Molecular Diagnostics in Pediatric Brain Tumors: Impact on Diagnosis and Clinical Decision-Making — A Selected Case Series

Abstract

Central nervous system (CNS) tumors account for the highest mortality among pediatric malignancies. Accurate diagnosis is essential for optimal clinical management. The increasing use of molecular diagnostics has opened up novel possibilities for more precise classification of CNS tumors. We here report a single-institutional collection of pediatric CNS tumor cases that underwent a refinement or a change of diagnosis after completion of molecular analysis that affected clinical decision-making including the application of molecularly informed targeted therapies. 13 pediatric CNS tumors were analyzed by conventional histology, immunohistochemistry, and molecular diagnostics including DNA methylation profiling in 12 cases, DNA sequencing in 8 cases and RNA sequencing in 3 cases. 3 tumors had a refinement of diagnosis upon molecular testing, and 6 tumors underwent a change of diagnosis. Targeted therapy was initiated in 5 cases. An underlying cancer predisposition syndrome was detected in 5 cases. Although this case series, retrospective and not population based, has its limitations, insight can be gained regarding precision of diagnosis and clinical management of the patients in selected cases. Accuracy of diagnosis was improved in the cases presented here by the addition of molecular diagnostics, impacting clinical management of affected patients, both in the first-line as well as in the follow-up setting. This additional information may support the clinical decision making in the treatment of challenging pediatric CNS tumors. Prospective testing of the clinical value of molecular diagnostics is currently underway.

Zusammenfassung

Die höchsten Mortalitätsraten pädiatrischer Krebserkrankungen sind durch Tumore des zentralen Nervensystems (ZNS) bedingt. Eine präzise Diagnose ist essentiell für eine optimale Behandlung. Durch die zunehmende Verwendung molekularer Diagnostik ergeben sich neue Möglichkeiten der präzisen Klassifizierung von ZNS-Tumoren. Hier berichten wir über eine Fallserie pädiatrischer ZNS-Tumore, deren Diagnose durch molekulare Diagnostik präzisiert oder geändert wurde, mit Einfluss auf die klinische Entscheidungsfindung bis hin zur Anwendung molekular informierter Therapien. Es wurden 13 pädiatrische ZNS Tumore mittels konventioneller Histologie, Immunhistochemie und molekularer Diagnostik analysiert, inklusive DNA-Methylierungsprofil in 12 Fällen, DNA-Sequenzierung in acht Fällen und RNA-Sequenzierung in 3 Fällen. Nach erfolgten molekularen Analysen wurde bei 3 Tumoren die Diagnose präzisiert und bei 6 Tumoren die Diagnose geändert. Eine gezielte Therapie wurde in 5 Fällen eingeleitet. Ein zugrundeliegendes Tumorprädispositionssyndrom wurde in 5 Fällen detektiert. Da diese Fallserie retrospektiver Natur und nicht bevölkerungsbezogen ist, ist die Aussagekraft insgesamt limitiert. Dennoch können wertvolle Einsichten bezüglich präziser Diagnosestellung und daraus folgendem klinischen Management in Einzelfällen gewonnen werden. Die Genauigkeit der Diagnose wurde in den hier vorgestellten Fällen verbessert, mit Einfluss auf das klinische Management der betroffenen Patienten bei Initialtherapie als auch in der Nachsorge. Diese zusätzliche Information kann die klinische Entscheidungsfindung in der Behandlung komplexer pädiatrischer ZNS Tumore unterstützen. Der klinische Nutzen molekularer Diagnostik wird aktuell in Studien geprüft.

Key words

brain tumor - molecular diagnostics - targeted therapy - cancer predisposition syndromes

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