Anaplastic astrocytoma, IDH-wildtype

CNS tumor
Diffuse astrocytic and oligodendroglial tumors
Anaplastic astrocytoma, IDH-wildtype

Authors: Meaghan Morris, M.D., Ph.D., Fausto J. Rodriguez, M.D.

Editor-in-Chief: Debra Zynger, M.D.

Topic Completed: 22 August 2019

Minor changes: 3 January 2020

Copyright: 2019, PathologyOutlines.com, Inc.

PubMed Search: Anaplastic astrocytoma IDH-wildtype

Page views in 2019: 932

Page views in 2020 to date: 1,386

Table of Contents

Cite this page: Morris M, Rodriguez FJ. Anaplastic astrocytoma, IDH-wildtype. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/cnstumoranaastroIDHwild.html. Accessed May 26th, 2020.

Definition / general

Infiltrating astrocytoma with elevated mitotic activity, at least moderate atypia and no isocitrate dehydrogenase 1 or 2 (IDH1/2) mutations by sequencing
Diagnosis encompassing a molecularly diverse set of tumors increasingly categorized by molecular alterations

Essential features

Infiltrating astrocytoma with elevated mitotic activity, at least moderate atypia and no isocitrate dehydrogenase 1 or 2 (IDH1/2) mutations by sequencing
Anaplastic astrocytomas involving midline structures, particularly the thalamus, brainstem or spinal cord, should also have no evidence of histone H3 K27M mutation either by immunohistochemistry or by sequencing
IDH-wildtype anaplastic astrocytomas represent a molecularly diverse set of tumors increasingly categorized by molecular alterations
Majority of IDH-wildtype anaplastic astrocytomas share molecular alterations with IDH-wildtype glioblastomas and have a similarly poor prognosis

Terminology

Final integrated diagnosis now determined by the presence or absence of specific molecular alterations (see Molecular / cytogenetics description)

ICD coding

ICD-O: 9401/3 - Anaplastic astrocytoma, IDH-wildtype
ICD-10: C71.9 - Malignant neoplasm of brain

Epidemiology

Onset in fifth decade, though wide age range can be affected (Acta Neuropathol 2015;129:585, Oncotarget 2017;8:20354)
Less common and with older average age of onset compared with IDH-mutant anaplastic astrocytomas (Acta Neuropathol 2015;129:585)
M:F = 1.8:1 (Oncotarget 2017;8:20354)

Sites

Frontal lobe, temporal lobe > parietal lobe > other CNS sites (J Am Med Inform Assoc 2013;20:1091)
Less predilection for the frontal lobe compared to IDH-mutant astrocytomas (J Neurooncol 2017;135:601, J Am Med Inform Assoc 2013;20:1091)

Pathophysiology

Though histologically WHO grade III tumors, the majority of IDH-wildtype anaplastic astrocytomas in adults share molecular alterations with IDH-wildtype glioblastomas and are thought to be equivalent to WHO grade IV tumors (N Engl J Med 2015;372:2481)

Etiology

Unknown at this time

Clinical features

Commonly presents with headache, seizures, mental status changes or focal neurologic signs

Diagnosis

MRI with contrast is the preferred imaging modality
Diagnosis is by biopsy or surgical resection

Radiology description

MRI shows T2/FLAIR bright infiltrative mass with indistinct borders and variable enhancement
Often the minority of the tumor enhances on post contrast T1 imaging (J Neurooncol 2017;135:601)

Radiology images

Contributed by Meaghan Morris, M.D., Ph.D.

Bright on FLAIR

Contrast enhancing

Prognostic factors

Average survival decreased compared with IDH-mutant anaplastic astrocytomas ( Engl J Med 2009;360:765)
MGMT promoter methylation is a favorable prognostic factor (Oncotarget 2017;8:20354)
- If molecularly equivalent to glioblastoma, MGMT promoter methylation should predict response to temozolomide chemotherapy, though clinical trials are ongoing (Lancet 2017;390:1645, Clin Cancer Res 2007;13:2606, N Engl J Med 2005;352:997)
Gross total surgical resection may improve prognosis (Oncotarget 2017;8:20354)

Case reports

9 year old boy with long term progression free survival (BMJ Case Rep 2019;12:e228153)
75 year old man with cerebellar anaplastic astrocytoma (World Neurosurg 2018;115:181)

Treatment

Surgical resection, if possible, followed by radiation and temozolomide chemotherapy (Lancet 2017;390:1645)

Gross description

Soft gray-tan tissue
Tumor may expand involved brain structures, however, it’s often not evident in fragmented surgical specimens

Frozen section description

Sections typically show slight to moderate hypercellularity with infiltrating neoplastic cells
Myxoid background may be present
Predominantly cells with atypical elongated hyperchromatic nuclei in a fibrillary background
- Variable quantity of cells with eccentric nuclei and glassy eosinophilic cytoplasm (gemistocytes)
Mitoses may be present but are often difficult to find
Smear most commonly shows predominantly smaller cells with fine fibrillar processes, elongated nuclei and nuclear atypia

Frozen section images

Contributed by Meaghan Morris, M.D., Ph.D.

Hypercellular with atypical cells and edema

Single cell infiltration

Microscopic (histologic) description

Histologic sections show infiltrating tumor cells with increased mitotic activity
- Myxoid background and microcyst formation may be present
- Cellularity can be variable
Morphology is typically cells with elongated nuclei and fine fibrillary processes or cells with eccentric nuclei and glassy eosinophilic cytoplasm (gemistocytes)
Tumor cells infiltrate in a diffuse single cell pattern, often with entrapped neurons and axons
Cannot be distinguished from IDH-mutant anaplastic astrocytoma on histology alone

Microscopic (histologic) images

Contributed by Meaghan Morris, M.D., Ph.D.

Astrocytoma with mitotic activity

Diffusely infiltrating astrocytoma

Single cell infiltration around axons

Gemistocytic morphology

OLIG2

Cytology description

Predominantly smaller cells with fine fibrillar processes, elongated nuclei and nuclear atypia

Cytology images

Contributed by Meaghan Morris, M.D., Ph.D.

Smear

Positive stains

GFAP, OLIG2 and S100
SOX10 (subset) (J Neurooncol 2006;76:115)
Ki67 labeling index typically elevated
ATDX (ATRX) expression retained
Neurofilament protein (highlights entrapped axons)

Negative stains

IDH1 (R132H mutant protein)
CAM5.2, CD45, CD20, Melan A

Molecular / cytogenetics description

By definition, sequencing of IDH1 and IDH2 shows no mutations
- Midline tumors with anaplastic astrocytoma histology, particularly thalamic, brainstem or spinal cord gliomas, must have negative H3 K27M immunohistochemistry or sequencing without evidence of an H3 K27M mutation (see Diffuse Midline Glioma, H3 K27M-mutant)
New diagnoses recommended for anaplastic astrocytomas with specific molecular alterations:
- Diagnosis: Diffuse astrocytic glioma, IDH-wildtype, with molecular features of glioblastoma (Acta Neuropathol 2018;136:805)
  - Comprises a significant portion of anaplastic astrocytomas in adults
  - Requires at least one of the following: EGFR amplification, TERT promoter mutation or combined gain of whole chromosome 7 and loss of whole chromosome 10
  - Anaplastic astrocytomas with these alterations behave similarly to IDH-wildtype glioblastomas
- Rarely, anaplastic astrocytomas affecting children and young adults show characteristic alterations with improved prognosis (Acta Neuropathol 2019;137:683)
  - Typically show histology of a diffuse astrocytoma but rarely may progress to anaplastic astrocytoma (Acta Neuropathol 2019;137:683)
  - Diagnostic molecular alterations for these “pediatric-type” astrocytomas: BRAF V600E without CDKN2A/B homozygous deletion, MYB or MYBL1 structural variation or amplification, FGFR1 internal tandem duplication of the tyrosine kinase domain or single nucleotide alteration or other MAPK pathway alteration (Acta Neuropathol 2019;137:683)
  - Diagnosis: Diffuse glioma, (list specific molecular features: MYB-altered/MYBL1-altered/FGFR1 TKD-duplicated/FGFR1-mutant/BRAF V600E-mutant/other MAPK alteration)

Sample pathology report

Brain, frontal lobe, resection:
- Anaplastic astrocytoma, IDH-wildtype (WHO grade III) (see comment)
- Comment: Next generation sequencing studies showed no mutations in IDH1 or IDH2.
Brain, frontal lobe, resection:
- Diffuse astrocytic glioma, IDH-wildtype, with molecular features of glioblastoma (WHO grade IV) (see comment)
- Comment: EGFR amplification was identified in this specimen using next generation sequencing. No mutations in IDH1 or IDH2 were identified.

Differential diagnosis

Anaplastic astrocytoma, IDH-mutant:
- Infiltrative glioma with astrocytic differentiation, nuclear atypia, moderate pleomorphism and elevated mitotic activity but lacks necrosis or microvascular proliferation
- IDH1/2 mutation present by immunohistochemistry or sequencing
- TP53 and ATRX alterations frequently present
Glioblastoma, IDH-wildtype:
- High grade infiltrative glial neoplasm with astrocytic differentiation, nuclear atypia, pleomorphism, elevated mitotic activity and must have either necrosis or microvascular proliferation
- IDH mutation is not present by immunohistochemistry or sequencing
Diffuse midline glioma, H3 K27M-mutant:
- Infiltrating astrocytoma with a K27M mutation in histone H3 and variable histologic grade, including anaplastic astrocytoma histology
- Often a pediatric tumor with preferential localization in midline CNS structures, most often the thalamus, brainstem or spinal cord
- H3 K27M mutation present by immunohistochemistry or sequencing
Anaplastic oligodendroglioma, IDH-mutant:
- High grade infiltrating glioma composed of round cells resembling oligodendrocytes, hyperchromatic rounded nuclei, perinuclear halos, increased mitotic activity, fine branching vasculature, scattered calcifications, variable microvascular proliferation and variable necrosis
- IDH1/2 mutation present by immunohistochemistry or sequencing and whole arm codeletion of chromosomes 1p and 19q present by molecular testing
Lymphoma:
- Parenchymal lymphomas in the central nervous system are typically diffuse large B cell lymphomas, which lack the fine fibrillar cell process typical of glial cells
- Diffuse large B cell lymphoma in the CNS often shows a perivascular tumor distribution and is positive for CD45 and CD20 but is negative for GFAP and OLIG2 by immunohistochemistry
- Single cell infiltration in CNS lymphoma in particular may mimic a diffuse glioma
Metastatic disease:
- Morphology varies by the site of origin, however, typically they lack the fine fibrillar processes found in glial tumors and are generally negative for OLIG2 and GFAP by immunohistochemistry
- More often demonstrate a sharp interface with brain parenchyma

Additional references

Board review style question #1

IDH1

IDH2

Anaplastic astrocytoma, IDH-mutant (WHO grade III)
Anaplastic astrocytoma, IDH-wildtype (WHO grade III)
Diffuse large B cell lymphoma
Glioblastoma, IDH-wildtype (WHO grade IV)
Oligodendroglioma (WHO grade II)

Board review answer #1

B. Anaplastic astrocytoma, IDH-wildtype. The image shows an anaplastic astrocytoma with mitotic activity, atypical elongated nuclei and scattered gemistocytes. As ancillary tests show no evidence of IDH mutation, the tumor cannot be an IDH-mutant anaplastic astrocytoma. A WHO grade II oligodendroglioma would not typically show this degree of nuclear atypia with nuclear elongation and the diagnosis of oligodendroglioma requires both an IDH1/2 mutation and whole arm codeletion of chromosomes 1p and 19q. There is no evidence of necrosis or microvascular proliferation to diagnose glioblastoma. While diffuse large B cell lymphoma is the most common primary CNS lymphoma, there is no typical perivascular distribution and the abundant eosinophilic cytoplasm of the neoplastic cells with scattered gemistocytes are not consistent with lymphoma.

Reference: Anaplastic astrocytoma, IDH-wildtype

Comment Here

Board review style question #2

IDH

Anaplastic astrocytoma, IDH-mutant
Dysembryoplastic neuroepithelial tumor
Glioblastoma, IDH-wildtype
Oligodendroglioma
Pleomorphic xanthoastrocytoma

Board review answer #2

C. Glioblastoma, IDH-wildtype. IDH-wildtype anaplastic astrocytomas share many of the same molecular alterations with IDH-wildtype glioblastomas and have a similar prognosis. Per recent recommendations, if specific molecular alterations are identified (EGFR amplification, TERT promoter mutation or combined whole chromosome 7 gain and whole chromosome 10 loss), the preferred diagnosis for an IDH-wildtype anaplastic astrocytoma is diffuse astrocytic glioma, IDH-wildtype, with molecular features of glioblastoma (WHO grade IV). The presence of an IDH mutation in an anaplastic astrocytoma confers a significantly better prognosis. Oligodendroglioma (WHO grade II), Dysembryoplastic neuroepithelial tumor (WHO grade I) and pleomorphic xanthoastrocytoma (WHO grade II) all have a significantly better prognosis than an IDH-wildtype anaplastic astrocytoma.

Reference: Anaplastic astrocytoma, IDH-wildtype

Comment Here