Medulloblastomas (MBs) are highly aggressive neoplasms of the central nervous system (CNS) and are considered the most common malignant brain tumor in childhood ^[1][2][1,2]. First described by Cushing and Bailey in 1925, these tumors derive from discrete neuronal lineages based on molecularly defined subgroups, as shown by recent studies. For example, the cells of origin for the SHH subgroup are the granule-neuron progenitors, whereas for Groups 3 and 4, early rhombic lip is considered the common source of origin ^[3][4][5][3,4,5].

Epidemiologically, the estimated annual incidence of the tumor in the US is approximately 500 cases per year and the median age of diagnosis is 6–8 years; it is very rarely diagnosed in adults [6].

Since 1990, when the estimated event-free survival (EFS) of MBs was 20–50% [7], and with the application of newer therapeutic techniques, the median overall survival of all subtypes is estimated to be 70% ^[8][9][10][8,9,10]. The tumor presents a significant biological heterogeneity, as it has been observed that about 30% of patients will be diagnosed with metastatic disease at presentation, and patients who survive may be diagnosed with subsequent malignancies during their life or develop treatment-related neurocognitive, endocrinological, or development disorders, highlighting the need for risk stratification of patients with MB. The aim of risk stratification is the appropriate selection and management of patients who can really benefit from treatment or who need treatment intensification. Clinical and histological factors were the initial determinants of prognosis and the main parameters used for patient categorization into standard and high risk ^[11][12][11,12]. However, the development of new molecular techniques has revolutionized the prognostication of MBs, creating new molecular subgroups with distinct clinical features, response to treatment options, and prognosis. Around 2010, several researchers reported that medulloblastomas comprise at least four distinct molecular subgroups: wingless signaling activated (WNT), Sonic-hedgehog signaling activated (SHH), Group 3, and Group 4, largely based on transcriptome profiles and a few known genetic alterations ^[13][14][15][13,14,15]. Thereafter, for the first time in 2016, molecular subgroups of MBs were incorporated into the WHO’s MB stratification ^[16][17][16,17]. The WNT subgroup accounts for approximately 10% of all MBs, whereas the SHH subgroup is most common in infants and young adults, accounting for 25% of all MBs ^[15][18][15,18]. Group 3 and Group 4 constitute approximately 65% of medulloblastoma cases and are characterized by great heterogeneity in clinical phenotypes and survival rates ^[19][20][19,20]. The most recent edition of CNS tumor classification (CNS 5), from 2021, divided medulloblastomas into “molecularly” and “histologically” defined, denoting the diverse biology of the tumor [21].

However, although recent research has mainly focused on a thorough investigation of molecular mechanisms behind MB pathogenesis and their contribution to risk stratification of patients, clinicopathological characteristics are also important factors for both relapse and prognosis and have been involved in recently developed prognostic nomograms [22].

2. Clinical and Histological Prognostic Factors

Before the establishment of molecular subgroups of MBs, patient risk stratification was mainly carried out based on their clinical characteristics, the histological features of the tumor, and the treatment approaches followed. Using the above factors as prognostic parameters, patients are categorized into two discrete subtypes: standard and high risk. Age < 3 years old, residual tumor > 1.5 cm², and large-cell/anaplastic histology are considered high-risk features, whereas patients not fulfilling the above criteria are considered standard risk ^[9][12][23][9,12,23].

3. Age

One of the clinical characteristics used for risk stratification is the age of the patient. In general, younger age at diagnosis seem to have a worse prognosis compared to older children and is considered a high-risk feature [24]. More precisely, infants and children < 3 years showed the worst prognosis, and various studies have investigated survival rates of those patients [25]. Rutkowski et al. reported a hazard ratio (HR) of 4.02 (95% CI 1.28–12.96) for higher risk for relapse or death for children below 2 years of age compared to children 2–3 years old, whereas results from a Canadian study concluded that children older than 18 months had better survival rates compared to infants below that threshold ^[26][27][26,27]. A possible explanation could be the avoidance of craniospinal irradiation of the tumor in that age group due to the defects that radiotherapy cause in the developing brain. Despite that, a recently published meta-analysis and a retrospective study from Brazil did not reach a statistical significance for age as a poor prognostic factor ^[8][28][29][8,28,29]. On the other hand, MBs in adults demonstrate a lower mutational rate, are less aggressive, and are associated with better prognosis compared to younger patients [30].

4. Extent of Disease

Another significant factor that affects the prognosis of childhood MBs and is included in the risk-stratification system is the extent of disease. Chang‘s staging is the main clinical classification system for MB patients and evaluates the local extent (T stage) and the tumor’s dissemination (M stage) ^[31][32][31,32]. Although the role of the local extent as a prognostic factor is debated, with some studies showing worse prognosis for tumors located in the midline or with involvement of the fourth ventricle and the brainstem ^{[26][33][34][35]}[26,33,34,35] and others not demonstrating similar findings ^[36][37][36,37], the contribution of metastasis to prognosis is well established. It is estimated that 30% of patients present with metastatic disease at diagnosis, which is accompanied by significantly diminished survival rates, with an eight-year OS of 65% and 27% in non-metastatic and metastatic patients, respectively [26]. Special consideration is given to stage M1 (tumor cells disseminated to CFS), which exhibits decreased OS similar to other metastatic stages, implying the need for prompt diagnosis of M1 staging, incorporation into high-risk features, and the implementation of intensifying treatment plans ^{[24][26][38][39]}[24,26,38,39].

5. Extent of Resection

Surgical resection comprises an important part of MB treatment plans, and the extent of resection poses a significant prognostic factor. The main goal of resection is the removal of the whole extent of the tumor, with gross total resection (GTR) demonstrating a favorable impact on both PFS and OS, as shown by observational studies and meta-analyses ^{[8][26][34][40]}[8,26,34,40]. On the other hand, residual disease after surgery, and especially residual tumors > 1.5 cm², is considered a poor prognostic factor, leading to local tumor relapses and worst survival rates. However, the benefit of extensive surgical resections may be counterbalanced for post-surgical neurologically adverse events, ranging from endocrinologic abnormalities to neurologic complications such as cerebellar-mutism syndrome, which are present in a considerable percentage of patients after GTR [41]. The latter is of paramount importance mainly for centrally located tumors, in whom total resection might not be feasible and which are categorized as high-risk tumors with a need for treatment intensification. Despite that, Thompson et al., when examining the prognostic value of GTR compared to near-total resection (NTR), along with the integration of clinical and molecular factors, did not conclude significant survival differences, and similar results were also shown by other studies ^[42][43][44][42,43,44]. Consequently, GTR demonstrates a favorable impact on the prognosis of MB patients, but the EOR should be evaluated in combination with other parameters, such as tumor location and post-surgical complications.

6. Histological Variant

There are four main histological subtypes of MBs: desmoplastic/nodular (DMN), classic (CMB), MBs with extensive nodularity (MBEN), and large cell/anaplastic (LCA). Each of them is characterized by different histological patterns and is associated with distinct molecular and genetic alterations, exhibiting diverse prognosis ^[3][45][46][3,45,46]. Multiple studies have examined the role of histology as a prognostic factor of MBs. Firstly, DMN, which is characterized by desmoplasia with pericellular fibrinogen deposits, demonstrates better prognosis compared to the classic subtype ([8], desmoplastic vs. classic, HR 0.41, 95% CI 0.31–0.56, OS, and [26], DMN/MBEN vs. classic, HR 0.44, 95% CI 0.31–0.64). Similarly, MBEN histology, which is mainly found in the early years of life, exhibits and good to excellent prognosis [47]. The above survival advantage seems to be maintained even in the presence of adverse prognostic factors (i.e., metastatic setting). In a more detailed way, Leary et al. suggested a similar EFS in non-metastatic compared to metastatic DMN, whereas Gupta et al. showed a better OS in extracranial metastatic desmoplastic compared to non-desmoplastic subtypes ^[48][49][48,49]. On the other hand, LCA, which is characterized by the presence of anaplasia in histopathology, exhibits the worst prognosis compared to other subtypes [46]. Semantically, the degree of anaplasia seems to affect prognosis in a significant manner, where severe anaplasia leads to worse OS and EFS compared to mild. The poor prognosis of that subtype could be attributed to the association of LCA with high-risk features, as it usually affects patients at a younger age, is diagnosed with metastasis at presentation, and is associated with specific molecular and genetic alternations such as LOH, isochromosome 17q, and MYC-family genes ^[50][51][52][50,51,52]. Especially for the latter, Ellison et al. and Ryan et al. demonstrated the co-expression of c-MYC amplification with severe anaplasia and high-risk features, implying a worse prognosis ^[53][54][53,54]. Despite that, the latest WHO classification combines all the above histological subtypes into one category, called histologically defined MBs, which are associated with specific molecular pathways, suggesting the need for a multilayered evaluation of specific tumor characteristics.

7. Other Prognostic Factors

Except for the above-described clinicopathological and molecular factors, hematological and serum markers are also described in the literature, which can predict the survival of MB patients. Li et al. investigated the role of serum markers on prognosis and revealed that an elevated preoperative neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) were detected more frequently in Group 3 and Group 4 MBs and were associated independently with worse PFS and OS [55]. In addition, lower levels of lymphocytes during radiotherapy (RT) were associated with increased risk of recurrence [56]. In agreement with this, Zhu et al. evaluated the prognostic value of a systemic inflammatory index (SII) and nutritional status along with serum markers and advocated that high levels of inflammatory markers impaired OS in multivariable models [57]. Apart from serum markers, recent research has focused on the fast-growing field of radiomics, where the incorporation of image analysis into risk-prediction models, which are based on well-established factors, could evaluate the prognosis of each patient preoperatively and at diagnosis. The latter is of paramount importance, as it would assist with further understanding of the diverse nature of MBs and the designation of appropriate treatment strategies. Until recently, radiomic analysis had managed to indirectly predict the prognosis of patients, as MRI findings were associated with the molecular subgroup of the tumor ^[58][59][58,59] or the dissemination to the CSF [60]. However, the co-estimation of imaging findings, clinical characteristics, and molecular subgroup led to the development of nomograms, predicting both PFS [61] and OS [62].