CORRESPONDENCE

Hepatocellular Carcinoma in a 12-Year-Old Child With PiZZ �1-Antitrypsin Deficiency

To the Editor:

We read with great interest the review by Rudnik and Perlmutter1

on the mechanisms of carcinogenesis in PiZZ �1-antitrypsin defi-ciency (A1ATD). We would like to endorse their hypothesis and pre-vious animal models2 by describing the development of hepatocellularcarcinoma (HCC) in a 12-year-old girl with end-stage liver diseaserelated to PiZZ A1ATD.

The diagnosis of PiZZ A1ATD was made at the age of 3.5 yearsfollowing investigations into the child’s hepatosplenomegaly. She wasnoted to have a history of unexplained prolonged neonatal jaundiceand mild developmental delay. Her clinical course was complicated byan episode of hematemesis at age 4 that required variceal sclerotherapy.At age 11, she suffered a blunt abdominal trauma. A computed tomog-raphy scan suggested a splenic infarction and significant splenic vari-ces, but no intrahepatic lesions. The child recovered clinically underconservative management. Eight months later, a follow-up ultrasoundscan detected a subcapsular nodule (diameter 2.6 cm) in segment V ofthe right lobe. A biphasic computed tomography scan indicated arte-rialization of the nodule and the presence of small para-aortic andmesenteric nodes. Her serum �-fetoprotein level was 4 (normal value�7 IU/L), her carcino-embryonic antigen level was less than 2 (nv �5�g/L), and her Ca-199 level was 11 (nv �37 kU/L). The child wasscheduled for liver transplantation, and a hepatectomy 5 months laterconfirmed a single subcapsular nodule measuring 0.8 � 2.5 � 1.5 cmlocated in the right lobe of the liver, which exhibited cirrhosis. Sixmonths after the operation, the child is well with normal graft functionand no signs of recurrence.

The tumor was composed of two-cell-thick liver cell plates sur-rounded by diffusely capillarized CD34-positive sinusoids. Lesionalhepatocytes showed minimal cytological atypias and no mitotic activ-ity. The proportion of proliferating hepatocytes was less than 1% usingKi67 (MIB-1) immunostaining (Fig. 1A). Only about a third of thelesional hepatocytes contained diastase-resistant periodic acid Schiff(dPAS)-positive fine intra-cytoplasmic granules, confirmed to be �1-antitrypsin via immunohistochemistry (Fig. 1B). Hepatocytes with�1-antitrypsin deposits were more present at the periphery of thetumor and in particular at the interface with fibrous tissue (Fig. 1C).The background liver showed periseptal hepatocytes containing abun-dant intracytoplasmic dPAS-positive deposits of variable size, rangingfrom fine granular material to globules up to 20 �m in diameter (Fig.1D).

The extent of deposition of dPAS-positive material is an age-relatedphenomenon in PiZ A1ATD3 that is also observed in older individualswho carry only one PiZZ allele.4,5 The diminished presence of dPAS-positive deposits in the HCC cells of our patient is compatible with thehypothesis that globule-containing periportal hepatocytes could gen-erate a proliferative stimulus, leading to a higher turnover of globule-devoid perivenular hepatocytes and, ultimately, neoplastic change.Whether the abdominal trauma suffered 8 months earlier played a rolein the development of HCC in our patient remains speculative. Theminimal atypia, very low proliferative rate, slow clinical progression,and incipient accumulation of the dPAS-positive material in the le-sional hepatocytes indicate that hepatocarcinogenesis in metabolicconditions, as recently postulated,1 may follow a different, less aggres-sive clinical course.

NEDIM HADZIC, M.D.1,2

ALBERTO QUAGLIA, PH.D.2

GIORGINA MIELI-VERGANI, PH.D.11Dept. of Child Health2Institute of Liver StudiesKing’s College HospitalDenmark Hill, London, UK

References1. Rudnik DA, Perlmutter DH. Alpha-1-antitrypsin deficiency: a new para-

digm for hepatocellular carcinoma in genetic liver disease. HEPATOLOGY

2005;42:514-521.2. Geller SA, Nichols WS, Kim S, Tolmachoff T, Lee S, Dycaico MJ, et al.

Hepatocarcinogenesis is the sequel to hepatitis in Z#2 �1-antitrypsintransgenic mice: histopathological and DNA ploidy studies. HEPATOLOGY

1994;19:389-397.3. Talbot IC, Mowat AP. Liver disease in infancy: histological features and

relationship to �1-antitrypsin phenotype. J Clin Pathol 1975;28:559-563.4. Vennarecci G, Gunson BK, Ismail T, Hubscher SG, Kelly DA, McMaster

P, et al. Transplantation for end stage liver disease related to alpha 1antitrypsin. Transplantation 1996:61:1488-1495.

5. Hadzic N, Francavilla R, Chambers SM, Castellaneta S, Portmann B, Mieli-Vergani G. Outcome of PiSS and PiSZ alpha-1-antitrypsin deficiency present-ing with liver involvement. Eur J Pediatr 2005;164:250-252.

Copyright © 2005 by the American Association for the Study of Liver Diseases.Published online in Wiley InterScience (www.interscience.wiley.com).DOI 10.1002/hep.21009Potential conflict of interest: Nothing to report.

Fig. 1. (A) The low proliferative rate of the tumor is demonstrated byimmunohistochemistry for Ki67 (MIB-1), which stained only a single HCChepatocyte (arrow) in this field (original magnification �400). (B) Immuno-histochemistry for �1-antitrypsin shows intracytoplasmic deposits in thehepatocytes (arrow) at the periphery of the tumor (original magnification�400). (C) The �1-antitrypsin deposits in the HCC hepatocytes are repre-sented as fine granules (arrow), in contrast to (D) fine granules and globulesof variable size in non-HCC hepatocytes (arrowheads), suggesting thataccumulation of �1-antitrypsin material in the tumor cells is a recent event(dPAS; original magnification �400).

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