Diagnostic aspects of pediatric embryonal tumors of the central nervous system: what should know pediatrician

Background. Early identification of pediatric central nervous system (CNS) tumors is important in relation to disease prognosis, as well as long-term treatment outcomes, which determine subsequent quality of life. The predominance of embryonal tumors (ETs) in early childhood actualizes the problem of timely verification of the diagnosis. Factors contributing to the extension of diagnostic time in the presented patient’s cohort include the inability to adequately verbalize complaints in young children, a wide range of clinical presentations, including nonspecific ones, the relatively low incidence of ET in the population and the low level of oncological alertness among specialists. This determines the need for a more careful assessment of the clinical manifestations and disease-associated symptoms by doctors of all specialties and, especially, primary care specialists. Aim. Analysis of clinical symptoms at the disease’s onset in pediatric CNS ET in order to determine their associations with the tumor’s characteristics (site, hystologic type) and the patient’s features. Materials and methods. A retrospective analysis of data from 124 pediatric patients with CNS ET who received treatment from 2010 to 2023 in the departments of pediatric oncology of the Almazov National Medical Research Center and the St. Petersburg Scientific Research Center for Medical Sciences (o) named after. N. P. Napalkov. The analyzed parameters were the age of manifestation, initial symptoms, duration of the anamnesis and the period before verification of the diagnosis, localization and histological type of tumors. For statistical analysis, Fisher’s exact test, modified Pearson test, Kruskal-Wallis and Mann-Whitney tests, as well as (to assess the duration of anamnesis) the Cox model were used. Results. The most common type of CNS ET in the study group was medulloblastoma (MB; 66.1%). The average age of patients, in general, was 61 months, boys predominated (58%). The median age varied depending on the histological tumor type: the maximum was 72 months in patients with medulloblastoma and the minimum was 9 months in children with atypical teratoid rhabdoid tumor (ATRT). Both medians are significantly different from the total median (29 months) of all other tumors (p = 6.53 ∙ 10-4 and p = 0.029, respectively). The most frequent symptoms in patients with ET were nausea and vomiting (68%), headache (50%), and gait disturbances (25.6%). Increased head circumference/bulging fontanel (p = 0.0016) and torticollis (p = 0.0057) were the most common symptoms associated with younger age. Headache (p = 1.30 ∙ 10-9), nausea and vomiting (p = 0.019), diplopia (p = 0.0057), weight loss (p = 0.017) and dizziness (p = 0.013) were associated with older age. Headache was predominated symptom in medulloblastoma (p = 2.60 ∙ 10-4) compared to other ETs, and less common in ATRT (p = 1.51 ∙ 10-4), which may be due to the patient’s age. Fontanel bulging in medulloblastoma, unlike other ET, was not observed, which is also associated with age. Seizures were observed in all cases of CNS neuroblastoma - significantly more often (p = 0.034) than in other ETs. The most common tumor location was the posterior cranial fossa (PCF) (83.6%). PCF localization was associated with headache (p = 0.05, borderline significance) and nausea/vomiting (p = 0.040). Parietal localization was associated with seizures (p = 0.041). Four patients in the cohort had asymptomatic disease’s manifestations. The diagnosis was established by a routine screening examination. The absence of symptoms was associated with location outside the PCF (p = 0.011) and with younger age (p = 0.053, borderline significance). The diagnosis was established in a significantly shorter time if children had symptoms such as nausea and vomiting (p=0.0017), paresis and paralysis (p=0.0059). Conclusion. In patients with CNS ETs, statistically significant relationships are revealed between age, histological type, tumor site and certain symptoms. Nevertheless, the absence of strictly specific clinical manifestation determines the indications for a careful assessment of the pediatric somatic and neurological status and timely neuroimaging in children when even potential symptoms typical for CNS tumors are identified.

children, pediatric oncology, tumors of central nervous system, symptoms, medulloblastoma, ATRT, early diagnostics

1. Ostrom Q. T., Cioffi G., Waite K. et al. CBTRUS Statistical Report: Primary Brain and Other Central Nervous System Tumors Diagnosed in the United States in 2014-2018. Neuro Oncol. 2021. 23(12 Suppl 2): iii1-iii105. doi: 10.1093/neuonc/noab200.

2. Ostrom Q. T., Price M., Ryan K. et al. CBTRUS Statistical Report: Pediatric Brain Tumor Foundation Childhood and Adolescent Primary Brain and Other Central Nervous System Tumors Diagnosed in the United States in 2014-2018. Neuro Oncol. 2022. 24(Suppl 3): iii1-iii38. doi: 10.1093/neuonc/noac161.

3. Kram D. E., Henderson J. J., Baig M. et al. Embryonal Tumors of the Central Nervous System in Children: The Era of Targeted Therapeutics. Bioengineering (Basel). 2018. 5(4). doi: 10.3390/bioengineering5040078.

4. Blessing M. M. and Alexandrescu S. Embryonal Tumors of the Central Nervous System: An Update. Surg Pathol Clin. 2020;13(2): 235-247. doi: 10.1016/j.path.2020.01.003.

5. Shih R. Y. and Koeller K. K. Embryonal Tumors of the Central Nervous System: From the Radiologic Pathology Archives. Radiographics. 2018;38(2):525-541 doi: 10.1148/rg.2018170182.

6. Louis D. N., Perry A., Wesseling P. et al. The 2021 WHO Classification of Tumors of the Central Nervous System: a summary. Neuro Oncol. 2021;23(8):1231-1251. doi: 10.1093/neuonc/noab106.

7. Goldman R. D., Cheng S., and Cochrane D. D. Improving diagnosis of pediatric central nervous system tumours: aiming for early detection. CMAJ. 2017;189(12): E459-E463. doi: 10.1503/cmaj.160074.

8. Wilne S., Koller K., Collier J. et al. The diagnosis of brain tumours in children: a guideline to assist healthcare professionals in the assessment of children who may have a brain tumour. Arch Dis Child. 2010;95(7):534-9 doi: 10.1136/adc.2009.162057.

9. Medina L. S., Kuntz K. M., Pomeroy S. Children with headache suspected of having a brain tumor: a cost-effectiveness analysis of diagnostic strategies. Pediatrics. 2001 Aug;108 (2):255-63. doi: 10.1542/peds.108.2.255.

10. Trofimova A., Vey B. L., Mullins M. E., Wolf D. S., Kadom N. Imaging of Children With Nontraumatic Headaches. AJR Am J Roentgenol. 2018 Jan; 210(1):8-17. doi: 10.2214/AJR.17.18561.

11. R Core Team. R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. 2023. https://www.R-project.org/

12. Therneau T. M. A Package for Survival Analysis in R. 2023. https://CRAN.R-project.org/package = survival

13. Therneau T. M., Grambsch P. M. Modeling Survival Data: Extending the Cox Model. Springer, New York. 2000. ISBN 0-387-98784-3.

14. Aragon T. J. epitools: Epidemiology Tools. R package version 0.5-10.1. 2020. https://CRAN.R-project.org/package = epitools

15. Cochran W. G. The χ2 Test of Goodness of Fit. Annals of Mathematical Statistics. 1952; 23:315-345. doi: 10.1214/aoms/1177729380.

16. Cochran, W. G. Some Methods for Strengthening the Common χ2 Tests. Biometrics. 1954, 10:417-451. doi: 10.2307/3001616.

17. Campbell I. Chi-squared and Fisher-Irwin tests of two-by-two tables with small sample recommendations. Stat Med. 2007; 26(19): 3661-3675. doi: 10.1002/sim.2832.

18. Cox D. R. Regression Models and Life-Tables. Journal of the Royal Statistical Society: Series B (Methodological). 1972;34:187-202. doi: 10.1111/j.2517-6161.1972.tb00899.x.

19. Kaplan E. L., Meier P. Nonparametric Estimation from Incomplete Observations. Journal of the American Statistical Association. 1958; 53(282): 457-481. doi: 10.1080/01621459.1958.10501452.

20. Muskens I. S., Feng Q., Francis S. S., et al. Pediatric glioma and medulloblastoma risk and population demographics: a Poisson regression analysis. Neurooncol Adv. 2020 Jul 22;2(1): vdaa089. doi: 10.1093/noajnl/vdaa089.

21. Ostrom Q. T., Adel Fahmedeh M., Cote D. J. et al. Risk factors for childhood and adult primary brain tumors. Neuro Oncol. 2021;21 (11): 1357-1375. doi: 10.1093/neuonc/noz123.

22. Woehrer A., Slavc I., Waldhoer T., et al. Incedence of atypical/teratoid rhabdoid tumors in children. ACS J. 2010; 116 (24): 5725-5732. doi: 10.1002/cncr.25540.

23. Nguyen T. M.K., Behnert A., Pietsch T., Vokuhl C., Kratz C. P. Proportion of children with cancer that have an indication for genetic counceling and testing based on the cancer type irrespective of other features. Fam. Cancer. 2021 Oct. 20;(4): 273-277. doi: 10.1007/s10689-021-00234-4.

24. Wilne S., Collier J., Kennedy C. et al. Presentation of childhood CNS tumours: a systematic review and meta-analysis. Lancet Oncol. 2007;8(8):685-95. doi: 10.1016/S1470-2045(07)70207-3.

25. Coven S. L., Stanek J. R., Hollingsworth E. et al. Delays in diagnosis for children with newly diagnosed central nervous system tumors. Neurooncol Pract. 2018. 5(4):227-233. doi: 10.1093/nop/npy002.

26. Chu T. P.C., Shah A., Walker D. et al. Where are the opportunities for an earlier diagnosis of primary intracranial tumours in children and young adults? Eur J Paediatr Neurol. 2017;21(2):388-395. doi: 10.1016/j.ejpn.2016.10.010.

27. Mehta V., Chapman A., McNeely P. D. et al. Latency between symptom onset and diagnosis of pediatric brain tumors: an Eastern Canadian geographic study. Neurosurgery. 2002. 51(2):365-72; discussion 372-3.

28. Wilne S. H., Ferris R. C., Nathwani A. et al. The presenting features of brain tumours: a review of 200 cases. Arch Dis Child. 2006;91(6):502-6. doi: 10.1136/adc.2005.090266.

29. Haimi M., Peretz Nahum M., and Ben Arush M. W., Delay in diagnosis of children with cancer: a retrospective study of 315 children. Pediatr Hematol Oncol. 2004; 21(1):37-48.

30. Dobrovoljac M., Hengartner H., Boltshauser E. et al. Delay in the diagnosis of paediatric brain tumours. Eur J Pediatr. 2002;161(12):663-7. doi: 10.1007/s00431-002-1088-4.

31. Brasme J. F., Chalumeau M., Doz F. et al.Interval between onset of symptoms and diagnosis of medulloblastoma in children: distribution and determinants in a population-based study. Eur J Pediatr. 2012;171(1):25-32. doi: 10.1007/s00431-011-1480-z.

32. Ramaswamy V., Remke M., Shih D. et al. Duration of the pre-diagnostic interval in medulloblastoma is subgroup dependent. Pediatr Blood Cancer. 2014;61(7):1190-4. doi: 10.1002/pbc.25002.

33. Kehoe K., Sivaguru H., Coulter I. et al. Delay in the diagnosis of paediatric brain tumours: a systematic review. Childs Nerv Syst. 2023;39(8):2053-2063. doi: 10.1007/s00381-023-06022-y.

34. Mazor K. M., Roblin D. W., Greene S. M. et al. Toward patient-centered cancer care: patient perceptions of problematic events, impact, and response. J Clin Oncol. 2012;30(15):1784-90. doi: 10.1200/JCO.2011.38.1384.

35. Jaju A., Li Y., Dahmoush H. et al. Imaging of pediatric brain tumors: A COG Diagnostic Imaging Committee/SPR Oncology Committee/ASPNR White Paper. Pediatr Blood Cancer. 2023. 70 Suppl 4 (Suppl 4): e30147. doi: 10.1002/pbc.30147.

36. Jaju A., Yeom K. W., and Ryan M. E., MR Imaging of Pediatric Brain Tumors. Diagnostics (Basel). 2022. 12(4). doi: 10.3390/diagnostics12040961.