Rare tumors II: Adrenocortical tumors, neuroendocrine tumors of the appendix, pheochromocytoma and paraganglioma, pancreatoblastoma and solid pseudopapillary tumors of the pancreas.

Very rare tumors are usually divided into two groups: One includes tumors that are rare among both children and adults; the other one encompasses tumors that frequently occur in adults but are rarely observed in children. In this review, we focus on adrenocortical tumors, neuroendocrine tumors of the appendix, pheochromocytoma and paraganglioma, pancreatoblastoma and solid pseudopapillary tumors of the pancreas, with special attention to the role of surgery as main curative intervention or as part of the multimodal treatment.

Childhood pancreatic neuroendocrine neoplasms: A national experience.

Pancreatic neuroendocrine neoplasms (pNENs) diagnosed in childhood are very rare, with few data available. The aim was to describe the clinical presentation and behavior of children with pNENs at a national level. METHODS: National multicenter retrospective study of all patients, aged from 0 to 17 years at diagnosis, treated from 2011 to 2020 for a pNEN and registered in the French National Registry of Childhood Cancers or FRACTURE database. RESULTS: Fifteen patients, 13 well-differentiated pancreatic neuroendocrine tumors (pNETs) and two neuroendocrine carcinomas (pNECs), were selected. Median age at diagnosis was 14 years (range, 7-17). Eight patients, all with localized disease, had a cancer predisposition syndrome (CPS), including five cases diagnosed during systematic screening. Five (31%) had metastatic disease at diagnosis: three grade 2 pNETs and two pNECs. First line therapy included exclusive pancreatectomy (seven cases, all M0), active surveillance (three cases, all M0), medical therapies (somatostatin analogues, chemotherapy; four cases, all M1), and surgery with medical therapy (one M1 case). Three-year progression-free survival was 57% (confidence interval [CI] 95%: 27-78) and was significantly better for patients with low-grade well differentiated (73 vs. 0%; p < 10-4) and localized (76 vs. 20%; p = .02) tumors. The two patients with pNECs died. Three-year overall survival was 92% (CI95%: 59-99) and was significantly better in patients with low-grade tumor (100 vs. 50%; p = 10-4). CONCLUSION: Childhood pNENs occur more frequently in adolescents with CPS. Localized low-grade pNETs in children have a very good prognosis, whereas the treatment of high-grade and metastatic pNETs/pNECs should be better defined.

Clinical, pathologic, and molecular features of inflammatory myofibroblastic tumors in children and adolescents.

BACKGROUND: Inflammatory myofibroblastic tumors (IMT) are rare, intermediate malignant tumors harboring frequent somatic molecular rearrangements. The management of IMT has not been standardized. METHODS: A retrospective multicenter study was conducted on all pediatric patients treated for IMT between 2000 and 2019. RESULTS: This series included 39 cases of IMT, with a median age at diagnosis of 7 years (range 20 days to 16 years). Tumor location included pelvis-abdomen (n = 16), thorax (n = 14), head and neck (n = 7), and limbs (n = 2). One patient had metastatic disease. Immunochemistry showed 21/39 (54%) anaplastic lymphoma kinase (ALK)-positive tumors. Somatic tyrosine kinase rearrangement was present in 31/36 (86%) of the tumors analyzed: 21 ALK, five ROS1, and five NTRK. Immediate surgery was performed in 24 patients (62%), with adjuvant therapy for three patients. Delayed surgery after neoadjuvant therapy was possible in 10 cases. Exclusive systemic therapy was delivered to four patients; one patient with orbital IMT was managed by watchful waiting. After a median follow-up of 33 months (range 5-124), eight (20%) recurrences/progressions occurred after surgery (seven after primary surgery and one after delayed surgery), after a median interval of 7 months (range 2-21), all in thoracic locations. The 3-year overall and disease-free survivals were 96.8% (95% CI: 79.2%-94.0%) and 77.4% (95% CI: 59.6%-88.1%), respectively. Relapses/progressions were more common in patients with a thoracic primary (p < .001) or after incomplete surgery with no adjuvant therapy (p = .027). CONCLUSION: Surgery is effective in most cases of pediatric IMT. Systematic analysis of tyrosine kinase rearrangement is recommended. When the tumor is deemed only partially resectable to preserve organs and function, neoadjuvant therapy may be proposed to allow adequate conservative surgery.

Management and outcome of hepatic artery thrombosis after pediatric liver transplantation.

BACKGROUND: Pediatric LT are at particular risk of HAT, and its management still constitutes a matter of debate. Our purpose was to study predisposing factors and outcome of HAT post-LT, including the impact of surgical revisions on survival and biliary complications. METHODS: Among 882 primary pediatric LT performed between 1993 and 2015, 36 HAT were encountered (4.1%, 35 fully documented). Each HAT case was retrospectively paired with a LT recipient without HAT, according to diagnosis, age at LT, type of graft, and era. RESULTS: Five-year patient survivals were 77.0% versus 83.9% in HAT and non-HAT paired groups, respectively (P = .321). Corresponding graft survivals were 20.0% versus 80.5% (P < .001), and retransplantation rates 77.7% versus 10.7%, respectively (P < .001). One-year biliary complication-free survivals were 16.6% versus 83.8% in the HAT and non-HAT groups, respectively (P < .001). Regarding chronology of surgical re-exploration, only HAT cases that occurred within 14 days post-LT were re-operated, fourteen of them being explored within 7 days post-LT (revascularization rate: 6/14), versus two beyond 7 days (no revascularization). When revascularization was achieved, graft and biliary complication-free survival rates at 1 year were 33.3% and 22.2%, respectively, both rates being 0.0% in case of failure. CONCLUSIONS: The pejorative prognosis associated with HAT in terms of graft survival is confirmed, whereas patient survival could be preserved through retransplantation. Results suggest that HAT should be re-operated if occurring within 7 days post-LT, but not beyond.

Living donor liver transplantation for hepatic malignancies in children.

BACKGROUND: Living donor liver transplantation is a treatment option for unresectable hepatic tumors in children. METHODS: We enrolled 45 living donor transplantations performed between 1993 and 2018 for liver malignacies, which included hepatoblastoma (n = 33), hepatocellular carcinoma (n = 10), hepatic angiosarcoma (n = 1), and rhabdomyosarcoma (n = 1). RESULTS: No mortality or major morbidities were encountered in any donor, and the complication rate was 9%. In the hepatoblastoma group, 5-year overall and event-free survival rate in recipients was 87.4% and 75.8%, respectively, and mortality was significantly higher in patients after rescue transplantation (p = .001). Inferior vena cava replacement in these recipients appeared to be associated with reduced mortality (p = .034), but this was not confirmed when rescue patients were excluded (p = .629). In hepatocellular carcinoma group, both 5-year overall and event-free survival rates were 75.4% each, and invasion of hepatic veins was significantly associated with increased risk of recurrence and death (p = .028). The patient with rhabdomyosarcoma died from EBV-induced lymphoma 2 months after transplantation. The patient with angiosarcoma was in complete remission at the last follow-up. Overall, 5-year graft survival rate was 81.3%, and one patient underwent re-transplantation due to chronic rejection. CONCLUSIONS: Pediatric oncological liver transplantation has become a key player in the management of malignancies with cancer cure in 84% of patients in this series. Living donor liver transplantation for pediatric recipients with unresectable tumors might be a beneficial surgical option, which is technically safe for donors and recipients, thus, allowing timely planning according to chemotherapy protocols.

Unusual presentations of enlarged parathyroid cysts: two case reports.

INTRODUCTION: Parathyroid cysts are infrequently encountered and have a variable presentation pattern depending on their size, location and secreting character. PATIENTS AND METHODS: We report two cases of parathyroid cysts characterized by their uncommon clinical presentation. RESULTS: In the first case the patient presented with a large cervical cystic mass without hypercalcemia, while in the second case, the patient experienced a hypercalcemic crisis associated with acute renal failure. The variable pattern of clinical manifestations is discussed. CONCLUSION: Parathyroid cysts are a rare entity. Surgical resection is the key to therapy when hyperparathyroidism or local compression are identified.

Paediatric hepatocellular adenomas: Lessons from a systematic review of relevant literature.

Hepatocellular adenomas (HCAs) are rare benign liver tumours. Predisposing factors and complication rates appear to differ among children and adults. In the present study, we aimed to systematically characterise paediatric HCAs and determine their course, complications, and management. Medical history, clinical symptoms, imaging, histopathology, and genetics of children with HCAs were collected through a systematic and comprehensive review of the published literature. A total of 316 children with HCAs were included in the present study. HCAs were diagnosed primarily in girls (59.3%) and at a mean age of 11.5 (range 0-17.7) years. The majority (83.6%) of HCAs occurred in children with predisposing diseases, of which glycogen storage disease was the most common, followed by portosystemic shunts and MODY3 (maturity-onset diabetes of the young type 3). Each of these diseases leads to a well-defined HCA molecular pattern. A significant number of HCAs either bled (24.7%) or transformed (14.8%) over time. HCA transformation was significantly more frequent in children with portosystemic shunts and in ß-catenin-mutated HCAs, while haemorrhages were more frequent in children exposed to hormones and those with larger lesions. Management was primarily guided by any predisposing conditions and the number of lesions. Therefore, vascular shunts were closed when possible, while complicated lesions were resected. Liver transplantation has made it possible to treat adenomatosis, as well as any underlying diseases. Progress in understanding genetic and/or malformative contributions, which appear to be significant in paediatric HCAs, have provided insights into tumour pathogenesis and will further guide patient surveillance and management.

Robot-assisted laparoscopic adrenalectomy: Extended application in children.

BACKGROUND: Minimally invasive surgery for paediatric adrenal tumours has evolved, but robot-assisted laparoscopic adrenalectomy (RALA) in children remains poorly studied. The current prospective study aims to demonstrate the safety and efficacy of RALA in treating children with adrenal tumours. METHODS: A prospective institutional analysis of children presenting with neuroblastic and endocrine tumours treated with RALA was undertaken over a six year-period. For each child, clinical parameters were collected relating to diagnosis, surgery and outcomes. RESULTS: A total 50 RALA were performed; 23 for unilateral neuroblastic tumours (87 % neuroblastomas) and 27 for endocrine tumours. Eight neuroblastic tumours (35 %) had image-defined risk factors (all due to tumour invading the renal pedicle). Median length of stay was two days. Resection margins were macroscopically clear in all cases. After median follow-up of 2.9 years (1.6-3.9), two children are under treatment for metastatic relapse (high-risk disease) and three died due to refractory disease. Sixteen children had endocrine tumours: pheochromocytoma (n = 13), or bilateral nodular adrenocortical hyperplasia with Cushing's syndrome (n = 14). One child required non-emergent conversion, and one complication occurred (grade IIIb) after median follow-up of 3.3 years (1.0-5.7). CONCLUSIONS: The current study is the largest reported experience in the literature and confirms the safety and effectiveness of RALA in carefully selected children with adrenal tumours. Through an iterative process and in the setting of a dedicated paediatric robotic surgical team indications have been clarified and extended. The current study confirms RALA has particularly utility in patients with severe disease (IDRF + metastatic neuroblastomas) or genetic predisposition syndromes.

Mutational signature, cancer driver genes mutations and transcriptomic subgroups predict hepatoblastoma survival.

BACKGROUND: Hepatoblastoma is the most frequent pediatric liver cancer. The current treatments lead to 80% of survival rate at 5 years. In this study, we evaluated the clinical relevance of molecular features to identify patients at risk of chemoresistance, relapse and death of disease. METHODS: All the clinical data of 86 children with hepatoblastoma were retrospectively collected. Pathological slides were reviewed, tumor DNA sequencing (by whole exome, whole genome or target) and transcriptomic profiling with RNAseq or 300-genes panel were performed. Associations between the clinical, pathological, mutational and transcriptomic data were investigated. RESULTS: High-risk patients represented 44% of our series and the median age at diagnosis was 21.9 months (range: 0-208). Alterations of the WNT/ß-catenin pathway and of the 11p15.5 imprinted locus were identified in 98% and 74% of the tumors, respectively. Other cancer driver genes mutations were only found in less than 11% of tumors. After neoadjuvant chemotherapy, disease-specific survival and poor response to neoadjuvant chemotherapy were associated with 'Liver Progenitor' (p = 0.00049, p < 0.0001) and 'Immune Cold' (p = 0.0011, p < 0.0001) transcriptomic tumor subtypes, SBS35 cisplatin mutational signature (p = 0.018, p = 0.001), mutations in rare cancer driver genes (p = 0.0039, p = 0.0017) and embryonal predominant histological type (p = 0.0013, p = 0.0077), respectively. Integration of the clinical and molecular features revealed a cluster of molecular markers associated with resistance to chemotherapy and survival, enlightening transcriptomic 'Immune Cold' and Liver Progenitor' as a predictor of survival independent of the clinical features. CONCLUSIONS: Response to neoadjuvant chemotherapy and survival in children treated for hepatoblastoma are associated with genomic and pathological features independently of the clinical features.