Journal of Pediatric Hematology/Oncology:
Management of Pancreatoblastoma in Children and Young Adults
Glick, Richard D. MD*; Pashankar, Farzana D. MD†; Pappo, Alberto MD‡; LaQuaglia, Michael P. MD§
*Steven and Alexandra Cohen Children’s Medical Center, Hofstra North Shore-LIJ School of Medicine, New Hyde Park
§Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY
†Yale University School of Medicine, New Haven, CT
‡St Jude Children’s Research Hospital, Memphis, TN
The authors declare no conflict of interest.
Reprints: Richard D. Glick, MD, Steven and Alexandra Cohen Children’s Medical Center, Hofstra North Shore-LIJ School of Medicine, 269-01 76th Avenue; Room 158, New Hyde Park, NY 11040 (e-mail: email@example.com).
Received January 23, 2012
Accepted February 1, 2012
Pancreatoblastoma is a very rare childhood tumor originating from the epithelial exocrine cells of the pancreas. It is the most common malignant pancreatic tumor in young children and has a mean age of diagnosis of 5 years. It is slow growing and its presentation is varied and often non-specific. Tumors tend to be quite large and appropriate cross sectional imaging is very important to assess for extent, metastatic disease, and resectability. Biopsy for tissue diagnosis is essential. Complete surgical resection is the goal of therapy although many patients are unresectable at initial diagnosis and require neoadjuvant chemotherapy. Adjuvant chemotherapy is also recommended and chemotherapeutic regimens involve cisplatin and doxorubicin. Even with curative resections, these lesions have a high recurrence rate and patients must be followed closely. Knowledge of this rare tumor is important for the clinician confronted with a large retroperitoneal mass in a young child.
Malignant pancreatic tumors are rare in children and adolescents,1–3 and include several kinds of cancers grouped by their histologic origin. Primary pancreatic tumors include exocrine epithelial/nonepithelial and endocrine tumors. Exocrine epithelial tumors of the pancreas include adenocarcinoma, adenosquamous carcinoma, acinar cell carcinoma, solid pseudopapillary tumor, and pancreatoblastomas. Nonepithelial tumors include liposarcomas, lymphomas, and teratomas. Endocrine tumors include malignant insulinomas, glucagonomas, and gastrinomas.3–5
Pancreatoblastomas are the most common malignant pancreatic tumors occurring in young children.4–6 Before the coining of the term pancreatoblastoma in 1977, these tumors were described as “infantile carcinoma of the pancreas” or “juvenile adenocarcinoma of the pancreas.”7 Pancreatoblastoma typically affects patients between the ages of 1 and 8 years, with a mean age of 5 years. It has been reported in other age groups, including neonates and the elderly. There is a slight preponderance in men (male:female ratio of 1.14:1) and in patients of Asian descent.8–13 With just over 70 cases reported in the literature, most as isolated cases, pancreatoblastoma is reported to have a very low incidence with a frequency of <1%: reportedly 0.5% of all pancreatic nonendocrine tumors. From 1973 to 2006, 69 patients under 20 years of age were registered in the North American population-based Surveillance, Epidemiology, and End Results database with a diagnosis of tumor arising from the pancreas.
A variety of different histotypes were registered, including 12 cases of pancreatoblastoma, 32 of carcinoma (with various subtypes), and 6 endocrine tumors. According to the Surveillance, Epidemiology, and End Results data, the estimated age-adjusted annual incidence of pancreatic tumors in 0- to 19-year-olds is 0.191 per million population.14,15 A recent report from the Tumori Rari in Eta’ Pediatrica project registered 21 patients younger than 18 years with pancreatic tumors, between January 2000 and July 2009. The tumor types were 4 pancreatoblastomas, 2 pancreatic carcinomas, 3 neoplasms of the endocrine pancreas, and 12 solid pseudopapillary tumors.3 The Office of Rare Diseases of the National Institute of Health lists it as a “rare disease.”1,16 Pancreatoblastoma has been associated with Beckwith-Wiedemann and Familial Adenomatous Polyposis syndromes. Genetic alterations include a high frequency of allelic loss on chromosome 11p15 and mutations in adenomatous polyposis coli/β-catenin pathways.17 Genetic predisposition has been demonstrated by other researchers.18 Kerr et al,19 in a study of 2 cases of pancreatoblastoma, had similar findings of allelic loss on chromosome 11p15.5.
Although not completely clear, pancreatoblastomas are thought to arise from the persistence of the fetal anlage of pancreatic acinar cells during the eighth week of embryonic development. These tumors can develop in any part of the pancreas, but commonly affect the head. Horie et al7 divided pancreatoblastoma, on the basis of the site of origin, into 2 categories: the ventral anlage/right-sided tumors and the dorsal anlage/left-sided tumors. Right-sided tumors have been noted to have no islet cells, no calcifications, and are thought to have a generally better prognosis. Left-sided tumors exhibit calcifications, contain islet cells, and have a poorer prognosis than their right-sided counterparts. More relevant literature is available.8,18 Several similarities exist between pancreatoblastoma and hepatoblastoma. They occur in similar age groups, both are associated with the Beckwith-Wiedemann syndrome,19 and both often express high levels of the tumor marker α-fetoprotein (AFP).18–21 Pancreatoblastomas are also able to secrete active hormones and have been associated with Cushing syndrome.22
This rare tumor indeed presents both diagnostic and therapeutic challenges to oncologists and surgeons. It is for these reasons that it has been included in this registry as a rare tumor requiring further studies, the goal being to optimize the care and outcome of this unusual pediatric cancer.
The presentation of pancreatic tumors in children is varied, and can be nonspecific. Pancreatoblastomas are slow growing and are often clinically occult until quite large, and symptoms may thus be because of a mass effect in the upper abdomen. Children may present with a large abdominal mass, abdominal distension, upper abdominal pain, and failure to thrive. Jaundice occurs less commonly in children than in adults with pancreatic tumors.21,23,24 It may be difficult to distinguish pancreatoblastoma from other pediatric abdominal masses, especially when the tumors are large and their site of origin may be uncertain. Hormonal secretion by these tumors can result in endocrine syndromes such as Cushing and the syndrome of inappropriate antidiuretic hormone. Clinicians should be careful to identify clinical features found in genetic syndromes associated with pancreatoblastomas, such as macroglossia, omphalocele, and hypoglycemia seen in Beckwith-Wiedemann syndrome.22,25,26
The head of the pancreas is the most frequent site of tumor occurrence although they may occur at any site in the pancreas. The liver is most common site of metastatic disease at the time of presentation. Other possible sites are lungs and regional lymph nodes. Vascular invasion, involvement of the omentum, peritoneum, and other adjacent structures have all been reported.24,27 Klimstra et al13 reported that 35% of patients presented with metastases. In a retrospective review of 7 cases in France, over a 20-year period, 3 patients had tumors in the head of the pancreas, 2 patients in the body and the tail, and 1 each in the tail and the body. One patient had liver metastases, whereas 3 had regional lymph node involvement.28 Over a 10-year span, the Seoul International University recorded 5 cases of pancreatoblastoma between the ages of 2 and 5 years. Symptoms included abdominal mass, abdominal pain, anorexia, vomiting, and weight loss. Elevated levels of AFP (up to 27,000 ng/mL) were also found. One case had liver metastases at presentation.14 Khoda et al29 studied 3 cases of pancreatoblastoma and reviewed another 59 cases. His group found tumors in the following locations: pancreatic head origin (24/54, 44%), pancreatic body, and tail origin (30/54, 56%). The following pathologic features were found: hemorrhage (16/17, 94%), capsule formation (24/26, 92%), necrosis (28/31, 90%), hypervascularity (10/14, 71%), cystic changes (11/16, 69%), and calcification (10/21, 48%). All neonatal cases demonstrated cystic changes: 3 of them were patients with Beckwith-Wiedemann syndrome. The production of AFP was found in 68% of the cases (19/28).
Pancreatoblastomas must be considered as a differential diagnosis for any child with an upper abdominal mass because of the difficulties distinguishing it from other pediatric tumors, presenting similarly.
Tumors are large (averaging 7 to 18 cm in diameter) and often encapsulated. Histologically, lobules and nests of acinar and gland-like cell formation are found together with squamous cell nests. There are often small pseudocysts or areas of necrosis and hemorrhage. Laboratory parameters may show elevated serum levels of AFP (33% to 70% of patients),12,14,18 α-1-antitrypsin, or lactate dehydrogenase, especially when there are metastases to the liver.8,18,30 Ultrasound, computed tomography (CT), and magnetic resonance imaging (MRI) can all be useful in the work-up although few studies have described characteristic radiologic findings of pancreatoblastoma. Lee et al30 described large well-defined, multilobulated masses with enhancing septae by CT, and mixed echogenicity by ultrasound. Similar findings were reported by Chung et al2 and Mergo et al.21 A CT of the abdomen should be performed with intravenous contrast. T2-weighted MRI images have a better signal intensity and yield excellent views of necrotic and hemorrhagic components.18,31
Definitive diagnosis must always be established with biopsy and histologic examination. Biopsy may be performed through laparotomy, laparoscopy, or percutaneous core needle. Immunohistochemistry is usually strongly positive for α-1-antitrypsin and glucose-6-phosphatase.32 Stains for chromogranin, synaptophysin, and neuron-specific enolase are also commonly positive. Trypsin and chymotrypsin are usually found in the acinar region. Positivity for AFP is usually found within the solid regions of the epithelial component of the tumor. Electron microscopy reveals multiple cytoplasmic neurosecretory zymogen granules.14 Tumor staging is usually performed using the American Joint Committee on Cancer classification, which can be found at http://www.cancer.gov/cancertopics/pdq/treatment/pancreatic/HealthProfessional/page3.
The goal of treatment is complete surgical resection. In fact, if possible, resection is the preferred initial treatment.1–5,28 The ability to resect depends on the local extent of the disease, its location, and obviously the existence or absence of metastatic disease. Resection may involve distal pancreatectomy with or without splenectomy for lesions of the body and tail. Lesions of the head may sometimes require pancreaticoduodenectomy (Whipple procedure). Long-term survival is usually possible with complete resection of the tumor, even though pancreatoblastoma has a high recurrence rate.1–5 Primary surgical resection is often not possible in many children. Indications for neoadjuvant systemic chemotherapy include (1) large tumors that involve adjacent major blood vessels or other organs; and (2) metastatic disease. Chemotherapy can be useful for unresectable, metastatic, or recurrent disease. However, the efficacy of various agents is quite variable as reported in the literature. A variety of chemotherapeutic regimens have been used in recent years. Cisplatin and doxorubicin are the most often recommended agents for this disease. The Italian Tumori Rari in Eta’ Pediatrica project developed guidelines for pancreatoblastoma. The recommended chemotherapy regimen was cisplatin at 80 mg/m2 as a continuous 24-hour intravenous infusion, followed by doxorubicin 60 mg/m2 over 48 hours (the cisplatin and doxorubicin regimen). Treatment guidelines suggested adjuvant chemotherapy with 4 cisplatin and doxorubicin courses for completely resected patients and 6 courses for resection with microscopic residual or nodal involvement. For cases with initial biopsy only or metastatic disease, 4 preoperative cisplatin and doxorubicin courses were recommended, followed by surgery and then 2 further courses.3 Defachelles et al28 recommended preoperative chemotherapy with cisplatin and doxorubicin to reduce the tumor volume if unresectable. Ogawa et al33 demonstrated disease response and long-term survival in a 4-year-old girl with pancreatoblastoma. The tumor was located in the body and head of the pancreas with invasion of the portal vein. It was substantially reduced with the administration of 3 cycles of chemotherapy comprising cyclophosphamide, cisplatin, etoposide, and pirarubicin. This allowed subsequent complete resection of the pancreatic tumor and long-term survival. Yonekura et al34 used high-dose chemotherapy with peripheral blood stem cell support in a 3-year-old with advanced pancreatoblastoma with long-term survival. Chemotherapy has also been used as an adjunct to surgery, in patients with vascular invasion. Lee and Hah35 used cisplatin, doxorubicin, ifosfamide, and etoposide for 1 year postoperatively in patients who had pancreatoblastoma with vascular invasion to avoid sequelae of local radiation in infants and young children. Radiotherapy was suggested only for selected inoperable cases.3 The effectiveness of using radiation therapy for local control in pediatric patients is not fully known. However, it is often utilized after incomplete resection, positive surgical margins, or tumor spillage.28,33
Pancreatoblastomas are malignant, slow growing, and characteristically present with advanced-stage disease. At least one third of patients have metastases at presentation. Although potentially curable with total resection of tumor, pancreatoblastomas have a substantial recurrence rate Long-term follow-up is necessary with the aim of quickly identifying and treating local recurrence or metastasis.1
Clinicians should monitor the child closely by history, physical examination, and serial imaging. In addition, serial monitoring of AFP levels may be useful to screen for recurrence (especially if the original tumor was AFP producing). Close follow-up can be tapered off in time according to the judgment of the clinician. There are no set protocols for follow-up at this time.
Pancreatoblastoma has a variable presentation, and there may be difficulties in distinguishing it from other causes of a large abdominal mass in the pediatric age group, such as neuroblastoma, Wilms tumor, hepatoblastoma, or Non-Hodgkin lymphoma. It should therefore be considered in the differential for children presenting with upper abdominal masses, especially in infants and very young children.2 Children with syndromes that put them at risk for this tumor (Familial Adenomatous Polyposis, Beckwith-Wiedemann) should be screened quite regularly from an early age.15–17 This is best accomplished with ultrasounds and cross-sectional imaging for suspicious findings.
Clinicians should monitor the child closely by history, physical examination, and serial imaging. Baseline followed by serial ultrasounds can be used to monitor any unusual changes in the area of resection. CT or MRI should be performed at longer intervals or for suspicious ultrasound findings. In addition, serial monitoring of AFP levels may be useful to screen for recurrence (especially if the original tumor was AFP producing). Close follow-up can be tapered off in time according to the judgment of the clinician. There are no set protocols for follow-up at this time.
1. Dhebri AR, Connor S, Campbell F, et al. Diagnosis, treatment and outcome of pancreatoblastoma. Pancreatology. 2004;4:441–451
2. Chung EM, Travis MD, Conran RM. Pancreatic tumors in children: radiologic-pathologic correlation. Radiographics. 2006;26:1211–1238
3. Dall’lgna P, Cecchetto G, Bisogno G, et al. Pancreatic tumors in children and adolescents: the Italian TREP project experience. Pediatr Blood Cancer. 2010;54:675–680
4. Vossen S, Goretzki PE, Goebel U, et al. Therapeutic management of rare malignant pancreatic tumors in children. World J Surg. 1998;22:879–882
5. Shorter NA, Glick RD, Klimstra DS, et al. Malignant pancreatic tumors in childhood and adolescence: The Memorial Sloan-Kettering experience, 1967 to present. J Pediatr Surg. 2002;37:887–892
6. Raffel A, Cupisti K, Krausch M, et al. Therapeutic strategy of papillary cystic and solid neoplasm (PCSN): a rare non-endocrine tumor of the pancreas in children. Surg Oncol. 2004;13:1–6
7. Horie A, Yano Y, Kotoo Y, et al. Morphogenesis of pancreatoblastoma, infantile carcinoma of the pancreas: report of two cases. Cancer. 1977;39:247–254
8. Davey MS, Cohen MD. Imaging of gastrointestinal malignancy in childhood. Radiol Clin North Am. 1996;34:717–742
9. Klöppel G, Maillet B. Classification and staging of pancreatic nonendocrine tumors. Radiol Clin North Am. 1989;27:105–119
10. Levey JM, Banner BF. Adult pancreatoblastoma: a case report and review of the literature. Am J Gastroenterol. 1996;91:1841–1844
11. Friedman AC, Edmonds PR. Rare pancreatic malignancies. Radiol Clin North Am. 1989;27:177–190
12. Robey G, Daneman A, Martin DJ. Pancreatic carcinoma in a neonate. Pediatr Radiol. 1983;13:284–286
13. Klimstra DS, Wenig BM, Adair CF, et al. Pancreatoblastoma. A clinicopathologic study and review of the literature. Am J Surg Pathol. 1995;19:1371–1389
14. National Cancer Institute, DCCPS, Surveillance Research Program, Cancer Statistics Branch, released April2008, based on the November 2007 submission. Available at: www.seer.cancer.gov
15. Perez EA, Gutierrez J, Koniaris L, et al. Malignant pancreatic tumors: incidence and outcome in 58 pediatric patients. J Pediatr Surg. 2009;44:197–203
16. Chun Y, Kim W, Park K, et al. Pancreatoblastoma. J Pediatr Surg. 1997;32:1612–1615
17. 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;159:1619–1627
18. Herman TE, Siegel MJ, Dehner LP. CT of pancreatoblastoma derived from the dorsal pancreatic anlage. J Comput Assist Tomogr. 1994;18:648–650
19. Kerr NJ, Chun YH, Yun K, et al. Pancreatoblastoma is associated with chromosome 11p loss of heterozygosity and IGF2 overexpression. Med Pediatr Oncol. 2002;39:52–54
20. Boring CC, Squires TS, Tong T. Cancer statistics. CA Cancer J Clin. 1993;43:7–26
21. Mergo PJ, Helmberger TK, Buetow PC, et al. Pancreatic neoplasms: MR imaging and pathologic correlation. Radiographics. 1997;17:281–301
22. Kletter GB, Sweetser DA, Wallace SF, et al. Adrenocorticotropin-secreting pancreatoblastoma. J Pediatr Endocrinol Metab. 2007;20:639–642
23. Mukhtar A, Prakash S, Muhamad Z, et al. Pancreatoblastoma: a rare tumor. Malays J Med Sci. 2008;15(suppl):148
24. Montemarano H, Lonergan GJ, Bulas DI, et al. Pancreatoblastoma: imaging findings in 10 patients and review of the literature. Radiology. 2000;214:476–482
25. Muguerza R, Rodriguez A, Formigo E, et al. Pancreatoblastoma associated with incomplete Beckwith-Wiedemann syndrome: case report and review of the literature. J Pediatr Surg. 2005;40:1341–1344
26. Passmore SJ, Berry PJ, Oakhill A. Recurrent pancreatoblastoma with inappropriate adrenocorticotrophic hormone secretion. Arch Dis Child. 1988;63:1494–1496
27. Gupta AK, Mitra DK, Berry M, et al. Sonography and CT of pancreatoblastoma in children. AJR Am J Roentgenol. 2000;174:1639–1641
28. Défachelles AS, Martin De Lassalle E, Boutard P, et al. Pancreatoblastoma in childhood: clinical course and therapeutic management of seven patients. Med Pediatr Oncol. 2001;37:47–52
29. Kohda E, Iseki M, Ikawa H, et al. Pancreatoblastoma. Three original cases and review of the literature. Acta Radiol. 2000;41:334–337
30. Lee JY, Kim IO, Kim WS, et al. CT and US findings of pancreatoblastoma. J Comput Assist Tomogr. 1996;20:370–374
31. Stephenson CA, Kletzel M, Seibert JJ, et al. Pancreatoblastoma: MR appearance. J Comput Assist Tomogr. 1990;14:492–493
32. Saif MW. Pancreatoblastoma. J Pancreas. 2007;8:55–63
33. Ogawa B, Okinaga K, Obana K, et al. Pancreatoblastoma treated by delayed operation after effective chemotherapy. J Pediatr Surg. 2000;35:1663–1665
34. Yonekura T, Kosumi T, Hokim M, et al. Aggressive surgical and chemotherapeutic treatment of advanced pancreatoblastoma associated with tumor thrombus in portal vein. J Pediatr Surg. 2006;41:596–598
35. Lee YJ, Hah JO. Long-term survival of pancreatoblastoma in children. J Pediatr Hematol Oncol. 2007;29:845–847
pancreatoblastoma; pancreatic tumor; childhood; treatment
© 2012 Lippincott Williams & Wilkins, Inc.
What does "Remember me" mean?
By checking this box, you'll stay logged in until you logout. You'll get easier access to your articles, collections,
media, and all your other content, even if you close your browser or shut down your
To protect your most sensitive data and activities (like changing your password),
we'll ask you to re-enter your password when you access these services.
What if I'm on a computer that I share with others?
If you're using a public computer or you share this computer with others, we recommend
that you uncheck the "Remember me" box.
Highlight selected keywords in the article text.
Data is temporarily unavailable. Please try again soon.
Readers Of this Article Also Read