Clinical and laboratory observations

tional, an exceedingly long time would be required for a single center to accrue a large-enough patient sample (and years at risk) to establish the cancer risk among older patients with CF. Such a follow-up registry should be considered as a project for a multiinstitutional CF patient registry.

REFERENCES 1. McIntosh JC, Schoumacher RA, Tiller RE. Pancreatic adenocarcinoma in a patient with cystic fibrosis. Am J Med 1988;85:592. 2. Davis T, Sawicka EH. Adenocarcinoma in cystic fibrosis. Thorax 1985;40:199-200. 3. Tedeseo F J, Brown R, Schuman BM. Pancreatic carcinoma in a patient with cystic fibrosis. Gastrointest Endosc 1986;32:25-6. 4. Redington AN, Spring R, Batten JC. Adenocarcinoma of the ileum presenting as nontraumatic clostridial myoneerosis in cystic fibrosis. Br Med J 1985;290:1871-2. 5. Siraganian PA, Miller RW, Swender PT. Cystic fibrosis and ileal carcinoma. Lancet 1987;2:1158. 6. Roberts JA, Tullett WM, Thomas J, Galloway D, Stack BHR. Bowel adenocarcinoma in a patient with cystic fibrosis. Scott Med J 1986;31:109.

The Journal of Pediatrics November 1991

7. Abdul-Karim FW, King TA, Dahms BB, Gauderer MWL, Boat TF. Carcinoma of extrahepatic biliary system in an adult with cystic fibrosis. Gastroenterology 1982;82:758-62. 8. Miller RW. Childhood cancer and congenital defects: a study of US death certificates during the period 1960-1966. Pediatr Res 1969;3:389-97. 9. Cole WQ, Pullen J. Cystic fibrosis with acute myelogenous leukemia. In: Cystic Fibrosis Club abstracts. Bethesda, Md.: Cystic Fibrosis Foundation 1970;14:33. 10. Biggs BG, Vaughan W, Colombo JL, Sanger W, Purtilo DT. Cystic fibrosis complicated by acute leukemia. Cancer 1986; 57:2441-3. 11. Moss RB, Blessing-Moore J, Bender SW, Weibel A. Cystic fibrosis and neuroblastoma. Pediatrics 1985;76:814-7. 12. Gorovoy JD. A malignant tumor associated with cystic fibrosis. In: Cystic Fibrosis Club abstracts. Bethesda, Md.: Cystic Fibrosis Foundation 1981;25:117. 13. A1-Jadar LN, West RR, Goodchild MC, Harper PS. Mortality from leukaemia among relatives of patients with cystic fibrosis. Br Med J 1989;298:164. 14. Stead RJ, Redington AN, Hinks LJ, Clayton BE, Hodson ME, Batten JC. Selenium deficiency and possible increased risk of carcinoma in adults with cystic fibrosis. Lancet 1985;ii:862-3. 15. Swinson CM, Slavin G, Coles EC, Booth CC. Coeliac disease and malignancy. Lancet 1983; i: I 11-5.

Risk of hepatoblastoma in familial adenomatous polyposis Francis M. Giardiello, MD, G, Johan A. Offerhaus, MD, MPH,PhD, Anne J. Krush, MS, Susan V, Booker, BA, Anne C. Tersmette, MPH, Jan-Willem R, Mulder, BA, Christopher N, Kelley, BS, and Stanley R, Hamilton, MD From the Departments of Medicine and Pathology and the Oncology Center, Johns Hopkins University School of Medicine and Hospital, Baltimore, Maryland

Familial adenomatous polyposis is an autosomal dominant disorder characterized by the development during adolesSupported in part by the Clayton and McAshan funds and by grant No. CA44555 from the National Institutes of Health, U.S. Department of Health and Human Services; by the Netherlands Organization for Scientific Research and the Netherlands Digestive Disease Foundation (Dr. Offerhaus); by a young faculty award from E. I. DuPont Nemours (Dr. Hamilton); and by award No. 314 from the International Cancer Research Technology Transfer of the International Union Against Cancer (Mr. Mulder). Submitted for publication May 6, 1991; accepted July 2, 1991. Reprint requests: Francis M. Giardiello, MD, Meyerhoff Digestive Disease Center, Blalock 935, Johns Hopkins Hospital, 600 N. Wolfe St., Baltimore, MD 21205. 9/22/32199

cence and young adulthood of hundreds to thousands of coloreetal adenomas. 1 If prophylactic colectomy is not performed, colorectal cancer will develop in virtually all affected individuals by the fifth decade of life. Familial adenomatous polyposis can be associated with extraintestinal lesions (Gardner syndrome) or can occur without extraintestinal manifestations (familial polyposis). FAP

Familial adenomatous polyposis

Hepatoblastoma is a rare malignant embryonat tumor of the liver that occurs in the first few years of life. 2 Recently an association between hepatoblastoma and F A P has been described), 4 The purpose of this study was to investigate

Volume 119 Number 5

Clinical and laboratory observations

7 6"I

T a b l e I. Relative risk of hepatoblastoma in FAP for subjects from birth through 4 years of age with adjustment for race, age, gender, and calendar time Age (yr)


Observed hepatoblastomas (No.)




RR (O/E) 846.92

Rate per 105 person-years

95% Cl 230.4-2168.1


CI, Confidenceinterval;O/E, observed/expectedratio; RR, relativerisk.

T a b l e II. Patients from Johns Hopkins Registry at risk for or affected with FAP in whom hepatoblastoma developed

Patient No.

Age at Dx of hepatoblastoma (yr)



Pedigree dx

1 2 3 4 5 6 7

0.1 0.7 1.4 2.5 3.4 3.8 4.6




Affected parent

Age at Dx of polyposls (yr)

Last contact (age in yr)

Father Mother Father Mother Father Father Father

-13.6 18.0 -----

Dead (0.1) Alive (20.7) Alive (22.0) Dead (5.3) Dead (3.4) Dead (3.8) Dead (6.1)

DX, Diagnosis. *Gardner syndrome(FAP with extraintestinalmanifestations). tFamiliaI polyposls(FAP without extraintestinaImanifestations).

the magnitude of the risk of hepatoblastoma in FAP pedigrees.

METHODS Data were collected from the Johns Hopkins Polyposis Registry, which contains 197 pedigrees with FAP. Information on all registry subjects was obtained through chart review and was subsequently computerized with a dBase III Plus software program (Ashton-Tate, Torrance, Calif.). The diagnosis of hepatoblastoma in the study population was verified by review of the original pathology slides (n = 6) or by report if the original slides were not available (n = 1).

For risk assessment, patients with FAP and their firstdegree relatives were considered at risk for hepatoblastoma from birth through 4 years of age, because hepatoblastoma almost never occurs after the age of 5 years. 2 Observation time was through 4 years of age or until date of last contact, death, date of diagnosis of hepatoblastoma, or closing date of the study. The period for analysis started Jan. 1, 1969, and ended Dec. 3 l, 1987. These dates were chosen because population rates of cancer for comparison were available from Surveillance, Epidemiology, and End Results (SEER) 5 only for this period. Thus three of seven registry patients

with hepatoblastoma diagnosed before 1969 were excluded from relative risk analysis. Person-years at risk were calculated according to gender-, race-, and age-specific categories through 4 years of age during subsequent 5-year calendar periods of observation with the use of a Fortran computer program. 6 We computed the ratio of observed tUmors to the expected number with 95% confidence limits, assuming a Poisson distribution.6, 7 This observed/expected ratio indicated the relative risk and compared the hepatoblastoma incidence in the study population with that in the general population, and is adjusted for race, age, gender, and also calendar time (to account for possible secular trends). RESULTS The person-year analysis covered 1220 person-years of follow-up (Table I). A highly significant relative risk of hepatoblastoma (847-fold) was observed for those affected by and at risk for FAP from birth through 4 years of age. Because of the relatively small number of cases observed, the 95% confidence interval is wide, indicating that the estimate is imprecise. The incidence rate of hepatoblastoma from birth through 4 years of age in the study population was 328 in 100,000 person-years (1/305 person-years). Table II lists the patients with hepatoblastoma in the


Clinical and laboratory observations

Johns Hopkins Registry. The cases of four of these patients (Nos. 1, 2, 5, and 7 in Table I) have been reported previously.4 Hepatoblastoma was diagnosed in all patients before 5 years of age. All patients had one parent with FAP and therefore were at 50% risk for the development of this autosomal dominant disorder. In five of the seven patients, the father was the affected parent. Two patients survived resection of their hepatoblastomas and are still alive; adenomatous polyposis of the large bowel developed in one patient at 18 years of age and in the other patient at 13.6 years of age. Five of the Seven patients died within the first 7 years of life and had no clinical evidence of colorectal polyposis. The absence of adenomatous polyposis in these patients is expected; the average age at diagnosis of adenomas in at-risk individuals is 25 years of age. I Hepatoblast0ma occurred in one family with familial polyposis (patient 6); the six other cases were in families with Gardner syndrome. DISCUSSION In this study the incidence of hepatoblastoma in patients with FAP in a large population-based registry was compared with that in the general population of the United States. A highly significant increased relative risk of hepatoblastoma was found in FAP pedigrees. The risk estimate is conservative because the study population includes unaffected at-risk individuals in the pedigrees, as well as family members who have inherited the polyposis gene. In previous studies 8 linkage of hepatoblastoma to FAP was thought to occur through the affected mother. By contrast, review of 7 current and 33 previously published cases reveals almost equal paternal and maternal linkage. 9 Hepatoblastoma is a rapidly progressive tumor that carries a grave prognosis when the malignancy has spread beyond the point at which surgical resection is feasible.5 However, as demonstrated by our patients 2 and 3 and two additional reported patients,I~ in if the lesion is solitary and sufficiently localized, surgery may be curative. Serum a-fetoprotein levels are elevated in about two thirds of patients with hepatoblastoma. Because of the magnitude of risk of hepatoblastoma (1/305 person-years) and its potential curability, screening with serum c~-fetoprotein levels and possibly computed tomography of the abdomen in infants and young children of parents affected with FAP may be prudent. With the availability of genetic tests and phenotypic markers that are evident early in life, identification of

The Journal of Pediatrics November 1991

neonates who have inherited the gene for potyposis is now p0ssible.4 For example, congenital hypertrophy of the retinal pigment epithelium is a sensitive and specific phenotypic marker for the inheritance of the polyposis gene and can be found by ophthalmoscopic examination in infancy. 4 These patients represent a target group for serum marker and possible radiologic screening in the first 5 years of life. However, definitive recommendations concerning surveillance await prospective investigation of the efficacy of screening tests and cost-benefit analysis. Finally, consideration should be given to examination for colorectal polyposis in parents of patients with hepatoblastoma and in adolescent survivors of this rare tumor.


1. Bussey H JR. Familial adenomatous polyposis toll. Family studies, histopathology, differential diagnosis, and results of treatment. Baltimore: Johns Hopkins University Press, 1975. 2. Lack EE, Neave C, Vawter GF. Hepatoblastoma: a clinical and pathologic study of 54 cases. Am J Surg Pathol 1982;6:693705. 3. Kingston JE, Draper G J, Mann JR. Heptoblastoma and poIyposis coli. Lancet 1982;1:457. 4. Krush AJ, Traboulsi EI, Offerhaus GJA, Maumenee IH, Yardley JH, Levin LS. Hepatoblastoma, pigmented ocular fundus lesions and jaw lesions in Gardner syndrome. Am J Med Genet 1988;29:323-32. 5. Surveillance, Epidemiology, and End Results (SEER) program: public use tape. Bethesda, Md.: National Cancer Institute, DCPC, Surveillance Program, Cancer Statistics Branch, 1990. 6. Coleman M, Doublas A, Hermon C, Peto L. Cohort study analysis with a Fortran computer program. Int J Epidemiol 1986;15:698-703. 7. Breslow NE, Day NE. Statistical methods in cancer research; vol 2. The design and analysis of cohort studies [IARC scientific publications No. 82]. Lyons, France: International Agency for Research on Cancer, 1987. 8. Kingston JE, Herbert A, Draper G J, Mann JR. Association between hepatoblastoma and polyposis coll. Arch Dis Child 1983;58:959-62. 9. Garber JE, Li FP, Kingston JE, et al. Hepatoblastoma and familial adenomatous polyposis. J Natl Cancer Inst 1988; 80:1626-8. 10. Li FP, Thurber WA, Seddon J, Holmes GE, Hepatoblastoma in families with polyposis coll. JAMA 1987;257:2475-7. 11. LeSher AR, Castronuovo JJ Jr, Filipone AL Jr. Hepatoblastoms in a patient with familial polyposis coll. Surgery 1989; 105:668-70.

Risk of hepatoblastoma in familial adenomatous polyposis.

766 Clinical and laboratory observations tional, an exceedingly long time would be required for a single center to accrue a large-enough patient sam...
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