Management of Pancreatoblastoma in Children and Young Adults

Abstract

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.

CLINICAL PRESENTATION

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).

DIAGNOSIS/STAGING

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.

MANAGEMENT RECOMMENDATIONS

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

FOLLOW-UP RECOMMENDATIONS

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.

SCREENING/PREVENTION RECOMMENDATIONS

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.