Medical and Pediatric Oncology 20:78-83 (1992)
Hepatocellular Carcinoma Associated With Arteriohepatic Dysplasia in a 4-Year-Old Girl Albert N. BCkdssy, MD, MSc, Stanislaw Carwicz, MD, PhD, Thomas Wiebe, MD, PhD, lnga Hagerstrand, MD, PhD, and Ove A. Jensen, MD, PhD Hepatocellular carcinoma and obliterated hepatic bile duct were found at postmortem examination in a 4-year-old girl with arteriohepatic dysplasia (Alagille’s syndrome). AFP level was extremely high. Liver cirrhosis was present on percutaneous nee-
dle biopsy 9 months before she succumbed in progressive liver failure. Episodes of repeated gastrointestinal, life-threatening hemorrhages occurred during the last 6 months of her life. Histopathologic findings of the eyes were documented at autopsy.
Key words: Alagille’s syndrome, child, hepatic carcinoma, liver cirrhosis, biliary atresia, autopsy, histopathology, eyes, liver, AFP
INTRODUCTION
CASE REPORT
Arteriohepatic dysplasia or Alagille’s syndrome was first described by Porter et al. in 1968 [I]. Alagille et al. in 1969 reported the association of hepatic ductular hypoplasia, facial features, pulmonary arterial stenosis, vertebral arch defects, and various abnormalities as a homogeneous, readily recognizable syndrome [2,3]. Somewhat later Watson and Miller described similar abnormalities in two or more members in each of five unrelated families. They named the syndrome arteriohepatic dysplasia [4].Riely et al. added anterior chamber and retinal pigmentary abnormalities of the eyes as hallmarks of this syndrome [5]. The prognosis of the syndrome, judged from about 100 reported cases, seems more favourable than in juvenile chronic cholestasis of other types. Patients with Alagille’s syndrome do usually not develop liver failure [&lo], but death due to cirrhosis occurred 111,121 in some cases. Hepatocellular carcinoma associated with familiar cholestatic syndromes [ 13-15] and congenital biliary atresia [15-171 has been reported in childhood. There are only two case reports on hepatocellular carcinoma associated with arteriohepatic dysplasia, one in a child [ 181 and one in an adult [ 191. We report the clinical and pathological findings including examination of the eyes in a 4%-year-old girl with classical Alagille’s syndrome, who developed hepatocellular carcinoma in association with extrahepatic biliary atresia.
First child to healthy unrelated parents born at term but small-for-gestational age (SGA), following normal pregnancy and delivery. Birth weight: 2,600 g. She needed intensive care for 2 months because of ventilation problems. When pericarditis and progressive jaundice developed, the level of conjugated hyperbilirubinemia was found constantly about 200 pmol/liter (normal < 20 pmol/liter). The elevated level of serum bile acids about 200 pmol/liter (normal < 8 pmol/liter) was responsible for itching. She had a systolic ejection heart murmur and echocardiographic findings were consistent with pulmonic valvular stenosis. The girl had an unusual appearance: the face had a prominent forehead, pointed chin, hypertelorism, and a flattened malar eminence. The following skeletal abnormalities were found: butterfly vertebrae (Th V-IX) and 11 ribs bilaterally, no increase
0 1992 Wiley-Liss, Inc.
From the Department of Pediatrics (A.N.B., S.C., T . W . ) andclinical Pathology (I.H.), University Hospital, Lund, Sweden; and the Eye Pathology Institute, The University of Copenhagen, Copenhagen, Denmark (0.A. J .) . Received October 29, 1990; accepted May 23, 1991 Address reprint requests to Dr. Albert N. Btkassy, Department of Pediatrics, University Hospital, S-221 85 Lund, Sweden. Abbreviations: AFP, u-fetoprotein; HE, hematoxylin-eosin; SGA, small-for-gestational age.
Hepatocellular Carcinoma Associated With Arteriohepatic Dysplasia
79
Fig. 1. Development into cirrhosis. (A) Primary liver biopsy, enlarged portal tract with inflammatory cells, and small bile ducts (arrowhead). Bile pigment in periportal hepatocytes (arrow). HE, X250. (B) Second liver biopsy 2’/2years later. Reticulin stain discloses thecirrhosis. No bile ducts present. HE, X50.
of the peduncular distance, and a short ulna. Ophthalmological examination revealed posterior embryotoxon and retinal pigmentary abnormalities. Since all findings were consistent with Alagille’s syndrome, surgical exploration was not performed. Percutaneous liver biopsy at three months of age showed cholestasis and portal inflammation (Fig. 1A). On subsequent biopsy 2% years later, development of cirrhosis with a paucity of bile ducts (Fig. 1B) was observed. The girl developed normally. She was icteric with itching and failed to gain weight. Oral A, D, E, and K vitamin supplementation was maintained. Cholestyramin treatment of itching failed because of her bad compliance. Progressive splenomegaly occurred at the age of 3% years. On abdominal ultrasound examination obstruction of the left portal vein was discovered. Three months later life-threatening upper gastrointestinal hemorrhages occurred necessitating large blood replacement and vasopressin administration. Advanced esophageal and grade I11 fundus varices were found on emergency gastric
endoscopy. The site and the origin of the bleeding could not be identified. Large, moderately polymorphic hepatocytes were found on a fine needle aspirate from a palpable node 5 X 5 cm in the enlarged right liver lobe (Fig. 3A). This was interpreted to be consistent with regeneration in a cirrhotic nodule. Profuse upper gastrointestinal bleedings reoccurred. Ascites and enlarged veins of the abdominal wall developed. The large spleen dipped toward the pubis. Coeliac and superior mesenteric arteriography showed thrombosis of the left portal vein and hepatofugal blood stream. Laboratory investigations showed normal blood chemistry, a stable level of conjugated bilirubin about 200 kmol/liter, and the level of total bile acids increased from 200 to 300 pmol/liter. Serum aminotransferases and alkaline phosphatase were elevated. Serology including examination for herpes simplex, hepatitis, CMV, and Toxoplasmosis was negative. Serum ar-fetoprotein level (s-AFP) was extremly high measuring 927.300 ng/ml (normal
Hepatocellular Carcinoma Associated With Arteriohepatic Dysplasia in a 4-Year-Old Girl Albert N. BCkdssy, MD, MSc, Stanislaw Carwicz, MD, PhD, Thomas Wiebe, MD, PhD, lnga Hagerstrand, MD, PhD, and Ove A. Jensen, MD, PhD Hepatocellular carcinoma and obliterated hepatic bile duct were found at postmortem examination in a 4-year-old girl with arteriohepatic dysplasia (Alagille’s syndrome). AFP level was extremely high. Liver cirrhosis was present on percutaneous nee-
dle biopsy 9 months before she succumbed in progressive liver failure. Episodes of repeated gastrointestinal, life-threatening hemorrhages occurred during the last 6 months of her life. Histopathologic findings of the eyes were documented at autopsy.
Key words: Alagille’s syndrome, child, hepatic carcinoma, liver cirrhosis, biliary atresia, autopsy, histopathology, eyes, liver, AFP
INTRODUCTION
CASE REPORT
Arteriohepatic dysplasia or Alagille’s syndrome was first described by Porter et al. in 1968 [I]. Alagille et al. in 1969 reported the association of hepatic ductular hypoplasia, facial features, pulmonary arterial stenosis, vertebral arch defects, and various abnormalities as a homogeneous, readily recognizable syndrome [2,3]. Somewhat later Watson and Miller described similar abnormalities in two or more members in each of five unrelated families. They named the syndrome arteriohepatic dysplasia [4].Riely et al. added anterior chamber and retinal pigmentary abnormalities of the eyes as hallmarks of this syndrome [5]. The prognosis of the syndrome, judged from about 100 reported cases, seems more favourable than in juvenile chronic cholestasis of other types. Patients with Alagille’s syndrome do usually not develop liver failure [&lo], but death due to cirrhosis occurred 111,121 in some cases. Hepatocellular carcinoma associated with familiar cholestatic syndromes [ 13-15] and congenital biliary atresia [15-171 has been reported in childhood. There are only two case reports on hepatocellular carcinoma associated with arteriohepatic dysplasia, one in a child [ 181 and one in an adult [ 191. We report the clinical and pathological findings including examination of the eyes in a 4%-year-old girl with classical Alagille’s syndrome, who developed hepatocellular carcinoma in association with extrahepatic biliary atresia.
First child to healthy unrelated parents born at term but small-for-gestational age (SGA), following normal pregnancy and delivery. Birth weight: 2,600 g. She needed intensive care for 2 months because of ventilation problems. When pericarditis and progressive jaundice developed, the level of conjugated hyperbilirubinemia was found constantly about 200 pmol/liter (normal < 20 pmol/liter). The elevated level of serum bile acids about 200 pmol/liter (normal < 8 pmol/liter) was responsible for itching. She had a systolic ejection heart murmur and echocardiographic findings were consistent with pulmonic valvular stenosis. The girl had an unusual appearance: the face had a prominent forehead, pointed chin, hypertelorism, and a flattened malar eminence. The following skeletal abnormalities were found: butterfly vertebrae (Th V-IX) and 11 ribs bilaterally, no increase
0 1992 Wiley-Liss, Inc.
From the Department of Pediatrics (A.N.B., S.C., T . W . ) andclinical Pathology (I.H.), University Hospital, Lund, Sweden; and the Eye Pathology Institute, The University of Copenhagen, Copenhagen, Denmark (0.A. J .) . Received October 29, 1990; accepted May 23, 1991 Address reprint requests to Dr. Albert N. Btkassy, Department of Pediatrics, University Hospital, S-221 85 Lund, Sweden. Abbreviations: AFP, u-fetoprotein; HE, hematoxylin-eosin; SGA, small-for-gestational age.
Hepatocellular Carcinoma Associated With Arteriohepatic Dysplasia
79
Fig. 1. Development into cirrhosis. (A) Primary liver biopsy, enlarged portal tract with inflammatory cells, and small bile ducts (arrowhead). Bile pigment in periportal hepatocytes (arrow). HE, X250. (B) Second liver biopsy 2’/2years later. Reticulin stain discloses thecirrhosis. No bile ducts present. HE, X50.
of the peduncular distance, and a short ulna. Ophthalmological examination revealed posterior embryotoxon and retinal pigmentary abnormalities. Since all findings were consistent with Alagille’s syndrome, surgical exploration was not performed. Percutaneous liver biopsy at three months of age showed cholestasis and portal inflammation (Fig. 1A). On subsequent biopsy 2% years later, development of cirrhosis with a paucity of bile ducts (Fig. 1B) was observed. The girl developed normally. She was icteric with itching and failed to gain weight. Oral A, D, E, and K vitamin supplementation was maintained. Cholestyramin treatment of itching failed because of her bad compliance. Progressive splenomegaly occurred at the age of 3% years. On abdominal ultrasound examination obstruction of the left portal vein was discovered. Three months later life-threatening upper gastrointestinal hemorrhages occurred necessitating large blood replacement and vasopressin administration. Advanced esophageal and grade I11 fundus varices were found on emergency gastric
endoscopy. The site and the origin of the bleeding could not be identified. Large, moderately polymorphic hepatocytes were found on a fine needle aspirate from a palpable node 5 X 5 cm in the enlarged right liver lobe (Fig. 3A). This was interpreted to be consistent with regeneration in a cirrhotic nodule. Profuse upper gastrointestinal bleedings reoccurred. Ascites and enlarged veins of the abdominal wall developed. The large spleen dipped toward the pubis. Coeliac and superior mesenteric arteriography showed thrombosis of the left portal vein and hepatofugal blood stream. Laboratory investigations showed normal blood chemistry, a stable level of conjugated bilirubin about 200 kmol/liter, and the level of total bile acids increased from 200 to 300 pmol/liter. Serum aminotransferases and alkaline phosphatase were elevated. Serology including examination for herpes simplex, hepatitis, CMV, and Toxoplasmosis was negative. Serum ar-fetoprotein level (s-AFP) was extremly high measuring 927.300 ng/ml (normal
