PPT JOURNAL READING UPDATE ON THE WHO DIAGNOSIS OF IDH-MUTANT GLIOMA.pptx

Mutations in IDH are common in human malignancies, particularly in gliomas.
In WHO grade II/III gliomas, IDH mutations are recognized in over 80% of cases.
IDH mutations are also prevalent in secondary glioblastoma (73% of cases) but less so in primary glioblastoma (3.7% of cases).
Gliomas with IDH mutations generally have a more favorable disease outcome, with prolonged median survival compared to those without IDH mutations.
However, the high incidence of IDH mutations in secondary glioblastoma suggests that lower-grade gliomas with IDH mutation may undergo malignant transformation to a higher grade.
IDH-mutated gliomas are also more likely to develop a hypermutation phenotype, which worsens prognosis.
Outside the central nervous system, IDH mutations are identified in other malignancies such as acute myeloid leukemia (16% of cases), intrahepatic cholangiocarcinoma (23% of cases), and central/periosteal chondrosarcoma (56% of cases

1. UPDATE ON THE WHO DIAGNOSIS OF IDH-MUTANT GLIOMA

2. IDH Mutation Mutations in IDH are common in human malignancies, particularly in gliomas. In WHO grade II/III gliomas, IDH mutations are recognized in over 80% of cases. IDH mutations are also prevalent in secondary glioblastoma (73% of cases) but less so in primary glioblastoma (3.7% of cases). Gliomas with IDH mutations generally have a more favorable disease outcome, with prolonged median survival compared to those without IDH mutations. However, the high incidence of IDH mutations in secondary glioblastoma suggests that lower-grade gliomas with IDH mutation may undergo malignant transformation to a higher grade. IDH-mutated gliomas are also more likely to develop a hypermutation phenotype, which worsens prognosis. Outside the central nervous system, IDH mutations are identified in other malignancies such as acute myeloid leukemia (16% of cases), intrahepatic cholangiocarcinoma (23% of cases), and central/periosteal chondrosarcoma (56% of cases).

3. IDH Mutation Over the past four years (2010), discoveries regarding mutations in the isocitrate dehydrogenase (IDH) enzymes have significantly impacted our understanding of gliomagenesis and neuro-oncology practice. Mutations in the IDH1 and IDH2 genes have been identified as the initiating event in the development of many gliomas. The presence of IDH mutations dictates a particular path for oncogenic progression and correlates with favorable clinical behavior in these cancers. According to research by Yang et al., oncogenic mutations in IDH1 and IDH2 exhibit four distinct biochemical features: 1. They are primarily somatic mutations. 2. They are universally heterozygous. 3. They involve a single amino acid substitution at specific residues in the enzyme active site (codon 132 in IDH1 and codon 172 or 140 in IDH2). 4. They occur in a mutually exclusive manner in most cases, suggesting a common underlying biochemical mechanism and physiological consequences.

4. IDH Mutation Isocitrate dehydrogenase (IDH) enzymes are essential for several metabolic processes such as the Krebs cycle, glutamine metabolism, lipogenesis, and redox regulation. There are three isoforms of IDH: IDH1, IDH2, and IDH3, each with distinct cellular locations. IDH1 is found in the cytoplasm and peroxisomes, while IDH2 and IDH3 are located in the mitochondrial matrix. IDH1 and IDH2 catalyze the conversion of isocitrate to α- ketoglutarate ( α- KG) using nicotinamide adenine dinucleotide phosphate (NADP+) and a divalent metal cation as cofactors. IDH3 also converts isocitrate into α- KG but uses nicotinamide adenine dinucleotide (NAD+) as its cofactor. The catalytic activity of IDH relies on homodimerization and a conformational change in the enzyme induced by isocitrate binding. Substrate recognition occurs in the active site of the enzyme, with arginine 132 (R132) being a frequently mutated residue in cancer.

5. Introduction The WHO Classification of Tumors of the Central Nervous System from 2021 represents the 5th edition (WHO CNS5) of the international standard classification for brain tumors. IDH-mutations are typical for diffuse lower grade astrocytomas and oligoden-drogliomas and associate with a far better prognosis than diffuse IDH-wildtype gliomas most frequently resembling glioblastomas, IDH-wildtype. Specific changes regarding IDH-mutant gliomas in WHO CNS5, unsolved issues and future perspectives will be reviewed and discussed in the following.

6. Technical Development Progress in understanding the molecular basis of brain tumors and consequential incorporation of molecular features in brain tumor classification implicates specific needs for molecular analyses. Availability of molecular analyses is fortunately increasing rapidly worldwide. it has to be emphasized that most diagnostically rel-evant molecular alterations may still be determined using more conventional techniques like Sanger sequencing (for IDH1/2 status determination), fluorescence in situ hybridi-zation (FISH; for 1p/19q and CDKN2A/B status determi -nation) or immunohistochemistry (for IDH1 R132H- and ATRX-testing).

7. Revised Taxonomy and Nomenclature The novel WHO classification aimed for simplification, standardization and harmonization with classifications from other organ systems. While in the 2016 update IDH-mutant tumors comprised 5 different entities T he novel classification recognizes just two entities, now termed “types”: “Astrocytoma, IDH-mutant” and “oligodendroglioma, IDH-mutant and 1p/19q-code-leted”. Grading is performed within these types and Arabic instead of Roman numerals are used. the term “CNS WHO grade” is endorsed  avoid confusion with grading systems from other organs. Of note, the term “glioblastoma” is persevered for IDH-wildtype tumors only and the former “glioblastoma, IDH-mutant” has been renamed “Astrocytoma, IDH-mutant, CNS WHO grade 4”. Additional terms like “diffuse” or “anaplastic” are not used anymore.

8. WHO 2016 WHO 2021 Diffuse Astrocytoma WHO grade II, IDH-mutant Astrocytoma, IDH-mutant CNS WHO grade 2 Anaplastic Astrocytoma WHO grade III, IDH-mutant Astrocytoma, IDH-mutant CNS WHO grade 3 Glioblastoma WHO grade IV, IDH-mutant Astrocytoma, IDH-mutant CNS WHO grade 4 Oligodendroglioma WHO grade II, IDH-mutant and 1p/19q-codeleted WHO grade II Oligodendroglioma, IDH-mutant and 1p/19q-codeleted CNS WHO grade 2 Anaplastic Oligodendroglioma WHO grade II, IDH-mutant and 1p/19q-codeleted WHO grade III   Oligodendroglioma, IDH-mutant and 1p/19q-codeleted CNS WHO grade 3

9. Layered diagnostics, integrated diagnosis and NOS diagnoses The WHO conform integrated diagnosis is based on combining histological and molecular information. Respective reports should include all information, including the integrated diagnosis and the different layers it is based on. A not-otherwise-specified (NOS) diagnosis indicates that a molecular workup for a WHO conform integrated diagnoses is not available or has failed, and therefore the diagnosis is purely based on histological assessment.

10. Essential and desirable diagnostic criteria WHO CNS5 provides essential criteria which must be present to make an integrated diagnoses and desirable criteria which clearly support a diagnosis but are not mandatory. Histological finding: "diffusely infiltrating glioma" Molecular finding: IDH1/2 hotspot mutation crucial for classifying astrocytoma and oligodendroglioma For oligodendroglioma: IDH-mutation analysis may be unnecessary when DNA methylome profiling unequivocally assigns the tumor to the methylation class "oligodendroglioma, IDH-mutant and 1p/19q-codeleted“

11. Tumor Type Essential Criteria Desirable Criteria Additional altered genes Astrocytoma, IDH-Mutant Diffusely infiltrationg glioma Astrocytic differentiation by morphology CDKN2A, CDKN2B, CDK4, CCND2, PDGFRA, MET, MYC, MYCN, RB1, PIK3R1, PIC3CA, others   IDH1/2 hotspot mutation TP53 mutation or strong nuclear expression of p53 in > 10% of tumor cells     ATRX loss or ATRX mutation OR exclusion of combined whole-arm deletions of 1p and 19q Methylation profile of astrocytoma, IDH-mutant   Oligodendroglioma, IDH-mutant and 1p/19q- codeleted Diffusely infiltrating glioma       Retained nuclear expression of ATRX   CDKN2A, CDKN2B, CIC, FUBP1,NOTCH1   IDH1/2 hotspot mutation TERT promoter mutation     Combined whole-arm deletions of 1p and 19q DNA methylome profile of oligodendroglioma, IDH-mutant and 1p/19q-codeleted  

12. Dual‑genotype and NEC diagnoses Not elsewhere classified (NEC) diagnoses: Reserved for situations when all appropriate information regarding histology, IDH1/2-mutation, ATRX, and 1p/19q status are available Results do not match a WHO diagnosis or are conflicting regarding WHO essential criteria Relevant for IDH-mutant gliomas, particularly "dual-genotype" IDH-mutant gliomas: Exceedingly rare Characterized by defining molecular alterations of both astrocytoma (ATRX loss/mutation and TP53 mutation) and oligodendroglioma (whole-arm 1p/19q codeletion) Features found in either two morphologically distinct regions of the same tumor mass or as a single clone in all tumor regions Due to falling out of the current WHO classification principle: Suggested to provide a layered diagnosis including all histological and molecular information with the addition of "NEC"

13. Grading of Astrocytoma Grading of astrocytoma IDH-mutant in WHO CNS5: Retains classic morphological features for grading Includes a new molecular feature: homozygous deletion of the CDKN2A and/or CDKN2B locus CDKN2A and/or CDKN2B homozygous deletions consistently associated with dismal prognosis in multiple studies Justifies grade 4 designation irrespective of additional features' presence or absence

14. Grading of Astrocytoma - Cutoff values or thresholds for mitotic activity and anaplasia not established . - Exception: Single mitosis in a very small biopsy may suffice for grade 3 designation.

15. Grading of oligodendroglioma, IDH-mutant and 1p/19q-codeleted Based mainly on classic histological features of malignancy: Cellularity Cytological atypia Mitotic activity ( ≥ 2.5 mitoses/mm2; equating to ≥ 6 mitoses/10 HPF of 0.55 mm in diameter and 0.24 mm 2 in area) Microvascular proliferation Necrosis Significance of microvascular proliferation and brisk mitotic activity suggested as prognostic indicators in some studies. In borderline cases, consideration of additional features like extent of KI-67 labeling or neuroradiological features recommended. Novelty: homozygous deletion involving CDKN2A and/or CDKN2B locus relevant for grading oligodendroglioma: Presence indicates WHO CNS grade 3. Testing may be restricted to borderline cases as found in subset of grade 3 tumors only.

16. Development beyond WHO CNS5 Current classification distinguishes between astrocytoma and oligodendroglioma, with various grades as subtypes. Recent studies indicate clinically significant (sub-)types of IDH-mutant gliomas, potentially impacting future classifications. Infratentorial IDH-mutant astrocytomas exhibit unique diagnostic features, including frequent non-IDH1 R132H mutations and reduced ATRX loss frequency. Clinical outcomes for infratentorial IDH-mutant astrocytomas are notably worse than those for supratentorial tumors . "Primary mismatch repair deficient IDH-mutant astrocytoma (PMMRDIA)" is proposed for tumors occurring in DNA mismatch repair deficiency syndromes, showing poor prognosis similar to IDH-wildtype glioblastomas. " Oligosarcoma , IDH-mutant" is identified as highly distinct from conventional oligodendroglioma, with significantly poorer clinical outcomes.

17. Conclusion, discussion and outlook WHO CNS5 classification prioritizes tumor biology and clinical needs. Older diagnoses of IDH-mutant gliomas may not align with the new classification. Grading IDH-mutant gliomas is important due to varied aggressiveness and outcomes. Traditional grading criteria may not work well with molecularly defined tumors. Debate exists over separating grade 2 from grade 3 astrocytomas , as some glioblastomas were once included in these grades. Including homozygous CDKN2A/B deletions as grading criteria may increase grade 4 tumors but may not change decisions for borderline cases between grades 2 and 3. More insights into tumor progression and therapeutic resistance are needed to improve classification and grading of IDH-mutant gliomas.

18. THANK YOU

19. NCCN Guidelines for Patients Brain Cancer: Gliomas

20. Refference : Lindberg 2 nd Ed.

21. WHO 2016 WHO 2021 Diffuse Astrocytoma WHO grade II, IDH-mutant Astrocytoma, IDH-mutant CNS WHO grade 2 Anaplastic Astrocytoma WHO grade III, IDH-mutant Astrocytoma, IDH-mutant CNS WHO grade 3 Glioblastoma WHO grade IV, IDH-mutant Astrocytoma, IDH-mutant CNS WHO grade 4 Oligodendroglioma WHO grade II, IDH-mutant and 1p/19q-codeleted WHO grade II Oligodendroglioma, IDH-mutant and 1p/19q-codeleted CNS WHO grade 2 Anaplastic Oligodendroglioma WHO grade II, IDH-mutant and 1p/19q-codeleted WHO grade III   Oligodendroglioma, IDH-mutant and 1p/19q-codeleted CNS WHO grade 3