Medulloblastoma patients, sharing the same WHO histopathological type, have peculiar genetic backgrounds and different prognoses. Therefore, diagnosis of MB requires a combined routine histopathological evaluation (including microscopic type and histological grade of malignancy “WHO Grade IV”) with additional molecular features, to give an accurate integrated (or the so-called “layered”) diagnosis, and to allow a more refined risk stratification [5].
In the current study, MB histopathological types included classic (35%), D/N (25%), and LCA (40%) of MBs. These histopathological types were significantly associated with tumor location, degree of anaplasia, molecular subgroups, and risk stratification. Most LCA cases showed marked degree anaplasia. Most of the classic and D/N cases in our results were of standard-risk group, while most of LCA cases were of high-risk group. These results were in harmony with Ellison et al., who reported that high-risk disease was associated with LCA phenotype and metastasis at diagnosis (M+) [1]. Also, Jiang et al. noted that LCA histology was an independent risk factor with a grave prognosis and claimed that such diagnoses should require intensive treatments [13].
In our results, no significant relation could be detected between the histopathological types and age of the patients. However, Al-Halabi et al. supposed that D/N medulloblastomas contributed to most MBs in infancy and adulthood, sparing the pediatric period [14].
The molecular subgroups in our study differed significantly in age distribution, tumor location, histopathological variants, and risk stratification. WNT tumors represented 10% of cases; most of them were detected among pediatric age (3-16 years) and were mainly of classic histology. Our results matched those of Ellison et al., who stated that WNT subgroup was the rarest (10% of all MBs) and that WNT medulloblastomas were almost all classic tumors (81% of their cases) and presented between the ages of 6-12 years [1]. According to Pietsch et al., WNT MBs mostly occur in children older than 3 years or teenagers [15]. Taylor et al. stated that WNT medulloblastomas rarely have LCA histology, but even with this histology, they showed an excellent prognosis [2].
In the current study, all WNT MBs located at midline, which was in agreement with Pietsch et al., who declared that WNT tumors were located mainly in the midline (their cell of origin derives from the lower rhombic lip) [15]. Gibson et al. also found that among MB cases in a mouse model study, WNT subgroup arose from the midline of the brain stem [16].
In our study, all WNT cases exhibited standard-risk stratification. Ellison et al. reported that some cases with high-risk features (including LCA morphology or M+) showed favorable outcomes, interestingly, when associated with WNT profile [1].
SHH tumors, in this study, enclosed 30% of cases. The same finding was detected by Northcott et al. and Pietsch et al., as SHH subgroup represented 30% of their MBs [5, 17]. SHH tumors in this study were detected in all age groups, mainly among pediatric age group (3-16 years). In contrast, Zhukova et al. and Pietsch et al. found that SHH tumors had a bimodal age distribution affecting both the infants and adults, sparing the pediatric period [5, 18]. Kool et al. reported that SHH medulloblastomas were found in infants and adults and occurred much less frequently in patients aged 3–15 years [19].
In the current study, most SHH MBs were laterally located. Gibson et al. reported that these tumors derived from the cerebellar granular precursor cells of the external granular layer (originated laterally from the cerebellar hemispheres) [16].
All D/N MBs in this study were of SHH type. Pietsch et al. reported that D/N variant was almost exclusive for SHH-MB, followed by classic and LCA subtypes [5]. Ellison et al. also stated that all desmoplastic tumors were included in the SHH pathway [1]. However, Taylor et al. reported that SHH medulloblastomas included both desmoplastic types and not desmoplastic/nodular types (up to 50%) [2].
Non-WNT/SHH MBs (60% of our cases), were predominantly diagnosed in the pediatric age group (3-16 years) and were located mainly at the midline. Most of its cases were LCA and classic MBs and were high-risk tumors. Cho et al. and Tamayo et al. reported that non-WNT/SHH MB constituted the most common molecular subgroup and that the MBs of this group located in the midline filling the fourth ventricle [6, 7]. According to their studies, two histologic variants are encountered in this group, classic and LCA. Also, they reported that non-WNT/SHH MBs were of high-risk group with dismal prognosis.
In this study, the 2-year OS was 50% and the 2-year PFS was 27.5%; Tarbell et al. reported a higher 5-year OS (60%) [20]. In our study, no association was detected between OS and age at diagnosis. However, Sirachainan et al. reported that the 5-year OS rate in children (3-16 years) was 60.6%, whereas children in a study by Nalita et al. had a 53.8% 5-year OS rate [21, 22]. Schwalbe et al. categorized SHH patients into two groups (SHH infant and SHH child); which had a 58 and 48% 10-year OS, respectively [4].
The OS and PFS in our study, associated significantly with histopathological types, molecular subgroups, and risk stratification. Histologically, classic and D/N types showed nearly similar OS (71.4% and 70%, respectively), with PFS of 42.9% and 30%, respectively. LCA histology exhibited the worst OS and PFS (18.8% and 12.5%, respectively). Similarly, Louis et al. reported that D/N variant exhibited the best prognosis, whereas, LCA variant had a poor prognosis [23]. Yet, Nalita et al. found no significant differences of survival rates between histological variants [22]. Gupta et al. suggested that MB histology could determine patients’ outcomes (rather than other prognostic factors such as age, concurrent CNS involvement, visceral metastases, or time to relapse) [24].
In this work, patients with severe anaplasia showed significantly worse PFS (5.6%), Giangaspero et al. also found that progression-free survival for MBs with severe anaplasia was significantly shorter than tumors with slight or moderate anaplastic features [25].
In our study, molecular subgroups were prognostically important, with significantly different survival rates. WNT tumors had the best outcome with excellent PFS, and non-WNT/SHH showed the worst and shortest OS (33.3%). SHH medulloblastomas had an intermediate (66.7%) OS. Ellison et al., Kool et al., Northcott et al., and Taylor et al. reported the best outcome and a high 5-year OS (~ 95%) for the WNT subgroup, an intermediate (75–80%) OS for SHH MBs, while the worst and shortest survival for non-WNT/SHH subgroup [1, 2, 17, 19]. Ramaswamy et al. also confirmed that the WNT subtype had the best clinical outcome, with a 5-year OS > 95% [26]. Cho et al. found that the SHH subgroup had intermediate prognosis, with a 70% 5-year OS [6].
According to Thompson et al., the prognosis of WNT MB was excellent, even in the presence of poor outcome indicators as somatic TP53 mutation, incomplete resection, and/or metastatic disease at presentation [27]. Many studies explained that the good outcome of WNT subgroup was due to the presence of WNT antagonistic secretions that modifies the permeability of blood-brain barrier; allowing high penetrance of chemotherapeutic agents into the tumor site [28]. This could permit a less aggressive approach in treating WNT tumors [3].
In combination with clinical and pathological outcome indicators, molecular markers are not only prognostically important but would also facilitate the use of targeted therapies, such as GDC-0449, a novel SHH pathway inhibitor, particularly in infants and adults [1].
In the current study, both OS and PFS were poor with high-risk group patients (22.7% and 9.1%, respectively), while in the standard-risk group, the OS and PFS were 83.3% and 50%, respectively. Nalita et al. also reported 84.4% and 42.8% OS rates of standard-risk and high-risk groups, respectively [22].
Tarbell et al., Ramaswamy et al., and Ramaswamy et al. reported higher 5-year survival rates (for high-risk MBs) reaching 60% [20, 26, 29]. Sirachainan et al. reported OS rates of standard-risk and high-risk groups of 58–85% and 32–70%, respectively [21]. Thompson et al. reported that patients with postsurgical residual tumor > 1.5 cm2 (an indicator of high-risk disease) had worse PFS and required aggressive treatment options [27].
Clinical trials should incorporate key molecular profiles, including subgroup information, genetic, cytogenetic, and epigenetic changes, of this diverse disease entity that can suggest precise patients’ outcomes or predict rational treatment strategies [30].
The rarity of some WHO subtypes of MB; specifically, medulloblastoma with extensive nodularity, is considered a limitation of this study. Larger studies including all the histopathological types of medulloblastoma are recommended.
