title: Immunohistochemistry panel segregates molecular types of hepatocellular carcinoma in Brazilian autopsy cases.
abstract: OBJECTIVE
  To assess the distribution of proteins coded by genes reported as relevant for the molecular classification of hepatocellular carcinoma (HCC).
  
  
  METHODS
  In this retrospective cross-sectional study, the following clinicopathological data were analyzed in 80 autopsied HCC patients: sex, age, ethnicity, alcohol intake, infection with hepatitis B and/or C virus, infection with human immunodeficiency virus, prior treatment, basic and immediate causes of death, liver weight, presence of cirrhosis, number and size of nodules, gross pattern, histological grade and variants, architectural pattern, invasion of large veins, and presence and location of extrahepatic metastases. The protein products of genes known to be involved in molecular pathogenesis of HCC, including epidermal growth factor receptor (EGFR), MET, keratin 19 (K19), vimentin, beta-catenin, mechanistic target of rapamycin (mTOR), extracellular signaling-related kinase (ERK)1, ERK2, Ki67, cyclin D1, caspase 3 and p53, were detected by immunohistochemistry on tissue microarrays. The expression levels were scored and statistically assessed for correlation with HCC parameters.
  
  
  RESULTS
  Infection with hepatitis C virus was identified in 49% of the 80 autopsy patients, cirrhosis in 90%, advanced tumors in 95%, and extrahepatic metastases in 38%. Expression of K19, p53 and ERK1 correlated to high-grade lesions. Expression of ERK1, nuclear beta-catenin, cyclin D1 and ERK2 correlated to higher rates of cell proliferation as determined by Ki67. Expression of MET, EGFR (> 0) and caspase 3 correlated with lower histological grades. Expression of EGFR correlated to that of caspase 3, and overexpression of EGFR (≥ 200/300) was observed in low-grade tumors more frequently (grades 1 and 2: 67% vs grade 3: 27% and grade 4: 30%). Expression of ERK1 was associated with that of K19 and vimentin, whereas expression of ERK2 was associated with that of cyclin D1, MET and membrane beta-catenin. Expression of vimentin was strongly correlated with that of K19.
  
  
  CONCLUSIONS
  Expression of K19, p53, ERK1, ERK2, vimentin and nuclear beta-catenin was related to higher-grade markers, as opposed to expression/overexpression of EGFR, MET and caspase 3.
authors.affiliation: Aloísio Felipe-Silva, LIM 14-Patologia Hepática, Faculdade de Medicina da USP, 01246-903 São Paulo SP, Brazil.
authors.forename: Aloísio
authors.initials: A
authors.lastname: Felipe-Silva
authors.affiliation: Aloísio Felipe-Silva, LIM 14-Patologia Hepática, Faculdade de Medicina da USP, 01246-903 São Paulo SP, Brazil.
authors.forename: Alda
authors.initials: A
authors.lastname: Wakamatsu
authors.affiliation: Aloísio Felipe-Silva, LIM 14-Patologia Hepática, Faculdade de Medicina da USP, 01246-903 São Paulo SP, Brazil.
authors.forename: Cinthya
authors.initials: C
authors.lastname: Dos Santos Cirqueira
authors.affiliation: Aloísio Felipe-Silva, LIM 14-Patologia Hepática, Faculdade de Medicina da USP, 01246-903 São Paulo SP, Brazil.
authors.forename: Venâncio Avancini Ferreira
authors.initials: VA
authors.lastname: Alves
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001344:Autopsy; D001938:Brazil; D006528:Carcinoma, Hepatocellular / Q000145:classification / Q000453:epidemiology / Q000378:metabolism* / Q000473:pathology; D016022:Case-Control Studies; D053148:Caspase 3 / Q000378:metabolism; D003430:Cross-Sectional Studies; D019938:Cyclin D1 / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism; D005260:Female; D015658:HIV Infections / Q000453:epidemiology; D019694:Hepatitis B, Chronic / Q000453:epidemiology; D019698:Hepatitis C, Chronic / Q000453:epidemiology; D006801:Humans; D007150:Immunohistochemistry; D053539:Keratin-19 / Q000378:metabolism; D019394:Ki-67 Antigen / Q000378:metabolism; D008103:Liver Cirrhosis / Q000453:epidemiology / Q000473:pathology; D008113:Liver Neoplasms / Q000145:classification / Q000453:epidemiology / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism; D012189:Retrospective Studies; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D046888:Tissue Array Analysis; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D014746:Vimentin / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism
chemical_list: C530104:CCND1 protein, human; D053539:Keratin-19; D019394:Ki-67 Antigen; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D014746:Vimentin; D051176:beta Catenin; D019938:Cyclin D1; C546842:MTOR protein, human; C512478:EGFR protein, human; D066246:ErbB Receptors; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met; D058570:TOR Serine-Threonine Kinases; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; C505407:CASP3 protein, human; D053148:Caspase 3
keywords: Autopsy; Classification; Epidermal growth factor receptor; Hepatocellular carcinoma; Immunohistochemistry; Liver