UV-radiation and MC1R germline mutations are risk factors for the development of conventional and spitzoid melanomas in children and adolescents.

BACKGROUND: Genomic characterisation has led to an improved understanding of adult melanoma. However, the aetiology of melanoma in children is still unclear and identifying the correct diagnosis and therapeutic strategies remains challenging. METHODS: Exome sequencing of matched tumour-normal pairs from 26 paediatric patients was performed to study the mutational spectrum of melanomas. The cohort was grouped into different categories: spitzoid melanoma (SM), conventional melanoma (CM), and other melanomas (OT). FINDINGS: In all patients with CM (n = 10) germline variants associated with melanoma were found in low to moderate melanoma risk genes: in 8 patients MC1R variants, in 2 patients variants in MITF, PTEN and BRCA2. Somatic BRAF mutations were detected in 60% of CMs, homozygous deletions of CDKN2A in 20%, TERTp mutations in 30%. In the SM group (n = 12), 5 patients carried at least one MC1R variant; somatic BRAF mutations were detected in 8.3%, fusions in 25% of the cases. No SM showed a homozygous CDKN2A deletion nor a TERTp mutation. In 81.8% of the CM/SM cases the UV damage signatures SBS7 and/or DBS1 were detected. The patient with melanoma arising in giant congenital nevus (CNM) demonstrated the characteristic NRAS Q61K mutation. INTERPRETATION: UV-radiation and MC1R germline variants are risk factors in the development of conventional and spitzoid paediatric melanomas. Paediatric CMs share genomic similarities with adult CMs while the SMs differ genetically from the CM group. Consistent genetic characterization of all paediatric melanomas will potentially lead to better subtype differentiation, treatment, and prevention in the future. FUNDING: Found in Acknowledgement.

Pre-operative dosing of dexamethasone for the management of children with posterior fossa tumours: are we getting it right?

INTRODUCTION: Posterior fossa (PF) tumours are associated with vasogenic oedema causing symptoms of raised intracranial pressure. Preoperatively this is managed with dexamethasone. To minimise steroid related complications, the lowest effective dose should be administered. No neurosurgical guidelines exist for pre-operative dosing of dexamethasone in PF tumours. METHODS: A retrospective review was performed of surgically managed cases for patients under 16 years of age between 2013 and 2018 to ascertain the initial dose of dexamethasone with symptomatic PF tumours. RESULTS: Thirty-six patients were identified of which 30 notes were available. Sixteen were male. Median age was 6 years (range 10 months - 15 years). Twenty-two (73%) were referrals from DGH and 8 (27%) presented to our neurosurgical centre. All patients presented with symptomatic PF tumours including headache (97%), vomiting (93%), gait disturbance (43%), and nystagmus (17%). Four (13%) had papilloedema. Average initial stat dexamethasone dose was 9.15 mg; 0.31 mg/kg (range 1-16.7 mg; 0.05 - 1.77 mg/kg). Stratified according to weight, average dose (and range) was 8.8 mg; 0.94 mg/kg (1-16.6 mg; 0.13 - 1.77 mg/kg) in those weighing <10 kg; 9.7 mg; 0.66 mg/kg (4-16.7 mg; 0.21 - 1.35 mg/kg) in 10-20 kg; 12.3 mg;0.52 mg/kg (8-16.7 mg; 0.27 - 0.73mg/kg) in 20-30 kg and 7.8 mg; 0.17mg/kg (2-16.7 mg; 0.0 - 0.39 mg/kg) in >30 kg up to a maximum of 16.6 mg in any 24h period. These results suggest that dosage was higher in those children weighing less. PPI was used in 24 (80%) of cases. All doses were reduced after review by the neurosurgical team and a PPI added. CONCLUSION: Pre-operative dexamethasone dosing does not always reflect the severity of clinical symptoms for PF tumours. Guidelines are required to correlate clinical symptoms with a suggested suitable dose of dexamethasone to prevent overdose and complications associated with corticosteroid use. We recommend a weight-based regimen as provided by the Food and Drug Administration. The current advice is for 0.02-0.3mg/kg/day in 3-4 divided doses.

Harnessing brain development to understand brain tumours.

Brain tumours are the commonest solid neoplasms in children, accounting for one quarter of all childhood cancers. Our growing knowledge of basic developmental mechanisms has significantly contributed to understanding the pathogenesis of these tumours and is beginning to impact clinical decisions on how children with these diseases are treated.

An unexpected diagnosis of paediatric subcutaneous sacrococcygeal extraspinal ependymoma: lessons learnt and review of the literature.

This case describes a 9-year-old male who presented to general surgical clinic with a 3-year history of persistent natal cleft swelling, previously unsuccessfully treated as a pilonidal abscess in the community with multiple courses of antibiotics. In clinic, a 50 × 30-mm soft tissue swelling was found in the natal cleft and a clinical diagnosis of a pilonidal cyst was made. A cream-coloured solid mass measuring 50 × 35 × 30 mm was subsequently excised under general anaesthetic, with specialist histology and immunostaining confirming an unexpected diagnosis of a subcutaneous extraspinal myxopapillary ependymoma, a tumour usually found in the neuraxis. Given the atypical anatomical site of the tumour, the case presented a unique management challenge. Ultimately, the patient underwent a re-operation after specialist multi-disciplinary discussion and is currently disease free at 18 months post-surgery. The authors wish to contribute their experiences of managing this rare extraspinal ependymoma to the few existing reports in the literature.

Anterior Mediastinal Mass in a Child-Known but Rare Entity.

Thymomas are exceedingly rare tumours of the anterior mediastinum in children. An early awareness helps timely surgical intervention. Thymomas can occasionally be extremely aggressive. The loss of contour on chest X-Ray, to be confirmed as a large anterior mediastinal mass at computerised tomography, serves identification of a typical bilobed thymic tumour.

Neuroendocrine late effects after tailored photon radiotherapy for children with low grade gliomas: Long term correlation with tumour and treatment parameters.

PURPOSE: To evaluate neuroendocrine late effects in paediatric patients with low grade glioma (LGG) who underwent radiotherapy. METHODS AND MATERIAL: We performed a retrospective evaluation of 40 children with LGG treated from July 2002 to January 2015 with external radiotherapy. Tumour locations were cerebral hemisphere (n=2); posterior fossa (n=15); hypothalamic-pituitary axis (HPA, n=15); spine (n=5). Three patients presented a diffuse disease. We looked for a correlation between endocrine toxicity and tumour and treatment parameters. The impact of some clinical and demographic factors on endocrinal and neuro toxicity was evaluated using the log-rank test. RESULTS: The median follow-up was 52months (range: 2-151). Median age at irradiation was 6. The dose to the HPA was significantly associated with endocrine toxicity (P value=0.0190). Patients who received chemotherapy before radiotherapy and younger patients, showed worse performance status and lower IQ. The 5-year overall survival (OS) and progression free survival (PFS) rates were 94% and 73.7%, respectively. CONCLUSION: Radiotherapy showed excellent OS and PFS rates and acceptable late neuroendocrine toxicity profile in this population of LGG patients treated over a period of 13years. In our experience, the dose to the HPA was predictive of the risk of late endocrine toxicity.

Angiocentric glioma transformed into anaplastic ependymoma: Review of the evidence for malignant potential.

Angiocentric glioma (AG) is a low grade glioma, that was first described in 2002. Since this description, 83 patients with AG have been described, including ours. AG typically presents in childhood with medically refractory seizures that are cured with gross surgical resection. Whilst the natural history is that of a benign tumour, there have been reports of recurrence, transformation, and malignant features that suggest that AG is potentially malignant. We add to the literature a case of a 16-year-old girl who presented in May 2011 with a 3-month history of complex partial seizures, with MRI showing a T2-weighted hyperintense lesion in the left insula and inferior frontal lobe. This was confirmed on biopsy as AG and was followed with surveillance imaging. In April 2012, she presented with disease progression and underwent a left temporal lobectomy, with histology showing both AG and grade II astrocytoma. Adjuvant radiotherapy of 50 Gray in 28 fractions was administered. A small area of contrast enhancement appeared in the left parietal lobe in December 2012, which progressed over subsequent months. In June 2013, she underwent a near total excision, with histology showing anaplastic ependymoma. She received six cycles of adjuvant temozolamide. Despite this, the tumour continued to progress, with her seizure control deteriorating, and the development of a right hemiparesis. The patient died in January 2014, aged 19years.

Thymoma and thymic carcinoma in children and adolescents: a report from the European Cooperative Study Group for Pediatric Rare Tumors (EXPeRT).

BACKGROUND: Thymomas and thymic carcinomas belong to a group of thymic epithelial tumours arising from the anterior mediastinum and, are extremely rare in children in which no therapeutic guidelines have been established. The aim is to describe paediatric characteristics of these tumours and give some therapeutic indications. METHODS: Retrospective analysis of clinical data and therapeutic characteristics of paediatric patients less than 18years with thymic tumours treated between 2000 and 2012 registered in the European Cooperative Study Group for Pediatric Rare Tumors (EXPeRT) database of the cooperating national rare paediatric tumour working groups from France, Italy, Germany and Poland. RESULTS: Sixteen children with thymoma, median age 11years and 20 patients with thymic carcinoma, median age 14years were enrolled into study. At diagnosis complete primary resection was possible in 11 patients with thymoma and one with thymic carcinoma; resection with microscopic residue was performed in three cases and incomplete resection with macroscopic residue in four patients. Chemotherapy with various regimens was administered to 22 children; 17 of them as neoadjuvant chemotherapy. Eight patients with thymic carcinoma received additional radiotherapy. Seventeen children died (15 thymic carcinoma, two thymoma). Five-year overall survival for patients with thymic carcinoma is 21.0±10.0%. CONCLUSIONS: This study confirms the possibility to perform European retrospective analysis even in very rare paediatric tumours. Thymic carcinoma is associated with paediatric patients to give a very poor prognosis independently despite multimodal management. Multidisciplinary, multicenter approach and collaboration with adults' physician are necessary in order to propose homogenous guidelines.

443 paediatric cases of malignant melanoma registered with the German Central Malignant Melanoma Registry between 1983 and 2011.

BACKGROUND: Malignant melanoma is a very rare paediatric tumour. This study was performed in order to understand clinical features and prognosis of malignant melanoma in children and adolescents. METHODS: 443 patients ⩽ 18 years of age with malignant melanoma were prospectively registered with the German Central Malignant Melanoma Registry between 1983 and 2011. Cases were collected from 58 participating centres. 276 paediatric cases with a follow-up >3 months were evaluated for survival probabilities and prognostic factors by Kaplan-Meier method. RESULTS: Age of diagnosis ranged from 3 months to 18 years (median age 16 years). The male to female ratio was 0.8 (202 male, 240 female). Most melanoma were located at the trunk (n = 195) and the lower extremity (n = 114). Patients with >3 months of follow-up (median 55 months) showed an overall survival (OS) of 94.8% in 5 years. Survival according to tumour stage was 98.5% for stage I (n = 190), 91.1% for stage II (n = 39) and 53.0% for stage III/IV tumours (n = 11). Worse outcome was seen in patients with nodular melanoma (OS 77.9%, n = 42) compared to superficial spread histotype (OS 100%, n = 138) or other histotype (OS 96.9%, n = 88) (p < 0.0001), in case of thicker tumours (Clark level IV or V, OS 87.1%, n = 84) compared to thinner tumours (Clark level I, II, III, OS 99.1%, n = 164) (p = 0.0008) and in case of ulceration (OS 65.6%, n = 17) compared to no ulceration (OS 99.2%, n = 182). CONCLUSION: Patient and tumour characteristics in paediatric melanoma patients show no evident differences to adult melanoma cases. The same clinical approach as in adults should be used.

[National network of paediatric central nervous system tumours reviewing by the Groupe d'Étude de Neuropathologie Oncologique Pediatrique (GENOP)]. / Réseau de relecture des tumeurs pédiatriques du système nerveux central par le Groupe d'étude de neuropathologie oncologique pédiatrique (GENOP).

Diagnosis of paediatric tumours of the central nervous system is often difficult because WHO classification criteria are mainly defined for adults tumours and do not always apply to their paediatric counterparts. These tumours are rare (400 cases/year among more than 50 pathological subtypes per year in France). Pathological diagnosis may be a challenge for a general pathologist with a too low number of paediatric cases in his recruitment. Hence, a reference group of paediatric neuropathologists was formed (GENOP) on the behalf of the comité "Tumeurs Cérébrales" de la Société Française de lutte contre les Cancers de l'Enfant. This network is supported by the Institut National du Cancer (INCa). GENOP aim is to structure a centralised review of paediatric central nervous system tumours in order to harmonise neuropathological diagnosis at the national level and enhance patients care. Cases assessed during the last 3 years led GENOP to better identify tumours subtypes for which there is a diagnostic challenge. A set of immunohistochemical or molecular specialised techniques was developed, leading to an increased diagnostic accuracy. It allowed a better distinction between diffuse and circumscribed glioma, a better recognition of glioneuronal differentiation and a better subtyping of embryonal tumours such as medulloblastomas. Inter-observer agreement varied according to the tumour subtypes.

Fine needle biopsy with cytology in paediatrics: the importance of a multidisciplinary approach and the role of ancillary techniques.

Fine needle biopsy (FNB) with cytology has long been regarded as an excellent technique as the first choice for diagnosing adult tumours. Being an inexpensive minimally invasive technique with high accuracy and diagnostic immediacy through rapid on-site evaluation, it is also ideal for implementation in the paediatric setting, particularly in developing countries. Furthermore, it allows complementary and advanced procedures such as flow cytometry, polymerase chain reaction (PCR) or fluorescence in situ hybridization (FISH), among others, which enhances the diagnostic capacity of this technique and gives it a key role in risk stratification and therapeutic decision-making for several tumours. The advantages of FNB are optimized in the setting of a multidisciplinary team where cytologist, clinician and radiologist play leading roles. Paediatric tumours are rare and most ancillary techniques are cost-effective but complex to be implemented in small centres with limited experience in paediatric pathology. Therefore reference centres are essential, in order to establish teams with extensive experience and expertise. Hence, any child with a suspected malignancy should be directly referred to a paediatric oncology unit. Focusing on a practical approach to the assessment of paediatric lymphadenopathies and non-central nervous system solid tumours we review the effectiveness of FNB as applied concurrently with ancillary techniques in a multidisciplinary approach to the diagnosis, prognosis and therapeutic decisions of paediatric tumours and tumour-like lesions.

Radiation Associated Meningiomas:The Case for Repeat Radiotherapy.

PURPOSE: To evaluate the circumstances relating to Radiation Associated Meningiomas (RAM) and whether repeat radiotherapy can be used. MATERIALS AND METHODS: In this Ethics Approved Study, databases of the Long Term Follow-Up Clinic at Sydney Children's Hospital and the Prince of Wales Cancer Centre were audited for patients who received radiotherapy to the head as a child, and subsequently developed an intracranial meningioma. Features noted were, initial diagnosis, extent of prior treatment, dose, latency to diagnosis, subsequent treatment, and outcome. RESULTS: There were 18 patients with an equal gender mix of males/females (9), the majority of patients being treated with whole brain radiotherapy for leukaemia prophylaxis. 6 patients had radiotherapy, 4 had follow-up out to 17 years with no further adverse event, and control of the meningioma. CONCLUSION: Surgery may still be the treatment of choice, however where appropriate radiotherapy can be considered, with good prospect of benefit to the patient.