title: Z and Mmalton-1-antitrypsin deficiency-associated hepatocellular carcinoma: a genetic study.
abstract: BACKGROUND
  The histological hallmark of alpha-1-antitrypsin deficiency (AATD) is the presence of periodic acid-Schiff diastase (PASD)-resistant positive globules in hepatocytes, with a heterogeneous distribution. It is noteworthy that hepatocellular carcinoma (HCC) arises specifically from the AAT-negative areas but the reason for this remains unclear.
  
  
  OBJECTIVE
  To determine whether the different distribution of AAT globules within neoplastic and non-neoplastic hepatocytes is the result of a self-induced correction of the genetic defect.
  
  
  METHODS
  Two HCV-positive patients with AATD-associated HCC were studied. One patient harboured a compound heterozygous PiSZ genotype whereas the other showed the rarer PiMMmalton in heterozygosity. In both cases, neoplastic hepatocytes appeared globule devoid, while non-neoplastic hepatocytes showed intracytoplasmic accumulation of PASD-positive globules. Laser-assisted microdissection was used to assess a genotype/phenotype correlation in single liver cells from HCC and from non-neoplastic hepatocytes.
  
  
  RESULTS
  Direct sequencing of DNA purified from globule-devoid and globule-filled hepatocytes demonstrated that all liver cells carried the same mutant genetic background.
  
  
  CONCLUSIONS
  Our findings indicate that (i) both variants of HCC arising in AAT deficiency (Z and Mmalton) do not accumulate the mutant protein and (ii) the different phenotypic appearance of hepatocytes is not the result of a retromutation during neoplastic transformation, but other mechanisms should be investigated.
authors.affiliation: Department of Pathology, Bambino Gesù Children's Hospital, Rome, Italy. francalanci@opbg.net
authors.forename: Paola
authors.initials: P
authors.lastname: Francalanci
authors.forename: Filippo M
authors.initials: FM
authors.lastname: Santorelli
authors.forename: Simona
authors.initials: S
authors.lastname: Saccani
authors.forename: Maria F
authors.initials: MF
authors.lastname: Bonetti
authors.forename: Daniela
authors.initials: D
authors.lastname: Medicina
authors.forename: Pierpaolo
authors.initials: P
authors.lastname: Coni
authors.forename: Gavino
authors.initials: G
authors.lastname: Faa
authors.forename: Francesco
authors.initials: F
authors.lastname: Callea
mesh_terms: D006528:Carcinoma, Hepatocellular / Q000209:etiology / Q000235:genetics*; D005260:Female; D005838:Genotype; D006801:Humans; D007150:Immunohistochemistry; D008113:Liver Neoplasms / Q000209:etiology / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D000515:alpha 1-Antitrypsin / Q000032:analysis / Q000235:genetics*; D019896:alpha 1-Antitrypsin Deficiency / Q000150:complications*
chemical_list: D000515:alpha 1-Antitrypsin