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Enrico Franceschi of the University of Bologna in Italy discussed histology and molecular typing, imaging diagnosis, surgery, chemoradiotherapy, novel targeted therapies and future research directions for adult medulloblastoma, and the results were published online in Cancers in July 2022
.
- Excerpted from the article chapter
【Ref: Franceschi E, et al.
Cancers (Basel).
2022 Jul 29; 14(15):3708.
doi: 10.
3390/cancers14153708.
】
Research background
In 1925, Bailey and Cushing first reported medulloblastoma (MB), a rare posterior fossa malignancy (WHO grade IV) that originates in the outer granule cell layer
of the cerebellar embryo.
The tumor grows in the fourth ventricle and spreads to the cerebellar vermis and brainstem, and metastasizes (droplet metastasis) in the subarachnoid space to the entire cerebrospinal system
.
MB is the second most common childhood brain tumor, accounting for 20% of all childhood brain tumors, with peaks at 2-4 years and 8-10 years, and a significant decrease in incidence after 15 years
.
MB in adults is very rare, accounting for only 0.
4-1% of all adult brain tumors, with an annual incidence of 0.
6-1
per million.
Treatment regimens are mainly drawn on MB in children, and prospective randomized clinical trials in adults are rare
.
The current standard of care for MB includes surgery and chemoradiotherapy, with a 50% to 90% 5-year survival rate, but associated adverse effects involve 80% of patients
.
Enrico Franceschi of the University of Bologna in Italy discussed histology and molecular typing, imaging diagnosis, surgery, chemoradiotherapy, novel targeted therapies and future research directions for adult medulloblastoma, and the results were published online in Cancers in July 2022
.
Research methods
According to the fourth (2016) and fifth (2021) editions of the WHO Classification of Central Nervous System Tumors, there are currently four molecular types of MB: wingless (WNT), sonic hedgehog (SHH)-activated TP53 wild type, SHH-activated TP53 mutant type, and non-WNT or non-SHH type (including groups 3 and 4).
Four histologic types: classical, connective hyperplasia/nodular, extensive nodular, and large cell/anaplastic.
Study results
Different molecular types show significantly different age, molecular, and clinical features
.
WNT type is mainly caused by abnormal activation of WNT pathway due to somatic mutations activated by the CTNNB1 gene, and has the best prognosis in all subgroups, rarely metastasis, and prone to intratumoral stroke
.
SHH type is the most common subgroup in the adult population, accounting for about 60% of adult MB, and the 5-year overall survival rate in the absence of TP53 mutations is about 50-70%.
After the discovery of different molecular types of MB, research on multiple targeted drugs
has begun.
The SHH type, in particular, has come into focus, as studies have shown that the SHH inhibitors Vimodegil and Sonydegib are effective against MB carrying SHH mutations, with no serious side effects
of premature fusion found in the adult population.
1.
The distribution of MB molecular types in adults and children in molecular genetics differs significantly, with SHH activation MB being the most widely
distributed among adults.
The 2021 edition of the taxonomy integrates molecular and histopathological features to determine the four molecular types of MB, allowing for more accurate risk stratification
.
Goschzik et al.
reported a 5-year event-free survival (EFS) of 60% and a 5-year overall survival (OS) of 75.
6%
in a 117-adult MB cohort.
The 5-year EFS and OS of SHH-activated TP53 mutant type were poor, while the 5-year EFS/OS of the other three groups were better, all between
60% and 80%.
In the absence of molecular information, MB is divided into classical type, connective tissue hyperplasia/(D/N), extensive nodular type (MBEN), and large cell type/anaplastic type (LC/A)
according to histology.
Classic MB is a blue cell tumor with no obvious structural features, varying in degree of nuclear interchange, and often the Homer-Wright wreath
.
The connective tissue hyperplasia/nodular type is characterized by varying degrees of neuronal differentiation, and the typical nodular morphology is confirmed
by perinodular reticular fiber staining.
Differentiated nodules are characterized by strong synaptophysin positivity and low Ki67 values
.
This type of MB is usually more localized
.
In contrast, extensive nodular MB is seen in young children and not adults
.
Large cell type/anaplastic is characterized by severe nuclear anaplastic and/or large cell appearance with a large round nucleus and prominent nucleoli
.
Diffusely positive
for synaptophysin staining.
MB cells are typically synaptophysin-positive and express GFAP, while OLIG2 staining is negative or at most only locally positive
.
Waveform protein staining is usually negative
.
A clear pattern of infiltrative growth can be seen, making it difficult to distinguish MB from diffuse high-grade gliomas occurring in the cerebellum
.
SHH-activated MB is typically GAB1 and YAP1 positive, and cytoplasmic expression β-catenin
.
WNT-activated forms usually express β-catenin in the nucleus; Expresses YAP1, not GAB1
.
Lymphatic enhancement factor, a transcription factor that mediates WNT/β-catenin signaling, is overexpressed
in WNT-activated forms.
Non-WNT, non-SHH YAP1 and GAB1 are negative, and cytoplasmic expression β catenin
.
p53 protein expression confirms most SHH-activated TP53 mutation states
.
There are two main limitations in immunohistochemistry, which do not distinguish between groups 3 and 4, but are not relevant to adults; Non-conclusive immunohistochemistry results, particularly rare subtypes (melanocyte/rhabdomyoblastic differentiation),
are present.
Therefore, molecular typing may be the key
to obtaining a definitive diagnosis.
The histologic type of molecular typing MB has a characteristic relationship
with molecular typing.
For example, morphological connective tissue hyperplasia/nodular types correspond to SHH-activated types, and most WNT-activated types correspond to classical types
.
However, this is not 100% corresponding
.
Molecular typing of MB can be achieved by a variety of techniques, including mRNA-based techniques (such as NanoString and RNA sequencing) or DNA analysis-based techniques (such as copy number variation).
Genome-wide methylation sequencing is currently the gold standard, but it is mainly used in children, while methylation data in adults are limited
.
The SHH type predominates in adults, usually the TP53 wild type, accounting for about 60% of adult MB, while the SHH-TP53 mutant type is mainly seen in children and adolescents
.
WNT is similar in adults and children (15% vs.
10%), and non-WNT/non-SHH is relatively rare in adults (2.
6% vs.
25%), consisting almost exclusively of group 4
.
TP53 mutant type is rare (2.
6%) in adults with SHH type, but may occur
in recurrent tumors.
In most cases, the type also shows mutations in the TERT promoter, DDX3X, and U1 snRNA
.
In adults, MYCN amplification and TP53 mutations tend to co-occur and are associated with
poor prognosis.
TP53 mutant chromosomes such as 17p, 3p, 10q, and 14q are lost and 3q is increased
.
Non-WNT/non-SHH types accounted for 22.
2% of adult MB and were divided into groups 3 and 4
.
Group 3 is extremely rare in adults, mostly in group
4.
The most common gene mutations in groups 3 and 4 involve KDM6A, OTX2, ZMM3, KMT2D, TBR1, and PRDM6
.
Abnormal overexpression of PRDM6 is specific to group 4
.
Groups 3 and 4 have recently been identified by DNA methylation profiles
.
An international meta-analysis found that there were eight subgroups
in groups 3 and 4.
Group 3 consists of
subgroups 2, 3 and 4.
Group 4 consists of
subgroups 6, 7 and 8.
Subgroups 1 and 5 are the middle subgroups
.
Most subgroups are classical, and large cell/anaplastic is more common in subgroup 2
.
In subgroups 2-5, metastasis
is common.
In subgroups 2 and 3, MYC/MYCN amplification was found with a poor
prognosis.
WNT-activated type is the least common in adults, accounting for about 14.
5%, mainly caused
by somatic mutations that activate the CTNNB1 gene.
To definitively diagnose WNT-activated type, sequencing is recommended to confirm CTNNB1 mutations
.
2.
Imaging diagnosis
Patients with MB typically present with obstructive hydrocephalus, elevated intracranial pressure, and cerebellar symptoms (eg, ataxia, gait disturbance).
Emergency CT shows a high-density mass
in the posterior fossa.
Further MRI (layer thickness <4mm) diagnosis, including FLAIR, T2W, DWI, and T1W (layer thickness <1mm)<b14> before and after reinforcement only.
To avoid confusion between vascular structure and leptomeninge brain metastases, three-dimensional T1-weighted fast spin-echo sequences
are recommended.
In addition, FLAIR images can be obtained after intravenous contrast media, which is highly sensitive
for detecting pia mater metastases.
MB on MRI shows clear tumor margins and less
edema.
T2W lesions range from low to high signal, and T1W is low signal
.
After intravenous contrast, lesions show moderate to marked enhancement
.
Because MB is cellular, routine diffusion-weighted imaging is recommended, with MB diffusion limited
.
In contrast to children's MB (located in the midline of the cerebellum, originating from the cerebellar vermis), adult MB is mainly SHH type, mostly located in the cerebellar hemisphere, DWI is hyperintense, and peritumor edema is more
.
Compared with other molecular types, adult WNT-activated tumors tend to be smaller in size and have less
subependymal metastasis.
To monitor treatment effectiveness, the RAPNO committee defines treatment response criteria
.
Complete response (CR) is defined as the complete absence of neoplastic lesions in the brain and spinal cord, which do not show lesions after enhanced MRI and are maintained for at least 4 weeks
.
Partial response (PR) is defined as a 50% reduction in the sum of the product of long diameters × short diameters perpendicular to the long diameter of all target lesions for at least 4 weeks
.
Disease progression (PD) is defined as a 25% increase in the sum of the product of long diameters perpendicular to the long diameter of all target lesions × the emergence of new lesions (all suspicious lesions should be biopsied).
If none of the above criteria are met, it is defined as disease stable (SD).
Postoperative MRI should be done within 48 hours to detect residual tumor
.
If postoperative changes are indistinguishable from tumor remains, repeat MRI 2-3 weeks
postoperatively is recommended.
Meloblastoma not only metastasizes along the meninges, but also seeds
along the spinal cord.
MRI should therefore include the entire spinal cord, although there is no consensus
on the length of follow-up for spinal cord MRI.
The PAPNO committee recommends that spinal cord MRI be synchronized
with head MRI if the patient is CNS tumor cells positive or evidence of meningeal spread is already present.
If the patient has extraneurologic symptoms, systematic examination (chest, abdomen and pelvic contrast CT, whole-body PET-CT, or bone scan)
is indicated.
Considering the high cost of molecular testing and the difficulty of widespread implementation, it is very necessary to determine the molecular typing
of tumors based on imaging.
Many research teams use artificial intelligence to analyze MRI for molecular typing
.
There are also molecular typing by machine deep learning MRI, such as distinguishing low-risk WNT types from high-risk SHH types
.
3.
Surgery
After brain and spinal cord MRI diagnosis, different treatment options should be discussed in detail, with particular emphasis on age, comorbidities, and surgical risks
.
Total resection is always attempted in children, but biopsy should be an option in older people if the risk of surgery is too high, but surgical resection
should be attempted if it is safe and feasible.
The goal of surgery is to take a specimen and treat potential hydrocephalus, reduce intracranial pressure, and reduce tumor burden
.
Preoperative corticosteroids, usually 8 mg of dexamethasone once a day in the morning, are given to reduce angiogenic edema
.
Patients without seizures do not need to prophylaxis against epilepsy
.
Patients may have seizures due to hydrocephalus, in which case anticonvulsant therapy
should be given preoperatively.
Medulloblastoma often presents with elevated intracranial pressure due to obstructive hydrocephalus, and moderate to severe hydrocephalus occurs in 30 to 40% of patients, which can require temporary emergency ventricular drainage or endoscopic third ventriculostomy
.
In most cases, resection resolves the development of hydrocephalus without further CSF
shunting.
Ventriculoperitoneal shunt is not recommended prior to tumor resection because of the risk
of hernia on the cerebellar tossormic notch and entry of tumor cells into the abdominal cavity.
Complete tumor resection should be sought, and it is recommended to maximize safe resection, with a residual tumor volume of less than 1.
5 cm²; do not cause neurological deficits
for total resection.
In addition, if the tumor has spread, it should be reduced to reduce symptoms
.
About 70% of adult medulloblastoma occurs in the cerebellar hemisphere, mainly SHH type; 90% of medulloblastomas in children occur in the midline
.
Therefore, adults often take the paramedian approach, and complete excision is safer
than in children.
A rare location for adult MB is the pontine cerebellar angle, which is surgically approached after the sigmoid sinus; Patients with retrosigmoid sinus approach lie on their side or supine with ipsilateral shoulder elevation
.
The suboccipital approach is taken in the prone position, and the lateral mid-approach is taken in the prone or lateral position
.
Intraoperative neuronavigation and ultrasound aspirators
are recommended.
Intraoperative neuromonitoring is recommended for rare pontine cerebellar angle tumors, but not for cerebellar tumors
.
Complete resection
is achieved in 60-90% of adult medulloblastomas.
Intraoperative MRI can be used to assess the extent of
resection.
MRI within 48 hours of surgery is necessary, and if residual tumor is found to exceed 1.
5 cm², surgery should be repeated
.
Surgical complications occur in up to 30%, including intracranial haematoma, cerebrospinal fluid leak, infection/meningitis, hydrocephalus, meningocele pseudomeningocele, and cranial nerve palsy
.
Postoperative hydrocephalus occurs in 14-37.
5% of patients, requiring cerebrospinal fluid
shunting.
Cerebellar mutism rarely occurs after surgery in adults and usually resolves within
30 days.
Retention of CSF specimens allows assessment of CSF metastasis, and the standard protocol is to sample CSF by lumbar puncture before or 2 weeks
postoperatively.
.
Whole-brain whole-spinal radiotherapy (23.
4 Gy, single dose 1.
8 Gy) combined with CCNU, cisplatin, and vincristine as standard therapy resulted in a 5-year survival rate > 80%.
Hyperfractionated radiotherapy does not achieve higher survival rates
than conventional radiation therapy.
Adults currently use the children's regimen, but translating the children's regimen directly into the adult regimen has limitations: mainly differences in molecular typing and drug toxicity between children and adults
.
(1) Molecular differences: SHH-MB (70%), Group 4 (20%) and WNT subtypes are the main genetically defining subtypes
.
SHH-MB in adults differs from SHH tumors in children in that p53 mutations are less frequent and TERT promoter mutations are more frequent
.
In general, adults with MB have a poor prognosis and are prone to relapse
.
(2) Toxicity differences: Hematological toxicity and peripheral neurotoxicity caused by chemotherapy were evident in adolescents and young adults, while central nervous toxicity was evident
in children.
In addition, young children are prone to growth disorders
after radiation therapy.
There are few studies of long-term harmful effects (such as neurotoxicity, ototoxicity, or endocrine disease) in adults, and further prospective studies
are needed.
In a phase II clinical trial in Italy, 26 high-risk patients who received two cycles of chemotherapy, followed by radiotherapy and chemotherapy, had a 5-year progression-free survival rate of 69% and a 5-year overall survival rate of 73%.
Low-risk patients from the same trial achieved 100% overall survival after radiotherapy with chemotherapy, compared with 78.
6% (p=0.
079)
in patients with radiotherapy alone.
In one large meta-analysis, adult patients receiving chemotherapy had significantly longer survival than those treated with radiotherapy alone (median overall survival 108 months, 95% CI, 68.
6 to 148.
4).
A retrospective analysis of the National Cancer Database registry confirmed that postoperative chemoradiotherapy was superior to radiotherapy
alone.
Over the past few decades, advanced 3D conformal radiotherapy (such as volumetric arc intensity modulated radiation therapy and tomotherapy has been introduced) to reduce the dose of off-target risk organs and improve efficacy, but there is also a risk
of secondary malignancy in other organs.
In contrast, proton therapy protects normal tissue outside the target organ from radiation, reduces hematotoxicity, endocrine dysfunction, cardiotoxicity, and ototoxicity, and may reduce the risk of secondary cancers in other organs
.
5.
Compared with traditional cytotoxic therapy, targeted therapy has less toxicity and strong
targeting.
Vimodegil and Sonydegib are two highly selective SHH inhibitors targeting SMO receptors that have shown good efficacy and low
toxicity in preclinical and clinical trials.
However, the problem with SHH inhibitors is easy drug resistance, mainly related to genetic changes within or downstream of SMO, between SUFU and GLI, and between phosphoinositol-3 kinase and MEK pathways; Therefore, combination therapy
with SMO inhibitors, PI3K/MEK inhibitors, and temozolomide is recommended.
6.
Conclusions and future directions
MB is a rare tumor in the post-pubertal population and is heterogeneous
.
Even though the 2021 edition of the WHO Diagnostic Classification of MB has made innovations in the field of pathology and molecular biology, there is still a lack of clinical trials to modify the current treatment regimen for MB, especially for adult MB.
Standard regimens of surgery combined with cerebrospinal cord radiotherapy and multi-agent chemotherapy have a variety of short- and long-term toxicities, resulting in hematological, neurocognitive, and endocrine damage, and significantly worsening quality of life in a large proportion of patients
.
Therefore, the development of new low-toxicity treatment options remains a hot area of research
.
The use of personalized targeted therapies has advantages, and future research dedicated to the treatment of MB in adults should be individualized according
to age and molecular characteristics.
