Hepatoma in a Child With Neurofibromatosis
Lawrence J. Ettinger, MD, Arnold I. Freeman, MD
· A 6-year-old girl had neurofibromato- sis and hepatocellular carcinoma (hepa- toma). Although neurofibromatosis is a common disorder, hepatic cancers are rare in childhood. Hepatic cancer, Wilms’ tumor, and adrenocortical neoplasia are all seen with increased frequency in asso- ciation with certain congenital anomalies, particularly with hemihypertrophy and various hamartomas. Neurofibromatosis, a hamartomatous disorder, is also seen with these congenital anomalies and it is reported with an unusually high incidence in patients with Wilms’ tumor. We there- fore suggest that these disorders may be related.
(Am J Dis Child 133:528-531, 1979)
A though primary hepatic cancers are rare in childhood, neverthe- less they are the third most frequent abdominal solid tumor in children. Only Wilms’ tumor and neuroblasto- ma are seen more commonly than hepatic cancers.1.2 It is theorized that the etiology of these tumors is related to liver disease and/or to metabolic disorders.3-7 Primary hepatic cancer, Wilms’ tumor, and adrenocortical neo-
From the Department of Pediatrics, Roswell Park Memorial Institute, Buffalo. Dr Ettinger is now with the Department of Pediatrics, Univer- sity of Rochester Medical Center, Strong Memo- rial Hospital, Rochester, NY.
Reprint requests to Department of Pediatrics, Roswell Park Memorial Institute, 666 Elm St, Buffalo, NY 14263 (Dr Freeman).
plasia are all associated with certain congenital abnormalities and with hamartomas. As similar associations are seen with neurofibromatosis, it- self a hamartomatous disorder, it has been suggested that hepatoma, Wilms’ tumor, adrenocortical neopla- sia, and neurofibromatosis may all have an etiologic relationship. 8-1.3
In this report, a patient is described who had both hepatocellular carcino- ma and neurofibromatosis, an asso- ciation not previously reported. The possible etiologic basis for this rela- tionship is discussed.
REPORT OF A CASE
A 61/2-year-old girl was referred to the Roswell Park Memorial Institute, Buffalo, in August 1976 for evaluation of hepato- megaly. The hepatomegaly had been noted on an examination after the girl had fallen from her bicycle and suffered a fracture (nonpathological) of her right clavicle. Prior to this, she had had a one-month history of being easily fatigued.
Her medical history showed that numer- ous café au lait spots had developed, begin- ning at the age of 1 year. They increased in size and in number until the time of her death. When she was 11/2 years of age a soft tissue mass developed in her left periorbi- tal and zygomatic regions. The orbit was explored and a portion of the mass excised. The pathological diagnosis of the mass was a nerve sheath myxoma (neurofibroma).
Within a year, this mass increased in size and extended to the left cheek and parotid gland. After a second excision, the patho- logical report was the same. One year later, the tumor again recurred, requiring a third and final excision.
During pregnancy, her mother had taken birth control pills throughout the first trimester and continued to have normal menstrual periods throughout the entire pregnancy. The kind of birth control pills taken by the mother could not be deter- mine by us.
There was no family history of neurofi- bromatosis or of liver disease. A maternal uncle had had basal cell carcinoma, a maternal grandaunt had died of breast cancer, and another had had rectal cancer. The patient’s two siblings and her mother were examined and manifested no stigma- ta of either neurofibromatosis or liver disease. The father and his family were unavailable for examination.
On admission, the girl was a thin, pale child with a protuberant abdomen. She did not have hemihypertrophy, hemangiomas, or lipomas. Her previous periorbital sur- gery had produced a deformity of the left eyelid. There were nine café au lait spots larger than 1 cm in diameter scattered over her body, with the largest measuring 1 x 3 cm. She had bilateral axillary freckling. Her abdomen was protuberant without demonstrable ascites. The liver span was 18 cm and the edge was palpable 13 cm below the right costal margin. It was hard, nodu- lar, and nontender. The spleen was nonpalpable. There was no increased
vascularity of her trunk nor were spider angiomata present.
Diagnosis and Treatment
Investigations included a liver-spleen scan that showed severe hepatomegaly with multiple space-occupying lesions within the liver. The spleen was normal in size and did not show any masses. Chest and skeletal roentgenograms and an intra- venous pyelogram were normal. Celiac angiograms showed multiple small and large, very vascular, mass lesions within the liver. There was a mild microcytic- hypochromic anemia. The initial SGOT level was 483 IU/L (normal, 10 to 40 IU/L); however, this was no higher than twice normal on multiple repeated determina- tions until near her death. At the time of diagnosis, the total serum bilirubin level was 1.9 mg/dL, the alkaline phosphatase level was 202 IU/L (normal, 65 to 210 IU/L), the total protein level was 7.4 g/dL, and the albumin level was 3.7 g/dL. The prothrombin time and the activated partial thromboplastin time were within normal limits. Tests for a-fetoprotein and for carcinoembryonic antigen were both nega- tive. An exploratory laparotomy showed massive replacement of the liver by tumor. Although direct extension of the tumor to the abdominal wall was present, no meta- static disease was noted. Hepatic artery cannulation was not technically feasible, but hepatic artery ligation was performed. The pathological diagnosis was hepatocel- lular carcinoma (hepatoma) of the liver (Fig 1). Underlying liver disease and/or cirrhosis were not present on the biopsy specimen. Review of the biopsy specimens from the periorbital mass confirmed the diagnosis of myxoma of nerve sheath (Fig 2 and 3).
After convalescence from her surgery, the patient was given doxorubicin hydro- chloride (Adriamycin) in courses of 30 mg/ sq m per day for three days to a total cumulative dose of 540 mg/sq m. This resulted in symptomatic improvement and a decrease in the size of the space-occupy- ing lesions seen on liver scan. After this, she was given high-dose methotrexate sodium (100 mg/kg of body weight over six hours) with leucovorin calcium rescue, cis- platinum [cis-dichlorodiammeplatinum (II)], cyclophosphamide (750 mg/sq m on alternate days for a total of 4 doses), and 5-fluorouracil. There was no response, her liver enlarged, and numerous pulmonary metastases developed. Tests for a-fetopro- tein and carcinoembryonic antigen re- mained negative on repeated determina- tions up to her death. She died 12 months after diagnosis. No autopsy was per- formed.
COMMENT
Two major types of hepatic cancer in infants and children have been described, hepatoblastoma and hepa- tocellular carcinoma (hepatoma).1.14-17 Primary hepatic cancer of either type is rare in the pediatric age group,3.4.17-20 although both tumors may be seen throughout childhood. Hepatoblastoma is usually found in children younger than the age of 4
years and hepatocellular carcinoma usually occurs in children older than the age of 6 years.
In a review of the death certificates for all children who died of cancer in the United States between 1960 and 1964, Fraumeni et alª noted that the mortality due to primary hepatic cancer in the 5- to 14-year-old age group was 0.47 per million white popu- lation of this age group per year. In
the 0- to 4-year-old age group, the mortality was more than four times as high and the male-female ratio was 1.3.
In several large groups of pediatric patients in both the United States and abroad, the incidence of primary hepatic cancer in infants and children was between 0.04 and 0.16 per 1,000 hospital admissions.4.17-20 These same reports also indicate that primary hepatic cancer accounts for 1.4% to 5.8% of all pediatric cancer, excluding leukemia.
Several reports describe familial aggregation of hepatocellular carcino- ma21-23 and there is one report of hepa- toblastoma in siblings.24 The specific etiology of the familial occurrences of these unusual tumors is unknown, although the possible relationship to environment, genetics, other underly- ing liver disease, and related anoma- lies has been examined. There is no hereditary pattern of liver cancer that has been identified to our knowl- edge.
Hepatic carcinomas may occur in children with underlying liver dis- eases. Jones” found concomitant non- specific cirrhosis in 6.2% of 128 patients with hepatic carcinomas re- viewed from the literature. Primary liver cancer has also been reported sporadically in patients with giant-cell hepatitis7 and biliary cirrhosis due to biliary atresia.6 Ishak and Glunz,4 in their review of the literature, reported
that primary epithelial hepatic neo- plasms (not necessarily malignant) are frequently associated with un- derlying liver diseases and metabolic disorders. However, as these are only single case reports it is difficult to determine whether there is an asso- ciation between prior hepatic insults and the development of neoplasms. Where cirrhosis is found it may be impossible to determine if the cirrho- sis is due to underlying liver disease or if it is secondary to the tumor. The role of hepatitis, other underlying liver diseases, and metabolic disorders in the development of hepatic neo- plasms is open to conjecture. It is conceivable that the liver in trying to repair itself may undergo malignant change, but proof for this conjecture is yet to be forthcoming.
Primary liver cancer, Wilms’ tumor, and adrenocortical neoplasia may all be associated with certain congenital abnormalities,9-11 especially hemihy- pertrophy. In a review of 282 death certificates and 76 hospital charts of children with primary hepatic cancer, Fraumeni et al3 found two cases with congenital hemihypertrophy and another with segmental hemihyper- trophy. They also found this anomaly in two of 62 children with adrenocor- tical neoplasia and noted an additional four such cases in the literature.9 Hemihypertrophy has also been de- scribed in patients with Wilms’ tumor10.11 and may also be seen with
the visceral cytomegaly syndrome and with various hamartomas, especially pigmented and vascular nevi. It has also been noted that visceral cytomeg- aly affects the same three organs (kid- ney, adrenal cortex, and liver) in which neoplasia develops in associa- tion with hemihypertrophy.
Hamartomas, in turn, occur exces- sively in patients with Wilms’ tumor, adrenocortical neoplasia, and hepatic tumors.3.9-11 For example, seven of 62 patients with adrenocortical neoplasia also demonstrated multiple cavernous angiomas, hemangiomas, large or ex- tensive pigmented nevi, lipomas, and extensive café au lait spots.9 In patients with Wilms’ tumor, hamarto- mas of the liver have also been seen along with widespread pigmented and vascular nevi, lipomas, and intestinal polyposis.1º Extensive hemangiomas have been seen in patients with hepat- ic cancer.3
Several patients have been reported who have both one of the aforemen- tioned neoplasms and an abnormality of the kidney, liver, or adrenal cortex. For example, patients with adrenocor- tical neoplasms have been seen in whom the contralateral adrenal gland was either hypertrophied (one of 62 patients) or had multiple cortical nodules (one of 62), or was absent (one of 62).9 Fraumeni and Miller® also found in the literature an additional seven cases with congenital agenesis of the contralateral adrenal gland. Five of the 62 patients reviewed had various urinary tract anomalies, in- cluding polycystic kidney disease, hy- poplastic kidney, and duplication of the upper urinary tract. Fraumeni et al3 noted one child who had Wilms’ tumor concomitantly with liver neo- plasia and another child who had agenesis of the adrenal gland. Still another patient was found to have a hepatoma, bilateral nephromegaly, and segmental hemihypertrophy. Fur- thermore, one patient with congenital hemihypertrophy had a virilizing adrenocortical adenoma at 8 months of age and had a Wilms’ tumor five years later,12 whereas another patient has been described with hepatoblasto- ma and congenital absence of the kidney and ureter.’
Neurofibromatosis is a hamartoma-
tous disorder of neural crest deriva- tion that is inherited as an autosomal dominant trait with variable pene- trance. However, there is also a very high rate of genetic mutation account- ing for patients with this syndrome who have no known familial pattern of inheritance. Neurofibromatosis, which occurs with a frequency of one case per 2,500 to 3,300 births, is char- acterized by multiple areas of pigmen- tation associated with overgrowth of nerve sheath and fibrous tissue ele- ments. In an extensive review,8 it was noted that 13% of patients have hemi- hypertrophy, but that there are no
1. Miller RW: Fifty-two forms of childhood cancer: United States mortality experience, 1960- 1966. J Pediatr 75:685-689, 1969.
2. Myers MH, Young JL Jr, Silverberg E, et al: Cancer incidence survival and mortality for chil- dren under 15 years of age. Professional Educa- tion Publication No. 3022. Am Cancer Soc, 1974.
3. Fraumeni JF Jr, Miller RW, Hill JA: Primary carcinoma of the liver in childhood: An epidemiologic study. J Natl Cancer Inst 40:1087- 1099, 1968.
4. Ishak KG, Glunz PR: Hepatoblastoma and hepatocarcinoma in infancy and childhood. Can- cer 20:396-422, 1967.
5. Jones E: Primary carcinoma of the liver with associated cirrhosis in infants and children. Arch Pathol 70:5-12, 1960.
6. Okuyama K: Primary liver cell carcinoma associated with biliary cirrhosis due to congenital bile duct atresia. J Pediatr 67:89-93, 1965.
7. Roth D, Duncan PA: Primary carcinoma of the liver after giant-cell hepatitis of infancy. Cancer 8:986-991, 1955.
8. Fienman NL, Yakovac WC: Neurofibroma- tosis in childhood. J Pediatr 76:339-346, 1970.
9. Fraumeni JF Jr, Miller RW: Adrenocortical neoplasms with hemihypertrophy, brain tumors,
cases with concomitant hepatic can- cer, Wilms’ tumor, or adrenocortical neoplasia. In another careful review of primary liver cancer in children, no cases of neurofibromatosis were not- ed.3 However, in a large group of patients with Wilms’ tumor, there was an unusually high incidence of neuro- fibromatosis.13 Although no clear-cut etiologic relationship between Wilms’ tumor and neurofibromatosis could be found, the multiplicity of shared lesions, such as dominant inheritance, high penetrance of genetic effect, high mutation rate, and congenital abnormalities, such as hemihypertro-
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This investigation was supported in part by grant CA07918 from the National Cancer Insti- tute, the Department of Health, Education, and Welfare, and the Association for the Research of Childhood Cancer.
Lenore Englander, MD, assisted with the path- ological specimens, Ataf Sayed, MB, assisted in the preparation of the manuscript, and Robert Miller, MD, and Robin Bannerman, MD, reviewed the manuscript.
Nonproprietary Name and Trademarks of Drug
Doxorubicin hydrochloride-Adriamycin, Doxy-II.
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