Pancreatic Tumors in Children: Radiologic-Pathologic Correlation

Appendix E1: Molecular Genetics

Pancreatoblastoma

Pancreatoblastomas have recently been found to have genetic alterations in common with certain heritable conditions and acinar cell carcinoma and distinct from those of ductal cell adenocarcinoma. Because of the occasional occurrence of pancreatoblastoma in patients with Beckwith-Wiedemann syndrome and familial adenomatous polyposis coli (FAP), and because both are genetic conditions associated with a high risk of development of neoplasms, pancreatoblastoma has been studied for related genetic alterations. Beckwith-Wiedemann syndrome is associated with dysregulation of cell-cycle genes on chromosome 11p15.5. FAP is caused by a germ-line mutation of the adenomatous polyposis coli (APC) gene on chromosome 5q.

Early studies have revealed a high frequency of allelic loss on chromosome 11p and mutations involving the APC/ß-catenin pathway in pancreatoblastoma. Abraham et al (1), in a study of seven pancreatoblastomas, found allelic loss on chromosome 11p15 in 86% of cases, strong nuclear and cytoplasmic accumulation of ß-catenin protein in 78% of cases, and mutations in the ß-catenin gene in 64% of cases. These alterations have also been found to a lesser degree in acinar cell carcinomas. In addition, no alterations were noted in the K-ras oncogene or in p53 tumor suppressor gene expression, which, respectively, are seen in more than 90% and 70% of ductal adenocarcinomas (1,2). These cytogenetic characteristics can aid in the pathologic diagnosis of pancreatoblastoma.

Solid-Pseudopapillary Tumor

Recent molecular studies of solid-pseudopapillary tumor reveal that the tumor is similar to tumors originating in acinar cells and distinct from ductal cell adenocarcinoma in that it demonstrates ß-catenin mutations but not the K-ras, p53, and DPC4 mutations seen in ductal adenocarcinomas (3).

Persistent Hyperinsulinemic Hypoglycemia of Infancy

All familial cases of persistent hyperinsulinemic hypoglycemia of infancy are of the diffuse form, caused by constitutional genetic abnormalities (4). The genetic abnormality is present throughout the pancreas and in the peripheral blood. Most cases are due to an autosomal recessive inheritance pattern, but an autosomal dominant form also exists. In the autosomal recessive forms, any of a number of mutations of one of two genes on chromosome 11p15 renders the adenosine triphosphate–sensitive potassium pump of the ß-cell potassium channel nonfunctional, leading to unregulated release of insulin (5). Patients in these families present in the neonatal period with severe hypoglycemia resistant to diazoxide therapy and invariably require surgery (6). The associated pathologic abnormality is diffuse adenomatosis.

Autosomal dominant forms are caused by mutations in the gene coding for the ß-cell enzyme glucokinase (7) or a defect in the glutamate dehydrogenase gene with associated hyperammonemia (8). These patients have a more variable presentation, milder symptoms, and a clinical response to diazoxide. They usually do not require surgery, so the pathologic findings are largely unknown (5,6). Despite recent advances in the understanding of the genetics of this disease, the precise genetic defect remains unknown in approximately half of patients.

The focal or tumoral form is caused by various somatic mutations of genes on chromosome 11p15 that regulate ß-cell growth (9,10). The genetic abnormality is limited to a focal pancreatic mass and is absent from the remainder of the pancreas and peripheral blood. The result is a focal hyperplastic lesion composed of hypersecreting cells.

Acinar Cell Carcinoma

Acinar cell carcinomas are genetically distinct from ductal adenocarcinomas. Evaluation of acinar cell carcinomas for abnormal expression of p53 and DPC4 protein and for the presence of a mutation of codon 12 of the K-ras oncogene yielded negative results; however, nearly all ductal adenocarcinomas demonstrate inactivation of the DPC4 and p53 tumor-suppressor gene and activation of the K-ras oncogene (2,11,12).

Acinar cell carcinomas do show molecular alterations that overlap with those of pancreatoblastoma. Allelic loss on chromosome 11p is the most common genetic alteration, found in half of acinar cell carcinomas. Molecular alterations in the APC/ß-catenin pathway have also been found in 23.5% of acinar cell carcinomas, most commonly truncating APC mutations and, less frequently, activating APC mutations. These alterations are also found in pancreatoblastomas, but at a higher frequency (2).

References

1. Abraham SC, Wu TT, Klimstra DS, et al. Distinctive molecular genetic alterations in sporadic and familial adenomatous polyposis-associated pancreatoblastomas: frequent alterations in the APC/beta-catenin pathway and chromosome 11p. Am J Pathol 2001;159(5):1619-1627.

2. Abraham SC, Wu TT, Hruban RH, et al. Genetic and immunohistochemical analysis of pancreatic acinar cell carcinoma: frequent allelic loss on chromosome 11p and alterations in the APC/beta-catenin pathway. Am J Pathol 2002;160(3):953-962.

3. Abraham SC, Klimstra DS, Wilentz RE, et al. Solid-pseudopapillary tumors of the pancreas are genetically distinct from pancreatic ductal adenocarcinomas and almost always harbor beta-catenin mutations. Am J Pathol 2002;160(4):1361-1369.

4. Solcia E, Capella C, Kl�ppel G. Atlas of tumor pathology: tumors of the pancreas. Washington, DC: Armed Forces Institute of Pathology, 1997.

5. Glaser B, Thornton P, Otonkoski T, Junien C. Genetics of neonatal hyperinsulinism. Arch Dis Child Fetal Neonatal Ed 2000;82(2):F79-F86.

6. Jaffe R. The pancreas. In: Stocker J, Dehner L, eds. Pediatric pathology. 2nd ed. Philadelphia, Pa: Lippincott Williams & Wilkins, 2002; 797-834.

7. Glaser B, Kesavan P, Heyman M, et al. Familial hyperinsulinism caused by an activating glucokinase mutation. N Engl J Med 1998;338(4):226-230.

8. Stanley CA, Lieu YK, Hsu BY, et al. Hyperinsulinism and hyperammonemia in infants with regulatory mutations of the glutamate dehydrogenase gene. N Engl J Med 1998;338(19):1352-1357.

9. Fournet JC, Mayaud C, de Lonlay P, et al. Unbalanced expression of 11p15 imprinted genes in focal forms of congenital hyperinsulinism: association with a reduction to homozygosity of a mutation in ABCC8 or KCNJ11. Am J Pathol 2001;158(6):2177-2184.

10. de Lonlay P, Fournet JC, Rahier J, et al. Somatic deletion of the imprinted 11p15 region in sporadic persistent hyperinsulinemic hypoglycemia of infancy is specific of focal adenomatous hyperplasia and endorses partial pancreatectomy. J Clin Invest 1997;100(4):802-807.

11. Morohoshi T, Kanda M, Horie A, et al. Immunocytochemical markers of uncommon pancreatic tumors: acinar cell carcinoma, pancreatoblastoma, and solid cystic (papillary-cystic) tumor. Cancer 1987;59(4):739-747.

12. Hoorens A, Lemoine NR, McLellan E, et al. Pancreatic acinar cell carcinoma: an analysis of cell lineage markers, p53 expression, and Ki-ras mutation. Am J Pathol 1993;143(3):685-698.

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