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Pancreatoblastoma in children: Clinical management and literature review

Highlights • Pancreatoblastoma (PB) is a rare malignant epithelial neoplasm in children.• There is limited data about the standard clinical treatment of relapse and/or metastasis PB.• Risk factors should be considered in therapeutic stratification of PB before surgery.• Low AFP levels might be poor prognostic factor.• The squamoid nests are considered a defining component for establishing the histological diagnosis.


Introduction
Pancreatoblastoma (PB) is an extremely rare pancreatic tumor that commonly occurs in infants and young children [1][2][3]. It comprises less than 1% of pancreatic tumors. The clinical presentations of PB are diverse and nonspecific, which leads to difficulties in its differentiation from other retroperitoneal tumors. Biological aggressiveness and elevated levels of serum α-fetoprotein (AFP) show similarities to hepatoblastoma [4]. The imaging features of CT and MRI are helpful in its differentiation from solid pseudopapillary neoplasms of the pancreas [5]. As such, a diagnosis of PB relies on its distinctive histological features [6].
PB is commonly considered to follow an indolent course and achieves long-term survival with surgical resection alone [7,8]; however, some studies have reported that the prognosis is poor in cases of metastasis or incomplete resection [9][10][11]. The standardized management for risk stratification in PB patients is rarely reported [9,12].
Moreover, there is limited data on the standard clinical treatment of 1; doxorubicin at 30 mg/m 2 on day 2,3) and ICE (ifosfamide at 1.5 g/m 2 on day 1-5, carboplatin at 450 mg/m 2 on day 1; etoposide at 100 mg/m 2 on day 1-3) were used. The literature search was conducted with the PubMed biomedical database, using keywords "pancreatoblastoma" and "pancreatoblastoma in children". Additional studies derived from the references were also analyzed.

Clinical features
There were three girls and one boy aged 3.6, 8.9, 5.5, and 4 years. Two patients presented with abdominal pain, and two patients presented with palpable abdominal masses. The imaging findings indicated well-defined heterogeneous masses in the pancreas, with tumor sizes of 7.6 cm, 5.2 cm, 18 cm, and 9.3 cm in maximum diameter, respectively. The invasion of the splenic vein and superior mesenteric artery, duodenum, and lymph nodes was observed. Liver recurrence was manifested in case 3. Cases 1 and 2 were treated with combination therapy (preoperative chemotherapy, pancreaticoduodenectomy, and postoperative chemotherapy), with a good outcome at follow-up. Case 3 underwent liver lobe resection and showed good outcome. Case 4 showed invasion of the splenic vein and superior mesenteric artery and died of severe ascites and multiple metastases.

Morphological features
Neoplastic cells usually showed an organoid arrangement of acinar, solid, trabecular, or ductal formations akin to acinar cell carcinomas. The solid component was comprised of polygonal tumor cells with whorled or nests, which were defined as squamous corpuscles. The nuclei were larger and more oval-shaped than those of the surrounding cells. The squamous corpuscles were detected in all tumors.

Case 1
A 3-year and 6-month-old girl was hospitalized in our unit due to an abdominal mass for 2 weeks. No tumor family history was provided. The physical examination showed a palpable abdominal mass below the right costal margin line. The AFP level reached to 2329.0 ng/ml (normal, <20.0 ng/ml), and the AFP variant was 278.48 ng/ml (normal, 0-1 ng/ml). Increased serum LDH (508 U/L; normal range, 106-211 U/ L) and NSE (69.8 ng/ml; normal range, 0-16.3 ng/ml) levels were presented. TORCH antigens, caused by Toxoplasma gondii, other (hepatitis viruses, parvovirus, human immunodeficiency virus, Epstein-Barr virus, syphilis), Rubella virus, Cytomegalovirus, and Herpes Simplex Virus were negative. US revealed a well-defined abdominal mass with heterogeneous echo in a local hospital. CT revealed a 7.6 × 7.5 cm mass in the pancreatic head with heterogeneous components, which was characterized by flocculent calcification and clear rim. The rich vasculum was identified by a CTA scan (Fig. 1a). The PET-CT image (Fig. 1e) showed that the surrounding duodenum liver, gallbladder, and gastric wall were compressed by the tumor, and tumor biopsy was performed though laparoscopic surgery according to multidisciplinary suggestions.
He was diagnosed with PB as pathological evidence. The patient was referred to oncologists and treated with four cycles of the PLADO regimen, consisting of cisplatin at 80 mg/m 2 on day 1 and doxorubicin at 30 mg/m 2 on day 2,3. CT revealed 5.5 × 4.7 cm (Fig. 1b) and 3.5 × 3.1 cm (Fig. 1c) masses, which were characterized by heterogeneous components and flocculent calcification after the second and fourth cycle of chemotherapy. The serum AFP level decreased to 159.0 ng/ml, 10.4 ng/ml, 3.49 ng/ml, and 4.02 ng/ml after the first, second, third, and fourth cycle, respectively. Similarly, the AFP variant level was <0.6 ng/ml after the third cycle. Subsequently, pancreaticoduodenectomy with Roux-en-Y end-to-end cholangiojejunostomy was performed. After surgery, the patient was treated with three cycles of the PLADO regimen. The follow-up data showed a good outcome for 11 months. There was no residual tumor or recurrence on postoperative US and CT (Fig. 1d). The serum AFP level was <5 ng/ml, and the AFP variant was <0.6 ng/ml.

Case 2
An 8-year and 9-month-old girl was admitted to a local hospital with intermittent nausea for 2 months. A palpable abdominal mass was identified by her parents 1 month prior to hospitalization. No family members presented with tumors. The physical examination showed an abdominal mass without enlarged lymph nodes. US showed a heterogenous echo in the middle of the abdomen and para-aortic hypoecho nodules. CT revealed a soft tissue shadow below the head of the pancreas with a size of 5.2 × 5.2 cm and surrounding lymphatic enlargement. Moreover, the duodenum and superior mesenteric vein invasion were noted.
Laboratory tests showed an elevated AFP level (323.00 ng/ml). Serum LDH (220 U/L; normal range, 106-211 U/L) and NSE (21.2 ng/ ml; normal range, 0-16.3 ng/ml) levels were slightly elevated. With these findings, a biopsy of the pancreatic head tumor was performed though laparoscopic surgery. The patient was diagnosed with PB according to the pathology results.
For further treatment, the patient came to our institution. Chemotherapy was given (cisplatin at 80 mg/m 2 on day 1; doxorubicin at 30 mg/m 2 on day 2,3). After the first cycle of chemotherapy, the tumor size was reduced to 4.1 × 3.5 cm (Fig. 2a), and the serum AFP level was reduced to 20 ng/ml. After the second cycle of chemotherapy, the serum AFP level was reduced to 6.83 ng/ml, and the AFP variant was <0.6 ng/ ml. Subsequently, pancreatoduodenectomy was performed. Four cycles of the aforementioned chemotherapy regimen was given after surgery. The follow-up data showed that there were no signs of recurrence for 9 months (Fig. 2b). The serum AFP level was 0.91 ng/ml, and the AFP variant was <0.6 ng/ml.

Case 3
A 5-year-and 5-month-old boy who suffered with abdominal pain for 1 month was hospitalized in a local hospital. An abdominal mass was detected by a physical examination. The serum AFP level was 1064.31 ng/ml, and a huge mass was identified in the body and tail of the pancreas by US. Enhanced CT revealed a huge mass with a size of 18 × 10 × 10 cm, and the duodenum was compressed by the tumor. A resection of the pancreatic tumor was performed, and PB was diagnosed based on morphological and immunohistochemical features. His family refused further postoperative chemotherapy because of socio-economic reasons.
After 10 months, he developed liver metastasis and was transferred to our unit. US showed liver mass with a size of 14.9 × 13.5 cm. CT showed multiple intrahepatic nodules and enlarged portal/hilar lymph nodes with abundant blood vessels. The serum AFP level increased to 121,000.00 ng/ml. Four cycles of the PLADO regimen were administrated. The serum AFP level was reduced to 7069.00 ng/ml and then 519.70 ng/ml, and the tumor size was 10.7 × 7.1 cm (US) and then 6.8 × 5.3 cm (CT) (Fig. 3b) after the first and second cycle, respectively. After the fourth cycle of chemotherapy, the AFP value was 36.85 ng/ml, and the tumor size was 5.6 × 4.6 cm by CT (Fig. 3c). The patient underwent resection of segments 6 and 7 of the right liver lobe. The serum AFP level decreased to 5.61 ng/ml on the first day after the surgery. Postoperative chemotherapy with cisplatin and doxorubicin was given for four cycles. Subsequently, the serum AFP level was 3.7 ng/ml. CT showed multiple small abnormal signals in the liver, further treatment was given according to the ICE regimen as follows: ifosfamide at 1.5 g/ m 2 on day 1-5, carboplatin at 450 mg/m 2 on day 1, and etoposide at 100 mg/m 2 on day 1-3. The follow-up data showed that there were no signs of recurrence for 43 months (Fig. 3d).

Case 4
A 4-year-old girl suffering from abdominal pain for 3 months was admitted to a local hospital. The physical examination showed moderate jaundice of the skin mucosa. CT showed a 9.3 × 8.8 cm heterogeneous mass with nodular calcification at the right retroperitoneal region. The adjacent organs, including the liver and gallbladder, were compressed. Multiple tumor thrombi in the splenic vein and superior mesenteric artery were detected. The laboratory examination showed an elevated serum AFP level (50.53 ng/ml). US-guided tumor biopsy was performed. According to the pathology results, she was diagnosed with PB.
She was transferred to our unit and was treated with the PLADO regimen. After one cycle, the patient's jaundice subsided, and the serum AFP value was reduced to 23.87 ng/ml. After three cycles, the serum AFP level was reduced to 11.0 ng/ml, and the tumor size was 4.2 × 5.1 cm by CT. Tumor thrombi in the splenic vein and superior mesenteric artery were still present. Unfortunately, her family refused subsequent treatment for socio-economic reasons. After 15 months, she died of progressive disease and multiple organ failure.
A definitive diagnosis of PB relies on the histological identification of epithelial differentiation (acinar, glandular, and trabecular architectures) and squamous corpuscles. The squamous corpuscles are unique, and they distinguish PB from neuroblastoma, hepatoblastoma, and other small round cell tumors [1,10,14,18]. In the immunohistochemical investigation, tumors were positive for trypsin, cytokeratin AE1/AE3, CK19, CK7, CEA, and VIM. The areas of squamous differentiation were also marked by CK5 and EMA. Endocrine markers, including SYN, CgA, and CD56, were positive seldomly.
In the cases we reviewed, more than half of the patients had metastases or invasion of the surrounding tissues (35/63, 55.5%). The liver (16/35, 45.7%) and veins (16/35, 45.7%) are the most common site of metastasis, although metastasis may also occur in regional lymph nodes (7/35, 20.0%), duodenum and colon (4/35, 11.4%), and lung (2/35, 5.7%). Therefore, the risk factors should be considered in the therapeutic stratification of PB, including vein involvement, extrasplenic abdominal disease, distant metastases, lymph node metastases, tumor rupture, and intraperitoneal hemorrhage [6,8,19]. Moreover, we observed that 14 cases experienced recurrence or died of progressing disease. In this series, 71% (10/14) of the children were older than 3 years old, suggesting that age might be considered in the therapeutic stratification of PB.
According to the risk factors, PB can be further divided into low-, intermediate-, or high-grade by the multi-disciplinary team at initial diagnosis. Complete surgical resection is strongly recommended, if achievable. The first-line of treatment is based on complete tumor resection, followed by chemotherapy (cisplatin and doxorubicin), which presents favorable outcomes [11,20]. Preoperative chemotherapy is recommended to shrink the tumor and to achieve the possibility of complete resection in intermediate-or high-grade PB [1,2,6,7,19,20]. Despite the small numbers, patients with an intermediate-grade show a better response in preoperative chemotherapy of PLADO or ICE-based regimens (etoposide, ifosfamide, and carboplatin) [1,9,19,21,22].
Patients with distant metastases are identified as high-grade PB. Although there are no strict recommendations, radiotherapy is performed in PB patients if the tumors do not respond to chemotherapy, or if recurrent, residual, and metastatic disease is present [3,8,19,23]. Several studies have reported that autologous hematopoietic stem cell transplantation has meaningful efficacy in a few cases of tumor recurrence [21,[23][24][25], suggesting it might be adopted in patients with high-grade PB. Picado et al. reported that liver transplantation may have a favorable outcome in pediatric PB with metastatic livers [26].
AFP is a glycoprotein that is derived from embryonic endoderm tissue cells. The serum AFP level is usually increased in PB, hepatoblastoma, and germ cell tumors, such as yolk sac tumors in children [27,28]. In our study, patients mostly show elevated serum AFP levels (>100 ng/ml, 38/50, 76%). After complete resection of the tumors, the AFP level in all patients was reduced, returning to the normal range at follow-up. These findings indicate that serum AFP might serve as a valuable tumor marker for preoperative diagnosis, and it can even indicate therapeutic effect and postoperative recurrence in PB patients.
In conclusion, PB is considered a curable tumor, and thus, a multidisciplinary diagnosis should be made early. Squamoid nests are considered as a defining component of histological diagnosis. The risk factors should be considered in the therapeutic stratification of PB. Fig. 1. Age and sex-specific incidence of 63 patients for PB. The first peak was observed before 1 year of age, and the second peak was observed at 4 years of age. The distribution of males and females showed no significant differences.

Ethics approval
This study was approved by the ethics committee of the Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine.

Informed consent
All patients enrolled provided written informed consent.

Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Funding
This work was supported by Shanghai Municipal Commission of Health and Family Planning (201840165) and National Natural Science Foundation of China (82000193).

Supplementary materials
Supplementary material associated with this article can be found, in the online version, at doi:10.1016/j.tranon.2022.101359.