Grading of Central Nervous System Tumors

Introduction

While many tumors are classified using both a grading and staging system, staging—which is determined by a tumor’s size and spread—is not often used in the context of central nervous system (CNS) tumors. This is because the brain lacks lymphatics, and thus CNS tumors rarely spread beyond the CNS. Therefore, the TNM (Tumor size, Nodal involvement, Metastases) system used for most non-CNS tumors is not commonly employed in the evaluation of CNS neoplasms.

As such, CNS tumor classification heavily relies on accurate grading, which reflects the degree of abnormal behavior displayed by the tumor cells themselves. Because neoplasms in the CNS have widely varying features, clinical courses, and prognoses, a robust and reliable grading system is essential for the proper evaluation of CNS tumors. Traditionally, grading has been determined using histologic observations from light microscopy, immunohistochemistry, and electron microscopy.^[1]

Grading Prior to 2021

In 1979, the World Health Organization (WHO) codified its first set of guidelines on the classification and staging of CNS tumors. Since then, the guidelines have been revised and fine-tuned as scientific understanding of CNS tumors improved, culminating in the fifth edition, published in 2021. In order to understand the current guidelines, it is important to briefly discuss the previous, pre-2021 guidelines.

Traditionally, a WHO CNS grade was an overarching predictor of cellular behavior that could be applied across multiple tumor entities. In 2016, the WHO defined tumor grades as shown in Table 1, below.

Table 1. Central Nervous System Tumor Grades - WHO 2016 (Open Table in a new window)

WHO Grade	Description	Examples
Grade I	Low proliferative potential Cure possible after surgical resection alone	Pilocytic Astrocytoma Craniopharyngioma
Grade II	Infiltrative in nature Low levels of proliferative activity Often recur	Diffuse Astrocytoma Oligodendroglioma
Grade III	Histologic evidence of malignancy: Nuclear Atypia Mitotic activity	Anaplastic Astrocytoma Anaplastic Oligodendroglioma
Grade IV	Cytologically malignant Mitotically active Necrosis-prone Rapid disease evolution	Glioblastoma Medulloblastoma
Adapted from World Health Organization.WHO Classification of Tumours of the Central Nervous System. Revised 4th Ed. International Agency for Research on Cancer; 2016.

As an example, consider the classification of anaplastic tumors as elaborated in the WHO guidelines and Louis et al.^[2]Prior to 2021, an “anaplastic” tumor was categorized as Grade III regardless of whether the tumor was an anaplastic astrocytoma, anaplastic oligodendroglioma, or anaplastic ependymoma.^[2]Grade was applied across tumor types, regardless of differences in the clinical course and molecular behavior of different anaplastic tumor entities. As such, under the older guidelines, one tumor entity could develop into another tumor entity with a different grade over the course of disease progression.^[1]

Current WHO Guidelines

Published in 2021, the fifth edition of the WHO Classification of Tumors of the CNS is the most recent version of the international standard for classifying brain and spinal cord tumors. In this edition, the grading of CNS tumors was modified to more closely resemble that of non-CNS tumors:

Entity-specific grading

Notably, the new edition provides a specific set of grades for each tumor type. This is in marked contrast to previous editions, in which a tumor type was assigned one grade, and a particular grade could span multiple tumor types. In the new edition, grades are assigned within—and not across—tumor types.^[3]Consequently, grading each tumor requires an integrated analysis of histologic features and molecular signatures specific to that tumor type. Due to this change, tumor grades more accurately reflect the cellular behavior and subsequent clinical course of each neoplasm. Table 2 delineates the possible grades for each specific tumor type described in the 2021 WHO Classification of CNS Tumors.^[3]

Molecular signatures in grading

Because the identification of key histopathologic features is highly sensitive to sampling, the new guidelines recommend using molecular signatures—which tend to be more diffuse and thus less sensitive to sampling—as a component in grading certain tumors and as a potential marker of clinical course and prognosis.^[2]The way in which inclusion of molecular signatures has changed grading protocols can be seen in the evaluation of astrocytomas.

Isocitrate dehydrogenase (IDH)–mutant astrocytomas (which encompass tumors previously known as diffuse astrocytomas, anaplastic astrocytomas, and glioblastomas) can be WHO CNS Grade 2, 3, or 4. Deletions in cyclin-dependent kinase inhibitor (CDKN) 2A and 2B genes have been found to be associated with a poor prognosis despite the prognostically beneficial IDH mutation.^[4]Consequently, under the 2021 WHO guidelines, an astrocytoma may be considered WHO CNS grade 4 in the absence of microvascular proliferation or necrosis (histopathologic characteristics traditionally characteristic of a high-grade astrocytoma) as long as homozygous deletions of CDKN2A or CDKN2B are present.^[4]

Moreover, under the 2021 WHO guidelines, an IDH wildtype (IDHwt) diffuse astrocytoma can be diagnosed as an IDHwt glioblastoma based on histologic and molecular features. Genetic signatures such as the Telomerase Reverse Transcriptase (TERT) promoter mutation, Epidermal Growth Factor (EGFR) amplification, and +7/-10 chromosomal copy number variations are now known to be associated with a poor prognosis.^[5]As such, the 2021 WHO guidelines specify that a tumor can only be diagnosed as an IDHwt glioblastoma if microvascular proliferation or necrosis is present histologically and at least one of those characteristic molecular signatures is present.^[3]

Grading and prognostic estimates

The 2021 WHO guidelines also discuss the prognostic value of the grading recommendations. Specifically, the WHO emphasizes that a grade is given regardless of the availability of effective therapeutics that may improve the prognosis—in other words, a grade correlates with a tumor’s natural history.

The guidelines present WNT-activated medulloblastoma as an example of this nuanced revision. There are effective treatments for WNT-activated medulloblastoma that are capable of achieving long-term survival in most patients. However, the WHO guidelines still designate WNT-activated medulloblastoma as WHO CNS Grade 4 due to its progression and lethality if left untreated.

This example demonstrates that not all high-grade tumors necessarily have a poor prognosis under standard therapy. As such, the WHO continues to emphasize that grading should be used in conjunction with other parameters such as age, performance status, genetic alterations, proliferation index, and extent of resection to gain a more holistic prognosis.

Conclusion

Accurate grading of tumors can serve as key indicators of the cellular behavior of specific tumors and ultimately play a role in determining clinical management and predicting prognosis.

Table 2.Central Nervous System Tumor Classification - WHO 2021 (Open Table in a new window)

TUMOR TYPE	WHO CNS GRADE
Gliomas, Glioneural Tumors, and Neuronal tumors
Adult-Type Diffuse Gliomas
Astrocytoma, IDH-mutant	2, 3, 4
Oligodendroglioma, IDH-mutant, and 1p/19q-codeleted	2, 3
Glioblastoma, IDH-wildtype	4
Pediatric-type diffuse low-grade gliomas
Diffuse astrocytoma, MYB- or MYBL1-altered	1
Angiocentric glioma	1
Polymorphous low-grade neuroepithelial tumor of the young	1
Diffuse low-grade glioma, MAPK pathway-altered	NOG
Pediatric-type diffuse high-grade gliomas
Diffuse midline glioma, H3 K27-altered	4
Diffuse hemispheric glioma, H3 G34-mutant	4
Diffuse pediatric-type high-grade glioma, H3-wildtype and IDH-wildtype	4
Infant-type hemispheric glioma	ND
Circumscribed astrocytic gliomas
Pilocytic astrocytoma	1
High-grade astrocytoma with piloid features	NOG (similar to 3)
Pleomorphic xanthoastrocytoma	2, 3
Subependymal giant cell astrocytoma	1
Chordoid glioma	2
Astroblastoma, MN1-altered	NOG
Glioneuronal and neuronal tumors
Ganglioglioma	1
Gangliocytoma	1
Desmoplastic infantile ganglioglioma / desmoplastic infantile astrocytoma	1
Dysembryoplastic neuroepithelial tumor	1
Diffuse glioneuronal tumor with oligodendroglioma-like features and nuclear clusters	ND
Papillary glioneuronal tumor	1
Rosette-forming glioneuronal tumor	1
Myxoid glioneuronal tumor	1
Diffuse leptomeningeal glioneuronal tumor	NOG (similar to 2)
Multinodular and vacuolating neuronal tumor	1
Dysplastic cerebellar gangliocytoma (Lhermitte-Duclos disease)	1
Central neurocytoma	2
Extraventricular neurocytoma	2
Cerebellar liponeurocytoma	2
Ependymal tumors
Supratentorial ependymoma Supratentorial ependymoma, ZFTA fusion–positive Supratentorial ependymoma, YAP1 fusion–positive	2, 3
Posterior fossa ependymoma Posterior fossa ependymoma, group PFbA Posterior fossa ependymoma, group PF	2, 3
Spinal ependymoma	2 (3 rare)
Spinal ependymoma, MYCN-amplified	NOG
Myxopapillary ependymoma	2
Subependymoma	1
Choroid plexus tumors
Choroid plexus papilloma	1
Atypical choroid plexus papilloma	2
Choroid plexus carcinoma	3
Ependymal tumors
Medulloblastoma	4
Medulloblastomas, molecularly defined Medulloblastoma, WNT-activated Medulloblastoma, SHH-activated and TP53-wildtype Medulloblastoma, SHH-activated and TP53-mutant Medulloblastoma, non-WNT/non-SHH
Medulloblastomas, histologically defined
Other CNS embryonal tumors
Atypical teratoid/rhabdoid tumor	4
Cribriform neuroepithelial tumor	ND
Embryonal tumor with multilayered rosettes	4
CNS neuroblastoma, FOXR2-activated	4
CNS tumor with BCOR internal tandem duplication	NOG
CNS embryonal tumor NEC/NOS	NOG (3/4)
Pineal tumors
Pineocytoma	1
Pineal parenchymal tumor of intermediate differentiation	2, 3
Pineoblastoma	4
Papillary tumor of the pineal region	2, 3
Desmoplastic myxoid tumor of the pineal region, SMARCB1-mutant	NOG
Cranial and paraspinal nerve tumors
Schwannoma	1
Neurofibroma	1
Perineurioma	1
Hybrid nerve sheath tumor	ND
Malignant melanotic nerve sheath tumor	ND
Malignant peripheral nerve sheath tumor	ND
Cauda equina neuroendocrine tumor (previously paraganglioma)	1
Meningiomas
Meningioma	1, 2, 3
Mesenchymal, non-meningothelial tumors
Soft tissue tumors
Fibroblastic and myofibroblastic tumors Solitary fibrous tumor	1,2,3
Vascular tumors Hemangiomas and vascular malformations Hemangioblastoma	ND 1
Skeletal muscle tumors Rhabdomyosarcoma	ND
Tumors of uncertain differentiation Intracranial mesenchymal tumor, FET-CREB fusion–positive CIC-rearranged sarcoma Primary intracranial sarcoma, DICER1-mutant Ewing sarcoma	ND 4 ND 4
Chondro-osseous tumors
Chondrogenic tumors Mesenchymal chondrosarcoma Chondrosarcoma	ND 1,2,3
Notochordal tumors
Chordoma (including poorly differentiated chordoma)	ND
Melanocytic tumors
Diffuse meningeal melanocytic neoplasms
Meningeal melanocytosis and meningeal melanomatosis	ND
Circumscribed meningeal melanocytic neoplasms
Meningeal melanocytoma and meningeal melanoma	ND
Hematolymphoid tumors
Lymphomas
CNS lymphomas Primary diffuse large B-cell lymphoma of the CNS Immunodeficiency-associated CNS lymphoma Lymphomatoid granulomatosis Intravascular large B-cell lymphoma	ND ND 1,2,3 ND
Miscellaneous rare lymphomas in the CNS MALT lymphoma of the dura Other low-grade B-cell lymphomas of the CNS Anaplastic large cell lymphoma (ALK+/ALK−) T-cell and NK/T-cell lymphomas	ND
Histiocytic tumors
Erdheim-Chester disease	ND
Rosai-Dorfman disease	ND
Juvenile xanthogranuloma	ND
Langerhans cell histiocytosis	ND
Histiocytic sarcoma	ND
Germ cell tumors
Mature teratoma	ND
Immature teratoma	ND
Teratoma with somatic-type malignancy	ND
Germinoma	ND
Embryonal carcinoma	ND
Yolk sac tumor	ND
Choriocarcinoma	ND
Mixed germ cell tumor	ND
Tumors of the sellar region
Adamantinomatous craniopharyngioma	1
Papillary craniopharyngioma	1
Pituicytoma, granular cell tumor of the sellar region, and spindle cell oncocytoma	ND
Pituitary adenoma/PitNET	NOG
Pituitary blastoma	ND
Metastases to the CNS
Metastases to the brain and spinal cord parenchyma
Metastases to the meninges
Adapted from World Health Organization Classification of Central Nervous System Tumors, 5^th edition CNS = Central nervous system; MALT = Mucosa-associated lymphoid tissue; ND = Grading not discussed in guidelines; NEC/NOS = Not elsewhere classified/not otherwise specified; NOG = No official grade assigned in the guidelines

Table 3. Key Diagnostic Genes, Molecules, and Pathways in Major Primary CNS Tumors (Open Table in a new window)

Tumor Type	Characteristically Altered Genes/Molecular Profiles
Astrocytoma, IDH-mutant	IDH1, IDH2, ATRX, TP53, CDKN2A/B
Oligodendroglioma, IDH-mutant, and 1p/19q-codeleted	IDH1, IDH2, 1p/19q, TERT promoter, CIC, FUBP1, NOTCH1
Glioblastoma, IDH-wildtype	IDH-wildtype, TERT promoter, chromosomes 7/10, EGFR
Diffuse astrocytoma, MYB- or MYBL1-altered	MYB, MYBL1
Angiocentric glioma	MYB
Polymorphous low-grade neuroepithelial tumor of the young	BRAF, FGFR family
Diffuse low-grade glioma, MAPK pathway-altered	FGFR1, BRAF
Diffuse midline glioma, H3 K27-altered	H3 K27, TP53, ACVR1, PDGFRA, EGFR, EZHIP
Diffuse hemispheric glioma, H3 G34-mutant	H3 G34, TP53, ATRX
Diffuse pediatric-type high-grade glioma, H3-wildtype, and IDH-wildtype	IDH-wildtype, H3-wildtype, PDGFRA, MYCN, EGFR (methylome)
Infant-type hemispheric glioma	NTRK family, ALK, ROS, MET
Pilocytic astrocytoma	KIAA1549-BRAF, BRAF, NF1
High-grade astrocytoma with piloid features	BRAF, NF1, ATRX, CDKN2A/B (methylome)
Pleomorphic xanthoastrocytoma	BRAF, CDKN2A/B
Subependymal giant cell astrocytoma	TSC1, TSC2
Chordoid glioma	PRKCA
Astroblastoma, MN1-altered	MN1
Ganglion cell tumors	BRAF
Dysembryoplastic neuroepithelial tumor	FGFR1
Diffuse glioneuronal tumor with oligodendroglioma-like features and nuclear clusters	Chromosome 14, (methylome)
Papillary glioneuronal tumor	PRKCA
Rosette-forming glioneuronal tumor	FGFR1, PIK3CA, NF1
Myxoid glioneuronal tumor	PDFGRA
Diffuse leptomeningeal glioneuronal tumor	KIAA1549-BRAF fusion, 1p (methylome)
Multinodular and vacuolating neuronal tumor	MAPK pathway
Dysplastic cerebellar gangliocytoma (Lhermitte-Duclos disease)	PTEN
Extraventricular neurocytoma	FGFR (FGFR1-TACC1 fusion), IDH-wildtype
Supratentorial ependymomas	ZFTA, RELA, YAP1, MAML2
Posterior fossa ependymomas	H3 K27me3, EZHIP (methylome)
Spinal ependymomas	NF2, MYCN
Medulloblastoma, WNT-activated	CTNNB1, APC
Medulloblastoma, SHH-activated	TP53, PTCH1, SUFU, SMO, MYCN, GLI2(methylome)
Medulloblastoma, non-WNT/non-SHH	MYC, MYCN, PRDM6, KDM6A (methylome)
Atypical teratoid/rhabdoid tumor	SMARCB1, SMARCA4
Embryonal tumor with multilayered rosettes	C19MC, DICER1
CNS neuroblastoma, FOXR2-activated	FOXR2
CNS tumor with BCOR internal tandem duplication	BCOR
Desmoplastic myxoid tumor of the pineal region, SMARCB1-mutant	SMARCB1
Meningiomas	NF2, AKT1, TRAF7, SMO, PIK3CA; KLF4, SMARCE1, BAP1 in subtypes; H3K27me3; TERT promoter, CDKN2A/B in CNS WHO grade 3
Solitary fibrous tumor	NAB2-STAT6
Meningeal melanocytic tumors	NRAS (diffuse); GNAQ, GNA11, PLCB4, CYSLTR2 (circumscribed)
Adapted from: World Health Organization.WHO Classification of Tumours of the Central Nervous System. 5th Ed. International Agency for Research on Cancer; 2021.

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Author

Jeffrey N Bruce, MD Edgar M Housepian Professor of Neurological Surgery Research, Vice-Chairman and Professor of Neurological Surgery, Director of Columbia Brain Tumor Center, Director of Bartoli Brain Tumor Laboratory, Department of Neurosurgery, Columbia University Vagelos College of Physicians and Surgeons

Jeffrey N Bruce, MD is a member of the following medical societies: Alpha Omega Alpha, American Association of Neurological Surgeons, American Society of Clinical Oncology, Congress of Neurological Surgeons, New York Academy of Sciences, North American Skull Base Society, Pituitary Society, Society for Neuro-Oncology, Society of Neurological Surgeons

Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: Theracle, Inc. <br/>Received grant/research funds from NIH for other.

Coauthor(s)

Cole M Chokran, AB MD/MS Candidate, Columbia University Vagelos College of Physicians and Surgeons

Disclosure: Nothing to disclose.

Nadine M Khoury MD Candidate, Columbia University Vagelos College of Physicians and Surgeons

Disclosure: Received research grant from: NIH.

Nina Teresa Yoh, MD Resident Physician, Department of Neurological Surgery, Columbia University Irving Medical Center, New York-Presbyterian Hospital

Nina Teresa Yoh, MD is a member of the following medical societies: Alpha Omega Alpha, American Association of Neurological Surgeons, Congress of Neurological Surgeons, Gold Humanism Honor Society, Neurocritical Care Society

Disclosure: Nothing to disclose.

Specialty Editor Board

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Christopher D Braden, DO Hematologist/Oncologist, Chancellor Center for Oncology at Deaconess Hospital; Medical Director, Deaconess Hospital Outpatient Infusion Centers; Chairman, Deaconess Hospital Cancer Committee

Christopher D Braden, DO is a member of the following medical societies: American Society of Clinical Oncology, American Society of Hematology

Disclosure: Nothing to disclose.

Chief Editor

Herbert H Engelhard, III, MD, PhD, FACS, FAANS Affiliated Professor of Bioengineering, University of Illinois at Chicago

Herbert H Engelhard, III, MD, PhD, FACS, FAANS is a member of the following medical societies: American Association for Cancer Research, American Association of Neurological Surgeons, American College of Surgeons, American Medical Association, Congress of Neurological Surgeons, Illinois State Medical Society

Disclosure: Nothing to disclose.

Additional Contributors

Benjamin C Kennedy, MD Assistant Professor of Neurosurgery, Perelman School of Medicine at the University of Pennsylvania; Director of Epilepsy and Functional Neurosurgery, The Children’s Hospital of Philadelphia

Disclosure: Nothing to disclose.