The impact of the route to diagnosis in nephroblastoma.

INTRODUCTION: Wilms tumor (WT) is the most common childhood kidney cancer. It is a rapid growing embryonal tumor in young children and can be diagnosed with and without tumor related symptoms. METHODS: We retrospectively analyzed the route to diagnosis of WT treated prospectively according to the SIOP 93-01/GPOH and 2001/GPOH in Germany between 1993 and 2022. Four routes were defined: diagnosis due to tumor-related symptoms, incidental diagnosis during another disease, diagnosis by preventive examinations, and diagnosis within a surveillance program. For these groups we compared clinical and tumor characteristics and outcome. RESULTS: Of 2549 patients with WT 1822 (71.5%) were diagnosed by tumor-related symptoms, 472 (18.5%) incidentally, 213 (8.4%) by preventive medical examinations, and 42 (1.6%) by surveillance. Age, general health status, tumor volume, and local and overall stage varied significantly between these groups. The youngest patients were those diagnosed by preventive medical examination (mean: 1.70 years). These patients also showed the best general health status. Tumor volume at diagnosis (549 mL) and after preoperative chemotherapy (255 mL) was significantly higher for children with tumor-related symptoms. The highest percentage of local stage I (78.6%) and the lowest percentage of metastatic disease (4.8%) was found in the surveillance group. The outcome of patients was not significantly different, with up to 19.0% relapses in the surveillance group and 3.0% deaths in the group with tumor-related symptoms. CONCLUSION: The route to diagnosis of WT correlates with age, general health status, tumor volume, and stage distribution, but does not impact the outcome of patients. Nonetheless, diagnosis without tumor related symptoms results in lower treatment burden and thus improved quality of life.

Lymph node metastases are more frequent in paediatric appendiceal NET ≥1.5 cm but without impact on outcome - Data from the German MET studies.

BACKGROUND: Paediatric appendiceal neuroendocrine tumours (appNET) are very rare tumours, mostly detected incidentally by histopathological evaluation after appendectomy. Treatment recommendations are based on adult data considering high-risk NET as defined by European Neuroendocrine Tumour Society (ENETS) guidelines for completion right-sided hemicolectomy (RHC). Recent data suggest that less aggressive therapy may be justified. PROCEDURE: Analysis of children and adolescents with appNET prospectively registered with the German Malignant Endocrine Tumour (MET) studies between 1997 and 2022. RESULTS: By December 2022, 662 patients (64.7% females, 35.3% male) had been reported. Median age was 13.3 years [4.5-17.9], median duration of follow-up 2.2 years [0-10.9]. No distant metastases were reported. Tumour size was <1 cm in 63.5%, 1-2 cm in 33.2%, and >2 cm in 3.2% of patients. WHO grade 1 and 2 tumours were diagnosed in 76.9% and 23.1% of patients, respectively. Lymphovascular invasion and lymph node metastases were associated with tumour size ≥1.5 cm. 27.0% of patients presented with high-risk NET according to ENETS criteria. Of those, only 55.9% underwent secondary oncological right hemicolectomy. Neither distant metastases, nor recurrences or disease-related deaths occurred in patients with appendectomy only as well as in patients with completion RHC. Overall and event-free survival were both 100%. CONCLUSIONS: Internationally harmonized consensus recommendations on treatment of children and adolescents with appendiceal NET are urgently needed to avoid completion RHC in high-risk patients.

How to improve initial diagnostic accuracy of kidney tumours in childhood?-A non-invasive approach.

Non-invasive differentiation of paediatric kidney tumours is particularly important in the SIOP-RTSG protocols, which recommend pre-operative chemotherapy without histological confirmation. The identification of clinical and tumour-related parameters may enhance diagnostic accuracy. Age, metastases, and tumour volume (TV) were retrospectively analysed in 3306 patients enrolled in SIOP/GPOH 9, 93-01, and 2001 including Wilms tumour (WT), congenital mesoblastic nephroma (CMN), clear cell sarcoma (CCSK), malignant rhabdoid tumour of the kidney (MRTK), and renal cell carcinoma (RCC). WT was diagnosed in 2927 (88.5%) patients followed by CMN 138 (4.2%), CCSK 126 (3.8%), MRTK 58 (1.8%) and RCC 57 (1.7%). CMN, the most common localized tumour (71.6%) in patients younger than 3 months of age, was diagnosed earliest and RCC the latest (median age [months]: 0 and 154, respectively) both associated with significantly smaller TV (median TV [mL]: 67.2 and 45.0, respectively). RCC occurred in >14% of patients older than 120 months or older than 84 months with TV <100 mL. Receiver operating characteristic analyses discriminated WT from CMN, RCC and MRTK regarding age (AUC = 0.976, 0.929 and 0.791) and TV (AUC = 0.768, 0.813 and 0.622). MRTK had the highest risk of metastasis (37.9%) despite young age, whereas the risk of metastasis increased significantly with age in WT. Age and TV at diagnosis can differentiate WT from CMN and RCC. MRTK must be considered for metastatic tumours at young age. Identification of CCSK without histology remains challenging. Combined with MRI-characteristics, including diffusion-weighted imaging, and radiomics and liquid biopsies in the future, our approach allows optimization of biopsy recommendations and prevention of misdiagnosis-based neoadjuvant treatment.

Corneal Infantile Myofibromatosis Caused by Novel Activating Imatinib-Responsive Variants in PDGFRB.

Purpose: To investigate the genetic cause, clinical characteristics, and potential therapeutic targets of infantile corneal myofibromatosis. Design: Case series with genetic and functional in vitro analyses. Participants: Four individuals from 2 unrelated families with clinical signs of corneal myofibromatosis were investigated. Methods: Exome-based panel sequencing for platelet-derived growth factor receptor beta gene (PDGFRB) and notch homolog protein 3 gene (NOTCH3) was performed in the respective index patients. One clinically affected member of each family was tested for the pathogenic variant detected in the respective index by Sanger sequencing. Immunohistochemical staining on excised corneal tissue was conducted. Functional analysis of the individual PDGFRB variants was performed in vitro by luciferase reporter assays on transfected porcine aortic endothelial cells using tyrosine kinase inhibitors. Protein expression analysis of mutated PDGFRB was analyzed by Western blot. Main Outcome Measures: Sequencing data, immunohistochemical stainings, functional analysis of PDGFRB variants, and protein expression analysis. Results: We identified 2 novel, heterozygous gain-of-function variants in PDGFRB in 4 individuals from 2 unrelated families with corneal myofibromatosis. Immunohistochemistry demonstrated positivity for alpha-smooth muscle actin and ß-catenin, a low proliferation rate in Ki-67 (< 5%), marginal positivity for Desmin, and negative staining for Caldesmon and CD34. In all patients, recurrence of disease occurred after corneal surgery. When transfected in cultured cells, the PDGFRB variants conferred a constitutive activity to the receptor in the absence of its ligand and were sensitive to the tyrosine kinase inhibitor imatinib. The variants can both be classified as likely pathogenic regarding the American College of Medical Genetics and Genomics classification criteria. Conclusions: We describe 4 cases of corneal myofibromatosis caused by novel PDGFRB variants with autosomal dominant transmission. Imatinib sensitivity in vitro suggests perspectives for targeted therapy preventing recurrences in the future. Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Combination of nivolumab with standard induction chemotherapy in children and adults with EBV-positive nasopharyngeal carcinoma : Protocol of a prospective multicenter phase 2 trial.

BACKGROUND: Treatment of Epstein-Barr virus(EBV)-positive nasopharyngeal carcinoma (NPC) with cisplatin/5-fluorouracil (5-FU) induction chemotherapy, followed by radiochemotherapy and subsequent interferon­ß, has yielded high survival rates in children, adolescents, and young adults. A previous study has shown that reduction of radiation dose from 59.4 to 54.0 Gy appears to be safe in patients with complete response (CR) to induction chemotherapy. As immune checkpoint-inhibitors have shown activity in NPC, we hypothesize that the addition of nivolumab to standard induction chemotherapy would increase the rate of complete tumor responses, thus allowing for a reduced radiation dose in a greater proportion of patients. METHODS: This is a prospective multicenter phase 2 clinical trial including pediatric and adult patients with their first diagnosis of EBV-positive NPC, scheduled to receive nivolumab in addition to standard induction chemotherapy. In cases of non-response to induction therapy (stable or progressive disease), and in patients with initial distant metastasis, treatment with nivolumab will be continued during radiochemotherapy. Primary endpoint is tumor response on magnetic resonance imaging (MRI) and positron emission tomography (PET) after three cycles of induction chemotherapy. Secondary endpoints are event-free (EFS) and overall survival (OS), safety, and correlation of tumor response with programmed cell death ligand 1 (PD-L1) expression. DISCUSSION: As cure rates in localized EBV-positive NPC today are high with standard multimodal treatment, the focus increasingly shifts toward prevention of late effects, the burden of which is exceptionally high, mainly due to intense radiotherapy. Furthermore, survival in patients with metastatic disease and resistant to conventional chemotherapy remains poor. Primary objective of this study is to investigate whether the addition of nivolumab to standard induction chemotherapy in children and adults with EBV-positive NPC is able to increase the rate of complete responses, thus enabling a reduction in radiation dose in more patients, but also offer patients with high risk of treatment failure the chance to benefit from the addition of nivolumab. TRIAL REGISTRATION: EudraCT (European Union Drug Regulating Authorities Clinical Trials Database) No. 2021-006477-32.

TRIM28 inactivation in epithelial nephroblastoma is frequent and often associated with predisposing TRIM28 germline variants.

Wilms tumors (WTs) are histologically diverse childhood cancers with variable contributions of blastema, stroma, and epithelia. A variety of cancer genes operate in WTs, including the tripartite-motif-containing-28 gene (TRIM28). Case reports and small case series suggest that TRIM28 mutations are associated with epithelial morphology and WT predisposition. Here, we systematically investigated the prevalence of TRIM28 inactivation and predisposing mutations in a cohort of 126 WTs with >2/3 epithelial cells, spanning 20 years of biobanking in the German SIOP93-01/GPOH and SIOP2001/GPOH studies. Overall, 44.4% (56/126) cases exhibited loss of TRIM28 by immunohistochemical staining. Of these, 48 could be further analyzed molecularly, revealing TRIM28 sequence variants in each case - either homozygous (~2/3) or heterozygous with epigenetic silencing of the second allele (~1/3). The majority (80%) of the mutations resulted in premature stops and frameshifts. In addition, we detected missense mutations and small deletions predicted to destabilize the protein through interference with folding of key structural elements such as the zinc-binding clusters of the RING, B-box-2, and PHD domains or the central coiled-coil region. TRIM28-mutant tumors otherwise lacked WT-typical IGF2 alterations or driver events, except for rare TP53 progression events that occurred with expected frequency. Expression profiling identified TRIM28-mutant tumors as a homogeneous subset of epithelial WTs that mostly present with stage I disease. There was a high prevalence of perilobar nephrogenic rests, putative precursor lesions, that carried the same biallelic TRIM28 alterations in 7/7 cases tested. Importantly, 46% of the TRIM28 mutations were present in blood cells or normal kidney tissue, suggesting germline events or somatic mosaicism, partly supported by family history. Given the high prevalence of predisposing variants in TRIM28-driven WT, we suggest that immunohistochemical testing of TRIM28 be integrated into diagnostic practice as the management of WT in predisposed children differs from that with sporadic tumors. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

[Peripheral neuroblastic tumors in childhood]. / Periphere neuroblastische Tumoren im Kindesalter.

Peripheral neuroblastic tumors represent the fourth-largest group of malignant tumors in childhood. The majority of these tumors are neuroblastomas, which can be classified into undifferentiated, poorly differentiated, and differentiating subtypes. In addition, peripheral neuroblastic tumors include ganglioneuroblastoma, a composite tumor composed of Schwannian cell stroma and neuroblasts as well as benign ganglioneuroma. In this overview, histopathological diagnostic criteria and grading systems, as well as common molecular alterations that are of prognostic and therapeutic significance, are discussed.

[Receptor tyrosine kinase- fusions in paediatric spindle cell tumors]. / Rezeptor-Tyrosinkinase-Fusionen in spindelzelligen Tumoren des Kindesalters.

Pediatric spindle cell tumors are rare and often difficult to diagnose due to a similar morphology and a non-specific immunohistochemical profile. Genetic characterization of these lesions has been constantly improving, which has led to the identification of new subgroups that were partly included in the WHO classification. Receptor tyrosine kinase fusions play a special role in these tumors and their verification has diagnostic relevance and can be an option for target-oriented therapies. In the case of pediatric spindle cell tumors, genetic fusions form especially with NTRK1­3, ALK, RET, and ROS1. Overall, pediatric tumors with receptor tyrosine kinase fusions are predominantly low-grade tumors, which are often subdivided into the group of intermediate-malign tumors.

Locally Advanced Adrenocortical Carcinoma in Children and Adolescents-Enigmatic and Challenging Cases.

BACKGROUND: Locally advanced tumors account for approximately 50% of children and adolescents with adrenocortical carcinoma (ACC), and of these, up to 50% relapse. We explored the five-item microscopic score and the pS-GRAS score for guiding management. METHODS: Data from children and adolescents with COG stage II and III ACC registered in the MET studies were included. The five-item and pS-GRAS score were retrospectively calculated. RESULTS: By December 2021, 55 patients with stage II and III (stage II n = 18, stage III n = 37) had been reported. Median age was 4.3 years [0.1-17.8], median duration of follow-up 6.0 years [0-16.7]. 3-year event-free survival (EFS) rate was 76.5% and 49.8% (p = 0.088), respectively. In stage II tumors, neither the five-item score (p = 0.872) nor pS-GRAS grouping (p = 0.218) had any effect as prognostic factors. In stage III patients, EFS was impaired in tumors with unfavorable histology according to the five-item score (100% vs. 30.8%, p = 0.018). No difference was observed for pS-GRAS groups (p = 0.798). CONCLUSIONS: In patients with COG stage III, but not stage II, the five-item score affected EFS. Further studies are needed to identify patients at risk in COG stage II.

[Updated AWMF Guideline on the Diagnosis and Treatment of Langerhans cell Histiocytosis in Children and Adolescents]. / Aktualisierte AWMF Leitlinie zur Diagnostik und Therapie der Langerhanszell Histiozytose (LCH) im Kindes- und Jugendalter.

Langerhans cell Histiocytosis is a rare neoplastic disease, which occurs mainly in children and adolescents. The disease may affect any organ, and therefore, the clinical symptoms vary widely. Some patients have a spontaneous remission of the disease, whereas others experience a rapid and potentially lethal clinical course. The therapeutic approach depends on the extent of the disease, and reaches from a watch-and-wait strategy to chemotherapy with the standard drugs vinblastine and prednisone. The identification of mutations in the MAPK-pathway resulted in growing interest in targeted therapy using compounds such as the BRAF inhibitors. Chronic relapses and permanent sequelae are important problems of LCH and are the focus of current research.

Solid pseudopapillary neoplasms of the pancreas in childhood and adolescence-an analysis of the German Registry for Rare Pediatric Tumors (STEP).

Solid pseudopapillary neoplasms (SPNs) are the most common entity among pediatric pancreatic tumors. Still, these are rare tumors with an annual incidence of 0.1-0.2/1,000,000, and little is known about their optimal treatment. This analysis aimed to increase knowledge about the occurrence and treatment strategies of SPN in childhood. Data regarding diagnostics, treatment, and outcome of children aged 0-18 years with SPN recorded in the German Registry for Rare Pediatric Tumors (STEP) were analyzed. Thirty-eight patients were identified with a median age of 14.5 years at diagnosis (range: 8-18) and a female preponderance (81.6%). The most frequent location of the tumor was the pancreatic tail. In histopathological and immunohistochemical examination, pseudopapillary, solid, and cystic lesions as well as expression of beta-catenin, progesterone receptors, and cyclin D1 were the most common findings. All patients underwent surgical resection. Most patients underwent open resection, predominantly tail resection for tumors in the tail region and pylorus-preserving pancreaticoduodenectomy for tumors in the head region. The main postoperative sequela was exogenous pancreatic insufficiency (23.7%), especially with SPN in the pancreatic head. No recurrence occurred during follow-up, although two patients underwent resection with microscopic residue. CONCLUSION: SPN of the pancreas in childhood are low-grade malignancies with usually favorable treatment outcomes. However, therapy can lead to relevant long-term sequelae. To prevent recurrence, complete surgical resection is recommended, sparing as much healthy pancreatic tissue as possible. Interdisciplinary collaboration between specialists is essential to optimize treatment. Molecular genetic analysis of these tumors could improve understanding of their genesis. WHAT IS KNOWN: • Solid pseudopapillary neoplasms (SPNs) of the pancreas are very rare tumors in childhood. • Little is known about tumorigenesis, and there are no specific guidelines for treatment and follow-up in pediatric patients. WHAT IS NEW: • Characteristics, treatment, and outcome were comprehensively assessed in a large cohort of pediatric patients with SPN. • We propose recommendations for diagnosis, treatment, and follow-up of children with SPN, based on our analysis and considering published experience.

Pathology of Hepatocellular Carcinoma and Tumor-Bearing Liver Tissue in Association with hTERT Promoter Mutation.

Background: The hTERT promoter mutation represents a common and early event in hepatocarcinogenesis, but its linkage to the morphological status of the underlying liver tissue is poorly understood. We analyzed the connection between the histopathological changes in tumor-bearing liver tissue and the occurrence of the hTERT promoter mutation in hepatocellular carcinoma (HCC), correlated with clinical data. Methods: The study cohort comprised 160 histologically confirmed HCC in patients with or without cirrhosis that were investigated for the hTERT promoter mutation. We evaluated the frequency of the hTERT promoter mutation in patients with HCC with or without cirrhosis and correlated it with potential clinical and histopathological drivers. In particular, we examined tumor-bearing noncirrhotic liver tissue regarding inflammation; the modified histological activity index (mHAI), fibrosis, and steatosis; and its correlation with the frequency of the hTERT promoter mutation in HCC. We evaluated overall survival with multivariate Cox regression. Furthermore, we compared hTERT antibody immunohistochemistry and molecular hTERT promoter mutation analysis of both HCC and background liver tissue. Results: The hTERT promoter mutation was especially related to HCC in cirrhotic compared with noncirrhotic liver (p < 0.001) and independently of cirrhosis in patients ≥ 60 years (p = 0.005). Furthermore, the hTERT promoter mutation was associated with cirrhosis caused by alcohol toxicity and hepatitis C virus infection. In noncirrhotic liver tissue, the frequency of hTERT-promoter-mutated HCC increased with the degree of inflammation and fibrosis. Nevertheless, 25% of the hTERT-promoter-mutated HCC developed in normal liver tissue without HCC risk factors. Multivariate Cox regression analysis did not reveal an influence of the hTERT promoter mutation in HCC on overall survival at 3, 5, and 16 years. Immunohistochemical analysis with the hTERT antibodies LS-B95 and 2D8 in hTERT-promoter-mutated HCC and hTERT-wildtype HCC showed a mildly stronger immunoreaction compared with the tumor-bearing liver tissue (LS-B95: p < 0.01, 2D8: p < 0.01). Conclusions: Our study reveals a connection between pathological changes in tumor-bearing liver tissue and the hTERT promoter mutation in most HCC, even in noncirrhotic liver tissue. Immunohistochemical hTERT antibodies do not discriminate between hTERT-promoter-mutated and wildtype HCC.

Rhabdoid tumors in patients conceived following ART: is there an association?

STUDY QUESTION: In children affected by rhabdoid tumors (RT), are there clinical, therapeutic, and/or (epi-)genetic differences between those conceived following ART compared to those conceived without ART? SUMMARY ANSWER: We detected a significantly elevated female predominance, and a lower median age at diagnosis, of children with RT conceived following ART (RT_ART) as compared to other children with RT. WHAT IS KNOWN ALREADY: Anecdotal evidence suggests an association of ART with RT. STUDY DESIGN, SIZE, DURATION: This was a multi-institutional retrospective survey. Children with RT conceived by ART were identified in our EU-RHAB database (n = 11/311 children diagnosed between January 2010 and January 2018) and outside the EU-RHAB database (n = 3) from nine different countries. A population-representative German EU-RHAB control cohort of children with RTs conceived without ART (n = 211) (EU-RHAB control cohort) during the same time period was used as a control cohort for clinical, therapeutic, and survival analyses. The median follow-up time was 11.5 months (range 0-120 months) for children with RT_ART and 18.5 months (range 0-153 months) for the EU-RHAB control cohort. PARTICIPANTS/MATERIALS, SETTING, METHODS: We analyzed 14 children with RT_ART diagnosed from January 2010 to January 2018. We examined tumors and matching blood samples for SMARCB1 mutations and copy number alterations using FISH, multiplex ligation-dependent probe amplification, and DNA sequencing. DNA methylation profiling of tumor and/or blood samples was performed using DNA methylation arrays and compared to respective control cohorts of similar age (n = 53 tumors of children with RT conceived without ART, and n = 38 blood samples of children with no tumor born small for gestational age). MAIN RESULTS AND THE ROLE OF CHANCE: The median age at diagnosis of 14 individuals with RT_ART was 9 months (range 0-66 months), significantly lower than the median age of patients with RT (n = 211) in the EU-RHAB control cohort (16 months (range 0-253), P = 0.03). A significant female predominance was observed in the RT_ART cohort (M:F ratio: 2:12 versus 116:95 in EU-RHAB control cohort, P = 0.004). Eight of 14 RT_ART patients were diagnosed with atypical teratoid rhabdoid tumor, three with extracranial, extrarenal malignant rhabdoid tumor, one with rhabdoid tumor of the kidney and two with synchronous tumors. The location of primary tumors did not differ significantly in the EU-RHAB control cohort (P = 0.27). Six of 14 RT_ART patients presented with metastases at diagnosis. Metastatic stage was not significantly different from that within the EU-RHAB control cohort (6/14 vs 88/211, P = 1). The incidence of pathogenic germline variants was five of the 12 tested RT_ART patients and, thus, not significantly different from the EU-RHAB control cohort (5/12 versus 36/183 tested, P = 0.35). The 5-year overall survival (OS) and event free survival (EFS) rates of RT_ART patients were 42.9 ± 13.2% and 21.4 ± 11%, respectively, and thus comparable to the EU-RHAB control cohort (OS 41.1 ± 3.5% and EFS 32.1 ± 3.3). We did not find other clinical, therapeutic, outcome factors distinguishing patients with RT_ART from children with RTs conceived without ART (EU-RHAB control cohort). DNA methylation analyses of 10 tumors (atypical teratoid RT = 6, extracranial, extrarenal malignant RT = 4) and six blood samples from RT_ART patients showed neither evidence of a general DNA methylation difference nor underlying imprinting defects, respectively, when compared to a control group (n = 53 RT samples of patients without ART, P = 0.51, n = 38 blood samples of patients born small for gestational age, P = 0.1205). LIMITATIONS, REASONS FOR CAUTION: RTs are very rare malignancies and our results are based on a small number of children with RT_ART. WIDER IMPLICATIONS OF THE FINDINGS: This cohort of patients with RT_ART demonstrated a marked female predominance, and a rather low median age at diagnosis even for RTs. Other clinical, treatment, outcome, and molecular factors did not differ from those conceived without ART (EU-RHAB control cohort) or reported in other series, and there was no evidence for imprinting defects. Long-term survival is achievable even in cases with pathogenic germline variants, metastatic disease at diagnosis, or relapse. The female preponderance among RT_ART patients is not yet understood and needs to be evaluated, ideally in larger international series. STUDY FUNDING/COMPETING INTEREST(S): M.C.F. is supported by the 'Deutsche Kinderkrebsstiftung' DKS 2020.10, by the 'Deutsche Forschungsgemeinschaft' DFG FR 1516/4-1 and by the Deutsche Krebshilfe 70113981. R.S. received grant support by Deutsche Krebshilfe 70114040 and for infrastructure by the KinderKrebsInitiative Buchholz/Holm-Seppensen. P.D.J. is supported by the Else-Kroener-Fresenius Stiftung and receives a Max-Eder scholarship from the Deutsche Krebshilfe. M.H. is supported by DFG (HA 3060/8-1) and IZKF Münster (Ha3/017/20). BB is supported by the 'Deutsche Kinderkrebsstiftung' DKS 2020.05. We declare no competing interests. TRIAL REGISTRATION NUMBER: N/A.

Bronchial carcinoid tumors in children and adolescents - A report and management considerations from the German MET studies.

OBJECTIVES: Bronchial carcinoid tumors (BC) are exceptionally rare in childhood, with an incidence of <0.2/1,000,000 per year. Typical low-grade BCs are distinguished from atypical, intermediate-grade BCs. Little is known about BCs in pediatric patients and management guidelines are missing. In this study, we explored characteristics and outcome of pediatric patients with BC prospectively registered with the Malignant Endocrine Tumor studies. MATERIAL AND METHODS: We performed a retrospective multicenter study in children, adolescents, and young adults (aged 0-20 years) with BC reported to the German MET registry between January 1997 and December 2022. Data were last updated on 28 of February 2023. RESULTS: Thirty-two patients were diagnosed at a median age of 15.0 years (range, 9.8-19.2). Atypical BCs (23.3%) were less frequent than typical, but more common than in adulthood. Lymph node metastases were present in 14.3% of cases (atypical BC: 28.6%, typical BC: 10.5%), distant metastases in one (3.1%) patient with atypical BC. 92.6% of patients were in complete remission after surgical resection (median follow-up: 2.7 years). The patient with metastatic spread and one patient with atypical BC and multiple recurrences were on treatment at last follow-up. 5-year event-free survival of typical BC was 100% and 83.3% in atypical BC. CONCLUSIONS: Completely resected localized BCs in pediatric patients have a favorable outcome also with lung tissue sparing surgery. Atypical BC with risk of metastatic spread and recurrence occurred more frequently compared to adults. Interdisciplinary management and collaborative efforts are needed to improve our understanding and the management of pediatric BC.

Progression and Relapse of Pediatric Soft Tissue Sarcoma: Individualized Approach of Treatment - Experience from a Major Pediatric Cancer Center in Europe.

BACKGROUND: The outcome of children with refractory or relapsed soft tissue sarcoma (STS) is extremely poor. Whereas larger clinical trials evaluated specific treatment modalities, real-life data on individual multimodal therapeutic strategies, given alone or in combination, are scarce. PATIENTS AND METHODS: We retrospectively analyzed the clinical course of 18 pediatric patients with progression of or relapsed STS treated between 2008 and 2018 in our institution. RESULTS: A total of 18 patients (median age 12.4 years) suffered from progression or relapse of alveolar (n=7), embryonal (n=5), undifferentiated (n=2) rhabdomyosarcoma or desmoplastic small round cell tumor (n=4). 14 patents had an initial stage IV disease. All but one patient died. Median survival was 12.5 months. Shortest survival was seen in patients with systemic progression of the disease, longest in patients with local relapse. Patients with an Oberlin score<2 at the time of relapse had a significant longer time of survival than those with a score≥2. No significant advantage of a specific therapeutic modality was observed. DISCUSSION: We critically analyzed the clinical course in the real-life setting, in which various treatment options were applied to an individual patient according to the best of available data. We observed that some patients died within a short period of time despite multiple treatment modalities, which underlines the need for better prognostic parameters. CONCLUSION: In addition to well characterized clinical factors such as local or systemic relapse, the Oberlin score could be helpful in counselling patients and their families for choosing the best strategy of care.

A multi-step approach to the treatment of giant scalp congenital hemangiomas: a report of two cases.

This is a review of two cases of neonatal giant scalp congenital hemangioma. Both patients were treated with propranolol using a similar multi-step approach that included transarterial embolization of the supplying arteries followed by surgical resection of the lesion. In this report, we discuss the treatments, complications, and clinical outcomes of interventions and surgical procedures.

ESTRO/ESGO/SIOPe Guidelines for the management of patients with vaginal cancer.

Primary vaginal malignancies are rare, comprising only 2% of all female genital tract malignancies in adults and 4.5% in children. As part of its mission to improve the quality of care for women with gynecological cancers across Europe, the European Society of Gynaecological Oncology (ESGO) jointly with the European Society for Radiotherapy & Oncology (ESTRO) and the European Society of Pediatric Oncology (SIOPe) developed evidence-based guidelines in order to improve the management of patients with vaginal cancer within a multidisciplinary setting.ESTRO/ESGO/SIOPe nominated practicing clinicians who are involved in the management of vaginal cancer patients and have demonstrated leadership through their expertise in clinical care and research, their national and international engagement and profile as well as dedication to the topics addressed to serve on the expert panel (13 experts across Europe comprising the international development group). To ensure that the statements were evidence based, the current literature was reviewed and critically appraised.In the case of absence of any clear scientific evidence, judgment was based on the professional experience and consensus of the international development group. Prior to publication, the guidelines were reviewed by 112 independent international practitionners in cancer care delivery and patient representatives and their comments and input were incorporated and addressed accordingly.These guidelines cover comprehensively the diagnostic pathways as well as the surgical, radiotherapeutical and systemic management and follow-up of adult patients (including those with rare histological subtypes) and pediatric patients (vaginal rhabdomyosarcoma and germ cell tumours) with vaginal tumours.

Consensus classification of pediatric hepatocellular tumors: A report from the Children's Hepatic tumors International Collaboration (CHIC).

BACKGROUND: Liver tumors are rare in children with histologic heterogeneity that makes diagnosis challenging. Systematic histopathological review, performed as part of collaborative therapeutic protocols, identified relevant histologic subtypes that are important to distinguish. The Children's Hepatic tumors International Collaboration (CHIC) was established to study pediatric liver tumors on a global scale and led to establishment of a provisional consensus classification for use in international clinical trials. The current study is the validation of this initial classification and first large-scale application by international expert reviewers. PROCEDURE: The CHIC initiative includes data from 1605 children treated on eight multicenter hepatoblastoma (HB) trials. Review of 605 available tumors was performed by seven expert pathologists from three consortia (US, EU, Japan). Cases with discordant diagnoses were collectively reviewed to reach a final consensus diagnosis. RESULTS: Of 599 cases with sufficient material for review, 570 (95.2%) were classified as HB by all consortia, and 29 (4.8%) as non-HB, which included "hepatocellular neoplasm, NOS" and malignant rhabdoid tumors. 453 of 570 HBs were classified as epithelial by final consensus. Some patterns (i.e., small cell undifferentiated, macrotrabecular, cholangioblastic) were selectively identified by reviewers from different consortia. All consortia identified a similar number of mixed epithelial-mesenchymal HB. CONCLUSIONS: This study represents the first large-scale application and validation of the pediatric malignant hepatocellular tumors consensus classification. It is a valuable resource to train future generations of investigators on accurate diagnosis of these rare tumors and provides a framework for further international collaborative studies and refinement of the current classification of pediatric liver tumors.