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Page 12 of 15 Dasgupta et al. J Transl Genet Genom 2018;2:15. I https://doi.org/10.20517/jtgg.2018.21

characteristics analysis, the area under the curve (AUC) was also generated to assess the reliability of the
nomograms. The predictive accuracy of SHH-subgroup nomogram (location on horizontal and vertical
axis, relationship with dorsal brainstem, heterogeneity of contrast-enhancement, and peri-tumoral edema
as the discriminating imaging features) was the highest followed by group 4-specific nomogram. Group 3
and WNT-subgroup nomograms had suboptimal predictive accuracy. For a sensitivity and specificity > 85%
each, a cut-off total score of 13.3 was obtained from the SHH-specific nomogram in the TC. When this was
tested in the VC, 93% of SHH-subgroup tumors still had total score above this threshold (13.3) as opposed to
only 5% of non-SHH tumors for a sensitivity of 93% and specificity of 95%. The nomogram identified even
midline SHH tumors with acceptable accuracy. AUC for the SHH subgroup was excellent, with a value of
0.939 and 0.991 in TC and VC respectively.

PRACTICAL AND CLINICAL IMPLICATIONS
With identification of different molecular subgroups, medulloblastoma is no longer considered a single en-
[4-6]
tity , but represents a heterogeneous group of diseases with a widely variable spectrum, mandating optimi-
zation of therapy within individual subgroups. In the past two decades, post-operative adjuvant treatment in
[35]
medulloblastoma has been largely based on a clinico-radiological risk-stratification system wherein patients
2
over the age of 3 years at initial diagnosis with post-operative residual tumor < 1.5 cm (R0) and absence of
metastases (M0) were classified as having average-risk/standard-risk disease. High-risk disease was defined
2
as the presence of any one of the following features viz. age < 3 years, residual tumor ≥ 1.5 cm (R+), and any
evidence of metastases (M+). This traditional clinico-radiological risk-classification has now been supplanted
by a more contemporary consensus risk-stratification schema (in the molecular era) into low-risk, standard-
risk, high-risk, and very high-risk categories with expected long-term overall survival > 90%, > 75%-90%, >
[36]
50%-75%, and < 50% respectively . Long-term treatment-related morbidity in medulloblastoma including
neuro-cognitive dysfunction is largely dependent upon the dose and volume of irradiation [37,38] .
Cerebellar mutism, motor deficits, and intellectual impairment can be differentially prevalent in individual
molecular subgroups , likely based on anatomic location of tumor and intensity of therapy. Consequently,
[39]
there is significant potential of de-intensification of treatment in children with low-risk disease (WNT-
pathway), while further intensification of treatment may be more appropriate for patients in the high-risk/
very high-risk category (metastatic group 3 or 4 tumors). The identification of specific genetic alterations
(PTCH1 or SUFU mutations) may allow the use of targeted therapies in particular subgroups (SHH-pathway),
[5,6]
leading to a more personalized approach in the future .

Tissue-based information remains the gold-standard for histo-morphology and molecular subgrouping
in medulloblastoma that cannot be replaced by any imaging-based classification. However, this tissue-
based information is not available pre-operatively to the operating neuro-surgeon, but only after surgical
resection of the tumor. The prognostic benefit of increased extent of resection becomes highly attenuated
after taking molecular subgroup affiliation into account. In a retrospective multi-institutional cohort
[40]
involving 787 patients , there was no significant survival benefit of greater extent of resection (gross total/
near total versus sub-total resection) for WNT, SHH, and group 3 tumors. Only in group 4 tumors, gross
total/near total resection was associated with significant benefit in progression-free survival compared
to sub-total resection, but not in overall survival. The authors concluded that although maximal safe
resection should remain the standard of care, aggressive neuro-surgical removal of small residual portions
of medulloblastoma should not be attempted, particularly when the anticipated morbidity is high. Several
different studies discussed herein, some of which were summarized in a review previously suggest that
MRI features can be a helpful and promising tool for early identification of molecular subgrouping in
[41]
medulloblastoma with potential to influence therapy . The availability of robust and reliable imaging-
based predictors of molecular subgrouping could aid neuro-surgical decision-making. The clinical utility
of tissue-based subgrouping, though undeniable, is greatly dependent upon the availability of resources
(expertise and infrastructure), costs, and turn-around time. The addition of molecular genetic information