Medulloblastoma

Signs and symptoms

Signs and symptoms are mainly due to secondary increased intracranial pressure due to blockage of the fourth ventricle and tumors are usually present for 1 to 5 months before diagnosis is made. The child typically becomes listless, with repeated episodes of vomiting, and a morning headache, which might lead to a misdiagnosis of gastrointestinal disease or migraine. Soon after, the child will develop a stumbling gait, truncal ataxia, frequent falls, diplopia, papilledema, and sixth cranial nerve palsy. Positional vertigo and nystagmus are also frequent, and facial sensory loss or motor weakness may be present. Decerebrate attacks appear late in the disease.

Extraneural metastasis to the rest of the body is rare, and when it occurs, it is in the setting of relapse, more commonly in the era prior to routine chemotherapy.

Pathogenesis

Medulloblastomas are usually found in the vicinity of the fourth ventricle, between the brainstem and the cerebellum. Tumors with similar appearance and characteristics originate in other parts of the brain, but they are not identical to medulloblastoma.

Although medulloblastomas are thought to originate from immature or embryonal cells at their earliest stage of development, the cell of origin depends on the subgroup of medulloblastoma. WNT tumors originate from the lower rhombic lip of the brainstem, while SHH tumors originate from the external granular layer.

Currently, medulloblastomas are thought to arise from cerebellar stem cells that have been prevented from dividing and differentiating into their normal cell types. This accounts for the histologic variants seen on biopsy. Both perivascular pseudorosette and Homer Wright pseudorosette formations are highly characteristic of medulloblastomas and are seen in up to half of cases. The classic rosette with tumor cells around a central lumen can be seen.

In the past, medulloblastoma was classified using histology, but integrated genomic studies have revealed that medulloblastoma is composed of four distinct molecular and clinical variants termed WNT/β-catenin, Sonic Hedgehog, Group 3, and Group 4. Of these subgroups, WNT patients have an excellent prognosis and group 3 patients have a poor prognosis. Also, a subgroup-specific alternative splicing further confirms the existence of distinct subgroups and highlights the transcriptional heterogeneity between subgroups. Amplification of the Sonic Hedgehog pathway is the best characterized subgroup, with 25% of human tumors having mutations in Patched, Sufu (Suppressor of Fused Homolog), Smoothened, or other genes in this pathway. Medulloblastomas are also seen in Gorlin syndrome as well as Turcot syndrome. Recurrent mutations in the genes CTNNB1, PTCH1, MLL2, SMARCA4, DDX3X, CTDNEP1, KDM6A, and TBR1 were identified in individuals with medulloblastoma. Additional pathways disrupted in some medulloblastomas include MYC, Notch, BMP, and TGF-β signaling pathways.

Diagnosis

The tumor is distinctive on T1- and T2-weighted MRI with heterogeneous enhancement and a typical location adjacent to and extension into the fourth ventricle. Histologically, the tumor is solid, pink-gray in color, and is well circumscribed. The tumor is very cellular, with high mitotic activity, little cytoplasm, and a tendency to form clusters and rosettes.

The Chang staging system can be used in making the diagnosis.

DNA methylation profiling of medulloblastoma allows robust sub-classification and improved outcome prediction using formalin-fixed biopsies.

Correct diagnosis of medulloblastoma may require ruling out atypical teratoid rhabdoid tumor.

Image:Cerebellar medulloblastoma (1) in adult.JPG|Cerebellar medulloblastoma in an adult Image:Cerebellar medulloblastoma (2) in adult.JPG|Cerebellar medulloblastoma in an adult

Treatment

Treatment begins with maximal surgical removal of the tumor. The addition of radiation to the entire neuraxis and chemotherapy may increase the disease-free survival. This combination may permit a 5-year survival in more than 80% of cases. Some evidence indicates that proton beam irradiation reduces the impact of radiation on the cochlear and cardiovascular areas and reduces the cognitive late effects of cranial irradiation.

The presence of desmoplastic features such as connective tissue formation offers a better prognosis. Prognosis is worse if the child is less than 3 years old, degree of resection is inadequate, or if any CSF, spinal, supratentorial, or systemic spread occurs. Dementia after radiotherapy and chemotherapy is a common outcome appearing two to four years following treatment. Side effects from radiation treatment can include cognitive impairment, psychiatric illness, bone growth retardation, hearing loss, and endocrine disruption. Increased intracranial pressure may be controlled with corticosteroids or a ventriculoperitoneal shunt. An approach to monitor tumor development and treatment response by liquid biopsy is promising, but remains challenging.

Chemotherapy

Chemotherapy is often used as part of treatment. Evidence of benefit, however, is not clear as of 2013. A few different chemotherapeutic regimens for medulloblastoma are used; most involve a combination of lomustine, cisplatin, carboplatin, vincristine, or cyclophosphamide. In younger patients (less than 3–4 years of age), chemotherapy can delay, or in some cases possibly even eliminate, the need for radiotherapy. However, both chemotherapy and radiotherapy often have long-term toxicity effects, including delays in physical and cognitive development, higher risk of second cancers, and increased cardiac disease risks.

Outcomes

Array-based karyotyping of 260 medulloblastomas resulted in the following clinical subgroups based on cytogenetic profiles:

• Poor prognosis: gain of 6q or amplification of MYC or MYCN
• Intermediate: gain of 17q or an i(17q) without gain of 6q or amplification of MYC or MYCN
• Excellent prognosis: 6q and 17q balanced or 6q deletion

Transcriptional profiling shows the existence of four main subgroups (Wnt, Shh, Group 3, and Group 4).

• Very good prognosis: WNT group,* CTNNB*1 mutation
• Infants good prognosis, others intermediate: SHH group, PTCH1/SMO/SUFU mutation, GLI2 amplification, or MYCN amplification
• Poor prognosis: Group 3, MYC amplification, photoreceptor/GABAergic gene expression
• Intermediate prognosis: Group 4, gene expression of neuronal/glutamatergic, CDK6 amplification, MYCN amplification

Survival

The historical cumulative relative survival rate for all age groups and histology follow-up was 60%, 52%, and 47% at 5 years, 10 years, and 20 years, respectively. Patients diagnosed with a medulloblastoma or PNET are 50 times more likely to die than a matched member of the general population. A population-based (SEER) 5-year relative survival rates indicated 69% overall: 72% in children (1–9 years) and 67% in adults (20+ years). The 20-year survival rate is 51% in children. Children and adults have different survival profiles, with adults faring worse than children only after the fourth year after diagnosis (after controlling for increased background mortality). Before the fourth year, survival probabilities are nearly identical. Long-term sequelae of standard treatment include hypothalamic-pituitary and thyroid dysfunction and intellectual impairment. The hormonal and intellectual deficits created by these therapies causes significant impairment of the survivors.

In current clinical studies, the patients are divided into low-, standard- and high-risk groups:

• Depending on the study, healing rates of up to 100% are achieved in the low-risk group (usually WNT-activated). The current efforts are therefore moving in the direction of reducing the intensity of the therapy and thus the negative long-term consequences while confirming the high healing rates.
• In the HIT-SIOP PNET 4 study, in which 340 children and adolescents of the standard-risk group between the ages of four and 21 from several European countries participated, the 5-year survival rate was between 85% and 87% depending on the randomization. Around 78% of the patients remained without relapse for 5 years and are therefore considered to be cured. After a relapse, the prognosis was very poor. Despite intensive treatment, only four of 66 patients were still alive 5 years after a relapse.
• A US study involved 161 patients between the ages of three and 21 with a high-risk profile. Depending on the randomization, half of the patients additionally received carboplatin daily during the radiation. The 5-year survival rate of patients with carboplatin was 82%, those without 68%. The European SIOP PNET 5 study is currently taking place and will run until April 2024, in which an attempt is made to confirm the promising results with carboplatin during irradiation in the standard risk group.

Epidemiology

Medulloblastomas affect just under two people per million per year, and affect children 10 times more than adults. Medulloblastoma is the second-most frequent brain tumor in children after pilocytic astrocytoma and the most common malignant brain tumor in children, comprising 14.5% of newly diagnosed brain tumors. In adults, medulloblastoma is rare, comprising fewer than 2% of CNS malignancies.

The rate of new cases of childhood medulloblastoma is higher in males (62%) than females (38%), a feature that is not seen in adults. Medulloblastoma and other PNETs are more prevalent in younger children than older children. About 40% of medulloblastoma patients are diagnosed before the age of five, 31% are between the ages of 5 and 9, 18.3% are between the ages of 10 and 14, and 12.7% are between the ages of 15 and 19.

Research models

Using gene transfer of SV40 large T-antigen in neuronal precursor cells of rats, a brain tumor model was established. The PNETs were histologically indistinguishable from the human counterparts and have been used to identify new genes involved in human brain tumor carcinogenesis. The model was used to confirm* p53* as one of the genes involved in human medulloblastomas, but since only about 10% of the human tumors showed mutations in that gene, the model can be used to identify the other binding partners of SV40 Large T- antigen, other than p53. In a mouse model, high medulloblastoma frequency appears to be caused by the down regulation of Cxcl3, with Cxcl3 being induced by Tis21. Consistently, the treatment with Cxcl3 completely prevents the growth of medulloblastoma lesions in a Shh-type mouse model of medulloblastoma. Thus, CXCL3 is a target for medulloblastoma therapy.

References

References

1. "Medulloblastoma".
2. (17 September 2018). "Medulloblastoma Diagnosis and Treatment".
3. (2011). "Cerebellum development and medulloblastoma".
4. (February 2015). "Focusing On Brain Tumors: Medulloblastoma". American Brain Tumor Association.
5. (May 2007). "Medulloblastoma: tumorigenesis, current clinical paradigm, and efforts to improve risk stratification". Nature Clinical Practice. Oncology.
6. Packer, Roger. (2002). "Medulloblastoma". Clinical Trials and Noteworthy Treatments for Brain Tumors.
7. "Medulloblastoma".
8. (2008). "Fitzpatrick's Dermatology in General Medicine". McGraw-Hill Medical.
9. "Adams and Victor's Principles of Neurology".
10. (April 2012). "Molecular subgroups of medulloblastoma: the current consensus". Acta Neuropathologica.
11. (April 2012). "Subgroup-specific alternative splicing in medulloblastoma". Acta Neuropathologica.
12. (January 2005). "Medulloblastoma: developmental mechanisms out of control". Trends in Molecular Medicine.
13. (December 2010). "Subtypes of medulloblastoma have distinct developmental origins". Nature.
14. (August 2012). "Dissecting the genomic complexity underlying medulloblastoma". Nature.
15. (September 2010). "Childhood medulloblastoma: novel approaches to the classification of a heterogeneous disease". Acta Neuropathologica.
16. (April 2011). "Integrative genomic analysis of medulloblastoma identifies a molecular subgroup that drives poor clinical outcome". Journal of Clinical Oncology.
17. (August 2012). "Subgroup-specific structural variation across 1,000 medulloblastoma genomes". Nature.
18. (March 2011). "Development and cancer of the cerebellum". Trends in Neurosciences.
19. "Medulloblastoma staging". wikidoc.
20. (March 2013). "DNA methylation profiling of medulloblastoma allows robust subclassification and improved outcome prediction using formalin-fixed biopsies". Acta Neuropathol.
21. (September 1998). "Atypical teratoid/rhabdoid tumor of the central nervous system: a highly malignant tumor of infancy and childhood frequently mistaken for medulloblastoma: a Pediatric Oncology Group study". The American Journal of Surgical Pathology.
22. (July 2008). "Proton versus photon radiotherapy for common pediatric brain tumors: comparison of models of dose characteristics and their relationship to cognitive function". Pediatric Blood & Cancer.
23. (July 2012). "Estimated clinical benefit of protecting neurogenesis in the developing brain during radiation therapy for pediatric medulloblastoma". Neuro-Oncology.
24. (Sep 2022). "Liquid biopsy for monitoring medulloblastoma.". Extracell Vesicles Circ Nucleic Acids.
25. (January 2015). "Chemotherapy for children with medulloblastoma". The Cochrane Database of Systematic Reviews.
26. (February 2009). "Pediatric medulloblastoma: toxicity of current treatment and potential role of protontherapy". Cancer Treatment Reviews.
27. (December 2007). "Medulloblastoma in childhood: new biological advances". The Lancet. Neurology.
28. (April 2009). "Outcome prediction in pediatric medulloblastoma based on DNA copy-number aberrations of chromosomes 6q and 17q and the MYC and MYCN loci". Journal of Clinical Oncology.
29. (March 2012). "Relative survival of childhood and adult medulloblastomas and primitive neuroectodermal tumors (PNETs)". Cancer.
30. Packer, Roger J.. (2010). "Medulloblastoma".
31. "Identifying Low-Risk Medulloblastoma to De-escalate Therapy".
32. (September 2012). "Hyperfractionated versus conventional radiotherapy followed by chemotherapy in standard-risk medulloblastoma: results from the randomized multicenter HIT-SIOP PNET 4 trial". Journal of Clinical Oncology.
33. (September 2016). "Relapse patterns and outcome after relapse in standard risk medulloblastoma: a report from the HIT-SIOP-PNET4 study". Journal of Neuro-Oncology.
34. (July 2012). "Outcome of children with metastatic medulloblastoma treated with carboplatin during craniospinal radiotherapy: a Children's Oncology Group Phase I/II study". Journal of Clinical Oncology.
35. {{ClinicalTrialsGov. NCT02066220. International Society of Paediatric Oncology (SIOP) PNET 5 Medulloblastoma
36. (November 2012). "The incidence of medulloblastomas and primitive neurectodermal tumours in adults and children". Journal of Clinical Neuroscience.
37. "Chapter 7: Tumors of the Central Nervous System". NEOMED.
38. (1999). "Cancer Incidence and Survival among Children and Adolescents: United States SEER Program 1975–1995". National Cancer Institute.
39. "Selected Primary Brain and Central Nervous System Tumor Age-Specific Incidence Rates". Central Brain Tumor Registry of the United States, 1998–2002.
40. "Selected Childhood Primary Brain and Central Nervous System Tumor Incidence Rates by Major Histology Groupings, Histology and Gender". Central Brain Tumor Registry of the United States, 1998–2002.
41. "Selected Childhood Primary Brain and Central Nervous System Tumor Age-Specific Incidence Rates". Central Brain Tumor Registry of the United States, 1998–2002.
42. (March 1994). "A model for primitive neuroectodermal tumors in transgenic neural transplants harboring the SV40 large T antigen". The American Journal of Pathology.
43. (November 1991). "p53 mutations in nonastrocytic human brain tumors". Cancer Research.
44. (February 2023). "From TP53 Mutations to Molecular Classification and Liquid Biopsy". Biology.
45. (October 2012). "Tis21 knock-out enhances the frequency of medulloblastoma in Patched1 heterozygous mice by inhibiting the Cxcl3-dependent migration of cerebellar neurons". The Journal of Neuroscience.
46. (2016). "Suppression of Medulloblastoma Lesions by Forced Migration of Preneoplastic Precursor Cells with Intracerebellar Administration of the Chemokine Cxcl3". Frontiers in Pharmacology.