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The increased availability of genetic technologies has significantly improved the detection of novel germline variants conferring a predisposition to tumor development in patients with malignant disease. The identification of variants of uncertain significance (VUS) represents a challenge for the clinician, leading to difficulties in decision-making regarding medical management, the surveillance program, and genetic counseling. Moreover, it can generate confusion and anxiety for patients and their family members. Herein, we report a 5-year-old girl carrying a VUS in the Succinate Dehydrogenase Complex Subunit C (SHDC) gene who had been previously treated for highrisk neuroblastoma and subsequently followed by the development of secondary acute myeloid leukemia. In this context, we describe how functional studies can provide additional insight on gene function determining whether the variant interferes with normal protein function or stability. [ABSTRACT FROM AUTHOR]

Background: Germ cell tumors (GCT) account for a minority of central nervous system (CNS) malignancies, highly prevalent in adolescents and young adults. Despite their aggressive biological behavior, prognosis is excellent in most cases with risk stratified treatment, consisting in a combination of chemotherapy and radiotherapy. Whole ventricular irradiation (WVI) and craniospinal irradiation, the treatment of choice for localized and metastatic disease, pose significant risk of collateral effects, therefore proton beam radiation (PBT) has been recently proposed for its steep dose fallout. Materials and methods: We report our experience in a consecutive series of 17 patients treated for CNS GCT at our Institution from 2015 to 2021. Results: Most frequent lesion location were sellar/suprasellar (35%) and bifocal germinoma (35%), followed by pineal (18%) and thalamic (12%). Two patients (12%), had evidence of disseminated disease at the time of diagnosis. At the latest follow-up all but one patient showed complete response to treatment. The only relapse was successfully rescued by additional chemotherapy and PBT. PBT was well tolerated in all cases. No visual, neurological or endocrinological worsening was documented during and after treatment. Neuropsychological evaluation demonstrated preservation of cognitive performance after PBT treatment. Conclusions: Our data, albeit preliminary, strongly support the favourable therapeutic profile of PBT for the treatment of CNS germ cell tumors. [ABSTRACT FROM AUTHOR]

Neuroblastoma (NB) is a childhood tumor that originates in the peripheral sympathetic nervous system and is responsible for 15% of cancer-related deaths in the pediatric population. Despite intensive multimodal treatment, many patients with high-risk NB relapse and develop a therapy-resistant tumor. One of the phenomena related to therapeutic resistance is intratumor heterogeneity resulting from the adaptation of tumor cells in response to different selective environmental pressures. The transcriptional and epigenetic profiling of NB tissue has recently revealed the existence of two distinct cellular identities in the NB, termed adrenergic (ADRN) and mesenchymal (MES), which can spontaneously interconvert through epigenetic regulation. This phenomenon, known as tumor plasticity, has a major impact on cancer pathogenesis. The aim of this review is to describe the peculiarities of these two cell states, and how their plasticity affects the response to current therapeutic treatments, with special focus on the immunogenic potential of MES cells. Furthermore, we will discuss the opportunity to combine immunotherapy with chemotherapy to counteract NB phenotypic interconversion. [ABSTRACT FROM AUTHOR]

Phosphatase and tensin homolog (PTEN) hamartoma tumor syndrome (PHTS) is a cancer predisposition syndrome characterized by an increased risk of developing benign and malignant tumors, caused by germline pathogenic variants of the PTEN tumour suppressor gene. PTEN gene variants often present in childhood with macrocephaly, developmental delay, and/or autism spectrum disorder while tumors and intestinal polyps are commonly detected in adults. PHTS is rarely associated with childhood brain tumors with only two reported cases of medulloblastoma (MB). We report the exceptional case of an infant carrying a germline and somatic pathogenic variant of PTEN and a germline and somatic pathogenic variant of CHEK2 who developed a MB SHH in addition to intestinal polyposis. [ABSTRACT FROM AUTHOR]

Simple Summary: Patients with thoracic neuroblastoma are at high risk of operative neurologic complications due to iatrogenic lesions of the artery of Adamkiewicz (AKA), reducing the possibilities of gross total resection. Therefore, the role of preoperative spinal angiography in such patients must be defined. This study aimed to investigate the role of spinal angiography in thoracic neuroblastoma and the impact of accurately identifying the AKA on surgical resection and neurological complications. Background: Patients with thoracic neuroblastoma (TNB) are at high risk of postoperative neurologic complications due to iatrogenic lesions of the artery of Adamkiewicz (AKA). The role of performing a preoperative spinal angiography (POSA) in these patients must be clarified. The present study sought to further understand the relationship between POSA and TNB, as well as the effects of identifying the AKA on surgical excision and neurological consequences. Methods: Data from patients with TNB who underwent POSA between November 2015 and February 2022 at our tertiary pediatric center were retrospectively analyzed. Results: Six patients were identified, five of whom (83%) were considered eligible for surgical excision. Gross total resection (GTR) was achieved in three patients (60%), which included two patients with an AKA contralateral to the tumor, and one with an homolateral AKAl. After a median follow-up of 4.1 years from diagnosis, no patients developed neurological complications; five (83%) were alive and well, and one died from refractory recurrence. Conclusions: Among patients with TNB, POSA was useful for identifying the AKA and defining the optimal surgical strategy. POSA should be considered in the preoperative evaluation of TNB to increase the likelihood of GTR and reduce the threats of iatrogenic neurologic sequelae. [ABSTRACT FROM AUTHOR]

Simple Summary: Central nervous system (CNS) metastatic spread in neuroblastoma (NB) is rare and occurs more often at relapse/progression. In this retrospective study, we reviewed the CNS imaging of all the patients treated at the Bambino Gesù Children Hospital over a 25-year period. CNS metastasis in NB is confirmed to be rare, occurring in 4.7% of patients, and associated with advanced disease and bone skull involvement. In the last decade, the involvement of CNS at relapse has been observed more frequently, supporting the rising concern of the impact of immunotherapy in the pattern of relapse in high risk (HR) NB. Further studies are needed to confirm a higher CNS relapse risk in the immunotherapy era as well as the need for including CNS imaging in follow-up. Central nervous system (CNS) metastatic spread in neuroblastoma (NB) is rare and occurs more often at relapse/progression. We report on CNS involvement in high risk (HR) NB over 25 years. For this retrospective study, we reviewed the CNS imaging of all the patients treated at Bambino Gesù Children Hospital from 1 July 1996 to 30 June 2022. A total of 128 patients with HR NB were diagnosed over 26 years. Out of 128 patients, CNS metastatic spread occurred in 6 patients: 3 patients presented a metastatic spread at diagnosis, while in 3 patients, CNS was involved at relapse. Overall, the rate of occurrence of CNS spread is 4.7% with the same distribution at diagnosis and at relapse, namely 2.3%. Interestingly, CNS spread at diagnosis was observed only before 2012, whereas CNS was observed at relapse only after 2012, in the immunotherapy era. CNS metastases presented similar imaging features at diagnosis and at relapse, with a peculiar hemorrhagic aspect and mainly hemispheric localization in patients with bone skull involvement at the time of diagnosis. The outcome is dismal, and 3 out of 6 patients died for progressive disease. [ABSTRACT FROM AUTHOR]

We reported a new pathogenic variant of LRBA deficiency with a complex phenotype—neonatal diabetes, very early-onset inflammatory bowel disease, and polyarthritis—who presented with lymph node enlargement. A case of Rosai-Dorfman’s disease (RDD) was confirmed. The occurrence of an RDD lesion in LRBA-deficiency has never been reported so far. [ABSTRACT FROM AUTHOR]

Neuroblastic tumors (NTs) represent the most common extracranial neoplasm occurring in childhood. Although ganglioneuroblastoma intermixed (GNBI) and ganglioneuroma (GN) are classified as very low-risk tumors, neuroblastoma (NB) and ganglioneuroblastoma-nodular (GNBN) may represent a serious risk to survival. Unfortunately, areas of GNBI and GNBN can coexist in the same mass, leading to incorrect risk staging when only biopsy is performed. Herein, we describe a case of multifocal NT (thoracic and abdominal localization) occurring in a 4-year-old male. Different histological subtypes, namely GNBI and GNBN, were revealed in the two lesions. We focus on the difficulties of proper diagnosis and risk stratification, underlining the usefulness of several diagnostic tools for appropriate management and therapeutic choices. [ABSTRACT FROM AUTHOR]

Primary leptomeningeal melanoma (PLMM) is a very rare disease in childhood with a poor prognosis. NRASQ16K mutation frequently drives malignant transformation in this population, so its evaluation should be considered in childhood PLMM diagnosis. In the presented case, the mutation was detected by Sanger sequencing performed on DNA extracted from cerebrospinal fluid neoplastic cells. Liquid biopsy has been shown to be a safe and reliable technique for the diagnosis of PLMM. Its use can potentially be extended to other neoplasms of the central nervous system bearing well-defined molecular mutations, sparing the patient invasive surgery and finally allowing a more rapid diagnosis and early initiation of targeted therapies. [ABSTRACT FROM AUTHOR]

Simple Summary: Ewing sarcoma is a rare and aggressive tumor of childhood and adolescence. Over the years, different prognostic factors have been explored to stratify high-risk patients. The roles of C-reactive protein (CRP) and serum lactate dehydrogenase (LDH) as potential new prognostic factors would be a useful and simple for risk stratification, but they have rarely been investigated. In our work, we analyze the role of LDH and CRP as prognostic factors in a population of pediatric and adolescent patients affected by Ewing sarcoma. Our study confirms the potential prognostic role of LDH at diagnosis as an independent prognostic factor. LDH evaluation is not expensive, and it can be beneficial for developing countries where diagnostic and staging resources in the pediatric oncology field are poor. Background: Ewing sarcoma (ES) is a rare and aggressive pediatric cancer. Numerous studies have attempted to identify new prognostic biomarkers. The predictive value of serum LDH and CRP has not been clearly described, to date. Methods: The objective of our retrospective study was to investigate the prognostic value of LDH and CRP levels and their association with overall survival in a series of ES patients. Results: Between 2004 and 2019, 89 ES patients were included. In a univariable analysis, high levels of LDH and CRP were associated with the worst prognosis. In a multivariable analysis, only higher LDH values remained associated with a lower survival. The high-LDH-level group experienced all 21 deaths registered in our population (24%) and about 90% of disease progressions. The 5-year overall survival was 66.4% in the high-LDH-level group, while no deaths were observed in the low-LDH-level group. The 5-year progression-free survival was 57.9% in the high-LDH-level group versus 80.4% in the low-LDH-level group. Conclusions: In our study, LDH levels at diagnosis were strongly correlated with the prognosis, and they might be considered a prognostic factor in Ewing sarcoma. The LDH value, along with its very low cost and its reproducibility in almost all centers, make it suitable as a potential prognostic biomarker in clinical practice. [ABSTRACT FROM AUTHOR]

Simple Summary: Neonatal cancer represents a heterogeneous group of neoplasms with a wide range of clinical, biological, and prognostic features. Characterizing genetic cancer risk is critical for improving short- and long-term patient care, notably in this category of patients. In this article we aimed to describe the main features of neonates diagnosed with cancer in our centre during a 15-year period and to emphasize the importance of genetic screening and its implication in treatment strategies and prognosis. The occurrence of cancer in newborns within the first 28 days of life is uncommon, with different clinical presentation from other age groups. Prenatal diagnosis is reported in about half of patients, while a genetic predisposition condition is supposed. The management of a newborn with cancer can be challenging and needs to be tailored according to the histology and the primary tumor site; surgery represents the main strategy, while chemotherapy should be considered with caution because of the higher toxicity and mortality due to different pharmacokinetics in neonates compared to older children. We describe the first Italian series over a 15-year period of patients affected by both benign and malignant neoplastic diseases diagnosed within the first 28 days of life; 74 newborns were diagnosed with neonatal tumors, representing 1.5% of the cancer population in the same period, and a prevalence of germ cell tumors (55%) and neuroblastoma (16%) was observed. Surgery was performed on 80% of patients, while chemotherapy was necessary for about 20% of patients. The 5-year overall survival (OS) exceeded 90%; treatment-related deaths are a major concern, representing 80% of overall deaths. A genetic/syndromic condition was detected in 16% of the population; additionally, a cancer predisposition syndrome (CPS) was identified in about 10% of patients. According to our experience, all newborns affected by cancer should warrant genetic counselling and a screening test for CPS. [ABSTRACT FROM AUTHOR]

Langerhans cell histiocytosis (LCH) is due to aberrant monoclonal proliferation and accumulation of dendritic cells, ranging from a self-limiting local condition to a rapidly progressive multisystem disease with poor prognosis. Pathogenic cells originate from a myeloid-derived precursor characterized by an activation of the MAPK/ERK signaling pathway in about 70% of cases. In particular, BRAF V600E mutation is usually associated with a more severe clinical course and poor response to chemotherapy. We report on a newborn with multisystem LCH in life-threatening medical conditions. At diagnosis, the patient was successfully treated with the early association of BRAF inhibitor Vemurafenib to standard chemotherapy representing a new approach in first-line treatment. A rapid clinical improvement with a prompt fever regression from day 2 and complete resolution of skin lesions by week 2 were observed; laboratory data normalized as well. Vemurafenib was discontinued after 12 months of treatment. No signs of relapse occurred after 12 months of discontinuation. This case indicates that early combination of target therapy with standard treatment may induce rapid response and prolonged disease remission without significant toxicities in infants. This approach represents a valid and safe option as first-line treatment in multisystem disease, especially in high-risk patients. [ABSTRACT FROM AUTHOR]

Inflammatory myofibroblastic tumor (IMT) is a rare disease that mainly involves the lung and the abdomen with an intermediate clinical course but a recurrence rate between 15–30%. Radical surgery represents the gold standard of treatment, while chemotherapy and radiotherapy are considered for unresectable lesions. The identification of ALK translocations in IMT opened the option for the use of target therapies. Indeed, the ALK inhibitors have changed the treatment approach for aggressive lesions, improving the prognosis. Intraluminal upper-way IMT is extremely rare and represents a medical challenge. We reported an endotracheal IMT case presenting a previously unknown TRAF3-ALK fusion transcript. [ABSTRACT FROM AUTHOR]

DICER1 syndrome is a rare genetic condition predisposing to hereditary cancer and caused by variants in the DICER1 gene. The risk to present a neoplasm before the age of 10 years is 5.3 and 31.5% before the age of 60. DICER1 variants have been associated with a syndrome involving familial pleuropulmonary blastoma (PPB), a rare malignant tumor of the lung, which occurs primarily in children under the age of 6 years and represents the most common life-threatening manifestation of DICER1 syndrome. Type I, II, III, and Ir (type I regressed) PPB are reported with a 5-year overall survival ranging from 53 to 100% (for type Ir). DICER1 gene should be screened in all patients with PPB and considered in other tumors mainly in thyroid neoplasms (multinodular goiter, thyroid cancer, adenomas), ovarian tumors (Sertoli-Leydig cell tumor, sarcoma, and gynandroblastoma), and cystic nephroma. A prompt identification of this syndrome is necessary to plan a correct follow-up and screening during lifetime. [ABSTRACT FROM AUTHOR]

Ectopic ACTH syndrome is rare in pediatric age. Sarcomas that cause Ectopic ACTH Syndrome (EAS) are even more uncommon. Currently, only three cases of EAS caused by Ewing' sarcoma have been reported. We detail a 10-year-old boy with Cushing's syndrome symptoms caused by ectopic ACTH production by a metastatic Ewing's sarcoma of the right ischio-pubic and ileo-pubic branches. The rapid appearance of cushingoid symptoms, with significant weight gain, acne, hirsutism, and hypercortisolism were implications of ectopic ACTH production as paraneoplastic Cushing's Syndrome. The very high levels of ACTH and non-suppression at the high dose dexamethasone test confirmed the clinical suspicion. We underline the possibility EAS was caused by an ACTH-secreting tumor, including soft tissue sarcomas. [ABSTRACT FROM AUTHOR]

Background: Retinoblastoma (RB) is the most common malignant childhood tumor of the eye and results from inactivation of both alleles of the RB1 gene. Nowadays RB genetic diagnosis requires classical chromosome investigations, Multiplex Ligation-dependent Probe Amplification analysis (MLPA) and Sanger sequencing. Nevertheless, these techniques show some limitations. We report our experience on a cohort of RB patients using a combined approach of Next-Generation Sequencing (NGS) and RB1 custom array-Comparative Genomic Hybridization (aCGH).Methods: A total of 65 patients with retinoblastoma were studied: 29 cases of bilateral RB and 36 cases of unilateral RB. All patients were previously tested with conventional cytogenetics and MLPA techniques. Fifty-three samples were then analysed using NGS. Eleven cases were analysed by RB1 custom aCGH. One last case was studied only by classic cytogenetics. Finally, it has been tested, in a lab sensitivity assay, the capability of NGS to detect artificial mosaicism series in previously recognized samples prepared at 3 different mosaicism frequencies: 10, 5, 1 %.Results: Of the 29 cases of bilateral RB, 28 resulted positive (96.5 %) to the genetic investigation: 22 point mutations and 6 genomic rearrangements (four intragenic and two macrodeletion). A novel germline intragenic duplication, from exon18 to exon 23, was identified in a proband with bilateral RB. Of the 36 available cases of unilateral RB, 8 patients resulted positive (22 %) to the genetic investigation: 3 patients showed point mutations while 5 carried large deletion. Finally, we successfully validated, in a lab sensitivity assay, the capability of NGS to accurately measure level of artificial mosaicism down to 1 %.Conclusions: NGS and RB1-custom aCGH have demonstrated to be an effective combined approach in order to optimize the overall diagnostic procedures of RB. Custom aCGH is able to accurately detect genomic rearrangements allowing the characterization of their extension. NGS is extremely accurate in detecting single nucleotide variants, relatively simple to perform, cost savings and efficient and has confirmed a high sensitivity and accuracy in identifying low levels of artificial mosaicisms. [ABSTRACT FROM AUTHOR]

Background: Local control is always considered in metastatic neuroblastoma (NBL). The aim of this study is to evaluate the impact of radical surgery on survival in children over 1 year of age. Methods: Fifty-eight patients older than 1 year of age with metastatic NBL were treated with conventional plus high-dose chemotherapy with or without addition of local radiotherapy (RT, 21Gy). Surgery was classified as radical surgery (complete resection and gross total resection) or non-radical surgery. The Kaplan-Meier method and the Cox proportional hazard model were used to calculate the probability of progression free and overall survival (PFS and OS) and for multivariate analysis. Results: The 5-year PFS and OS for patients with radical surgery were 26% (95% CI 14-40%) and 38% (95% CI 23-53%) respectively, while the PFS and OS for patients without radical surgery were 33% (95% CI 10-59%) and 31% (95% CI 10-55%) (respectively, P 0.85 and P 0.42). The 5-year PFS and OS for patients who received RT were 36% (95% CI 19-53%) and 46% (95% CI 26-64%) respectively, while the 5-year PFS and OS for patients who did not receive RT were 22% (95% CI 9-38%) and 27% (95% CI 13-42%) respectively (P 0.02 for PFS). Multivariate analysis confirmed the role of well-known prognostic factors, such as the presence of MYCN amplification, age and response before high-dose chemotherapy. Conclusions: Our data suggest that the degree of resection does not influence survival in metastatic NBL patients treated with high-dose chemotherapy; local RT contributes to local disease control. [ABSTRACT FROM AUTHOR]

Background Medulloepithelioma (ME) is a rare embryonal tumor predominantly located in the eye or in the central nervous system without an established treatment. Case presentation We report of a case of a localized peripheral ME treated with conventional and high dose chemotherapy, surgery and local radiotherapy. At relapse, the tumor tissue revealed a different molecular signature compared to the initial tumor mass. This molecular signature revealed a high expression of platelet derived growth factor receptor (PDGFR). Sorafenib plus irinotecan and temozolomide was started with a 5 month progression free survival. Conclusion Our experience suggests a possible role of sorafenib or different PDGFR inhibitors in ME. Targeting treatment could represent an adjuvant and/or alternative therapy for ME and other rare tumors. [ABSTRACT FROM AUTHOR]

Neuroblastoma (NB), the most common solid cancer in early childhood, usually occurs sporadically but also its familial occurance is known in 1-2% of NB patients. Germline mutations in the ALK and PHOX2B genes have been found in a subset of familial NBs. However, because some individuals harbouring mutations in these genes do not develop this tumor, additional genetic alterations appear to be required for NB pathogenesis. Herein, we studied an Italian family with three NB patients, two siblings and a first cousin, carrying an ALK germline-activating mutation R1192P, that was inherited from their unaffected mothers and with no mutations in the PHOX2B gene. A comparison between somatic and germline DNA copy number changes in the two affected siblings by a high resolution array-based Comparative Genomic Hybridization (CGH) analysis revealed a germline gain at NKAIN2 (Na/K transporting ATPase interacting 2) locus in one of the sibling, that was inherited from the parent who does not carry the ALK mutation. Surprisingly, NKAIN2 was expressed at high levels also in the affected sibling that lacks the genomic gain at this locus, clearly suggesting the existence of other regulatory mechanisms. High levels of NKAIN2 were detected in the MYCN-amplified NB cell lines and in the most aggressive NB lesions as well as in the peripheral blood of a large cohort of NB patients. Consistent with a role of NKAIN2 in NB development, NKAIN2 was down-regulated during all-trans retinoic acid differentiation in two NB cell lines. Taken together, these data indicate a potential role of NKAIN2 gene in NB growth and differentiation. [ABSTRACT FROM AUTHOR]

Background: Ewing Sarcoma Family Tumours (ESFT) are rare in early childhood. The aim of this study was to report the clinical characteristics and outcome of children under 6 years of age affected by ESFT of the bone in Italy. Methods:The records of all the children diagnosed with osseous ESFT in centres members of the Associazione Italiana di Ematologia ed Oncologia Pediatrica (AIEOP) from 1990 to 2008 were reviewed. The Kaplan--Meier method was used for estimating overall and progression-free survival (OS, PFS) curves; multivariate analyses were performed using Cox proportional hazards regression model. Results:This study includes 62 patients. An axial primary localization was present in 66% of patients, with the primary site in the chest wall in 34%. Fourteen (23%) patients presented metastatic disease. The 5-year OS and PFS were 73% (95% confidence interval, CI, 58-83%) and 72% (95% CI 57-83%) for patients with localized disease and 38% (95% CI 17-60%) and 21% (95% CI 5-45%) for patients with metastatic disease. Metastatic spread, skull/pelvis/spine primary localization, progression during treatment and no surgery predicted worse survival (P<0.01), while patients treated in the last decade had better survival (P = 0.002). In fact, the 5-year OS and PFS for patients diagnosed in the period 2000-2008 were 89% (95% CI 71-96%) and 86% (95% CI 66-94%), respectively. Conclusion: The axial localization is the most common site of ESFT in pre-scholar children. Patients treated in the most recent period have an excellent outcome. [ABSTRACT FROM AUTHOR]