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Neurology India
Medknow Publications on behalf of the Neurological Society of India
ISSN: 0028-3886 EISSN: 1998-4022
Vol. 54, Num. 1, 2006, pp. 16-23
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Neurology India, Vol. 54, No. 1, January-March, 2006, pp. 16-23
Review Article
Medulloblastomas: New directions in risk stratification
Sarkar Chitra, Deb Prabal, Sharma MeharChand
Department of Pathology, All India Institute of Medical Sciences, New Delhi
Correspondence Address:Department of Pathology, All India Institute
of Medical Sciences, Ansari Nagar, New Delhi - 110 029, drchitrasarkar@yahoo.com
Code Number: ni06003
Abstract
Medulloblastomas (MBs) are the most common malignant brain tumors in children. Current therapeutic approaches combine surgery, radiotherapy, and chemotherapy. Although, there has been significant improvement in long-term survival rates, the tumor remains incurable in about a third of patients while cognitive deficits and other sequelae of therapy are common among long-term survivors. Hence a major challenge remains to differentiate high-from low-risk patients and to tailor therapy based on the degree of biological aggressiveness. A clinical risk-stratification system has been widely used in MBs based on age, extent of resection and the Chang staging system. However, recent reports indicate that these clinical variables are inadequate methods of defining disease risk. This has prompted search for new markers for MB stratification. Recent studies indicate that the classification of MBs according to profiles of histopathology and molecular abnormalities possibly help better risk-stratification of patients, thereby rationalizing approaches to therapy, increasing cure rate, reducing long-term side effects and developing novel therapeutic strategies. The most accurate outcome prediction till date has been obtained through microarray gene expression profiling. In this article, the current histopathological classification and the recent advances in molecular genetics of MBs are reviewed. Global efforts to translate this knowledge of disease biology into clinical practice especially as outcome predictors are highlighted.
Keywords: Histopathology, medulloblastoma, molecular genetics,
prognostic factors, risk-stratification.
Medulloblastoma (MB) is one of the five embryonal tumors of the central nervous system (CNS) included in the current WHO classification (WHO Grade IV).[1] It is a highly malignant tumor of the cerebellum occurring predominantly in children and accounting for 12-25% of all pediatric CNS tumors.[2],[3],[4],[5],[6] It is less frequent in adults, constituting only 0.5-1% of all intracranial neoplasms.[7],[8],[9],[10],[11]
A. Risk stratification by clinical factors
Since the mid-1990s, the risk classification for relapse and selection
of treatment of MB patients has remained strictly clinical, with cases
stratified into two-risk groups, viz. ′average risk′ and ′high risk,′based
on the following criteria: (i) age, (ii) extent of resection, and (iii)
Chang metastasis staging [Table - 1].[12],[13]
According to this classification, average-risk patients are those
older than 3 years of age with nonmetastatic disease and totally or near
totally resected tumors (< 1.5 cm of residual tumor on postoperative
MR). Patients not fulfilling these criteria are regarded as high-risk . This clinical staging has been helpful as a broad guide for predicting prognosis. However a major drawback is that this does not differentiate high- from low-risk patients within the same clinical stage. It is a well-observed fact that patients with similar neoplasms and similar clinical stage, receiving identical therapies can have widely disparate clinical outcomes, owing to biological differences within the tumor.[14] Further,
two different trials, German trial HIT′91 and CCG 921[13],[15] have established that overall survival (OS) is not significantly different between children staged as M0 vs those staged as M1. Also, brain stem invasion (stage III b), previously regarded as an indicator of high-risk, is now believed not to affect prognosis.[13]
Based on this clinical staging system, a multimodality therapeutic approach has been designed for MBs, with maximum surgical resection, neuraxis radiation and chemotherapy.[16] This
has led to a reduction in the mortality rate by twofold in the last 30
years, with OS rates ranging from 50 to 60% at 5 years and 40-50% at
10 years.[17] However, in long-term survivors of MBs, this aggressive protocol is associated with severe side effects in the form of neuropsychological sequelae and neurocognitive decline.[18],[19].[20],[21]
In short, the major criticism of the current clinical staging is that
it does not identify the 20-30% of average-risk patient with resistant disease or the average-risk patients who might be over treated with the current protocol.[18] Hence, an important goal is to improve the chances of survival for all children with MB, and to tailor specific therapies to individual lesions based both on their degree of clinical as well as biological risk, so that patients are not over- or under-treated, and side effects are minimized.
All this has prompted search for new biological markers - histological
and molecular - for MB stratification. It is hoped that a greater understanding
of MB biology will not only translate into refinements in risk classification,
but also lead to risk-based tailoring of therapies to individuals. It
will also help in improvements in the way existing therapies are used,
which is crucial in minimizing their devastating long-term side effects.
B. Risk stratification by histopathological factors
Recent studies have conclusively demonstrated that the following
three histological factors have a distinct role in the determination
of clinical outcome in MB viz. histopathological subtype, extent of nodularity
and grade, as well as, extent of anaplasia [Table - 2]. The other factors
implicated to have prognostic significance include desmoplasia, cell
differentiation, proliferation, apoptosis, and ploidy. However, their
definite role still remains controversial.
1. Histopathological subtypes
Six distinct histological subtypes of MB have been included
in the current WHO classification.[4]
Classic MBs are characterized by sheets of densely packed cells with
hyperchromatic small round to oval nuclei, indiscernible cytoplasm, numerous
mitoses, conspicuous apoptosis, and formation of occasional Homer Wright/neuroblastic
rosettes.[4],[22],[23]
Desmoplastic MBs, on the other hand, show typical nodular architecture
comprising of reticulin-free pale nodules and reticulin-rich internodular
regions.[4],[22],[23]
Medulloblastomas with extensive nodularity and advanced neuronal differentiation
(MBEN) are a distinct subtype, occurring in infants less than 3 years
of age and demonstrating a striking grape-like nodularity on imaging.[24] Histologically,
they show a predominant nodular architecture with round uniform cells
inside nodules arranged in a streaming pattern within a fine fibrillary
neuropil-like matrix. Thus they differ from desmoplastic MBs in showing
uniform neurocytic differentiation with little or no internodular component.[4],[22],[23]
LC/A MBs comprise of large cells with pleomorphic nuclei, prominent nucleoli
and more abundant cytoplasm than most MBs. High mitotic and apoptotic
rate along with large areas of necrosis are also common.[4],[22],[23],[25]
Melanotic MBs, are characterized by melanin production in scattered cells,[26],[27] while
medullomyoblastomas consist of cells displaying variable rhabdomyoblastic
differentiation,[28],[29],[30],[31] both
in a background of classic MB.
Of all the six variants the best prognostic outcome is noted with MBENs.[24],[32] This
is intriguing because it generally affects young infants who according
to the clinical stage belong to the high-risk category. The worst outcome
is associated with LC/A MBs, which are extremely aggressive with high
incidence of local recurrence, CSF spread, systemic metastasis and death
within 1-2 years of diagnosis.[25],[33]
Difference in prognosis between the classic and desmoplastic variants
remains controversial. Desmoplastic MBs have been variably correlated
with better outcome[34],[35],[36] by
some, while others found it to be either associated with worse prognosis,[37] or
without any correlation with survival time.[9],[38],[39]
Melanotic MBs and medullomyoblastomas have poor outcome, with survival
ranging from 2 months to 2.5 years, in the former, and generally less
than 1 year, in the latter subtype.[26],[29]
2. Extent of nodularity
Eberhart et al[38] demonstrated
nodularity in 29% of 330 similarly treated cases of pediatric MB from the Pediatric Oncology Group (POG, USA). However, nodule formation in MBs can be variable - from diffuse to very focal. Hence, they graded the extent of nodularity into five categories - extensive (96-100%), widespread (51-95%), moderate (11-50%), slight (1-10%), and none (0%),
and observed that only tumors with extensive nodules were associated with
better survival. All other grades of nodularity showed no correlation with
outcome.[38]
3. Anaplasia
The concept of anaplasia in MBs is relatively new[14] and
analogous to anaplasia in Wilm′s tumor, which has well defined clinical
implications.[40] Anaplastic
MBs have currently been proposed as the variant with most aggressive biological
behavior.
Anaplastic MBs are characterized by markedly atypical cells having
angular pleomorphic nuclei with coarse chromatin, wrapping around each
other, with
frequent moulding.[14],[38],[41],[42] Earlier
studies suggested that anaplasia was only confined to the large cell variant
of MB. However, recent studies have shown that they can also arise by malignant
progression of classic and desmoplastic MBs, as well as medullomyoblastomas.[14],[42],[43] These
cells are thought to represent focally aggressive clones capable of undergoing
malignant progression, based on the observation that they often co-exist
focally within MBs, or manifest only after recurrence or metastasis.[14],[43],[44],[45]
Brown et al[41] in a review
of 474 MBs from POG patients, reported that the long-term survival of LC-MB
with anaplasia was 10% compared to more than 50% in LC-MB
without anaplasia. Eberhart et al[38] on
reevaluating 330 of the POG patients reported by Brown et al[41] observed
that while tumors with diffuse anaplasia were most aggressive, even focal
anaplasia was significantly associated with poor outcome. Further patients
with tumors having moderate to severe anaplasia (anaplastic group) had
significantly shorter event-free survival (EFS) and OS as compared to those
with slight to no anaplasia (nonanaplastic group). The 5-year survival
probability was 42% inpatients with anaplastic variant in contrast to 68% for
patients with nonanaplastic disease. In fact, on log-rank analysis, grade
of anaplasia allowed better stratification of patients with respect to
outcome than the current clinical stage, indicating that histological grading
is not a surrogate for clinical staging, but rather an independent predictor
of survival. Similar results of association of anaplasia with poor outcome
have also been shown by MacManamy et al.[33]
4. Desmoplasia
Conflicting reports on relationship of desmoplasia to outcome are chiefly
attributable to different definitions of desmoplasia.[42] In
addition to conventional desmoplastic MBs, rarely MBs show an intense pericellular
desmoplasia without any obvious nodule formation. Further invasion of leptomeninges
by classic MB also produces intense desmoplasia.[42]
In a retrospective review of 330 POG patients, Eberhart et al[38] noted
desmoplasia in 22% of cases. However there was no significant association
of desmoplasia with clinical outcome (either EFS or OS).
5. Cell differentiation
Another histopathological prognostic parameter in MBs, which has received
considerable attention but little agreement, is differentiation along glial
or neuronal cell lines.[46] Positivity
for GFAP have been variably correlated with better prognosis[47],[48] by
some, while others found it to be either associated with poor prognosis,[49],[50] or
without any correlation with survival time.[51],[52]
6. Proliferation/labeling index (LI)
Cell proliferation is another prognostic parameter whose significance
is not clear. Ito et al[53] showed
that tumors with Bromodeoxyuridine (BudR) LI greater than 20% had
a trend to worse prognosis. In contrast, Giordana et al[37] and
Schiffer et al[54] showed
no correlation in both adult and pediatric MBs. Studies of Sarkar et al[6] suggested
that MBs in children have higher MIB-I proliferative indices and lower
apoptotic indices than those in adults.
7. Apoptotic index (AI)
Since it is the balance between cell proliferation and cell death that
determines the rate of tumor growth, the impact of apoptosis on outcome
has also been considered. Apoptosis has been suggested as a favorable prognostic
feature by some[55] and as
a negative feature by others.[56],[57] Korshunov
et al[57] calculated
AI of> 1.5% to be associated with shorter survival, while Eggert
et al[58] found that expression
of Apo3 was significantly associated with prolonged survival of MB patients.
Haslam et al[55] demonstrated
that patients with a high AI had substantially improved outcome compared
to all other patients, independently from the assignment to a high- or
low-risk group at the time of diagnosis.
8. Ploidy
A more favorable prognosis has been associated with aneuploidy in MBs.
Ramachandran et al[59] found
that patients with aneuploid tumors responded well to treatment regimens
as compared to those with diploid tumors. Also, patients with progressive
disease had a high S-phase fraction in the tumor cell population as compared
with patients with favorable response to treatment.
C. Risk stratification by molecular and cytogenetic factors
It is widely accepted that identification of genetic and molecular
alterations allows a clinically relevant subgrouping of MBs with particular
profiles of biological behavior and outcome [Table - 2]. [60],[61],[62],[63],[64],[65],[66] The
molecular genetic alterations in MBs have been worked out extensively and
can be divided into three heads:
- Nonrandom chromosomal abnormalities,
- Gene profiling,
- Abnormalities in signal transduction pathways.
1. Nonrandom chromosomal abnormalities
(i) Loss of 17p/isochromosome 17q
The most frequent genetic alteration present in 30-50% of
MB cases is partial or complete deletion of the short arm of chromosome
17
(17p), [67],[68],[69],[70],[71] which
may occur in isolation, but more frequently as a component of an isochromosome
of 17q [i(17q)].[69],[72],[73],[74] A
recent study suggested that 17p loss /isochromosome 17q is more frequent
in LC/A MBs than in classic MBs.[14]
Several authors have observed that 17p deletion and/or i(17q) are prognostically
unfavorable being associated with poor response to therapy, metastatic
disease and shortened survival.[75],[76] However,
other studies have refuted this suggestion.[72],[77] Scheurlen
et al[76] reported that MBs
with concomitant 17p alterations and c-myc alterations have worse
prognosis, indicating possible interaction between these two genetic alterations
in promoting aggressive behavior.
Mutations of the tumor suppressor gene, p53 , located at 17p13.1
region are infrequent in MBs.[78],[79] However,
an association of intense p53 immunostaining with significant reduced disease-free
survival in MB patients has been shown by Woodburn et al[80] Similarly,
hypermethylation of the HIC-1 gene, on 17p13.3 region has been
demonstrated to be a predictor of poor outcome in MB.[81]
(ii) Myc gene (c-myc and N-myc) amplification
Amplification of c-myc and/or N-myc occurs in 5-10% of
MBs, being most commonly associated with the LC/A variant.[45],[82],[83],[84],[85],[86],[87] Eberhart
et al[45] found amplification
of c-myc in
4 (12%) and N-myc in 5 (15%) of 33 MBs, all with
anaplastic foci. A very high rate of c-myc amplification of 17% was
reported by Scheurlen et al[76] among
a population of clinically high-risk MBs.
There is clear evidence that patients whose tumors show c - myc gene
amplification have worse clinical outcome, being resistant to therapy and
having an aggressive course with short survival and fatal outcome. Aldosari
et al[82] found 4 of 77 MBs
with c-myc amplification
(5.2%) all of whom died within 7 months of diagnosis. One case having
amplification for both c-myc and N-myc and four cases with
only N-myc amplification were also associated with short survival
time. In the series of Badiali et al[84] no
long-term survivors were observed among cases with c-myc amplification.
Similarly Scheurlen et al[76] showed
that all tumors with c-myc amplification were resistant to therapy
and had fatal outcome.
A similar negative correlation of outcome with c-myc mRNA levels was
shown by Herms et al[87] and
Grotzer et al[88] Around
42% of MBs showed c-myc mRNA expression, and this parameter was
found to be an independent prognostic criteria and more predictive than
standard clinical factors.[87]
High rate of immunopositivity for both c-myc protein (90%)[89] and
N-myc protein (84%)[90] have
also been reported in MBs. A tendency of N-myc immunopositive MBs to be
associated with poor outcome was shown by Moriuchi et al.[90] Hence
there is a need of identifying MBs with myc gene amplification or myc mRNA
over expression, since a large body of evidence now indicates its association
with aggressive clinical behavior.
(iii) Other chromosomal abnormalities
In 20-40% of MB cases, loss of chromosomes 1q and 10q has been
demonstrated.[91],[92] Isolated
examples of deletions of 3q, 6q, 9q, 10q, 11p, 11q, and 16q as well as
gains of distal regions of 4p, 5p, 5q, 7q, 8q, and 9p have also been detected
in MBs.[83],[93],[94] However,
till date no prognostic correlation has been attached to any of these chromosomal
abnormalities, with the exception of 9q loss (locus of PTCH Gene).
Lusher et al[95] has reported
inactivation of the RASSF-1A gene
on chromosome 3p21 in 79% of MBs (both in adult and pediatric MBs
and in all histological variants).
Recently, Tong et al[96] performed
the first genomic survey of multiple oncogenes amplifications involved
in the development of MBs. For the first time they identified gene amplifications
involving PGY1 at 7q21.1, MDM2 at 12q14.3-q15, and Erb2
at 17q21.2, by performing comparative genomic hybridization (CGH) and array-based
CGH, in a series of 14 cases. Overall the highest frequency of oncogene
gains was observed in D17S1670 (61.5%), PIK3CA (46.2%), PGY1 (38.5%), MET (38.5%),
and CSE1L (38.5%). Gene amplification in MBs was further
confirmed by using fluorescence in-situ hybridization (FISH) analysis in
34 additional archival MB cases. In future, gains in these genes may possibly
qualify as candidates for molecular markers and therapeutic targets of
MBs.
2. Gene profiling
Pomeroy et al[97] studied
gene expression profile of MB cases using oligonucleotide microarrays.
The genes most closely correlated with MBs were ZIC and NSCL1 ,
which encode transcription factors specific to cerebellar granule cells.
They also identified a number of genes, which correlated with favorable
outcome, including many genes characteristic of cerebellar differentiation
( vesicle coat protein β-NAP, NSCL1, TrkC, sodium channels ), and
genes encoding extracellular matrix proteins ( procollagen-lysine-2-oxoglutarate 5-dioxygenase, lysyl hydroxylase, collagen type V α-I, elastin ).
In contrast, genes related to cerebellar differentiation were underexpressed
in poor prognosis tumors, which were dominated by the expression of genes
related to cell proliferation and metabolism [ MYBL2, enolase I, LDH, HMG1 (Y), cytochrome C oxidase ]
and multidrug resistance ( sorcin gene ).
Their study further demonstrated that outcome predictions based on
gene expression (with a model made up of eight genes) was statistically
significant:
patients with a certain pattern, expected to have a good prognosis, had
a 5-year OS of 80% compared with 17% for those not having
that pattern, for whom a poor outcome was predicted.
In another study of gene expression profiles, MacDonald et al[98] described
that the platelet derived growth factor receptor alpha (PDGFR-α) and the
Ras/mitogen-activated protein (MAP) kinase pathway genes were significantly
upregulated in metastatic (M+) tumors but not in nonmetastatic (M0) MBs, This finding suggests that the PDGFR-α and Ras/MAP kinase signal transduction pathway may be rational therapeutic targets for M+ disease.
3. Abnormalities in signal transduction pathways
(i) Neurotrophin signaling pathway - TrkC expression and outcome
This pathway plays a major role in cerebellar development. It comprises
of the neurotrophin family, which includes a set of ligands viz. nerve
growth factor (NGF), brain derived neurotrophic factor (BDNF), neurotrophin
factors 3, 4, and 5 (NT3 and NT4/5). These are essentially trophic factors
for the growth differentiation, survival and apoptosis of neurons. The
other major constituent of this pathway are three members of the tyrosine
kinase receptor family viz. TrkA, B, C. These Trk proteins function as
classical growth factor receptors, each binding to one of the four neurotrophins
resulting in their activation and upregulation of second messenger signaling
pathway systems.[99],[100],[101]
TrkC expression has been reported in 48-85% of MBs in different
series.[102],[103] This
high TrkC expression has been found to be the single most powerful independent
predictor of favorable outcome in MBs, independent of other clinico-pathological
variants. It was Segal et al[104] who
first reported 5-year survival rates as high as 89%, in patients having tumors with high TrkC expression, as compared to 46% for
those with low TrkC expression levels. Subsequently Kim et al[105] in
a study of 42 cases of MB found that the median survival in high expressers
of TrkC was 92 months, in contrast to only 39 months for the low expressers.
In a larger study of 81 MBs and 6 PNETs, Grotzer et al[106] reported
a 4.8-fold greater risk of death in children with tumors having low TrkC
mRNA expression. They identified TrkC mRNA expression as a powerful independent
prognostic factor for predicting progression-free and OS. In another study,[88] they
showed 100% progression-free survival in a group of PNET/MB patients
having combined low c-myc and high TrkC mRNA expression in their tumors
after a median follow up time of 55 months. Contradictory results have
been reported by Gajjar et al[18] who
found no correlation of TrkC expression with clinical outcome.
(ii) ErbB receptor signaling pathway - ErbB2 expression and outcome
The class-I receptor tyrosine kinases (RTK1), also termed ErbB/HER
receptors constitute a signal transduction pathway that is important in
both cerebellar development and MB tumorigenesis.[107],[108] Of
the four members of this family viz. ErbB1, B2, B3, and B4, Erb B2 receptor
appears to play a central role in MB tumorigenesis, along with neuregulin-1b
(NRG-1b). ErbB2 expression has been reported in> 80% of MBs, with co-expression of ErbB4 in 54% and expression of NRG-1b in 87.5% of
tumors.[62],[107],[109],[110],[111] However,
Gajjar et al[18] found
ErbB2 expression in only 40% of tumors, most frequently in the LC/A
variant.
Association between reduced patient survival and increased ErbB2 expression
has been demonstrated by several workers.[18],[62],[110],[111],[112] Gilbertson
et al[110] first
reported a 48% 10-year survival rate in cases with less than 50% ErbB2-positive tumor cells, while the corresponding figures for cases ≥ 50% positive cells was 10%. This prognostic significance was maintained in a further extension of the study to 70 cases, with 25-year survival rates for cases with < 50% and ≥ 50 ErbB2 expression being 46 and 17%,
respectively.[111] In the
same study, they[111] also
showed that co-expression of ErbB2 and ErbB4 significantly correlated with
reduced OS, being independent of other clinical variables like age and
tumor stage. Further, co-expression of all three components viz. ErbB2,
ErbB4, and NRG-1b was significantly associated with presence of CNS metastasis
at diagnosis.[107]
It has been shown that combined analysis of molecular and clinical factors
gives better risk stratification than clinical factors alone. Thus in an
analysis of 41 MBs, Gilbertson et al[62] found
that sub-total tumor resection, metastatic disease at diagnosis, high expression
of ErbB2 and isolated 17 p loss, all negatively correlated with survival.
Similarly Gajjar et al[18] in
a study of clinical average-risk childhood MBs reported 100% 5-year survival in ErbB2-negative disease cases, as compared to only 54% in
ErbB2-positive tumors.
(iii) Hedgehog - (SHH/PTCH) signaling pathway
Sonic hedgehog (SHH), the principal member of the hedgehog pathway,
is a family of ligands, which are involved in cerebellar development by
promoting replication of granule cells.[113] PTCH (patched)
is a tumor suppressor gene located on 9q22.3, which encodes a trans-membrane
PTCH protein product. This is activated by SHH and functions as part of
a signaling pathway controlling normal CNS development.[114],[115],[116] The
SHH/PTCH pathway has been implicated in the development of both sporadic
and heritable forms of MB. Mutations in several components of the SHH pathway
occur in about 25% of sporadic MB cases, commonest being mutation
of the PTCH gene, reported in 8-12% of tumors.[117],[118],[119] In
patients with Gorlin′s syndrome or NBCCS who have germ-line mutations
of the PTCH gene the lifetime risk of developing MB is about 4%.[114],[116],[120] It
has been observed that MBs that carry mutations in the SHH/PTCH pathway
preferentially but not exclusively show nodular desmoplastic morphology.[121],[122] However,
till date no association has been found of alterations in this signaling
pathway with prognosis in MBs.
(i) Wingless (WNT/WG) pathway
The WNT pathway co-ordinates a diverse array of developmental processes
including the proliferation and fate of neural progenitor cells.[122],[123] The
components of this pathway include β-catenin, the key transcriptional activator
which in turn associates in the cytoplasm with a complex, which includes
adenomatous polyposis coli ( APC ) gene, glycogen synthase kinase-3
(GSK3β) and AXIN-1.[122],[123]
Mutations in proteins of the WNT pathway, especially of β-catenin and APC gene
occur in about 15% of sporadic MBs. [124],[125],[126],[127],[128] Mutations
of APC gene
are also the cause of Turcot′s syndrome, a tumor predisposition
syndrome characterized by development of bowel tumors and MB.[129]
No correlation again has been found with this pathway and prognosis. However
an increasing number of anti-cancer drugs are being designed to target
this pathway. Cyclopamine, is one example of a plant-derived teratogen,
that specifically inhibits the SHH pathway in MB cells, causing anti-tumor
activity.[130] Conclusion
There has been marked improvement in the 5-year survival rates in MBs
from 2-30% in the 1970s to 50-70% currently. A major challenge, however, remains to differentiate high- and low-risk patients, and to individualize patient therapies, so as to prevent long-term side effects. In this regard, clinical staging alone has been shown in various studies to have its limitations. Two histological parameters currently assuming prognostic importance in MBs are the histopathological variant and grading of anaplasia. It is becoming apparent that homogenous lumping of all MBs as grade IV, highly aggressive neoplasms may be unjustified. The new concept therefore is to categorize MBs into favorable versus unfavorable histological groups, which is comparable to the classification used for peripheral neuroblastomas and Wilms′tumors.
Molecular prognostic markers also hold promise, though global, multi-institutional
studies with larger number of patients are required to prospectively
validate their role as well as the methodologies used for the assessment
of their expression levels.
The detailed mechanisms of how the different
signaling pathways mediate an oncogenic effect need to be identified
if we are to exploit these pathways fully for patient prognostication
and management. Further, several questions need to be answered -which
pathways initiate MB formation and which are involved in disease progression;
how specific pathways affect MB histopathology and behavior; and whether
any signal pathways mediate resistance to conventional treatments.
It is possible that in such a complex interaction of several factors,
a final scenario will emerge where in a combination of clinical,
histopathological and molecular factors will provide a more reliable
means of disease
stratification in patients of MB, rather than any single parameter
alone. The role of the Pathologist will then assume great importance
in guiding clinicians regarding biological risk assessment and tailoring
therapeutic strategies.
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