Histopathological and Molecular Prognostic Markers in Medulloblastoma

Abstract

Several molecular and histopathological prognostic markers have been proposed for the therapeutic stratification of medulloblastoma patients. Amplification of the c-myc oncogene, elevated levels of c-myc mRNA, or tumor anaplasia have been associated with worse clinical outcomes. In contrast, high TrkC mRNA expression generally presages longer survival. The goal of this study was to evaluate the prognostic value of c-myc, N-myc and TrkC expression in medulloblastomas and compare them to histopathological classification. We used in situ hybridization to measure expression of these molecular markers. c-myc mRNA was detected in 18 of 59 (31%) cases, and was significantly associated with shorter patient survival times on both univariate and multivariate analyses (p = 0.04). The presence of c-myc mRNA was also significantly associated with tumor anaplasia. While survival rates were higher for patients with low N-myc or high TrkC expression, these differences were not statistically significant. The group of patients with either moderate or severely anaplastic tumors showed only a trend towards shorter survival (p = 0.11). However, severe anaplasia alone was significantly prognostic (p = 0.002). Given the prognostic import of c-myc, we investigated 2 potential mechanisms by which its expression might be regulated: Wnt signaling and Mxi-1 mutation. Nuclear translocation of beta-catenin, a marker of Wnt pathway activation, was more common in medulloblastomas with high c-myc than in tumors overall, but the difference was not statistically significant. No Mxi-1 mutations were detected in the 22 cases examined. The association we describe between c-myc expression, tumor anaplasia, and worse clinical outcomes provides further evidence for the importance of this oncogene in medulloblastoma pathobiology.

Accumulation of genomic aberrations during clinical progression of medulloblastoma

“…Clinical staging systems based on age, metastatic stage at diagnosis and, in some studies, extent of surgical resection have so far been the most useful methods for the stratiWcation of patients into standard and high risk therapy groups [1,26,27]. Additionally, after reWnement of the histological classiWcation of MB in the 2007 WHO classiWcation, the histological subtype is of potential prognostic relevance: large cell/anaplastic MB behaves more aggressively, while nodular/ desmoplastic variants show a more favorable clinical course as compared to the large group of classic MB [3,5,7,10,13,14,17]. Some recent studies have extended the concept of anaplasia in MB and suggested that this phenomenon reXects malignant progression of a tumor and may occur in various MB subtypes independent of large cell histology [3,4,12].…”

“…Cytogenetic aberrations in MB involving chromosome 17 as well as ampliWcations of the MYC or MYCN oncogenes have previously been associated with large cell histology and poor patient survival in diVerent studies [6,7,9,11,13,15,17,18,23,24]. In contrast, several recent reports have identiWed monosomy of chromosome 6 to be associated with consecutive WNT pathway activation and favorable clinical outcome [2,8,25].…”

Embryonal neural tumours and cell death

“…Both medulloblastoma and neuroblastoma belong to the most challenging oncologic diseases of childhood and serve as useful models for development of targeted therapy based on novel biological understanding. Amplification of the MYCN oncogene characterizes the subset of most aggressive neuroblastomas [6], whereas in medulloblastoma, activation of the c-MYC oncogene has been shown to be one of the most reliable prognostic factors [9,10]. Even though MYCN-amplification also occurs in medulloblastoma, its value as a prognostic factor has not been clearly established ( [10] and reviewed in [11]).…”

“…Amplification of the MYCN oncogene characterizes the subset of most aggressive neuroblastomas [6], whereas in medulloblastoma, activation of the c-MYC oncogene has been shown to be one of the most reliable prognostic factors [9,10]. Even though MYCN-amplification also occurs in medulloblastoma, its value as a prognostic factor has not been clearly established ( [10] and reviewed in [11]). Despite intensive multimodal therapy, often resulting in good immediate response in many children, both high-risk neuroblastoma and metastatic medulloblastoma frequently acquire therapy resistance with fatal clinical outcome.…”

“…On the other hand, favourable lowrisk neuroblastoma prone to differentiation or regeression through apoptosis, expresses high levels of both the highaffinity NGF receptor TrkA, and the low affinity receptor p75 [102][103][104]. Similarly, different expression levels of Trk receptors also occurs in medulloblastoma with high expression of the NT-3 receptor TrkC being indicative of a favourable outcome [10,105]. High TrkC expression is also found in favourable neuroblastoma although TrkA is a more reliable prognostic indicator [104,106,107].…”