrecht A Katoonizadeh et al ldquoNu-clear 120573-catenin staining and absence of steatosis are indicatorsof hepatocellular adenomas with an increased risk of malig-nancyrdquo Histopathology vol 51 no 6 pp 855ndash856 2007

[21] A F Manichon B Bancel M Durieux-Millon et al ldquoHepa-tocellular adenoma evaluation with contrast-enhanced ultra-sound andMRI and correlationwith pathologic and phenotypicclassification in 26 lesionsrdquo HPB Surgery vol 2012 Article ID418745 12 pages 2012

[22] M Sasaki N Yoneda S Kitamura Y Sato and Y NakanumaldquoCharacterization of hepatocellular adenoma based on the phe-notypic classification the Kanazawa experiencerdquo HepatologyResearch vol 41 no 10 pp 982ndash988 2011

[23] SM vanAalten J Verheij T Terkivatan R S Dwarkasing ADe Man and J N M Ijzermans ldquoValidation of a liver adenomaclassification system in a tertiary referral centre implicationsfor clinical practicerdquo Journal of Hepatology vol 55 no 1 pp120ndash125 2011

[24] C O C Bellamy R SMaxwell S Prost I A Azodo J J Powelland J R Manning ldquoThe value of imunophenotyping hepato-cellular adenomasmdashconsecutive resections at one UK centrerdquoHistopathology vol 62 no 3 pp 431ndash445 2012

[25] P Bioulac-Sage H Laumonier G Couchy et al ldquoHepatocel-lular adenoma management and phenotypic classification theBordeaux experiencerdquo Hepatology vol 50 no 2 pp 481ndash4892009

[26] M Ronot S Bahrami J Calderaro et al ldquoHepatocellular ade-nomas accuracy of magnetic resonance imaging and liverbiopsy in subtype classificationrdquo Hepatology vol 53 no 4 pp1182ndash1191 2011

[27] H Laumonier P Bioulac-Sage C Laurent J Zucman-Rossi CBalabaud andHTrillaud ldquoHepatocellular adenomasmagneticresonance imaging features as a function ofmolecular patholog-ical classificationrdquoHepatology vol 48 no 3 pp 808ndash818 2008

[28] S M van Aalten M G Thomeer T Terkivatan et al ldquoHepa-tocellular adenomas correlation of MR imaging findings withpathologic subtype classificationrdquo Radiology vol 261 pp 172ndash181 2011

[29] M Bieze J W van den Esschert C Y Nio et al ldquoDiagnosticaccuracy of MRI in differentiating hepatocellular adenomafrom focal nodular hyperplasia prospective study of the addi-tional value of gadoxetate disodiumrdquo American Journal ofRoentgenology vol 199 no 1 pp 26ndash34 2012

[30] L Grazioli M P Bondioni H Haradome et al ldquoHepatocellularadenoma and focal nodular hyperplasia value of gadoxeticacid-enhanced MR imaging in differential diagnosisrdquo Radiol-ogy vol 262 pp 520ndash529 2012

[31] H Laumonier H Cailliez C Balabaud et al ldquoRole of contrast-enhanced sonography in differentiation of subtypes of hepa-tocellular adenoma correlation with MRI findingsrdquo AmericanJournal of Roentgenology vol 199 no 2 pp 341ndash348 2012

[32] T Denecke I G Steffen S Agarwal et al ldquoAppearance ofhepatocellular adenomas on gadoxetic acid-enhanced MRIrdquoEuropean Radiology vol 22 no 8 pp 1769ndash1775 2012

[33] J W van den Esschert T M Van Gulik and S S K SPhoa ldquoImaging modalities for focal nodular hyperplasia andhepatocellular adenomardquoDigestive Surgery vol 27 no 1 pp 46ndash55 2010

[34] V S Katabathina C O Menias A K Shanbhogue J JagirdarR M Paspulati and S R Prasad ldquoGenetics and imaging ofhepatocellular adenomas 2011 updaterdquo Radiographics vol 31no 6 pp 1529ndash1543 2011

[35] N Yoneda O Matsui A Kitao et al ldquoBeta-catenin-acti-vated hepatocellular adenoma showing hyperintensity onhepatobiliary-phase gadoxetic-enhanced magnetic resonanceimaging and overexpression of OATP8rdquo Japanese Journal ofRadiology vol 30 no 9 pp 777ndash782 2012

[36] S Dokmak V Paradis V Vilgrain et al ldquoA single-centersurgical experience of 122 patients with single and multiplehepatocellular adenomasrdquo Gastroenterology vol 137 no 5 pp1698ndash1705 2009

[37] SM vanAalten C DWitjes R A deMan J N Ijzermans andT Terkivatan ldquoCan a decision-making model be justified in themanagement of hepatocellular adenomardquo Liver Internationalvol 32 no 1 pp 28ndash37 2012

[38] T Terkivatan and J N M Ijzermans ldquoHepatocellular adenomashould phenotypic classification direct managementrdquo NatureReviews Gastroenterology andHepatology vol 6 no 12 pp 697ndash698 2009

[39] S M van Aalten M E Broker J J van Busschbach et alldquoPregnancy and liver adenoma management PALM studyrdquoBMC Gastroenterology vol 12 p 82 2012

[40] S M van Aalten R A de Man J N IJzermans and T Terki-vatan ldquoSystematic review of haemorrhage and rupture ofhepatocellular adenomasrdquo British Journal of Surgery vol 99 no7 pp 911ndash916 2012

[41] V A L Huurman and A F M Schaapherder ldquoManagement ofruptured hepatocellular adenomardquoDigestive Surgery vol 27 no1 pp 56ndash60 2010

[42] Y C Bo and M H Nguyen ldquoThe diagnosis and managementof benign hepatic tumorsrdquo Journal of Clinical Gastroenterologyvol 39 no 5 pp 401ndash412 2005

[43] J F Gibbs A M Litwin andM S Kahlenberg ldquoContemporarymanagement of benign liver tumorsrdquo Surgical Clinics of NorthAmerica vol 84 no 2 pp 463ndash480 2004

[44] L Chiche T Dao E Salame et al ldquoLiver adenomatosis reap-praisal diagnosis and surgical management eight new casesand review of the literaturerdquo Annals of Surgery vol 231 no 1pp 74ndash81 2000


[45] H Yoshidome K M McMasters and M J Edwards ldquoMan-agement issues regarding hepatic adenomatosisrdquo AmericanSurgeon vol 65 no 11 pp 1070ndash1076 1999

[46] A Perrakis V Muller K Oeckl et al ldquoIndications and long-term outcome after elective surgery for hepatocellular ade-nomardquoThe American Surgeon vol 78 pp 80ndash85 2012

[47] M Abu Hilal F Di Fabio R D Wiltshire M Hamdan DM Layfield and N W Pearce ldquoLaparoscopic liver resectionfor hepatocellular adenomardquo World Journal of GastrointestinalSurgery vol 27 no 3 pp 101ndash105 2011

[48] M Abu Hilal F Di Fabio M J Teng D A Godfrey J NPrimrose and N W Pearce ldquoSurgical management of benignand indeterminate hepatic lesions in the era of laparoscopicliver surgeryrdquo Digestive Surgery vol 28 pp 232ndash236 2011

[49] C HWilson DMManas and J J French ldquoLaparoscopic liverresection for hepatic adenoma in pregnancyrdquo Journal of ClinicalGastroenterology vol 45 no 9 pp 828ndash833 2011

[50] S Dardenne C Hubert C Sempoux et al ldquoConservative andoperative management of benign solid hepatic tumours asuccessful stratified algorithmrdquo European Journal of Gastroen-terology and Hepatology vol 22 no 11 pp 1337ndash1344 2010

[51] J F Buell H Tranchart R Cannon and I Dagher ldquoMan-agement of benign hepatic tumorsrdquo Surgical Clinics of NorthAmerica vol 90 no 4 pp 719ndash735 2010

[52] A G Lopes Jr and A C M Duarte ldquoClinical presentation andmanagement of liver adenoma hemorrhagic complicationsrdquoAmerican Surgeon vol 76 no 6 pp 654ndash655 2010

[53] M A F Ribeiro Junior E Chaib W A Saad L A C DrsquoAlbu-querque and I Cecconello ldquoSurgical management of sponta-neous ruptured hepatocellular adenomardquo Clinics vol 64 no 8pp 775ndash779 2009

[54] S W Cho J W Marsh J Steel et al ldquoSurgical management ofhepatocellular adenoma take it or leave itrdquo Annals of SurgicalOncology vol 15 no 10 pp 2795ndash2803 2008

[55] J F Gigot C Hubert R Banice and M L Kendrick ldquoLaparo-scopic management of benign liver diseases where are werdquoHPB Journal vol 6 no 4 pp 197ndash212 2004

[56] C Toso P Majno A Andres et al ldquoManagement of hepatocel-lular adenoma solitary-uncomplicated multiple and rupturedtumorsrdquo World Journal of Gastroenterology vol 11 no 36 pp5691ndash5695 2005

[57] K J Evason J P Grenert L D Ferrell and S Kakar ldquoAtypicalhepatocellular adenoma-like neoplasms with 120573-catenin activa-tion show cytogenetic alterations similar to well-differentiatedhepatocellular carcinomasrdquo Human Pathology 2012

[58] J H Stoot R J Coelen M C De Jong and C H DejongldquoMalignant transformation of hepatocellular adenomas intohepatocellular carcinomas a systematic review including morethan 1600 adenoma casesrdquo HPB Journal vol 12 no 8 pp 509ndash522 2010

[59] O Farges N Ferreira S Dokmak et al ldquoHepatocellular car-cinoma arising from hepatocellular adenoma in a hepatitis Bvirus-associated cirrhotic liverrdquo Clinical Radiology vol 67 no4 pp 329ndash333 2012

[60] M Sasaki N Yoneda S Kitamura Y Sato and Y NakanumaldquoA serum amyloid A-positive hepatocellular neoplasm arisingin alcoholic cirrhosis a previously unrecognized type of inflam-matory hepatocellular tumorrdquoModern Pathology vol 25 no 12pp 1584ndash1593 2012

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014


MEDIATORSINFLAMMATION

of


Behavioural Neurology

EndocrinologyInternational Journal of



Disease Markers


BioMed Research International

OncologyJournal of



Oxidative Medicine and Cellular Longevity


PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of



Computational and Mathematical Methods in Medicine

OphthalmologyJournal of


Diabetes ResearchJournal of



Research and TreatmentAIDS


Gastroenterology Research and Practice


Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom


1 Introduction

The knowledge of benign hepatocellular tumors that is focalnodular hyperplasia (FNH) and hepatocellular adenoma(HCA) has considerably progressed in the last 10 yearsthanks tomolecular biology followed by immunohistochem-ical applications Following these advances new classificationis now largely used first in France andmore recently in otherEuropean American and East countries

2 A Brief Overview of Focal NodularHyperplasia and Hepatocellular Adenoma

21 Focal Nodular Hyperplasia It is the secondmost frequentbenign liver nodule (after hemangioma) occurring in 08of an adult autopsy population and has been reported in06ndash3 of the general population In 80ndash90 of cases FNHis discovered in women in their third or fourth decade Incountries (ie China) where OC use has been less prevalentFNH tends to be a lesion of adult men or children of eithergender

FNH is solitary in 23 of cases Most lesions are asymp-tomatic and are therefore discovered as incidental findingsduring surgery autopsy or imaging procedures for unrelatedsymptoms Large lesions can present with abdominal painor compression of adjacent organs Reports of hemorrhageor malignant transformation probably do not exist or areexceptional and require confirmation FNH lesions mayregresswith age as shownbydisappearance of presumedFNHlesions on serial imaging studies

The background liver is usually normal FNH is associ-ated with hepatic hemangioma in 20 of cases Coexistencewith HCA is not rare Associated lesions outside the liverhave been reported such as hemihypertrophy hemangiomaof cervix vascular malformations of brain and meningioma

211 Typical FNH Morphological Features

(1) Gross Findings On cut section classical FNH is a palefirm mass measuring from a few millimeters to more than10 centimeters in diameter The margin is well delimitedand the mass is lobulated and non encapsulated The lesionis composed of nodules each measuring 2-3mm separatedby zones of atrophy that give the lesion a multinodularappearance The lesion characteristically has a central oreccentric stellate fibrous scar with radiating extensions thatpartially surround some component nodules

(2)Microscopic Findings FNH lesions are composed of nod-ules of benign-appearing hepatocytes arranged in plates notmore than 2 cells in thickness Steatosis may occur usuallyfocal The central scar is often edematous or congested andcontains one or more large dystrophic vessels accompaniedby numerous small arteriolesThe large vessels have irregularfibrous thickening of the intima with focal thinning of themedia The internal elastic lamina is poorly formed andreduplicated The portal vein is absent The central fibrous

region has radiating branches composed of portal tract-like structures that contain an artery unaccompanied byportal veins or ducts When fibrous septation is prominentthe appearance may be indistinguishable from cirrhosisespecially in biopsy specimens A lymphocytic or mixedinflammatory infiltrate is frequent in fibrous regions At theinterface between fibrous regions and nodules there are oftenfeatures of cholate stasis including feathery degeneration ofhepatocytes Mallory-Denk bodies and a ductular reactionthat may be highlighted with CK7 and CK19 immunos-taining Sinusoids adjacent to arterial sources are lined byCD34-positive endothelium Glutamine synthetase is a veryuseful immunostain showing a characteristic broadband ofexpression in hepatocytes often near the hepatic veins

212 Atypical FNH Incomplete or early forms may lacka central scar they have an incompletion (or absence) ofmultinodular organization and sometimes exhibit more orless prominent regions of congestion

213 Molecular Features Clonal analysis using theHUMARA test demonstrated the reactive polyclonal natureof liver cells in FNH in 50ndash100 of the cases [2 7] MessengerRNA (mRNA) expression levels of the angiopoietin genes(ANGPT1 and ANGPT2) involved in vessel maturation arealtered with the ANGPT1ANGPT2 ratio increased com-pared with normal liver cirrhosis and other liver tumorsThese data support the importance of vascular alterations inthe pathogenesis of FNH The beta-catenin pathway is acti-vated including the downstream target glutamine synthetase[9] This activation explains the expansion of hepatocytesexpressing glutamine synthetase that is so useful for histo-logic diagnosis The molecular mechanisms of this activationare uncertain but do not involve demonstrable mutations inbeta-catenin or Axin1

The pathogenesis of FNH is not fully established Theassociation with conditions having local or systemic vascularanomalies and the presence of unusually large vessels withinthe lesions has led to the belief that FNH is a nonspecificresponse to focally increased blood flow

22 Hepatocellular Adenoma It is a rare benign liver neo-plasm composed of hepatocytes The incidence is around 3-4100 000 in Europe and North America and is lower in Asia85 of cases occur in young women HCA is rare in childrenmen and the elderly

The major risk factor for development of HCA is theexposure to estrogenic or androgenic steroids In youngwomen 80have been users of oral contraceptives (OC)Therisk increases with the duration and type of OC usage Theprevalence appears to be declining as low-estrogen prepa-rations have become more widely used The lesions usuallydecrease in size after stopping OC or after menopause Theclinical presentation of HCA may include abdominal painabdominal mass intraperitoneal hemorrhage abnormal livertests or space occupying lesion found incidentally on animaging study HCA can be single or multiple When 10 or






Briefly
































193 with HCC 19 13 0 0

(5) Grenoble 19 (18) 18 3 12 0 1

(6) Lille 31 (26)1 with HCC 30 25 39 2 6

(7) Lyon (1) 49 (41)4 with HCC 13 17 16 4 7

(1 with HCC)

(8) Lyon (2) 16 (13)1 with HCC 25 14 22 0 4


(10) Nice 32 (31)1 with HCC 28 3 25 3 1



International




HCC) 2UHCA

14 22 14



9UHCA




with HCC)



































120573-catc


Certain


Doubtful

Doubtful

GS

GS(pivotal role)

Abnormal


See Figure 1b


CRPSAAT+NTminus

CRPSAATminusNTminus

CRPSAAT+NTminus

CRPSAATminusNTminus

120573-IHCA 120573-HCA120573-IHCA 120573-HCA

Stop Stop

Stop

Stop Stop

ALLminusT+NTminus

LFABBTminusNT+

H-HCA IHCA UHCA

Stop Stop Stop


(120573-HCA)

IHCHCA subtyping

HCA FNH

Normala

CRPSAAb

(a)



All markers


All markers

LFABPminus CRP+

120573-HHCA 120573-IHCA 120573-HCA

LFABPminus

H-HCA

CRP+

IHCA

Allmarkers-

Allmarkers-

UHCAd

(b)




FNH HCA HCC




H-HCA IHCA

gt5 cm lt5 cm






Then every 2 years

Then every 5 years

Every 10 years












CEUSMRI

H-HCA IHCA Other







fferent









(a) LFABP


(b) CRP


(c) GS




5 Conclusion


Acknowledgments



References




































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of





















Briefly
































193 with HCC 19 13 0 0

(5) Grenoble 19 (18) 18 3 12 0 1

(6) Lille 31 (26)1 with HCC 30 25 39 2 6

(7) Lyon (1) 49 (41)4 with HCC 13 17 16 4 7

(1 with HCC)

(8) Lyon (2) 16 (13)1 with HCC 25 14 22 0 4


(10) Nice 32 (31)1 with HCC 28 3 25 3 1



International




HCC) 2UHCA

14 22 14



9UHCA




with HCC)



































120573-catc


Certain


Doubtful

Doubtful

GS

GS(pivotal role)

Abnormal


See Figure 1b


CRPSAAT+NTminus

CRPSAATminusNTminus

CRPSAAT+NTminus

CRPSAATminusNTminus

120573-IHCA 120573-HCA120573-IHCA 120573-HCA

Stop Stop

Stop

Stop Stop

ALLminusT+NTminus

LFABBTminusNT+

H-HCA IHCA UHCA

Stop Stop Stop


(120573-HCA)

IHCHCA subtyping

HCA FNH

Normala

CRPSAAb

(a)



All markers


All markers

LFABPminus CRP+

120573-HHCA 120573-IHCA 120573-HCA

LFABPminus

H-HCA

CRP+

IHCA

Allmarkers-

Allmarkers-

UHCAd

(b)




FNH HCA HCC




H-HCA IHCA

gt5 cm lt5 cm






Then every 2 years

Then every 5 years

Every 10 years












CEUSMRI

H-HCA IHCA Other







fferent









(a) LFABP


(b) CRP


(c) GS




5 Conclusion


Acknowledgments



References




































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of





































193 with HCC 19 13 0 0

(5) Grenoble 19 (18) 18 3 12 0 1

(6) Lille 31 (26)1 with HCC 30 25 39 2 6

(7) Lyon (1) 49 (41)4 with HCC 13 17 16 4 7

(1 with HCC)

(8) Lyon (2) 16 (13)1 with HCC 25 14 22 0 4


(10) Nice 32 (31)1 with HCC 28 3 25 3 1



International




HCC) 2UHCA

14 22 14



9UHCA




with HCC)



































120573-catc


Certain


Doubtful

Doubtful

GS

GS(pivotal role)

Abnormal


See Figure 1b


CRPSAAT+NTminus

CRPSAATminusNTminus

CRPSAAT+NTminus

CRPSAATminusNTminus

120573-IHCA 120573-HCA120573-IHCA 120573-HCA

Stop Stop

Stop

Stop Stop

ALLminusT+NTminus

LFABBTminusNT+

H-HCA IHCA UHCA

Stop Stop Stop


(120573-HCA)

IHCHCA subtyping

HCA FNH

Normala

CRPSAAb

(a)



All markers


All markers

LFABPminus CRP+

120573-HHCA 120573-IHCA 120573-HCA

LFABPminus

H-HCA

CRP+

IHCA

Allmarkers-

Allmarkers-

UHCAd

(b)




FNH HCA HCC




H-HCA IHCA

gt5 cm lt5 cm






Then every 2 years

Then every 5 years

Every 10 years












CEUSMRI

H-HCA IHCA Other







fferent









(a) LFABP


(b) CRP


(c) GS




5 Conclusion


Acknowledgments



References




































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of













































120573-catc


Certain


Doubtful

Doubtful

GS

GS(pivotal role)

Abnormal


See Figure 1b


CRPSAAT+NTminus

CRPSAATminusNTminus

CRPSAAT+NTminus

CRPSAATminusNTminus

120573-IHCA 120573-HCA120573-IHCA 120573-HCA

Stop Stop

Stop

Stop Stop

ALLminusT+NTminus

LFABBTminusNT+

H-HCA IHCA UHCA

Stop Stop Stop


(120573-HCA)

IHCHCA subtyping

HCA FNH

Normala

CRPSAAb

(a)



All markers


All markers

LFABPminus CRP+

120573-HHCA 120573-IHCA 120573-HCA

LFABPminus

H-HCA

CRP+

IHCA

Allmarkers-

Allmarkers-

UHCAd

(b)




FNH HCA HCC




H-HCA IHCA

gt5 cm lt5 cm






Then every 2 years

Then every 5 years

Every 10 years












CEUSMRI

H-HCA IHCA Other







fferent









(a) LFABP


(b) CRP


(c) GS




5 Conclusion


Acknowledgments



References




































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of


















FNH HCA HCC




H-HCA IHCA

gt5 cm lt5 cm






Then every 2 years

Then every 5 years

Every 10 years












CEUSMRI

H-HCA IHCA Other







fferent









(a) LFABP


(b) CRP


(c) GS




5 Conclusion


Acknowledgments



References




































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of


















(a) LFABP


(b) CRP


(c) GS




5 Conclusion


Acknowledgments



References




































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of






































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















Research Article Focal Nodular Hyperplasia and Hepatocellular...

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