PDF herunterladen
Semin Liver Dis 2006; 26(4): 328-336
DOI: 10.1055/s-2006-951600
Copyright © 2006 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA.

Molecular Diagnostic Approach to Liver Tissue as an Ancillary Tool for Liver Histopathology

Louis Libbrecht1 , Tania Roskams1
  • 1Liver Research Unit of the Laboratory of Morphology and Molecular Pathology and Department of Pathology, University and University Hospitals of Leuven, Leuven, Belgium
Weitere Informationen

Publikationsverlauf

Publikationsdatum:
18. Oktober 2006 (online)

    Lizenzen und Reprints

ABSTRACT

Diagnostic liver histopathology is currently based on the microscopic assessment of morphological and immunohistochemical features in a biopsy. In other fields of diagnostic pathology, it has been shown that the diagnostic process can be improved by the incorporation of ancillary molecular techniques and this will most likely also occur in liver pathology in the future. This article gives an overview of several liver diseases for which the diagnosis could be improved by the addition of a molecular technique to the classical histopathologic working method. For each of these diseases, the most promising molecular techniques are discussed. It is very likely that ancillary molecular techniques will be applied in routine practice to improve diagnosis and prognostication of liver tumors in the foreseeable future.

KEYWORDS

Molecular diagnosis - liver diagnosis - microarray - real-time reverse-transcriptase PCR

REFERENCES

  • 1 McSween R NM, Burt A D, Portmann B, Ishak K G. Pathology of the Liver. 4th ed. London; Churchill Livingstone 2002
    Google Scholar
  • 2 Crocker J. Demystified: molecular pathology in oncology.  Mol Pathol. 2002;  55 337-347
    PubMedGoogle Scholar
  • 3 Pietrangelo A. Molecular insights into the pathogenesis of hereditary haemochromatosis.  Gut. 2006;  55 564-568
    CrossrefPubMedGoogle Scholar
  • 4 Jansen P LM, Sturm E. Genetic cholestasis, causes and consequences for hepatobiliary transport.  Liver Int. 2003;  23 315-322
    CrossrefPubMedGoogle Scholar
  • 5 Ryder S D. Progression of hepatic fibrosis in patients with hepatitis C: a prospective repeat liver biopsy study.  Gut. 2004;  53 451-455
    CrossrefPubMedGoogle Scholar
  • 6 Rubbia-Brandt L, Fabris P, Paganin S et al.. Steatosis affects chronic hepatitis C progression in a genotype specific way.  Gut. 2004;  53 406-412
    CrossrefPubMedGoogle Scholar
  • 7 Camps J, Crisostomo S, Garciagranero M et al.. Prediction of the response of chronic hepatitis C to interferon alfa: a statistical analysis of pretreatment variables.  Gut. 1993;  34 1714-1717
    PubMedGoogle Scholar
  • 8 Massard J, Ratziu V, Thabut D et al.. Natural history and predictors of disease severity in chronic hepatitis C.  J Hepatol. 2006;  44 S19-S24
    PubMedGoogle Scholar
  • 9 Wilson L E, Torbenson M, Astemborski J et al.. Progression of liver fibrosis among injection drug users with chronic hepatitis C.  Hepatology. 2006;  43 788-795
    CrossrefPubMedGoogle Scholar
  • 10 Jensen D M, Morgan T R, Marcellin P et al.. Early identification of HCV genotype 1 patients responding to 24 weeks peginterferon alpha-2a (40 kd)/ribavirin therapy.  Hepatology. 2006;  43 954-960
    CrossrefPubMedGoogle Scholar
  • 11 Feld J J, Liang T J. Hepatitis C: identifying patients with progressive liver injury.  Hepatology. 2006;  43 S194-S206
    CrossrefPubMedGoogle Scholar
  • 12 Smith M W, Walters K A, Korth M J et al.. Gene expression patterns that correlate with hepatitis C and early progression to fibrosis in liver transplant recipients.  Gastroenterology. 2006;  130 179-187
    CrossrefPubMedGoogle Scholar
  • 13 Chen L, Borozan I, Feld J et al.. Hepatic gene expression discriminates responders and nonresponders in treatment of chronic hepatitis C viral infection.  Gastroenterology. 2005;  128 1437-1444
    CrossrefPubMedGoogle Scholar
  • 14 Hayashida K, Daiba A, Sakai A et al.. Pretreatment prediction of interferon-alfa efficacy in chronic hepatitis C patients.  Clin Gastroenterol Hepatol. 2005;  3 1253-1259
    CrossrefPubMedGoogle Scholar
  • 15 Yeung E, Chung R T. Microarrays and prediction of interferon response in chronic hepatitis C: not yet ready for prime time.  Clin Gastroenterol Hepatol. 2005;  3 1192-1194
    CrossrefPubMedGoogle Scholar
  • 16 Kim I J, Kang H C, Park J G. Evaluation of microarray analysis for predicting treatment responsiveness in patients with chronic hepatitis C viral infection.  Gastroenterology. 2005;  129 1803
    PubMedGoogle Scholar
  • 17 Grassi G, Pozzato G, Moretti M, Giacca M. Quantitative analysis of hepatitis C virus RNA in liver biopsies by competitive reverse transcription and polymerase chain reaction.  J Hepatol. 1995;  23 403-411
    CrossrefPubMedGoogle Scholar
  • 18 Gervais A, Martinot M, Boyer N et al.. Quantitation of hepatic hepatitis C virus RNA in patients with chronic hepatitis C: relationship with severity of disease, viral genotype and response to treatment.  J Hepatol. 2001;  35 399-405
    CrossrefPubMedGoogle Scholar
  • 19 McHutchison . Hepatic HCV RNA before and after treatment with interferon alone or combined with ribavirin.  Hepatology. 2002;  35 688-693
    CrossrefPubMedGoogle Scholar
  • 20 Lee W M. Acute liver failure in the United States.  Semin Liver Dis. 2003;  23 217-226
    Artikel in Thieme ConnectPubMedGoogle Scholar
  • 21 Nunez-Martinez O, De la Cruz G, De Diego A et al.. Liver transplantation for fulminant and subfulminant hepatic failure.  Transplant Proc. 2003;  35 1855-1856
    CrossrefPubMedGoogle Scholar
  • 22 Tessier G, Villeneuve E, Villeneuve J P. Etiology and outcome of acute liver failure: experience from a liver transplantation centre in Montreal.  Can J Gastroenterol. 2002;  16 672-676
    PubMedGoogle Scholar
  • 23 Huang Q, Jin X, Gaillard E T et al.. Gene expression profiling reveals multiple toxicity endpoints induced by hepatotoxicants.  Mutat Res. 2004;  549 147-167
    PubMedGoogle Scholar
  • 24 Ulrich R G, Rockett J C, Gibson G G, Pettit S D. Overview of an interlaboratory collaboration on evaluating the effects of model hepatotoxicants on hepatic gene expression.  Environ Health Perspect. 2004;  112 423-427
    PubMedGoogle Scholar
  • 25 Waring J F, Ciurlionis R, Jolly R A et al.. Microarray analysis of hepatotoxins in vitro reveals a correlation between gene expression profiles and mechanisms of toxicity.  Toxicol Lett. 2001;  120 359-368
    CrossrefPubMedGoogle Scholar
  • 26 Inkinen K, Lahesmaa R, Brandt A et al.. DNA microarray-based gene expression profiles of cytomegalovirus infection and acute rejection in liver transplants.  Transplant Proc. 2005;  37 1227-1229
    CrossrefPubMedGoogle Scholar
  • 27 Krukemeyer M G, Moeller J, Morawietz L et al.. Description of B lymphocytes and plasma cells, complement, and chemokines/receptors in acute liver allograft rejection.  Transplantation. 2004;  78 65-70
    PubMedGoogle Scholar
  • 28 Cookson S, Doherty D G, Todryk S et al.. Hepatic expression of IL-15 mRNA is associated with liver graft acceptance.  Transpl Immunol. 2003;  11 39-48
    PubMedGoogle Scholar
  • 29 Flach R, Speidel N, Flohe S et al.. Analysis of intragraft cytokine expression during early reperfusion after liver transplantation using semi-quantitative RT-PCR.  Cytokine. 1998;  10 445-451
    CrossrefPubMedGoogle Scholar
  • 30 Hytiroglou P, Theise N D. Differential diagnosis of hepatocellular nodular lesions.  Semin Diagn Pathol. 1998;  15 285-299
    PubMedGoogle Scholar
  • 31 Vander Borght S, Libbrecht L, Blokzijl H et al.. Diagnostic and pathogenetic implications of the expression of hepatic transporters in focal lesions occurring in normal liver.  J Pathol. 2005;  207 471-482
    PubMedGoogle Scholar
  • 32 Makhlouf H R, Abdul-Al H M, Goodman Z D. Diagnosis of focal nodular hyperplasia of the liver by needle biopsy.  Hum Pathol. 2005;  36 1210-1216
    CrossrefPubMedGoogle Scholar
  • 33 Fabre A, Audet P, Vilgrain V et al.. Histologic scoring of liver biopsy in focal nodular hyperplasia with atypical presentation.  Hepatology. 2002;  35 414-420
    CrossrefPubMedGoogle Scholar
  • 34 Chen Z ME, Crone K G, Watson M A et al.. Identification of a unique gene expression signature that differentiates hepatocellular adenoma from well-differentiated hepatocellular carcinoma.  Am J Surg Pathol. 2005;  29 1600-1608
    PubMedGoogle Scholar
  • 35 Bioulac-Sage P, Rebouissou S, Cunha A S et al.. Clinical, morphologic, and molecular features defining so-called telangiectatic focal nodular hyperplasias of the liver.  Gastroenterology. 2005;  128 1211-1218
    CrossrefPubMedGoogle Scholar
  • 36 Paradis V, Benzekri A, Dargere D et al.. Telangiectatic focal nodular hyperplasia: a variant of hepatocellular adenoma.  Gastroenterology. 2004;  126 1323-1329
    CrossrefPubMedGoogle Scholar
  • 37 Paradis V, Bieche I, Dargere D et al.. A quantitative gene expression study suggests a role for angiopoietins in focal nodular hyperplasia.  Gastroenterology. 2003;  124 651-659
    CrossrefPubMedGoogle Scholar
  • 38 Zucman-Rossi J, Jeannot E, Van Nhieu J T et al.. Genotype-phenotype correlation in hepatocellular adenoma: new classification and relationship with HCC.  Hepatology. 2006;  43 515-524
    CrossrefPubMedGoogle Scholar
  • 39 Wilkens L, Bredt M, Flemming P et al.. Diagnostic impact of fluorescence in situ hybridization in the differentiation of hepatocellular adenoma and well-differentiated hepatocellular carcinoma.  J Mol Diagn. 2001;  3 68-73
    PubMedGoogle Scholar
  • 40 Wilkens L, Bredt M, Flemming P et al.. Differentiation of liver cell adenomas from well-differentiated hepatocellular carcinomas by comparative genomic hybridization.  J Pathol. 2001;  193 476-482
    PubMedGoogle Scholar
  • 41 Matsui O. Detection and characterization of hepatocellular carcinoma by imaging.  Clin Gastroenterol Hepatol. 2005;  3 S136-S140
    CrossrefPubMedGoogle Scholar
  • 42 Bolondi L, Gaiani S, Celli N et al.. Characterization of small nodules in cirrhosis by assessment of vascularity: the problem of hypovascular hepatocellular carcinoma.  Hepatology. 2005;  42 27-34
    CrossrefPubMedGoogle Scholar
  • 43 Krinsky G. Imaging of dysplastic nodules and small hepatocellular carcinomas: experience with explanted livers.  Intervirology. 2004;  47 191-198
    CrossrefPubMedGoogle Scholar
  • 44 Bruix J, Sherman M, Llovet J M et al.. Clinical management of hepatocellular carcinoma. Conclusions of the Barcelona-2000 EASL Conference.  J Hepatol. 2001;  35 421-430
    CrossrefPubMedGoogle Scholar
  • 45 Libbrecht L, Desmet V, Roskams T. Preneoplastic lesions in human hepatocarcinogenesis.  Liver Int. 2005;  25 16-27
    CrossrefPubMedGoogle Scholar
  • 46 Libbrecht L, Severi T, Cassiman D et al.. Glypican-3 expression distinguishes small hepatocellular carcinomas from cirrhosis, dysplastic nodules and focal nodular hyperplasia-like nodules.  Am J Surg Pathol. , In press
    PubMedGoogle Scholar
  • 47 Capurro M, Wanless I R, Sherman M et al.. Glypican-3: a novel serum and histochemical marker for hepatocellular carcinoma.  Gastroenterology. 2003;  125 89-97
    CrossrefPubMedGoogle Scholar
  • 48 Chang H Y, Nuyten D SA, Sneddon J B et al.. Robustness, scalability, and integration of a wound-response gene expression signature in predicting breast cancer survival.  Proc Natl Acad Sci USA. 2005;  102 3738-3743
    CrossrefPubMedGoogle Scholar
  • 49 Di Bisceglie A M. Pretransplant treatments for hepatocellular carcinoma: do they improve outcomes?.  Liver Transpl. 2005;  11 S10-S13
    CrossrefPubMedGoogle Scholar
  • 50 Befeler A S, Hayashi P H, Di Bisceglie A M. Liver transplantation for hepatocellular carcinoma.  Gastroenterology. 2005;  128 1752-1764
    CrossrefPubMedGoogle Scholar
  • 51 Wiesner R H. Patient selection in an era of donor liver shortage: current US policy.  Nat Clin Pract Gastroenterol Hepatol. 2005;  2 24-30
    PubMedGoogle Scholar
  • 52 Cillo U, Vitale A, Bassanello M et al.. Liver transplantation for the treatment of moderately or well-differentiated hepatocellular carcinoma.  Ann Surg. 2004;  239 150-159
    PubMedGoogle Scholar
  • 53 Thorgeirsson S S, Grisham J W. Molecular pathogenesis of human hepatocellular carcinoma.  Nat Genet. 2002;  31 339-346
    CrossrefPubMedGoogle Scholar
  • 54 Kurokawa Y, Matoba R, Takemasa I et al.. Molecular-based prediction of early recurrence in hepatocellular carcinoma.  J Hepatol. 2004;  41 284-291
    CrossrefPubMedGoogle Scholar
  • 55 Iizuka N, Oka M, Yamada-Okabe H et al.. Oligonucleotide microarray for prediction of early intrahepatic recurrence of hepatocellular carcinoma after curative resection.  Lancet. 2003;  361 923-929
    CrossrefPubMedGoogle Scholar
  • 56 Ye Q H, Qin L X, Forgues M et al.. Predicting hepatitis B virus-positive metastatic hepatocellular carcinomas using gene expression profiling and supervised machine learning.  Nat Med. 2003;  9 416-423
    CrossrefPubMedGoogle Scholar
  • 57 Michiels S, Koscielny S, Hill C. Prediction of cancer outcome with microarrays: a multiple random validation strategy.  Lancet. 2005;  365 488-492
    CrossrefPubMedGoogle Scholar
  • 58 Ein-Dor L, Zuk O, Domany E. Thousands of samples are needed to generate a robust gene list for predicting outcome in cancer.  Proc Natl Acad Sci USA. 2006;  103 5923-5928
    CrossrefPubMedGoogle Scholar
  • 59 Lee J S, Chu I S, Heo J et al.. Classification and prediction of survival in hepatocellular carcinoma by gene expression profiling.  Hepatology. 2004;  40 667-676
    CrossrefPubMedGoogle Scholar
  • 60 Hu Z, Fan C, Oh D S et al.. The molecular portraits of breast tumors are conserved across microarray platforms.  BMC Genomics. 2006;  7 96
    CrossrefPubMedGoogle Scholar
  • 61 Lee J S, Heo J, Libbrecht L et al.. A novel prognostic subtype of human hepatocellular carcinoma derived from hepatic progenitor cells.  Nat Med. 2006;  12 410-416
    CrossrefPubMedGoogle Scholar
  • 62 Marsh J W, Finkelstein S D, Schwartz M E et al.. Advancing the diagnosis and treatment of hepatocellular carcinoma.  Liver Transpl. 2005;  11 469-472
    CrossrefPubMedGoogle Scholar
  • 63 Libbrecht L, Lee Y S, Durnez A et al.. Microvascular invasion in hepatocellular carcinoma is correlated with differentiation grade, tumor diameter and with unsupervised classification based on gene expression patterns. Abstract book of the EASL/AASLD/JSH monothematic conference on hepatocellular carcinoma 2005: 10
    Google Scholar
  • 64 Marsh J W, Finkelstein S D, Demetris A J et al.. Genotyping of hepatocellular carcinoma in liver transplant recipients adds predictive power for determining recurrence-free survival.  Liver Transpl. 2003;  9 664-671
    CrossrefPubMedGoogle Scholar
  • 65 Sherman M. Screening for hepatocellular carcinoma.  Best Pract Res Clin Gastroenterol. 2005;  19 101-118
    CrossrefPubMedGoogle Scholar
  • 66 Bruix J, Sherman M. Management of hepatocellular carcinoma.  Hepatology. 2005;  42 1208-1236
    CrossrefPubMedGoogle Scholar
  • 67 Fattovich G, Llovet J M. Risk factors for hepatocellular carcinoma in HCV-cirrhosis: what we know and what is missing.  J Hepatol. 2006;  44 1013-1016
    CrossrefPubMedGoogle Scholar
  • 68 Velazquez R F, Rodriguez M, Navascues C A et al.. Prospective analysis of risk factors for hepatocellular carcinoma in patients with liver cirrhosis.  Hepatology. 2003;  37 520-527
    CrossrefPubMedGoogle Scholar
  • 69 Ganne-Carrie N, Chastang C, Chapel F et al.. Predictive score for the development of hepatocellular carcinoma and additional value of liver large cell dysplasia in western patients with cirrhosis.  Hepatology. 1996;  23 1112-1118
    PubMedGoogle Scholar
  • 70 Suzuki S, Kondo Y, Hirashima N et al.. Evaluation of loss of heterozygosity before and after interferon therapy in patients with hepatitis C virus infection who developed hepatocellular carcinoma during follow up.  J Gastroenterol Hepatol. 2003;  18 1364-1372
    CrossrefPubMedGoogle Scholar
  • 71 Roncalli M, Bianchi P, Grimaldi G C et al.. Fractional allelic loss in non-end-stage cirrhosis: correlations with hepatocellular carcinoma development during follow-up.  Hepatology. 2000;  31 846-850
    CrossrefPubMedGoogle Scholar
  • 72 Kim S, Park Y M. Specific gene expression patterns in liver cirrhosis.  Biochem Biophys Res Commun. 2005;  334 681-688
    CrossrefPubMedGoogle Scholar
  • 73 Kim J W, Ye Q, Forgues M et al.. Cancer-associated molecular signature in the tissue samples of patients with cirrhosis.  Hepatology. 2004;  39 518-527
    CrossrefPubMedGoogle Scholar

Tania RoskamsM.D. Ph.D. 

Department of Pathology, UZLeuven, Minderbroedersstraat 12

3000 Leuven, Belgium

      >