American Journal of Medical Genetics 43:1023-1025 (1992)
Risk of Hepatoblastoma in Familial Adenomatous Polyposis Linda J. Hughes and Virginia V. Michels Visiting Mayo Medical School Clerkship (L.J.H.), the University of Health Sciences, College of Osteopathic Medicine, Kansas City, Missouri; Department of Medical Genetics (V.V.M.),Mayo Clinic, Rochester, Minnesota Infantile and childhood hepatoblastoma occurs more frequently in persons heterozygous for the familial adenomatous polyposis (FAP) gene than in the general population. This observation is based on numerous case reports plus the results of an international survey of FAP registries. However, the frequency of this rare tumor in FAP patients is unknown. In a retrospective review of our family history data, 2/470 (0.42%)children born to 241 patients with FAP had hepatoblastoma. This figure is significantly higher than the 1/100,000 incidence of hepatoblastoma in the general population. However, for genetic counseling purposes, an empiric risk of 4% for hepatoblastoma can be cited to persons with FAP for their children. o 1992 Wiley-Liss, Inc.
KEY WORDS: infantile hepatoblastoma, familial adenomatous polyposis, liver cancer INTRODUCTION In addition to colon cancer, familial adenomatous polyposis (FAP) has been associated with various other neoplasms of the thyroid, ovaries, adrenals, duodenum, Ampulla of Vater, and central nervous system [Plail et al., 1987; Kropilak et al., 19891. In addition, there have been several reports of patients with hepatoblastoma whose ancestors had FAP [Kingston et al., 1983; Krush et al., 19881 or who later developed adenomatous polyposis themselves [Li et al., 1987; Garber et al., 1988; Toyama and Wagner, 19901. It has been suggested that the incidence of FAP in the ancestry of hepatoblastoma patients is approximately 100 times that of the general population [Kingston et al., 19831. In an international survey of 25 FAP registries, 11cases of hepatoblastoma were found [Garber et al., 19881.However, the frequency Received for publication September 30, 1991; revision received January 9, 1992. Address reprint requests to Dr. Virginia V. Michels, Department of Medical Genetics, Mayo Clinic, Rochester, MN 55905.
0 1992 Wiley-Liss, Inc.
of hepatoblastoma among children of FAP patients has not been determined previously. Therefore we reviewed the family history data on 242 FAP patients known to our Department of Medical Genetics t o determine the frequency of hepatoblastoma in their children.
CLINICAL REPORTS Family 1 The index patient (Fig. 11, 11-3, presented at age 57 years because of abdominal pain and nausea. He had had a total colectomy for FAP a t age 30 years. A duodenal polyp was removed surgically and was shown to be a tubular villous adenoma with moderate atypia. Multiple additional tiny polyps were present in the duodenum and gastric fundus. Three years later, the patient died of duodenal adenocarcinoma. His sister (11-1)was diagnosed with FAP at age 26 years, and subsequently his daughter (111-2) and niece (111-1) were found to be affected. His son, (111-3)had presented to this institution at age 5.5 months in 1958 with an abdominal mass, 6 years prior to the diagnosis of FAP in this family. Abdominal exploration showed almost complete replacement of the right lobe of the liver by tumor, and wedge biopsy showed grade 4 small cell carcinoma. The patient subsequently was treated with radiotherapy and died a t age 8 months. Autopsy documented primary hepatic carcinoma, with metastases to the lung, pleura, and abdominal lymph nodes. When the histological material was reviewed, findings were consistent with anaplastic hepatoblastoma. This patient had been reported to the authors of the international survey [Garber et al., 19881. Family 2 The index patient (11-2) (Fig. 1)was evaluated at age 24 years because of a history of FAP in her mother (1-1) and brother (11-11, as confirmed by review of outside medical records. The patient had had bright red rectal bleeding, and the diagnosis of FAP was confirmed by colonoscopy which showed hundreds of polyps. Total proctocolectomy was performed, and histology examination confirmed the adenomatous nature of these polyps. Her brother (11-3)had died at 18 months of liver cancer. His records documented that he had had surgery for a primary liver cancer. The histological findings were
Hughes and Michels
1024
Family 1
Family 2 I II
1
21
3
4
1
2
Fig. 1. Pedigrees of 2 families in which hepatoblastoma has ochepatic curred among the children of patients with FAP. 0,FAP; cancer.
m,
consistent with a diagnosis of hepatoblastoma, from which he later died.
METHODS The Department of Medical Genetics a t the Mayo Clinic has records on 140 index patients, 60 males and 80 females, with FAP. All of these patients were examined and interviewed within the Department of Medical Genetics for a complete 3 to 4 generation family history; they will be referred to as Group I patients. A review of the pedigrees documented 121 first degree relatives, 55 males and 66 females, who also had been diagnosed with FAP. Their diagnoses were confirmed by review of medical records, but not all of them were interviewed at the clinic; therefore information regarding their offspring was often obtained from the index patient. These patients will be referred to as Group I1patients. A review of the family histories of the FAP patients was performed to determine the number of children with hepatoblastoma who were born t o Group I and Group I1 patients. The age and gender of each patient and child were noted. RESULTS Group I Ofthe 133 children born to Group I patients, 1(0.75%) case of hepatoblastoma was detected (Family 1).The incidence among male offspring was 1/70 (1.43%).None of the 63 female offspring were affected. Group I1 Of the 337 children born to Group I1 patients, 1 (0.30%)case of hepatoblastoma was detected. The incidence among male offspring was 1/172 (0.58%).None of the 165 female offspring were affected. Thus in Groups I and I1 combined, 2 cases of hepatoblastoma in a total of 470 children (0.42%),were reported. DISCUSSION There have been published reports of at least 30 patients with FAP or a family history of FAP who also had primary liver malignancies, either as an incidental
finding in adults [Zeze et al., 19831 or as symptomatic tumors in infants or young children [Weinberger et al., 1981; Kingston et al., 1983; Li et al., 1987; Krush et al., 1988; Garber et al., 1988;LeSher et al., 1989;Phillips et al., 1989; Toyama and Wagner, 19901. Some of the survivors of childhood liver cancer later developed colonic polyposis [Garber et al., 1988; Krush et al., 19881. There is a t least one family with FAP in which 2 third degree cousins were affected with hepatoblastoma (personal communication, anonymous reviewer). The age range of the patients presenting in childhood with hepatoblastoma, or its counterpart hepatocellular carcinoma which tends t o occur after 3 years of age [Gauthier et al., 19861, was birth to 11.5 years. The median age was 2 years. The male to female ratio of reported childhood cases was 2, the same as for hepatoblastoma in the general population [Phillips et al., 19891. The incidence of hepatoblastoma in the United Kingdom is approximately 1 per 100,000 among children under 15 years of age [Kingston et al., 19831. In the United States the incidence of hepatoblastoma has been reported to be approximately 1 per 1,000,000 population, based on data collected from 9 different populationbased registries over the 10-year period from 1973 to 1982 as part of the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) Program [Young et al., 19861. The results of our study indicate that the incidence of hepatoblastoma in the children of persons affected with FAP could be as high as 0.75%,or 750 to 7,500 times that of the general population. Thus, there is ample evidence of an increased incidence of primary liver malignancies in infants and children who have inherited the gene for FAP. Kingston et al. [19831 concluded that the frequency of FAP in parents of patients with hepatoblastoma was 100 fold that of the general population. However, the risk of hepatic malignancy in children born to patients with FAP was unknown, because literature reports have been based on case reports or tumor registries, which did not specify the total number of FAP patients at risk. If only our Group I patients are considered, for whom the most reliable family history data are available, the frequency of liver cancer in children born to FAP patients may be as high as 0.75%.Although significantly higher than the general population risk of 1 per 100,000-1,000,000, the risk that can be stated for genetic counseling purposes is ~ 1 % . Abdominal enlargement with a right upper quadrant mass is the most common clinical presentation of liver tumors in infancy and early childhood [Stocker and Ishak, 19871. Based on the increased frequency of liver tumors in children born to parents who have FAP, it is recommended that physicians caring for these children be alerted to the need to perform careful abdominal examinations a t regular intervals, particularly in the first 3 years of life. Serum alpha-fetoprotein are elevated in most patients with hepatoblastoma a t the time of diagnosis when a mass is clinically evident. Levels are less frequently elevated in children with hepatocellular carcinoma. Whether or not screening at-risk children by alpha-fetoprotein levels would lead to earlier detection
Hepatoblastoma in Familial Adenomatous Polyposis
1025
Krush AJ, Traboulsi EI, Offerhaus GJA, Maumenee IH, Yardley JH, Levin LS (1988): Hepatoblastoma, pigmented ocular fundus lesions andjaw lesions in Gardner syndrome. Am J Med Genet 29:323-332. LeSher AR, Castronuovo JJ Jr, Filippone AL Jr (1989): Hepatoblastoma in a patient with familial polyposis coli. Surgery 105:668ACKNOWLEDGMENTS 670. We thank Hymie Gordon, M.D., for his work in assem- Li FP, Thurber WA, Seddon J, Holmes GE (1987): Hepatoblastoma in families with polyposis coli. JAMA 257:2475-2477. bling a FAP registry a t the Mayo Clinic and Pamela S. Phillips M, Dicks-Mireaux C, Kingston J , Malone M, Mitchell C, Karnes, M.D., for helpful discussions. Pritchard J , Shafford E, Spitz L (1989): Hepatoblastoma and polyposis coli (familial adenomatous polyposis). Med Pediatr Oncol NOTE ADDED IN PROOF 17:441-447. After submission of this manuscript, a n article ap- Plail RO,Bussey HJR, Glazer G, Thomson JPS (1987): Ademonatous peared (Giardiello et al.: J Pediatr 119: 766-768,1991) polyposis: a n association with carcinoma of the thyroid. Br J Surg 74:377-380. reporting a relative risk for hepatoblastoma of 327.8 per 105 person-years in children from families with FAP. Stocker JT, Ishak KG (1987): Hepatoblastoma. In Okuda K, Ishak KG (eds): “Neoplasms of the Liver.” Tokyo: Springer-Verlag, pp 127136. REFERENCES Toyama WM, Wagner S (1990): Hepatoblastoma with familial polyGarber JE, Li FP, Kingston J E , Krush AJ, Strong LC, Finegold MJ, posis coli: Another case and corrected pedigree (letter to the editor). Bertario L, Bulow S, Filippone A Jr, Gedde-Dahl T Jr, Jarvinen H J Surgery 108:123-124. (1988): Hepatoblastoma and familial adenomatous polyposis. Weinberger JM, Cohen Z, Berk T (1981): Polyposis coli preceded by J Natl Cancer Inst 80:1626-1628. hepatocellular carcinoma: report of a case. Dis Colon Rectum Gauthier F, Valayer J, Le Thai B, Sinico M, Kalifa C (1986): Hepato24:296-300. blastoma and hepatocarcinoma in children: analysis of a series of 29 Young J L Jr, Ries LG, Silverberg E, Horm JW, Miller RW (1986): cases. J Pediatr Surg 21:424-429. Cancer incidence, survival, and mortality for children younger than Kingston JE, Herbert A, Draper GJ, Mann J R (1983): Association age 15 years. Cancer 58:598-602. between hepatoblastoma and polyposis coli. Arch Dis Child 58:959Zeze F, Ohsato K, Mitani H, Ohkuma R, Koide 0 (1983):Hepatocellular 962. carcinoma associated with familial polyposis of the colon: report of a Kropilak M, Jagelman DG, Fazio VW, Lavery IL, McGannon E (1989): case. Dis Colon Rectum 26:465-468. Brain tumors in familial adenomatous polyposis. Dis Colon Rectum 32:778-782.
or improved outcome is unknown. Ultrasound imaging of the liver also could be considered for these infants [Stocker and Ishak, 19871.
Risk of Hepatoblastoma in Familial Adenomatous Polyposis Linda J. Hughes and Virginia V. Michels Visiting Mayo Medical School Clerkship (L.J.H.), the University of Health Sciences, College of Osteopathic Medicine, Kansas City, Missouri; Department of Medical Genetics (V.V.M.),Mayo Clinic, Rochester, Minnesota Infantile and childhood hepatoblastoma occurs more frequently in persons heterozygous for the familial adenomatous polyposis (FAP) gene than in the general population. This observation is based on numerous case reports plus the results of an international survey of FAP registries. However, the frequency of this rare tumor in FAP patients is unknown. In a retrospective review of our family history data, 2/470 (0.42%)children born to 241 patients with FAP had hepatoblastoma. This figure is significantly higher than the 1/100,000 incidence of hepatoblastoma in the general population. However, for genetic counseling purposes, an empiric risk of 4% for hepatoblastoma can be cited to persons with FAP for their children. o 1992 Wiley-Liss, Inc.
KEY WORDS: infantile hepatoblastoma, familial adenomatous polyposis, liver cancer INTRODUCTION In addition to colon cancer, familial adenomatous polyposis (FAP) has been associated with various other neoplasms of the thyroid, ovaries, adrenals, duodenum, Ampulla of Vater, and central nervous system [Plail et al., 1987; Kropilak et al., 19891. In addition, there have been several reports of patients with hepatoblastoma whose ancestors had FAP [Kingston et al., 1983; Krush et al., 19881 or who later developed adenomatous polyposis themselves [Li et al., 1987; Garber et al., 1988; Toyama and Wagner, 19901. It has been suggested that the incidence of FAP in the ancestry of hepatoblastoma patients is approximately 100 times that of the general population [Kingston et al., 19831. In an international survey of 25 FAP registries, 11cases of hepatoblastoma were found [Garber et al., 19881.However, the frequency Received for publication September 30, 1991; revision received January 9, 1992. Address reprint requests to Dr. Virginia V. Michels, Department of Medical Genetics, Mayo Clinic, Rochester, MN 55905.
0 1992 Wiley-Liss, Inc.
of hepatoblastoma among children of FAP patients has not been determined previously. Therefore we reviewed the family history data on 242 FAP patients known to our Department of Medical Genetics t o determine the frequency of hepatoblastoma in their children.
CLINICAL REPORTS Family 1 The index patient (Fig. 11, 11-3, presented at age 57 years because of abdominal pain and nausea. He had had a total colectomy for FAP a t age 30 years. A duodenal polyp was removed surgically and was shown to be a tubular villous adenoma with moderate atypia. Multiple additional tiny polyps were present in the duodenum and gastric fundus. Three years later, the patient died of duodenal adenocarcinoma. His sister (11-1)was diagnosed with FAP at age 26 years, and subsequently his daughter (111-2) and niece (111-1) were found to be affected. His son, (111-3)had presented to this institution at age 5.5 months in 1958 with an abdominal mass, 6 years prior to the diagnosis of FAP in this family. Abdominal exploration showed almost complete replacement of the right lobe of the liver by tumor, and wedge biopsy showed grade 4 small cell carcinoma. The patient subsequently was treated with radiotherapy and died a t age 8 months. Autopsy documented primary hepatic carcinoma, with metastases to the lung, pleura, and abdominal lymph nodes. When the histological material was reviewed, findings were consistent with anaplastic hepatoblastoma. This patient had been reported to the authors of the international survey [Garber et al., 19881. Family 2 The index patient (11-2) (Fig. 1)was evaluated at age 24 years because of a history of FAP in her mother (1-1) and brother (11-11, as confirmed by review of outside medical records. The patient had had bright red rectal bleeding, and the diagnosis of FAP was confirmed by colonoscopy which showed hundreds of polyps. Total proctocolectomy was performed, and histology examination confirmed the adenomatous nature of these polyps. Her brother (11-3)had died at 18 months of liver cancer. His records documented that he had had surgery for a primary liver cancer. The histological findings were
Hughes and Michels
1024
Family 1
Family 2 I II
1
21
3
4
1
2
Fig. 1. Pedigrees of 2 families in which hepatoblastoma has ochepatic curred among the children of patients with FAP. 0,FAP; cancer.
m,
consistent with a diagnosis of hepatoblastoma, from which he later died.
METHODS The Department of Medical Genetics a t the Mayo Clinic has records on 140 index patients, 60 males and 80 females, with FAP. All of these patients were examined and interviewed within the Department of Medical Genetics for a complete 3 to 4 generation family history; they will be referred to as Group I patients. A review of the pedigrees documented 121 first degree relatives, 55 males and 66 females, who also had been diagnosed with FAP. Their diagnoses were confirmed by review of medical records, but not all of them were interviewed at the clinic; therefore information regarding their offspring was often obtained from the index patient. These patients will be referred to as Group I1patients. A review of the family histories of the FAP patients was performed to determine the number of children with hepatoblastoma who were born t o Group I and Group I1 patients. The age and gender of each patient and child were noted. RESULTS Group I Ofthe 133 children born to Group I patients, 1(0.75%) case of hepatoblastoma was detected (Family 1).The incidence among male offspring was 1/70 (1.43%).None of the 63 female offspring were affected. Group I1 Of the 337 children born to Group I1 patients, 1 (0.30%)case of hepatoblastoma was detected. The incidence among male offspring was 1/172 (0.58%).None of the 165 female offspring were affected. Thus in Groups I and I1 combined, 2 cases of hepatoblastoma in a total of 470 children (0.42%),were reported. DISCUSSION There have been published reports of at least 30 patients with FAP or a family history of FAP who also had primary liver malignancies, either as an incidental
finding in adults [Zeze et al., 19831 or as symptomatic tumors in infants or young children [Weinberger et al., 1981; Kingston et al., 1983; Li et al., 1987; Krush et al., 1988; Garber et al., 1988;LeSher et al., 1989;Phillips et al., 1989; Toyama and Wagner, 19901. Some of the survivors of childhood liver cancer later developed colonic polyposis [Garber et al., 1988; Krush et al., 19881. There is a t least one family with FAP in which 2 third degree cousins were affected with hepatoblastoma (personal communication, anonymous reviewer). The age range of the patients presenting in childhood with hepatoblastoma, or its counterpart hepatocellular carcinoma which tends t o occur after 3 years of age [Gauthier et al., 19861, was birth to 11.5 years. The median age was 2 years. The male to female ratio of reported childhood cases was 2, the same as for hepatoblastoma in the general population [Phillips et al., 19891. The incidence of hepatoblastoma in the United Kingdom is approximately 1 per 100,000 among children under 15 years of age [Kingston et al., 19831. In the United States the incidence of hepatoblastoma has been reported to be approximately 1 per 1,000,000 population, based on data collected from 9 different populationbased registries over the 10-year period from 1973 to 1982 as part of the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) Program [Young et al., 19861. The results of our study indicate that the incidence of hepatoblastoma in the children of persons affected with FAP could be as high as 0.75%,or 750 to 7,500 times that of the general population. Thus, there is ample evidence of an increased incidence of primary liver malignancies in infants and children who have inherited the gene for FAP. Kingston et al. [19831 concluded that the frequency of FAP in parents of patients with hepatoblastoma was 100 fold that of the general population. However, the risk of hepatic malignancy in children born to patients with FAP was unknown, because literature reports have been based on case reports or tumor registries, which did not specify the total number of FAP patients at risk. If only our Group I patients are considered, for whom the most reliable family history data are available, the frequency of liver cancer in children born to FAP patients may be as high as 0.75%.Although significantly higher than the general population risk of 1 per 100,000-1,000,000, the risk that can be stated for genetic counseling purposes is ~ 1 % . Abdominal enlargement with a right upper quadrant mass is the most common clinical presentation of liver tumors in infancy and early childhood [Stocker and Ishak, 19871. Based on the increased frequency of liver tumors in children born to parents who have FAP, it is recommended that physicians caring for these children be alerted to the need to perform careful abdominal examinations a t regular intervals, particularly in the first 3 years of life. Serum alpha-fetoprotein are elevated in most patients with hepatoblastoma a t the time of diagnosis when a mass is clinically evident. Levels are less frequently elevated in children with hepatocellular carcinoma. Whether or not screening at-risk children by alpha-fetoprotein levels would lead to earlier detection
Hepatoblastoma in Familial Adenomatous Polyposis
1025
Krush AJ, Traboulsi EI, Offerhaus GJA, Maumenee IH, Yardley JH, Levin LS (1988): Hepatoblastoma, pigmented ocular fundus lesions andjaw lesions in Gardner syndrome. Am J Med Genet 29:323-332. LeSher AR, Castronuovo JJ Jr, Filippone AL Jr (1989): Hepatoblastoma in a patient with familial polyposis coli. Surgery 105:668ACKNOWLEDGMENTS 670. We thank Hymie Gordon, M.D., for his work in assem- Li FP, Thurber WA, Seddon J, Holmes GE (1987): Hepatoblastoma in families with polyposis coli. JAMA 257:2475-2477. bling a FAP registry a t the Mayo Clinic and Pamela S. Phillips M, Dicks-Mireaux C, Kingston J , Malone M, Mitchell C, Karnes, M.D., for helpful discussions. Pritchard J , Shafford E, Spitz L (1989): Hepatoblastoma and polyposis coli (familial adenomatous polyposis). Med Pediatr Oncol NOTE ADDED IN PROOF 17:441-447. After submission of this manuscript, a n article ap- Plail RO,Bussey HJR, Glazer G, Thomson JPS (1987): Ademonatous peared (Giardiello et al.: J Pediatr 119: 766-768,1991) polyposis: a n association with carcinoma of the thyroid. Br J Surg 74:377-380. reporting a relative risk for hepatoblastoma of 327.8 per 105 person-years in children from families with FAP. Stocker JT, Ishak KG (1987): Hepatoblastoma. In Okuda K, Ishak KG (eds): “Neoplasms of the Liver.” Tokyo: Springer-Verlag, pp 127136. REFERENCES Toyama WM, Wagner S (1990): Hepatoblastoma with familial polyGarber JE, Li FP, Kingston J E , Krush AJ, Strong LC, Finegold MJ, posis coli: Another case and corrected pedigree (letter to the editor). Bertario L, Bulow S, Filippone A Jr, Gedde-Dahl T Jr, Jarvinen H J Surgery 108:123-124. (1988): Hepatoblastoma and familial adenomatous polyposis. Weinberger JM, Cohen Z, Berk T (1981): Polyposis coli preceded by J Natl Cancer Inst 80:1626-1628. hepatocellular carcinoma: report of a case. Dis Colon Rectum Gauthier F, Valayer J, Le Thai B, Sinico M, Kalifa C (1986): Hepato24:296-300. blastoma and hepatocarcinoma in children: analysis of a series of 29 Young J L Jr, Ries LG, Silverberg E, Horm JW, Miller RW (1986): cases. J Pediatr Surg 21:424-429. Cancer incidence, survival, and mortality for children younger than Kingston JE, Herbert A, Draper GJ, Mann J R (1983): Association age 15 years. Cancer 58:598-602. between hepatoblastoma and polyposis coli. Arch Dis Child 58:959Zeze F, Ohsato K, Mitani H, Ohkuma R, Koide 0 (1983):Hepatocellular 962. carcinoma associated with familial polyposis of the colon: report of a Kropilak M, Jagelman DG, Fazio VW, Lavery IL, McGannon E (1989): case. Dis Colon Rectum 26:465-468. Brain tumors in familial adenomatous polyposis. Dis Colon Rectum 32:778-782.
or improved outcome is unknown. Ultrasound imaging of the liver also could be considered for these infants [Stocker and Ishak, 19871.
