Abstract Background Accurate oncological diagnoses are essential to provide personalized and optimum care for patients. In children, renal tumors account for approximately one in 20 malignancies. Diagnostic workup in pediatric renal tumors is current focused on epidemiology, radiology, and histology, with a very limited role for molecular analysis outside of suspected cancer predisposition. Methods Retrospective clinical record review of seven pediatric and young adult renal tumor patients presenting to a single principal treatment center in the East of England, UK. Data collection was focused on their clinical presentation, radiology, histopathology, and molecular investigations including whole genome sequencing (WGS), treatment and outcomes. We analyzed the impact of molecular analysis on the care of these patients. Results Four patients presented with histologically difficult to classify renal tumors. Subsequent nephrectomy provided no additional information over biopsy in the two cases where a biopsy was performed first. Two young patients with histological concerns over renal cell carcinoma (RCC) had somatic mutations reported in Wilms tumor (WT) and responded well to WT treatment. One patient had histologically mixed features of papillary RCC and epithelial WT. WGS revealed a copy number profile consistent with papillary RCC as well as somatic WT changes and responded well and durably to chemo/radiotherapy, not expected for RCC alone. A young adult with an atypical RCC was shown to harbor a ERC1::CCNY fusion likely defining a novel entity. A further three cases, who did not have classical features of WT/cancer predisposition, were found to harbor mosaic/germline predisposition variants; allowing for appropriate treatment as per syndromic WT protocols. Discussion Diagnostic uncertainty is a challenge for oncologists, their patients, and families. Here we provide evidence that agnostic molecular analysis, including whole genomic sequencing (WGS), can be helpful in delineating such cases. In two children the molecular analysis helped to define the diagnosis as WT despite histological concerns for RCC. A novel tumor with mixed WT/RCC phenotype and genotype was responsive to chemo/radiotherapy. Molecular analysis thus improves the accuracy of diagnosis and helps to define novel entities. WT is well recognized to occur in the context of cancer predisposition syndromes. At present, genetics referrals and investigations are limited to those with suggestive family history or clinical features. Routinely undertaking molecular analysis will increase the rate of detection of underlying predisposition. We propose rapid turn-around molecular analysis for those undergoing pre-operative chemotherapy (as practiced in Europe) to identify patients and to plan for nephron-sparing surgery to reduce the risk of long-term renal replacement therapy. The molecular multidisciplinary team is crucial for the interpretation of routinely performed agnostic molecular analysis in children and young people with renal tumors given the evolving complexity of such cases. Citation Format: Sarah M. Leiter, Aisosa Guobadia, Ben Fleming, Thankamma Ajithkumar, James Armitage, Ruth Armstrong, GA Amos Burke, Charlotte Burns, Tanzina Chowdhury, Nicholas Coleman, Helen Hatcher, Gail Horan, Lisa Howell, Anna-May Long, Sarah McDonald, Thomas J. Mitchell, James C. Nicholson, Thomas Roberts, Grant D. Stewart, John A. Tadross, Patrick Tarpey, Claire Trayers, Jamie Trotman, James Watkins, Anne Y. Warren, Godran Vujanic, C. Elizabeth Hook, Sam Behjati, Matthew J. Murray. Molecular analysis improves the diagnosis of young people with renal tumors [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pediatric Cancer Research; 2024 Sep 5-8; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl):Abstract nr A011.

Wilms tumor (WT) is the commonest cause of renal cancer in children. In Europe, a diagnosis is made for most cases on typical clinical and radiological findings, prior to pre-operative chemotherapy. Here, we describe a case of a young boy presenting with a large abdominal tumor, associated with raised serum alpha-fetoprotein (AFP) levels at diagnosis. Given the atypical features present, a biopsy was taken, and histology was consistent with WT, showing triphasic WT, with epithelial, stromal, and blastemal elements present, and positive WT1 and CD56 immunohistochemical staining. During pre-operative chemotherapy, serial serum AFP measurements showed further increases, despite a radiological response, before a subsequent fall to normal following nephrectomy. The resection specimen was comprised of ~55% and ~45% stromal and epithelial elements, respectively, with no anaplasia, but immunohistochemistry using AFP staining revealed positive mucinous intestinal epithelium, consistent with the serum AFP observations. The lack of correlation between tumor response and serum AFP levels in this case highlights a more general clinical unmet need to identify WT-specific circulating tumor markers.

Catecholamine producing tumours of childhood include neuroblastic tumours, phaeochromocytoma and paraganglioma (PPGL). PPGL and neuroblastic tumours can arise in similar anatomical locations and clinical presentations can overlap resulting in diagnostic challenges. Distinguishing between these tumour types is critical as management and long-term surveillance strategies differ depending on the diagnosis. Herein we describe two clinical cases and illustrate key considerations in the diagnostic work up of a neuroblastoma versus PPGL for patients presenting with adrenal, pelvic, and retroperitoneal masses in childhood.

There is increasing evidence to support the use of temozolomide therapy for the treatment of metastatic phaeochromocytoma/paraganglioma (PPGL) in adults, particularly in patients with SDHx mutations. In children however, very little data is available. In this report, we present the case of a 12-year-old female with a SDHB-related metastatic paraganglioma treated with surgery followed by temozolomide therapy. The patient presented with symptoms of palpitations, sweating, flushing and hypertension and was diagnosed with a paraganglioma. The primary mass was surgically resected six weeks later after appropriate alpha- and beta-blockade. During the surgery extensive nodal disease was identified that had been masked by the larger paraganglioma. Histological review confirmed a diagnosis of a metastatic SDHB-deficient paraganglioma with nodal involvement. Post-operatively, these nodal lesions demonstrated tracer uptake on 18F-FDG PET-CT. Due to poor tumour tracer uptake on 68Ga-DOTATATE and 123I-MIBG functional imaging studies radionuclide therapy was not undertaken as a potential therapeutic option for this patient. Due to the low tumour burden and lack of clinical symptoms, the multi-disciplinary team opted for close surveillance for the first year, during which time the patient continued to thrive and progress through puberty. 13 months after surgery, evidence of radiological and biochemical progression prompted the decision to start systemic monotherapy using temozolomide. The patient has now completed ten cycles of therapy with limited adverse effects and has benefited from a partial radiological and biochemical response.