-
Categories
-
Pharmaceutical Intermediates
-
Active Pharmaceutical Ingredients
-
Food Additives
- Industrial Coatings
- Agrochemicals
- Dyes and Pigments
- Surfactant
- Flavors and Fragrances
- Chemical Reagents
- Catalyst and Auxiliary
- Natural Products
- Inorganic Chemistry
-
Organic Chemistry
-
Biochemical Engineering
- Analytical Chemistry
-
Cosmetic Ingredient
- Water Treatment Chemical
-
Pharmaceutical Intermediates
Promotion
ECHEMI Mall
Wholesale
Weekly Price
Exhibition
News
-
Trade Service
Mary Jane Lim-Fat et al.
of the Department of Neurology, Sunnybrook Health Science Center, University of Toronto, Canada, proposed a consensus guideline for CNS tumor molecular detection in the AYA population based on literature and expert opinions, which was published online in Frontiers in Oncology in September 2022
.
- Excerpted from the article chapter
【Ref: Lim-Fat MJ, et al.
Front Oncol.
2022 Sep 23; 12:960509.
doi: 10.
3389/fonc.
2022.
960509.
eCollection 2022.
】
Research background
The 2016 World Health Organization (WHO) Classification of Central Nervous System Tumors revised to introduce molecular genetic features to complement histological diagnosis and grading; After the update of the Consortium for Molecular Information and Practice Methods for Classification of Central Nervous System Tumors (cIMPACT-NOW), the fifth edition of the WHO Classification of Central Nervous System Tumors (WHO CNS5) in 2021 combines molecular diagnosis with tumor diagnosis methods established by tissue morphology and immunohistochemistry
.
The National Cancer Institute defines people aged 15-39 as adolescent and young adults (AYA).
There are many different subtypes of AYA CNS tumors, including gliomas (adult and pediatric types), medulloblastoma/embryonic tumors, and ependymomas
.
Currently, there are no clear guidelines
for the diagnosis or treatment of patients in this age group.
Mary Jane Lim-Fat et al.
of the Department of Neurology, Sunnybrook Health Science Center, University of Toronto, Canada, proposed a consensus guideline for CNS tumor molecular detection in the AYA population based on literature and expert opinions, which was published online in Frontiers in Oncology in September 2022
.
Study results
The WHO CNS5 divides gliomas, glial neuronal tumors, and neuronal tumors into 6 different subtypes: adult-type diffuse glioma, pediatric-type diffuse low-grade glioma, pediatric-type diffuse high-grade glioma, localized astrocytic glioma, glial neurons and neuronal tumors, and ependymomas
.
The clinical and molecular distinction between adult-type diffuse glioma and pediatric-type diffuse glioma is the most important change
in WHO CNS5.
Stratification of gliomas in adults and children is shown in Table 1
.
Table 1.
Patients with AYA glioma are recommended for testing biomarkers and their clinical significance
.
.
From the previous 15 types, it is divided into 3 types: astrocytoma, isocitrate dehydrogenase (IDH) mutant, oligodendroglioma; IDH mutation with 1p/19q combined deletion, glioblastoma; IDH wild type
.
In IDH mutant gliomas, ATRX deletion is sufficient to diagnose astrocyte line tumors without the need for a 1p/19q codeletion analysis
.
In contrast, patients with IDH-mutant gliomas expressing the ATRX gene should be analyzed for 1p/19q codeletion
.
All IDH-mutant diffuse astrocytomas are classified as a single type, astrocytoma, and IDH mutations can be classified into grades 2, 3, and 4 (the term anaplastic is no longer used).
Even in the absence of microangiogenesis or focal necrosis, cyclin-dependent kinase inhibitor (CDKN) 2A/B homozygous deletion predicts a poor prognosis, classified as astrocytoma, IDH mutation, CNS WHO grade
4.
In WHO CNS5, glioblastoma (GBM) no longer refers to IDH-mutant astrocytic glioma
.
Astrocytomas with wild-type IDH and histone H3 status with necrosis or microangiogenesis are classified as IDH wild-type WHO grade 4 glioblastoma
.
In the absence of necrosis or microangiogenesis, genetic alterations such as EGFR amplification, telomerase reverse transcriptase (TERT) promoter mutations, and/or chromosome 7 amplification and chromosome 10 deletion (Chr7+/10-) should be assessed, and if more than one of these changes is present, the tumor should be classified as IDH wild-type glioblastoma
.
Of note, some diffuse astrocytomas (WHO grade 2) are accompanied by a mutation in the TERT promoter alone
.
Most GBMs, especially those with typical histologic features, are more common
in older people.
In the absence of these three genetically modified IDH wild-type diffuse astrocytomas, particularly in patients with AYA, pediatric gliomas
should be considered.
Subtypes such as gliosarcoma and giant cell glioblastoma are no longer listed
.
Pediatric glioma Child-type diffuse low-grade gliomas (LGG).
Diffuse low-grade gliomas in children in the WHO CNS5 are subdivided into diffuse astrocytomas with MYB or MYBL1 changes, altered mitogen-activated protein kinase (MAPK) pathway (usually BRAF or FGFR1 changes), angiocentric gliomas (MYB-QKI fusion), juvenile multitype low-grade neuroepithelial tumors (FGFR2 fusion).
From a histopathological point of view, low-grade gliomas (LGG) in children with altered MAPK pathway are diffuse gliomas with low cell density and mild atypia.
Usually manifested as OLIG2 immunopositive, GFAP expressed
to varying degrees.
Tumors with MYB or MYBL1 alterations consist of cells of relatively single glial origin, with microcircular or spindle-like nuclei in the fibrous stroma, possibly with ambiguous vascular center polarity
.
Often presents as GFAP-positive and OLIG2-negative
.
Child-type diffuse high-grade gliomas (HGGs) are in contrast to adult-type gliomas (which may be transformed from low-grade tumors), in which pediatric-type HGGs are produced
by different molecular drivers.
Within the AYA group, child-type diffuse HGGs can be further subdivided into diffuse midline gliomas (DMGs) with H3 k27 mutation, diffuse hemispherical glioma, with H3 G34 mutation, diffuse pediatric HGG, H3 and IDH wild type
.
Diffuse midline gliomas (brainstem, thalamus, or spinal cord) in children and adolescents are mainly due to heterozygous mutations in the genes encoding H3.
3 or H3.
1 histones (H3-3A, H3C2, respectively), resulting in the replacement of lysine at position 27 by methionine
.
Microscopically, DMGs are astrocyclical, but may exhibit a variety of cytologic features such as hairy, oligodendroglia, giant cells, epithelioid or undifferentiated, elevated mitotic index, microangiogenesis, and/or necrosis, but do not affect the prognosis
of patients with DMGs.
In immunophenotypic, DMGs can express OLIG2, MAP2, S100, and GFAP expression to varying degrees
.
H3-G34 mutant diffuse hemispheric gliomas usually occur in older children and adolescents, with a median age of 25 years
reported in some studies.
Has the histologic features of glioblastoma, typically a high-grade invasive astrocytoma with common nuclear division with microangiogenesis and/or necrosis
.
Some tumor cells resemble embryonic tumors of the central nervous system, or small blue round cells with uniform arrangement and density can be seen, without obvious microvascular hyperplasia or necrosis
.
Its molecular pathology is characterized by positive GFAP, loss of ATRX and P53 nuclear expression, and negative OLIG2
.
H3 and IDH wild-type HGGs in AYA patients are a heterogeneous group of tumors
.
Low-grade tumor deterioration may also occur in this subtype, and further research on the molecular drivers (BRAF, p.
V600E, FGFR, p53, and mismatch repair gene mutations)
is needed.
Compared with IDH wild-type adult-type HGGs, the prognostic correlation of markers such as MGMT promoter methylation in child-type HGGs is unclear
.
Localized astrocytic glioma in the AYA population mainly include hairocytic astrocytoma, high-grade astrocytoma with hairy features, pleomorphic yellow astrocytoma, subependymal giant cell astrocytoma and chordate glioma
.
Currently, classification and grading of diagnosis rely on histologic features
.
KIAA1549-BRAF fusion (hairy cell astrocytoma) and BRAF-p.
V600E mutations (pleomorphic xanthoastrocytoma) not only aid in tumor diagnosis, but also provide guidance
for targeted therapy.
For most AYA gliomas, surgical resection for histopathologic diagnosis is recommended unless MRI shows stable, small, asymptomatic, non-enhancing tumors and deep tumors located in functional areas
.
Histopathological testing
is not recommended for patients with NF1 complicated by optic nerve pathway glioma or diffuse endogenous pontine glioma.
All gliomas should be removed
as safely as possible.
In addition to reducing tumor cells, adequate tumor tissue is essential
for morphological assessment, immunohistochemical staining, and molecular testing.
For CNS diffuse glioma in AYA, regardless of histological grade, immunohistochemistry (IDH1 R132H antibody) is recommended to assess for the presence of IDH mutations and, if IDH is negative, to perform atypical IDH mutation genotyping
.
If IDH mutations are present, further analysis
should be performed with 1p/19q codeletion (for diagnosis of oligodendroglioma) and ATRX staining (for staining loss for astrocyte lineage).
In patients with AYA glioma, if the R132H immunostaining result is negative, sequencing of IDH1 and IDH2 is recommended to detect less common IDH1 and IDH2 mutations (Figure 1).
Figure 1.
AYA high-grade glueMolecular detection of
plasmidomas.
Currently, treatment of patients with IDH mutant glioma still relies on prognostic markers such as grade, patient constitutional status, age, extent of resection, and neurological symptoms
.
About 25% of patients with AYA HGGs have IDH mutants
.
For patients with high-risk IDH mutant tumors (WHO grade 3/4, older adults, residual tumors, and associated with clinical lesions), standard of care after initial tumor surgical resection usually includes radiation therapy and combination chemotherapy
with temozolomide or PCV (procarazine, lomustine, and vincristine).
Studies have shown that patients with diffuse glioma not only have IDH mutations, but may also be accompanied by changes
in the PI3K-mTOR-AKT signaling pathway.
Mismatch repair deficiency (MMRD) is associated
with alkylated chemotherapy for IDH-mutant gliomas.
The targetability of this resistant pathway is still being studied for these recurrent tumors, which tend to be of higher grade and less responsive to treatment, and assessing the mutational burden and MMRD in these patients may help open up clinical trials or treatment pathways
.
It is clinically useful to detect MMRD (immunostaining or sequencing) in newly diagnosed patients with high-grade IDH-mutant gliomas or AYA relapsed gliomas previously treated with alkylated chemotherapy
.
In the AYA population, the molecular detection method for IDH wild-type HGG is slightly different
because HGG with the molecular characteristics of adult-type GBM appears less in the elderly.
In midline IDH wild-type HGG, H3 p.
K27 mutations
should be assessed by H3 K27me3 and H3.
3 p.
K27M immunostaining.
If H3K27 is altered, molecular characterization may help advance into clinical trials
.
Evaluation of co-mutations may also provide options
for targeted therapy.
Currently, children with H3 p.
k27 mutations have a poor prognosis for DMGs and are similar to adult-type GBM (median survival 18.
5 months).
For hemispheric HGGs, immunohistochemical detection of H3 p.
G34R
is recommended.
This mutation has a better prognosis than adult-onset GBM or DMG with altered H3 k27, but worse than HGG with IDH mutations (median survival 36.
2 months).
Currently, the treatment of H3 G34R-mutant HGGs is similar to that of adult GBM, with maximum safe resection combined with chemoradiotherapy (telmozolomide).
H3p.
G34R mutant HGGs may also have platelet-derived growth factor receptor α (PDGFRA) mutations, which may have implications
for future treatments.
In confirmed H3 and IDH wild-type HGGs, molecular assays will be able to assess for associated copy number changes and chromosomal arm changes (chromosome 7 amplification and chromosome 10 deletion, EGFR amplification), as well as other relevant mutations
in non-GBM IDH wild-type tumors (TERT promoter, BRAFV600E, MYCN, MMR, EGFR, PDGFRA, p53).
Non-GBM patients with IDH wild-type glioma AYA should be screened for other mutations
by single nucleotide polymorphism (SNP) analysis and/or RNA sequencing.
MGMT promoter methylation is a prognostic biomarker for IDH wild-type GBM
.
Identification of these mutations could open the door
to targeted therapies for BRAF/MEK and FGFR inhibitors, as well as clinical trials.
All gliomas are usually stained
for IDH1 R132H, p53, and ATRX immunohistochemistry.
If ATRX is positive and p53 is negative, determine whether 1p/19q is co-missing
.
If IDH1 R132H is negative, sequencing of atypical IDH is usually done in younger patients, or based on clinical history
.
Finally, in IDH-mutant astrocytoma, the CDKN2A gene is evaluated for grading
.
When IDH is negative, GBM and child-type diffuse glioma
must be distinguished at the molecular level.
In this case, BRAF p.
V600E can be detected with immunohistochemistry, and other alterations that may occur in AYA patients with IDH wild-type LGGs (FGFR1, FGFR2, MYB, MYBL1, and BRAF) require molecular testing for diagnosis (Figure 2).
Figure 2.
Molecular assays for patients with AYA low-grade gliomas
.
Among the mixed tumors of glial neurons, neurons and glia, ganglionic gliomas and dysembryoplastic neuroepithelial tumors (DNETs) are the two most common gliomas
.
Other glial neuron tumors include diffuse glial neuronal tumors with oligodendrocytocytoma-like features and clustered nuclei, glial neuronal tumors forming daisy-shaped clusters, papillary glial neuron tumors, myxoid glial neuron tumors, diffuse pia mater glial neuron tumors, gangrocytomas, multinodular and vacuolar neuron tumors, and Lhermitte-Dublos disease
.
CNS cell tumors are classified as neuronal tumors
.
Glial neuronal tumors occasionally have potentially targeted molecular alterations
.
Germline or FGFR1 somatic mutations are common among DNETs, while BRAF p.
V600E mutations are rare
.
In ganglion gliomas, BRAF p.
V600E mutations occur in 10% to 60% of cases (depending on tumor location).
Rose-shaped glial neuronal tumors can develop FGFR1 mutations with PIK3CA and NF1 comutations
.
The WHO CNS5 divides ependymomas into 10 subgroups based on histopathological, anatomical, and molecular characteristics (Figure 3).
Due to the immaturity of molecular characteristic data, ependymomas of different sites can be classified into grade
2-3 according to histological characteristics.
In WHO CNS5, the term "anaplastic" has been removed and is no longer considered a subtype of ependymoma due to the lack of clinical use of morphological variants of classical ependymoma (papillary, clear cell, stretched cells), but is included in the histological type
.
Figure 3.
Age of ependymoma diagnosis and classification
based on anatomical site, histological, and molecular features.
.
Clinical consensus suggests that treatment should be tailored
for different molecular variants of ependymoma until more trial data are available.
Figure 4 shows the molecular detection rules
for patients with AYA ependymoma.
Figure 4.
AYA's molecular detection of
ependymomas.
Supratentorial ependymoma (STE) WHO CNS5 divided STE into two groups: ZFTA (C11orf95) gene fusion positive and YAP1 gene fusion positive; ZFTA gene fusion-positive people were mainly affected by AYA, and YAP1 gene fusion-positive affected people were mainly infants and young children
.
For patients with supratentorial ependymoma in AYA, ZFTA fusion detection by fluorescence in situ hybridization (FISH), reverse transcriptase polymerase chain reaction (RT-PCR), next-next-generation sequencing (NGS), or digital genetic testing is recommended, and if ZFTA fusion is not present, alternative diagnoses such as GBM with ependymal differentiation or MN1 fusion or BCOR1 fusion neuroepithelial tumors
should be considered.
For patients with positive STE with ZFTA fusion at WHO grade 2, further analysis of CDKN2A homozygous deletion
by FISH, SNP, methylation analysis is required.
However, further clinical trials
are needed for molecularly targeted therapy of STEs.
Posterior fossa ependymomas in WHO CNS5 are divided into PFA ependymomas (methylation deletion and EZH inhibitory protein EZHIP overexpression) and PFB ependymomas (methylation preservation)
according to the overall level of histone H3 K27 radicalization.
Most adult ependymomas in the posterior fossa belong to the PFB category, while the vast majority of PFA ependymomas are children under 8 years of age (median age is 3 years).
In the AYA population, PFB ependymomas are more common and have a better
prognosis than PFA ependymomas.
Spinal ependymoma classifies myxoplasmoma as grade 2 due to its clinical prognosis comparable to classical ependymoma by WHO CNS5
.
Another rare form of ependymoma with MYCN amplification
.
Because ependymomas are defined by morphology rather than molecules, no molecular testing is required unless the tumor is aggressive or disseminated, in which case MYCN amplification
should be detected by FISH, SNP.
Medulloblastoma (MB) and embryonal tumors central nervous system embryonal tumors are highly malignant and poorly differentiated neuroepithelial tumors
.
Because medulloblastoma in children and adults has different subgroups and prognostic markers, treatment strategies and prognostic predictors should be different
.
The MB molecular types in WHO CNS5 are: WNT-activated, SHH-activated, TP53 wild-based, SHH-activated and TP53 mutant, non-WNT/
non-SHH-activated.
Histology is classified as: classic (CL), connective tissue hyperplasia/nodular medulloblastoma (DN), medulloblastoma with extensive nodularity (MBEN) and large cell/anaplastic medulloblastoma (large cell/ anaplastic，LC/A）
。
The majority of adult MB is SHH-activated, followed by Group 4 and WNT-activated, and Group 3 MB is rare
in adults.
Within each subgroup, further transcriptional and epigenetic changes have been shown to contribute to risk stratification (Table 2).
Table 2.
Clinical, molecular information, and risk stratification
of medulloblastoma subgroups.
About 15%-20% of adult MB is WNT-activated; Adult MB is less likely to have chromosome 6 haploid than in children with MB
.
Most WNT-activated MB are accompanied by exon 3 mutations in the CTNNB1 gene, resulting in reduced cytoplasmic degradation and β-Catenin nuclear accumulation
.
In children, β-Catenin nuclear accumulation is associated with a good prognosis, while this prognostic value
is not found in adults.
In adults, SH-activated MB is common, while the wild subtype TP53 is the most common in SH-activated MB, accounting for 70%.
P53 mutations are less likely to be associated with genetic cancer susceptibility (Li-Fraumeni syndrome) than childhood MB, and P53 negative is not a prognostic marker in adults
.
TP53 wild-type SHH medulloblastoma enriched with TERT promoter mutations, showing loss or deletion of functional mutations in PTCH1, or change in copy number (10q loss).
Adult SHH medulloblastoma has frequent upstream pathway changes (PTCH1 and SMO mutations), but few downstream pathway changes (SUFU, MYCN amplification).
The presence of 10q deletion is a strong predictor
of poor survival.
SHH tumors with chromosome 3p deletion, 17p deletion, and PTCH1 mutation have a poor
prognosis.
Group 3 medulloblastoma is mainly seen in infants and older children
.
Most patients are male and have a poor prognosis, especially those
with MYC amplification.
Other cytogenetic features include the 17q isoarm chromosome and the 8q chromosome chain
.
Genetic mutations include SMARCA4, KBTBD4, CTDNEPI and KMT2D
.
Group 4 medulloblastoma often presents with cytogenetic aberrations, 7 or 17q chromosome amplification, deletion of 8, 11, or 17p chromosomes, and 17q equi-arm chromosomes
.
Loss of chromosome 8 has been shown to be associated with increased survival in both children and adults, while other childhood markers, such as total loss of chromosome 11, have not been found to be associated with
prognosis in adults.
Group 4 MB in children with chromosome 8 loss is associated with survival advantage; Amplification of MYC or MYCN has been shown to be associated with
low survival of child-type MB when amplified by MYCN and CDK6 and overexpression of PRDM6 and mutations in the histone modification genes KDM6A, AMYM3, KMT2C, and KBTBD4.
In contrast, CDK6 is found almost exclusively in adults and is associated with
adverse outcomes.
The diagnosis of medulloblastoma is divided into 4 main subgroups by immunohistochemical and molecular methods, with the latter being preferred
.
Immunohistochemical testing β-catenin identified the WNT subgroup (β-catenin positive), while the SHH subgroup, Group 3 and Group 4 were negative for β-catenin
.
In the SHH subgroup, GAB1 and filament protein A were positive, but Group 3 and Group 4 were negative
.
There are currently no reliable immunohistochemical methods to distinguish between Group 3 and Group 4
.
Children with SHH-activated MB should receive genetic counseling to evaluate germline TP53 and SHH pathway mutations (Gorlin syndrome), and WNT patients without somatic CTNNB1 mutations require genetic counseling to evaluate APC sequencing
.
In contrast, adult patients with SHH-activated MB usually do not require genetic testing because older patients rarely have germline TP53 mutations unless there are other clinical or familial concerns
.
