Cancer Treatment Reviews 40 (2014) 356–365
Contents lists available at ScienceDirect
Cancer Treatment Reviews journal homepage: www.elsevierhealth.com/journals/ctrv
Tumour Review
Recent developments and current concepts in medulloblastoma N.U. Gerber a,⇑, M. Mynarek b, K. von Hoff b, C. Friedrich b, A. Resch b, S. Rutkowski b a b
Department of Oncology, University Children’s Hospital, CH-8032 Zurich, Switzerland Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, D-20246 Hamburg, Germany
a r t i c l e
i n f o
Article history: Received 14 August 2013 Received in revised form 26 November 2013 Accepted 29 November 2013
Keywords: (MeSH): Medulloblastoma Brain neoplasms Child Cancer Therapy Molecular targeted therapy
a b s t r a c t Medulloblastoma is the most common malignant brain tumor of childhood. While prognosis has significantly improved in the last decades with multimodal therapy including surgery, radiotherapy, and chemotherapy, one third of patients still succumb to their disease. Further research is needed to find more efficient treatment strategies for prognostically unfavorable patient groups and to minimize long-term sequelae of tumor treatment. This review gives a summary of the current state of treatment concepts including an outlook on the near future. We describe recent advances in the understanding of molecular mechanisms, their potential impact on risk stratification in upcoming clinical trials, and perspectives for the clinical implementation of targeted therapies. Ó 2013 Elsevier Ltd. All rights reserved.
Introduction Medulloblastoma (MB), an embryonal tumor of the cerebellum, is the most common malignant brain tumor of childhood. It occurs at all ages, peaking in incidence between 4 and 7 years, while rarely diagnosed in adults [1–3]. It has the propensity to disseminate along the cerebrospinal fluid (CSF) pathway, and metastatic disease at diagnosis is found in approximately 30% of patients. Spread outside the central nervous system (CNS) is very rare at diagnosis. While some genetic disorders (i.e. Gorlin syndrome, Turcot syndrome, Li-Fraumeni syndrome, Rubinstein-Taybi syndrome, and ataxia telangiectasia) are associated with an increased risk of MB, for most patients the etiology is unknown [2,4]. The management of MB has evolved over the last 3 decades as a result of prospective multicentric clinical trials. Multimodal treatment including surgical resection, radiotherapy, and chemotherapy has led to an improvement of outcomes with around two thirds of the patients being long-term survivors [5]. However, treatment-related toxicity often has a major impact on long-term quality of survival. In order to reduce sequelae, the concept of stratification into risk groups according to clinical variables (e.g. age, presence of metastases detected by imaging or cytological evaluation of CSF,
⇑ Corresponding author. Address: Department of Oncology, University Children’s Hospital, Steinwiesstrasse 75, CH-8032 Zurich, Switzerland. Tel.: +41 44 266 31 17; fax: +41 44 266 34 61. E-mail addresses: [email protected] (N.U. Gerber), [email protected] (M. Mynarek), [email protected] (K. von Hoff), [email protected] (C. Friedrich), [email protected] (A. Resch), [email protected] (S. Rutkowski). 0305-7372/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ctrv.2013.11.010
and post-operative residual tumor status) has been developed in the last decades, adjusting the intensity of therapy to the risk of relapse [6]. While the principal treatment strategies have not significantly changed over the past few years, enormous progress has been made in understanding of tumor biology, which has led and most likely will continue to lead to further refinements of risk stratification and to the development of novel therapy approaches using targeted drugs in a personalized way [7]. In this review, we present a summary of clinical characteristics, diagnostic measures, surgical aspects, and the currently used risk stratification, followed by a view on molecular biologic advances and their implications on future stratification and therapy in upcoming clinical trials. We then describe current and future treatment strategies for different patient subgroups, followed by a section on late sequelae, focusing on neurotoxicity.
Clinical diagnosis, staging, and surgical treatment The median interval from the first symptoms to the diagnosis is two months with a range from days to possibly years [8]. Presenting symptoms and signs usually arise from hydrocephalus or cerebellar dysfunction, and comprise vomiting, macrocephalus, loss of developmental achievements in infants, and headache, vomiting, ataxia, and cranial nerve palsy in older patients. Magnetic resonance imaging (MRI) shows a cerebellar tumor, often with compression of the fourth ventricle and dilatation of the lateral and the third ventricles due to obstruction of the CSF flow. Besides
N.U. Gerber et al. / Cancer Treatment Reviews 40 (2014) 356–365
the cranial MRI, the assessment for metastases comprises a spinal MRI and a cytological assessment of the lumbar CSF. Although a short prediagnostic symptomatic interval has not been associated with a better survival in medulloblastoma [8], this does not justify delays in diagnostic procedures. In the individual patient, delayed diagnosis may lead to potentially life-threatening complications of intracranial hypertension and may have adverse effects on neurological and neuro-psychological outcome as well as quality of life. The aims of surgery are a maximum resection of the primary tumor with minimal damage of neurological function in order to reduce any mass effect, to debulk vital tumor tissue, to establish the biopathological diagnosis, and, if possible, to restore CSF flow. In view of the efficacy of the adjuvant treatment, a microsurgically complete resection should only be intended in case of tolerable risk. Complications of tumor surgery include bleeding, transient diabetes insipidus, syndrome of inappropriate antidiuretic hormone secretion, infection, and non-obstructive hydrocephalus. Among the neurological complications, posterior fossa syndrome is of special relevance affecting one quarter of patients and consisting of mutism, swallowing difficulties, truncal ataxia, and emotional instability. Symptoms typically appear within 24–48 h after surgery, may persist for months longer and often are associated with long-term neurocognitive impairment [9–11]. While the pathogenesis is not fully understood, injury of the dentate-thalamic-cortical tracts has been implicated, and surgical measures such as a telovelar approach avoiding the splitting of the vermis have been advocated to reduce the risk [12]. Clinically, left-handedness, MB histology and localized damage within the right cerebello-thalamo-cortical pathway have been identified as risk factors for posterior fossa syndrome in a series of children with posterior fossa tumors [13]. A high percentage of patients present with obstructive hydrocephalus at diagnosis. There is no consensus on the optimum management. While in a part of the patients the CSF flow can be restored by the tumor resection itself (in some patients following the placement of an external ventricular diversion due to a transient tumor- or surgery-induced disturbance of CSF flow), a ventriculoperitoneal shunt is implanted in a significant portion of patients. Pre-resectional endoscopic third ventriculostomy has been suggested as an efficient alternative measure [14]. In order to minimize the risk of artifacts, the post-operative MRI, which is performed to assess the residual tumor status, should be performed in the first 72 h after surgery. Some groups prefer to have the MRI between 24 and 72 h after surgery. The value of intraoperative MRI is not clear yet. In case of significant residual tumor, particularly in non-metastatic disease, second-look surgery should be discussed either directly after the primary operation or in the course of further treatment. For staging, the clinical classification according to the modified Chang system [15] has been generally accepted. It comprises an MRI examination of the full craniospinal axis and an evaluation of lumbar CSF cytology. As immediate post-operative assessment of CSF can yield false positive results due to surgical detritus, the optimum timeframe for lumbar puncture is between 14 days after surgery and start of adjuvant treatment. Postoperative contrast enhancement (sometimes up to a few weeks) and post-punctional MRI alterations (e.g. subdural enhancement) may be difficult to distinguish from metastases or laminar meningeosis. Therefore, spinal MRI should be performed before lumbar puncture or – in case of suspicion of MB – ideally even before tumor surgery.
Current risk stratification Starting in the mid-twentieth century, the first decades of curative MB treatment were characterized by a growing number
357
of long-term survivors by means of gradual treatment intensification, albeit often at the price of a relevant impairment of quality of life [16]. In the past two decades, with increasing knowledge on clinical risk factors, stratification of patients into different risk groups has allowed controlled de-escalation of treatment intensity within clinical trials. Established risk factors for an adverse prognosis in terms of progression-free and overall survival are: metastatic disease at diagnosis, a residual tumor of >1.5 cm [2] (largest extent in an axial plane) on post-operative imaging, young age, and anaplastic or large-cell histological subtype (for summary see Table 1). For past and currently open trials, MB in patients aged from 3 to 5 years up to 21 years at diagnosis with gross-total or near total resection, without macroscopic or CSF metastases, and, in most trials, with non-anaplastic and non-large-cell histological subtype has been considered as ‘standard-risk’ (or ‘average-risk’) disease, while the other patients are counted as ‘high-risk’, with infants and very young children posing particular therapeutic challenges [6,17–23]. Tumor biology – new insights and their possible impact on future risk stratification and targeted therapy Despite the merits of a risk stratification based on clinical factors, the outcome of patients within the distinct risk groups is still highly heterogeneous. Thus, a purely clinical stratification algorithm has not proved satisfactory. The increasing knowledge of biologic heterogeneity of MB has led to a paradigm shift holding the promise of a much better tailored approach to risk stratification. The first approach towards ‘biologic’ MB subgrouping was based on histology, dividing these tumors into classic, large-cell, anaplastic, desmoplastic variants, and MB with extensively nodularity [2,24]. Together with clinical factors, histological subtyping has been increasingly used for prognostication and stratification. For example, patients with large-cell morphology or anaplasia were excluded from the standard-risk group in several trials due to their adverse prognosis in other series [22], while in infants and young children desmoplasia and extensive nodularity were shown to be prognostically favorable [23]. As for molecular biologic factors, in the last decade the focus lay on the exploration of one or two handful of markers [25]. Among others, the nuclear accumulation of beta-catenin [26], and the mRNA expression level of the neurotrophin receptor TrkC [27] were found to be associated with a favorable outcome, while the opposite was shown in tumors with myc amplification [22,28], and chromosome 17 imbalance [29] (Table 1). In the past few years, knowledge about MB biology has evolved faster than ever by the use of high-throughput methods for transcriptomics. Based on gene expression patterns in tumor tissue, MB can be classified into distinct subgroups [30–33]. According to the current consensus, four main groups can be distinguished: WNT, SHH, Group 3, and Group 4 (Fig. 1) [34,35]. Most likely, biological classification will continue to evolve, and further refined subgrouping has already been suggested [7,35,36], Table 2 gives an outlook on a possible future risk classification in medulloblastoma. WNT group medulloblastoma In this group, comprising roughly 10% of MBs, somatic mutations in the CTNNB1 gene encoding b-catenin (often associated with monosomy 6) leads to a hyperactivation of the WNT pathway by rendering b-catenin resistant to degradation, leading to nuclear accumulation of the protein and consecutive transcription of genes involved in proliferation. A minority of patients have a germline mutation in the APC tumor suppressor gene, which results in loss of inhibition of the WNT pathway in individuals with Turcot
358
N.U. Gerber et al. / Cancer Treatment Reviews 40 (2014) 356–365
Table 1 Selection of risk factors for adverse outcome. Abbreviation
Explanation
Selected References Packer 2003 [6]
S0 S1 S2 S3 S4 M0 M1 M2 M3 M4
Cut-offs between 3 and 5 years are used among different groups to differentiate infant from childhood-medulloblastoma No residual tumor Residual tumor 6 1.5cm2 Residual tumor > 1.5cm2 Residual tumor infiltrating the brain stem Residual tumor leaving the posterior cranial cavity No metastasis Microscopic tumor cells found in the CSF Macroscopic intracranial metastasis Macroscopic spinal metastasis Extra-CNS metastasis Classical Medulloblastoma Desmoplastic Medulloblastoma Medulloblastoma with extensive nodularity Large-cell Medulloblastoma Anaplastic Medulloblastoma Medulloblastoma with activated wingless-pathway
Rutkowski 2005 [17], Von Bueren 2011 [70] Rutkwoski 2010 [23], Leary 2011 [106]
Clinical parameters Age Postoperative residual tumor (modified from Chang 1969)
M-Stage
Biological parameters Histology
Molecular Group
Molecular Markers
CMB DMB MBEN LCMB AMB WNT SHH Group 3 Group 4 myc Chromosome 17 ß-catenin TrkC FSTL5
Medulloblastoma with activates sonic hedgehog pathway Amplification indicates poor prognosis
Zeltzer 1999 [19], Lannering 2012 [20]
Zeltzer 1999 [19], Kortmann 2000 [54], Taylor 2005 [64]
Northcott 2010 [34], Taylor 2012 [35], Kool 2012 [43],
Imbalance associated with poor prognosis
Von Hoff 2010 [22], Ryan 2012 [107] Pfister 2009 [29]
Nuclear accumulation correlates with WNT-group High mRNA levels are associated with good prognosis FSTL5 expression is associated with poor prognosis
Ellison 2005 [26] Grotzer 2000 [27] Remke 2011 [108]
syndrome [37]. WNT MB patients are often older children, histology is generally classic, and most tumors are non-metastatic. While still no targeted treatment has shown convincing efficacy, prognosis in this subgroup is excellent with survival rates around 90%, which makes those patients ideal candidates for treatment de-escalation [26,38].
SHH group medulloblastoma While most patients with Gorlin syndrome harbor germline mutations in the PTCH tumor suppressor gene, predisposing them to SHH (sonic hedgehog) MB, the majority of patients with SHH MB have somatic mutations in one of several genes of the SHH pathway (e.g. PTCH1, SUFU, or SMO) in sporadic tumors. Although these often are desmoplastic or extensively nodular tumors, classic and – more rarely – large-cell/anaplastic morphology are also found. Many are non-metastatic at presentation, and age distribution is biphasic with mostly infants/very young children and adults affected. Prognosis of infants and very young children with desmoplastic or extensively nodular MB is excellent, predestining these patients for treatment de-escalation [17,23]. Molecular targeting with various SHH pathway inhibitors (e.g. LDE-225/Erismodegib [39,40], GDC-0449/Vismodegib [41]) is currently being studied in clinical trials for patients with relapsed MB. Group 3 medulloblastoma
Cho (2010) should read: Cho (2011) Figure 1. Comparison of the various subgroups of medulloblastoma including their affiliations with previously published papers on medulloblastoma molecular subgrouping. (From: Taylor MD, Northcott PA, Korshunov A, Remke M, Cho YJ, Clifford SC, et al. Molecular subgroups of medulloblastoma: the current consensus. Acta Neuropathol. 2012;123:465–7235, with the permission of the editor) Errratum: Cho (2010) should read: Cho (2011).
Group 3 MB is almost exclusively found infants and children, rarely adolescents and not in adults. Patients are more often male than female and have a high incidence of metastatic disease at diagnosis. As a group, these patients have the poorest prognosis. While most cases of large-cell or anaplastic MB belong to this group, the most frequent histological subtype seen in this group is classic. Also, most cases of myc amplification seem to be confined to a subgroup of Group 3 MB [34]. Both the myc-pathway [42] as well as the TGF-b signaling pathway [36] may be future candidates for pharmacologic intervention. Group 4 medulloblastoma As a group, these are the most common MB, occurring at all ages, in part metastatic, and associated with an intermediate prognosis.
359
N.U. Gerber et al. / Cancer Treatment Reviews 40 (2014) 356–365
Table 2 Schematic model of future risk-adapted treatment stratification by clinical and biological parameters. Not all possible constellations are specified (e.g. metastatic WNT-MB in patients over 3 to 5 years). AMB: anaplastic medulloblastoma; CMB: classic medulloblastoma; DMB: demoplastic medulloblastoma; LCMB: large cell medulloblastoma; MBEN: medulloblastoma with extensive nodularity; SHH: medulloblastoma with activated sonic hedgehog pathway; WNT: medulloblastoma with activated wingless pathway; residual tumor is described according to S-classification (see Table 1); M0: no evidence of metastasis; M+: metastatic medulloblastoma. Medulloblastoma in older children (over 3–5 years)*
Early childhood medulloblastoma (below 3–5 years)⁄ Definition (all parameters required)
Estimated frequency within age group
Expected EFS
Definition (all parameters required)
Estimated frequency within age group (%)
Expected EFS (%)
Low risk
DMB/MBEN SHH-group Any degree of resection Any M-stage
30%
60–90%
CMB/DMB/MBEN WNT-group S0/S1 M0
10
>85
Standard risk
–
–
–
CMB/DMB/MBEN Non-WNT-group S0/S1 M0 c-myc neg
50
80
High risk
CMB/LCMB/AMB Non-SHH-group M0 c-myc neg CMB/LCMB/AMB
50%
Contents lists available at ScienceDirect
Cancer Treatment Reviews journal homepage: www.elsevierhealth.com/journals/ctrv
Tumour Review
Recent developments and current concepts in medulloblastoma N.U. Gerber a,⇑, M. Mynarek b, K. von Hoff b, C. Friedrich b, A. Resch b, S. Rutkowski b a b
Department of Oncology, University Children’s Hospital, CH-8032 Zurich, Switzerland Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, D-20246 Hamburg, Germany
a r t i c l e
i n f o
Article history: Received 14 August 2013 Received in revised form 26 November 2013 Accepted 29 November 2013
Keywords: (MeSH): Medulloblastoma Brain neoplasms Child Cancer Therapy Molecular targeted therapy
a b s t r a c t Medulloblastoma is the most common malignant brain tumor of childhood. While prognosis has significantly improved in the last decades with multimodal therapy including surgery, radiotherapy, and chemotherapy, one third of patients still succumb to their disease. Further research is needed to find more efficient treatment strategies for prognostically unfavorable patient groups and to minimize long-term sequelae of tumor treatment. This review gives a summary of the current state of treatment concepts including an outlook on the near future. We describe recent advances in the understanding of molecular mechanisms, their potential impact on risk stratification in upcoming clinical trials, and perspectives for the clinical implementation of targeted therapies. Ó 2013 Elsevier Ltd. All rights reserved.
Introduction Medulloblastoma (MB), an embryonal tumor of the cerebellum, is the most common malignant brain tumor of childhood. It occurs at all ages, peaking in incidence between 4 and 7 years, while rarely diagnosed in adults [1–3]. It has the propensity to disseminate along the cerebrospinal fluid (CSF) pathway, and metastatic disease at diagnosis is found in approximately 30% of patients. Spread outside the central nervous system (CNS) is very rare at diagnosis. While some genetic disorders (i.e. Gorlin syndrome, Turcot syndrome, Li-Fraumeni syndrome, Rubinstein-Taybi syndrome, and ataxia telangiectasia) are associated with an increased risk of MB, for most patients the etiology is unknown [2,4]. The management of MB has evolved over the last 3 decades as a result of prospective multicentric clinical trials. Multimodal treatment including surgical resection, radiotherapy, and chemotherapy has led to an improvement of outcomes with around two thirds of the patients being long-term survivors [5]. However, treatment-related toxicity often has a major impact on long-term quality of survival. In order to reduce sequelae, the concept of stratification into risk groups according to clinical variables (e.g. age, presence of metastases detected by imaging or cytological evaluation of CSF,
⇑ Corresponding author. Address: Department of Oncology, University Children’s Hospital, Steinwiesstrasse 75, CH-8032 Zurich, Switzerland. Tel.: +41 44 266 31 17; fax: +41 44 266 34 61. E-mail addresses: [email protected] (N.U. Gerber), [email protected] (M. Mynarek), [email protected] (K. von Hoff), [email protected] (C. Friedrich), [email protected] (A. Resch), [email protected] (S. Rutkowski). 0305-7372/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ctrv.2013.11.010
and post-operative residual tumor status) has been developed in the last decades, adjusting the intensity of therapy to the risk of relapse [6]. While the principal treatment strategies have not significantly changed over the past few years, enormous progress has been made in understanding of tumor biology, which has led and most likely will continue to lead to further refinements of risk stratification and to the development of novel therapy approaches using targeted drugs in a personalized way [7]. In this review, we present a summary of clinical characteristics, diagnostic measures, surgical aspects, and the currently used risk stratification, followed by a view on molecular biologic advances and their implications on future stratification and therapy in upcoming clinical trials. We then describe current and future treatment strategies for different patient subgroups, followed by a section on late sequelae, focusing on neurotoxicity.
Clinical diagnosis, staging, and surgical treatment The median interval from the first symptoms to the diagnosis is two months with a range from days to possibly years [8]. Presenting symptoms and signs usually arise from hydrocephalus or cerebellar dysfunction, and comprise vomiting, macrocephalus, loss of developmental achievements in infants, and headache, vomiting, ataxia, and cranial nerve palsy in older patients. Magnetic resonance imaging (MRI) shows a cerebellar tumor, often with compression of the fourth ventricle and dilatation of the lateral and the third ventricles due to obstruction of the CSF flow. Besides
N.U. Gerber et al. / Cancer Treatment Reviews 40 (2014) 356–365
the cranial MRI, the assessment for metastases comprises a spinal MRI and a cytological assessment of the lumbar CSF. Although a short prediagnostic symptomatic interval has not been associated with a better survival in medulloblastoma [8], this does not justify delays in diagnostic procedures. In the individual patient, delayed diagnosis may lead to potentially life-threatening complications of intracranial hypertension and may have adverse effects on neurological and neuro-psychological outcome as well as quality of life. The aims of surgery are a maximum resection of the primary tumor with minimal damage of neurological function in order to reduce any mass effect, to debulk vital tumor tissue, to establish the biopathological diagnosis, and, if possible, to restore CSF flow. In view of the efficacy of the adjuvant treatment, a microsurgically complete resection should only be intended in case of tolerable risk. Complications of tumor surgery include bleeding, transient diabetes insipidus, syndrome of inappropriate antidiuretic hormone secretion, infection, and non-obstructive hydrocephalus. Among the neurological complications, posterior fossa syndrome is of special relevance affecting one quarter of patients and consisting of mutism, swallowing difficulties, truncal ataxia, and emotional instability. Symptoms typically appear within 24–48 h after surgery, may persist for months longer and often are associated with long-term neurocognitive impairment [9–11]. While the pathogenesis is not fully understood, injury of the dentate-thalamic-cortical tracts has been implicated, and surgical measures such as a telovelar approach avoiding the splitting of the vermis have been advocated to reduce the risk [12]. Clinically, left-handedness, MB histology and localized damage within the right cerebello-thalamo-cortical pathway have been identified as risk factors for posterior fossa syndrome in a series of children with posterior fossa tumors [13]. A high percentage of patients present with obstructive hydrocephalus at diagnosis. There is no consensus on the optimum management. While in a part of the patients the CSF flow can be restored by the tumor resection itself (in some patients following the placement of an external ventricular diversion due to a transient tumor- or surgery-induced disturbance of CSF flow), a ventriculoperitoneal shunt is implanted in a significant portion of patients. Pre-resectional endoscopic third ventriculostomy has been suggested as an efficient alternative measure [14]. In order to minimize the risk of artifacts, the post-operative MRI, which is performed to assess the residual tumor status, should be performed in the first 72 h after surgery. Some groups prefer to have the MRI between 24 and 72 h after surgery. The value of intraoperative MRI is not clear yet. In case of significant residual tumor, particularly in non-metastatic disease, second-look surgery should be discussed either directly after the primary operation or in the course of further treatment. For staging, the clinical classification according to the modified Chang system [15] has been generally accepted. It comprises an MRI examination of the full craniospinal axis and an evaluation of lumbar CSF cytology. As immediate post-operative assessment of CSF can yield false positive results due to surgical detritus, the optimum timeframe for lumbar puncture is between 14 days after surgery and start of adjuvant treatment. Postoperative contrast enhancement (sometimes up to a few weeks) and post-punctional MRI alterations (e.g. subdural enhancement) may be difficult to distinguish from metastases or laminar meningeosis. Therefore, spinal MRI should be performed before lumbar puncture or – in case of suspicion of MB – ideally even before tumor surgery.
Current risk stratification Starting in the mid-twentieth century, the first decades of curative MB treatment were characterized by a growing number
357
of long-term survivors by means of gradual treatment intensification, albeit often at the price of a relevant impairment of quality of life [16]. In the past two decades, with increasing knowledge on clinical risk factors, stratification of patients into different risk groups has allowed controlled de-escalation of treatment intensity within clinical trials. Established risk factors for an adverse prognosis in terms of progression-free and overall survival are: metastatic disease at diagnosis, a residual tumor of >1.5 cm [2] (largest extent in an axial plane) on post-operative imaging, young age, and anaplastic or large-cell histological subtype (for summary see Table 1). For past and currently open trials, MB in patients aged from 3 to 5 years up to 21 years at diagnosis with gross-total or near total resection, without macroscopic or CSF metastases, and, in most trials, with non-anaplastic and non-large-cell histological subtype has been considered as ‘standard-risk’ (or ‘average-risk’) disease, while the other patients are counted as ‘high-risk’, with infants and very young children posing particular therapeutic challenges [6,17–23]. Tumor biology – new insights and their possible impact on future risk stratification and targeted therapy Despite the merits of a risk stratification based on clinical factors, the outcome of patients within the distinct risk groups is still highly heterogeneous. Thus, a purely clinical stratification algorithm has not proved satisfactory. The increasing knowledge of biologic heterogeneity of MB has led to a paradigm shift holding the promise of a much better tailored approach to risk stratification. The first approach towards ‘biologic’ MB subgrouping was based on histology, dividing these tumors into classic, large-cell, anaplastic, desmoplastic variants, and MB with extensively nodularity [2,24]. Together with clinical factors, histological subtyping has been increasingly used for prognostication and stratification. For example, patients with large-cell morphology or anaplasia were excluded from the standard-risk group in several trials due to their adverse prognosis in other series [22], while in infants and young children desmoplasia and extensive nodularity were shown to be prognostically favorable [23]. As for molecular biologic factors, in the last decade the focus lay on the exploration of one or two handful of markers [25]. Among others, the nuclear accumulation of beta-catenin [26], and the mRNA expression level of the neurotrophin receptor TrkC [27] were found to be associated with a favorable outcome, while the opposite was shown in tumors with myc amplification [22,28], and chromosome 17 imbalance [29] (Table 1). In the past few years, knowledge about MB biology has evolved faster than ever by the use of high-throughput methods for transcriptomics. Based on gene expression patterns in tumor tissue, MB can be classified into distinct subgroups [30–33]. According to the current consensus, four main groups can be distinguished: WNT, SHH, Group 3, and Group 4 (Fig. 1) [34,35]. Most likely, biological classification will continue to evolve, and further refined subgrouping has already been suggested [7,35,36], Table 2 gives an outlook on a possible future risk classification in medulloblastoma. WNT group medulloblastoma In this group, comprising roughly 10% of MBs, somatic mutations in the CTNNB1 gene encoding b-catenin (often associated with monosomy 6) leads to a hyperactivation of the WNT pathway by rendering b-catenin resistant to degradation, leading to nuclear accumulation of the protein and consecutive transcription of genes involved in proliferation. A minority of patients have a germline mutation in the APC tumor suppressor gene, which results in loss of inhibition of the WNT pathway in individuals with Turcot
358
N.U. Gerber et al. / Cancer Treatment Reviews 40 (2014) 356–365
Table 1 Selection of risk factors for adverse outcome. Abbreviation
Explanation
Selected References Packer 2003 [6]
S0 S1 S2 S3 S4 M0 M1 M2 M3 M4
Cut-offs between 3 and 5 years are used among different groups to differentiate infant from childhood-medulloblastoma No residual tumor Residual tumor 6 1.5cm2 Residual tumor > 1.5cm2 Residual tumor infiltrating the brain stem Residual tumor leaving the posterior cranial cavity No metastasis Microscopic tumor cells found in the CSF Macroscopic intracranial metastasis Macroscopic spinal metastasis Extra-CNS metastasis Classical Medulloblastoma Desmoplastic Medulloblastoma Medulloblastoma with extensive nodularity Large-cell Medulloblastoma Anaplastic Medulloblastoma Medulloblastoma with activated wingless-pathway
Rutkowski 2005 [17], Von Bueren 2011 [70] Rutkwoski 2010 [23], Leary 2011 [106]
Clinical parameters Age Postoperative residual tumor (modified from Chang 1969)
M-Stage
Biological parameters Histology
Molecular Group
Molecular Markers
CMB DMB MBEN LCMB AMB WNT SHH Group 3 Group 4 myc Chromosome 17 ß-catenin TrkC FSTL5
Medulloblastoma with activates sonic hedgehog pathway Amplification indicates poor prognosis
Zeltzer 1999 [19], Lannering 2012 [20]
Zeltzer 1999 [19], Kortmann 2000 [54], Taylor 2005 [64]
Northcott 2010 [34], Taylor 2012 [35], Kool 2012 [43],
Imbalance associated with poor prognosis
Von Hoff 2010 [22], Ryan 2012 [107] Pfister 2009 [29]
Nuclear accumulation correlates with WNT-group High mRNA levels are associated with good prognosis FSTL5 expression is associated with poor prognosis
Ellison 2005 [26] Grotzer 2000 [27] Remke 2011 [108]
syndrome [37]. WNT MB patients are often older children, histology is generally classic, and most tumors are non-metastatic. While still no targeted treatment has shown convincing efficacy, prognosis in this subgroup is excellent with survival rates around 90%, which makes those patients ideal candidates for treatment de-escalation [26,38].
SHH group medulloblastoma While most patients with Gorlin syndrome harbor germline mutations in the PTCH tumor suppressor gene, predisposing them to SHH (sonic hedgehog) MB, the majority of patients with SHH MB have somatic mutations in one of several genes of the SHH pathway (e.g. PTCH1, SUFU, or SMO) in sporadic tumors. Although these often are desmoplastic or extensively nodular tumors, classic and – more rarely – large-cell/anaplastic morphology are also found. Many are non-metastatic at presentation, and age distribution is biphasic with mostly infants/very young children and adults affected. Prognosis of infants and very young children with desmoplastic or extensively nodular MB is excellent, predestining these patients for treatment de-escalation [17,23]. Molecular targeting with various SHH pathway inhibitors (e.g. LDE-225/Erismodegib [39,40], GDC-0449/Vismodegib [41]) is currently being studied in clinical trials for patients with relapsed MB. Group 3 medulloblastoma
Cho (2010) should read: Cho (2011) Figure 1. Comparison of the various subgroups of medulloblastoma including their affiliations with previously published papers on medulloblastoma molecular subgrouping. (From: Taylor MD, Northcott PA, Korshunov A, Remke M, Cho YJ, Clifford SC, et al. Molecular subgroups of medulloblastoma: the current consensus. Acta Neuropathol. 2012;123:465–7235, with the permission of the editor) Errratum: Cho (2010) should read: Cho (2011).
Group 3 MB is almost exclusively found infants and children, rarely adolescents and not in adults. Patients are more often male than female and have a high incidence of metastatic disease at diagnosis. As a group, these patients have the poorest prognosis. While most cases of large-cell or anaplastic MB belong to this group, the most frequent histological subtype seen in this group is classic. Also, most cases of myc amplification seem to be confined to a subgroup of Group 3 MB [34]. Both the myc-pathway [42] as well as the TGF-b signaling pathway [36] may be future candidates for pharmacologic intervention. Group 4 medulloblastoma As a group, these are the most common MB, occurring at all ages, in part metastatic, and associated with an intermediate prognosis.
359
N.U. Gerber et al. / Cancer Treatment Reviews 40 (2014) 356–365
Table 2 Schematic model of future risk-adapted treatment stratification by clinical and biological parameters. Not all possible constellations are specified (e.g. metastatic WNT-MB in patients over 3 to 5 years). AMB: anaplastic medulloblastoma; CMB: classic medulloblastoma; DMB: demoplastic medulloblastoma; LCMB: large cell medulloblastoma; MBEN: medulloblastoma with extensive nodularity; SHH: medulloblastoma with activated sonic hedgehog pathway; WNT: medulloblastoma with activated wingless pathway; residual tumor is described according to S-classification (see Table 1); M0: no evidence of metastasis; M+: metastatic medulloblastoma. Medulloblastoma in older children (over 3–5 years)*
Early childhood medulloblastoma (below 3–5 years)⁄ Definition (all parameters required)
Estimated frequency within age group
Expected EFS
Definition (all parameters required)
Estimated frequency within age group (%)
Expected EFS (%)
Low risk
DMB/MBEN SHH-group Any degree of resection Any M-stage
30%
60–90%
CMB/DMB/MBEN WNT-group S0/S1 M0
10
>85
Standard risk
–
–
–
CMB/DMB/MBEN Non-WNT-group S0/S1 M0 c-myc neg
50
80
High risk
CMB/LCMB/AMB Non-SHH-group M0 c-myc neg CMB/LCMB/AMB
50%
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