A Tale of Two Tumors: Pediatric and Adult Medulloblastoma

In their review, Shonka et al nicely summarize the available literature relating to the history, staging, molecular classification, and management of medulloblastoma, contrasting pediatric vs adult cases in the process. The review is well written, appropriately referenced, contemporary, and interesting. Consistent with its embryonal origin, adult medulloblastoma is exceedingly rare, and therefore many studies of adult medulloblastoma involve limited numbers of patients. Nearly all studies are retrospective in nature. Limited power affects the ability to draw meaningful conclusions from many studies, and although differences between adult and pediatric medulloblastoma exist, ultimately it has not been established whether adults and children with medulloblastoma should be managed differently. As a result, the management of adult patients stems largely from the pediatric experience.

As noted by the authors, the prognosis of patients with medulloblastoma has classically been dependent on the Chang M stage,[1] and to some degree on tumor histology, as some studies have indicated a better or worse prognosis with desmoplastic[2,3] vs large-cell/anaplastic histology,[4] respectively. However, M stage and pathologic features alone cannot account for the variation in outcome, and it is likely that molecular factors play a large role in prognosis as well.[5] As mentioned by the authors, the four molecular subtypes of medulloblastoma include the WNT/wingless pathway tumors, tumors with sonic hedgehog (SHH) aberrations, Group C tumors, and Group D tumors.[6] Interestingly, as mentioned by the authors, Group C tumors appear to be more rare in the adult population,[7] and recently published data indicate that tetraploidy appears to be an early event in pediatric patients with Group C and D tumors.[8] WNT pathway signaling mutations, which are associated with a more favorable prognosis in children,[9] are only present in 10% to 15% of adult cases and may not be associated with a favorable prognosis in the adult population.[7] Recently published data suggest that mutations in DDX3X, an RNA helicase gene, provide a component of the pathogenic WNT/β-catenin signaling pathway.[10,11] In addition, as noted by the authors, specific amplifications appear to be different in pediatric vs adult patients. As an example, MYC amplifications, while common in children, are rare in adults. Due to all these differences, investigators have called for age-specific risk-stratification models based on molecular subtyping criteria.[12]

Ultimately, as the authors note, it appears that clinical, histologic, and molecular features of individual tumors should determine prognostication schemes as well as clinical trial designs. However, more important than the prognostic implications of molecular subtyping are the opportunities to individualize the treatment of affected patients by personalization of therapy. Already, inhibitors of the SHH pathway are being tested, and have the potential to be used in the 30% of pediatric cases and nearly 60% of adult cases stemming from aberrations in the SHH pathway.[13-15] In addition, in both pediatric and adult patients, therapies targeting somatic copy number aberrations in the TGF-β and NF-κβ pathways, common in Group C and D tumors, respectively, show significant potential.[16]

As mentioned by the authors, there is a paucity of literature relating to medulloblastoma in adults, as it comprises less than 1% of adult brain tumors.[17] Whether treatment for adults should be similar to that used for children remains unknown, especially given differences in the tumor location (more likely to be lateralized in adults)[18] and histology (higher rates of desmoplastic histology in adults in some studies),[19] and the aforementioned differences in molecular subtyping between adult and pediatric patients.[20] In addition, adult patients may have a recurrence later than pediatric patients.[19,21] Currently, however, the standard of care for adult patients with medulloblastoma begins with maximal safe resection.[22] Risk stratification is two-tiered and is based on the extent of residual disease following surgery, the presence of disseminated disease to the spine or cerebrospinal fluid, and the presence of large-cell/anaplastic histology, in a manner similar to risk stratification for pediatric medulloblastoma patients. Craniospinal radiation followed by narrowed-field boost and chemotherapy form the basis of adjuvant therapy, although the dose of craniospinal irradiation and the optimal chemotherapy agents remain undefined in adults, as does the role of de-escalation of therapy in patients with either favorable histology or favorable molecular classification.[22]

In summary, there are important differences between pediatric and adult patients with medulloblastoma, as appropriately described by Shonka et al. Whether such differences affect prognosis or justify alternate treatment regimens remains unclear. Future studies of adult medulloblastoma should include whole genome sequencing and identification of the tumorigenic cell origin of adult medulloblastoma. Ultimately, quality prospective trials are needed in adult medulloblastoma patients in order to optimize the management of this rare and complex disease.

Disclosures:

The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

References:

References

1. Chang CH, Housepian EM, Herbert C, Jr. An operative staging system and a megavoltage radiotherapeutic technic for cerebellar medulloblastomas. Radiology. 1969;93:1351-9.

2. Sure U, Berghorn WJ, Bertalanffy H, et al. Staging, scoring and grading of medulloblastoma. A postoperative prognosis predicting system based on the cases of a single institute. Acta Neurochir (Wien). 1995;132:59-65.

3. Rutkowski S, von Hoff K, Emser A, et al. Survival and prognostic factors of early childhood medulloblastoma: an international meta-analysis. J Clin Oncol. 2010;28:4961-8.

4. Massimino M, Antonelli M, Gandola L, et al. Histological variants of medulloblastoma are the most powerful clinical prognostic indicators. Pediatr Blood Cancer. 2012; Jun 12 [Epub ahead of print].

5. von Hoff K, Hartmann W, von Bueren AO, et al. Large cell/anaplastic medulloblastoma: outcome according to myc status, histopathological, and clinical risk factors. Pediatr Blood Cancer 2010;54:369-76.

6. Northcott PA, Korshunov A, Witt H, et al. Medulloblastoma comprises four distinct molecular variants. J Clin Oncol. 2011;29:1408-14.

7. Remke M, Hielscher T, Northcott PA, et al. Adult medulloblastoma comprises three major molecular variants. J Clin Oncol. 2011;29:2717-23.

8. Jones DT, Jager N, Kool M, et al. Dissecting the genomic complexity underlying medulloblastoma. Nature. 2012;488:100-5.

9. Kool M, Korshunov A, Remke M, et al. Molecular subgroups of medulloblastoma: an international meta-analysis of transcriptome, genetic aberrations, and clinical data of WNT, SHH, Group 3, and Group 4 medulloblastomas. Acta Neuropathol. 2012;123:473-84.

10. Pugh TJ, Weeraratne SD, Archer TC, et al. Medulloblastoma exome sequencing uncovers subtype-specific somatic mutations. Nature. 2012;488:106-10.

11. Robinson G, Parker M, Kranenburg TA, et al. Novel mutations target distinct subgroups of medulloblastoma. Nature. 2012;488:43-8.

12. Korshunov A, Remke M, Werft W, et al. Adult and pediatric medulloblastomas are genetically distinct and require different algorithms for molecular risk stratification. J Clin Oncol. 2010;28:3054-60.

13. Romer J, Curran T. Targeting medulloblastoma: small-molecule inhibitors of the Sonic Hedgehog pathway as potential cancer therapeutics. Cancer Res. 2005;65:4975-8.

14. Coon V, Laukert T, Pedone CA, et al. Molecular therapy targeting Sonic hedgehog and hepatocyte growth factor signaling in a mouse model of medulloblastoma. Mol Cancer Ther. 2010;9:2627-36.

15. Elamin MH, Shinwari Z, Hendrayani SF, et al. Curcumin inhibits the Sonic Hedgehog signaling pathway and triggers apoptosis in medulloblastoma cells. Mol Carcinog. 2010;49:302-14.

16. Northcott PA, Shih DJ, Peacock J, et al. Subgroup-specific structural variation across 1,000 medulloblastoma genomes. Nature. 2012;488:49-56.

17. Wrensch M, Minn Y, Chew T, et al. Epidemiology of primary brain tumors: current concepts and review of the literature. Neuro Oncol. 2002;4:278-99.

18. Ang C, Hauerstock D, Guiot MC, et al. Characteristics and outcomes of medulloblastoma in adults. Pediatr Blood Cancer. 2008;51:603-7.

19. Chan AW, Tarbell NJ, Black PM, et al. Adult medulloblastoma: prognostic factors and patterns of relapse. Neurosurgery. 2000;47:623-31.

20. Lai SF, Wang CW, Chen YH, et al. Medulloblastoma in adults: treatment outcome, relapse patterns, and prognostic factors. Strahlenther Onkol. 2012;188:878-886.

21. Abacioglu U, Uzel O, Sengoz M, et al. Medulloblastoma in adults: treatment results and prognostic factors. Int J Radiat Oncol Biol Phys. 2002;54:855-60.

22. NCCN Clinical Practice Guidelines in Oncology. Central nervous system cancers. Available from www.nccn.org.