Anna Campello

Introduction : Gorlin syndrome (GS) is a known cancer predisposing syndrome, mainly associated with basal cell carcinomas (BCCs), fibromas, meningiomas and medulloblastoma (MB). However, a number of different tumours have been increasingly associated with GS, and a thorough understanding of the spectrum of associated cancers is key to counselling families and designing appropriate surveillance protocols. Methods : This is a retrospective case series of paediatric patients with GS identified at the Royal Marsden Hospital and South West Thames Regional Genetic Service between 2000 and 2021. Clinical information, including data on genotype, were retrospectively collected. Patients with a cancer diagnosis were described in detail, and results from somatic NGS were reported, when available. Results : Fifty-five patients across 34 families were identified. Nine (16%) patients developed one or more benign or malignant tumours, other than BCCs, before the age of 18, including SHH-activated MB (n=4); Sertoli-Leydig tumour, myelodysplasia, Wilms tumour, low grade myofibroblastic spindle cell proliferation, ganglioneuroma, macroprolactinoma and breast fibroadenoma (n=1 each). Somatic analysis showed PTCH1 /SUFU loss of heterozygosity (LOH) in 4 out of 6 cases analysed. Conclusion : This case series expands the spectrum of tumours described in patients with GS, raising the possibility of novel links with Sertoli-Leydig tumour, myofibroblastic tumours and ganglioneuroma. Somatic analyses provided further evidence for PTCH1/SUFU LOH as a potential driver in the pathogenesis of GS–associated tumours.

Background/Objectives: Adrenocortical tumors (ACTs), including adrenocortical adenoma (ACA) and carcinoma (ACC), represent 0.3–0.4% of pediatric tumors. Beckwith–Wiedemann spectrum (BWSp) confer an increased risk of ACTs, but prognosis, management, and associated molecular characteristics are unclear. Methods: This paper combines a literature review of 54 published cases of BWSp-ACT with a report of one newly identified patient, totaling 55 cases with a confirmed BWSp clinical and/or molecular diagnosis. Results: Nineteen patients with ACA, 33 with ACC, and 3 with ACT of uncertain malignant potential (umACT) were included. Twenty patients had uniparental disomy of chromosome 11p15.5 (patUPD11), 11imprinting Center 2 Loss-of-methylation (IC2-LoM), and had 2 11p15 locus duplication. Eleven patients were diagnosed during cancer screening procedures, including two metastatic at diagnosis ACC. Conclusions: Almost half of ACC patients reached the minimum score for clinical BWSp diagnosis only after ACC onset, suggesting that the BWSp score has limited value for the early diagnosis in such a setting. Two patients with metastatic ACC had a histopathological Wieneke score ≤2, not correlating with clinical malignancy and confirming limitations of the current histopathological classification, as previously documented. Ultrasound screening failed identifying the ACC before metastasis in two cases, indicating an urgent need to develop new strategies for screening of ACTs in BWSp. Furthermore, some cases of metastatic ACC exhibited unexpectedly indolent behavior despite being malignant.

Summary: Ewing’s Sarcoma (EWS) has been reported in seven children with Down Syndrome (DS). To date, a detailed assessment of this solid tumor in DS patients is still missing. Here, we characterized a chemo-resistant mediastinal EWS in a 2-year-old DS child, the youngest ever reported case, by exploiting sequencing approaches. The tumor showed a neuroectodermal development driven by the EWSR1-FLI1 fusion. The inherited myeloperoxidase deficiency of the patient caused failure of neutrophil-mediated cell death and promoted genomic instability. In this context, the tumor underwent nearly genome-wide haploidization resulting in a massive overexpression of pro-inflammatory cytokines. Recruitment of defective neutrophils fostered the fast evolution of this EWS.

Giant cell tumors (GCTs) of the skull base are rare entities. Although considered histologically benign, GCTs are locally aggressive with a high rate of local recurrence. The present case describes a 14-year-old girl with a clival GCT who underwent long-term therapy with denosumab after local relapse. To our knowledge, it is the second case described with a follow-up term >2 years from the start of denosumab and who did not receive any other adjuvant treatment besides denosumab. The patient achieved a local control of the disease. According to the few available data, radical excision with adjuvant therapy helps in long-term control in uncommon sites, such as the skull. However, the definitive treatment is still controversial because of their rarity and few follow-up data. The present case highlights the benefit of denosumab and its safety as long-term therapy and contributes to the existing literature with analysis and evaluation of the management strategies and prognosis.

Osteosarcoma (OS) is a rare bone malignant tumour with a poor prognosis in the case of recurrence. So far, there is no agreement on the best systemic therapy for relapsed OS. The availability of next generation sequencing techniques has recently revolutionized clinical research. The sequencing of the tumour and its matched normal counterpart has the potential to reveal a wide landscape of genetic alterations with significant implications for clinical practice. The knowledge that the genomic profile of a patient’s tumour can be precisely mapped and matched to a targeted therapy in real time has improved the development of precision medicine trials (PMTs). PMTs aiming at determining the effectiveness of targeted therapies could be advantageous for patients with a tumour refractory to standard therapies. Development of PMTs for relapsed OS is largely encouraging and is in its initial phase. Assessing OS features, such as its rarity, its age distribution, the technical issues related to the bone tissue origin, and its complex genomic landscape, represents a real challenge for PMTs development. In this light, a multidisciplinary approach is required to fully exploit the potential of precision medicine for OS patients.