Anaplastic astrocytoma, IDH mutant

CNS tumor
Diffuse astrocytic and oligodendroglial tumors
Anaplastic astrocytoma, IDH mutant

Author: John DeWitt, M.D., Ph.D.

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

Topic Completed: 13 September 2019

Minor changes: 13 September 2019

Copyright: 2019, PathologyOutlines.com, Inc.

PubMed Search: anaplastic astrocytoma IDH mutant [title]

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Table of Contents

Cite this page: Dewitt J. Anaplastic astrocytoma, IDH mutant. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/anaastroidhmutant.html. Accessed May 29th, 2020.

Definition / general

WHO 2016 definition: diffusely infiltrating astrocytoma with focal or dispersed anaplasia, significant proliferative activity, and a mutation in either the IDH1 or IDH2 gene

Essential features

May arise from lower grade diffuse astrocytoma, IDH mutant but are often diagnosed de novo
Most cases contain concurrent ATRX mutations but are not necessary for the diagnosis
Histologic features suggestive of oligodendroglioma are still consistent with the diagnosis in the absence of 1p19q codeletion
Tends to progress to grade IV glioblastoma, IDH mutant

Terminology

Anaplastic astrocytoma, high grade astrocytoma (this definition also includes glioblastoma)

ICD coding

ICD-10: C71.9 - malignant neoplasm of brain, unspecified

Epidemiology

Peak incidence age 38 years (Acta Neuropathol 2015;129:867)
M:F = 1.4:1, based strictly on histologic diagnosis (Neuro Oncol 2014;16:iv1)

Sites

Most commonly found in the cortex and white mater of the cerebral hemispheres; can occur anywhere in the CNS
Frontal lobe the most common location

Pathophysiology

Cell of origin is unknown; commonality of IDH mutation across IDH mutant astrocytoma, oligodendroglioma and glioblastoma suggests a common histogenesis in these tumors as does single cell sequencing of IDH mutant gliomas (Acta Neuropathol 2009;118:469, Science 2017;355:pii:eaai8478)

Etiology

Majority of tumors are sporadic
Ionizing radiation appears to be a risk factor
Small percentage are associated with familial cancer syndromes such as neurofibromatosis, tuberous sclerosis and Li-Fraumeni syndrome (Neuro Oncol 2014;16:896)

Clinical features

Often present after a clinical history of neurologic symptoms of a few months
Other common presenting symptoms include seizure, increasing neurologic deficits, signs of increased intracranial pressure or mental status change

Grading

Grade III of IV
Some studies have indicated only a modestly worse prognosis than diffuse astrocytoma, IDH mutant (which lack histologic anaplasia and proliferative activity) suggesting future refinement of IDH mutant astrocytoma may be necessary (Clin Cancer Res 2012;18:2490, Acta Neuropathol 2015;129:867, Nat Genet 2015;47:458)

Radiology description

Typically presents as a poorly defined mass with low density
At least partial contrast enhancement is usually present, unlike in grade II diffuse astrocytoma, IDH mutant
Despite contrast enhancement, the ring-like enhancement with central necrosis as often seen in grade IV glioblastoma, IDH mutant, is typically not seen
Evidence of mass effect and peritumoral edema may be seen

Radiology images

Contributed by John DeWitt, M.D., Ph.D.

MRI axial T1 FLAIR

MRI axial T1 precontrast

MRI axial T1 postcontrast

MRI axial T1 FLAIR

MRI axial T1 postcontrast

MRI coronal T1 precontrast

MRI coronal T1 postcontrast

Prognostic factors

Historically, median survival has been 3 - 5 years, although a study including only IDH mutant tumors showed a median survival of 9.3 years (Acta Neuropathol 2015;129:867)
Older patients, or those with a poor performance status have a worse prognosis
Extent of surgical resection is also an important factor (J Clin Oncol 2009;27:5874)
With stratification by IDH status, survival now varies widely

Case reports

40 year old man with long term daily temozolomide (Cancer Chemother Pharmacol 2017;80:1043)
49 year old man with synchronous gemistocytic astrocytoma IDH mutant and oligodendroglioma IDH mutant and 1p/19q codeleted with CCDC26 polymorphism (Acta Neuropathol 2017;134:317)
Case of concomitant IDH wildtype glioblastoma and IDH1 mutant anaplastic astrocytoma with constitutional mismatch repair deficiency syndrome (Neuropathol Appl Neurobiol 2018;44:233)
2 cases with IDH mutations in the elderly (Neuropathology 2018 Apr 10 [Epub ahead of print])

Treatment

Complete resection as extensively as is safely possible (Neuro Oncol 2015;17:868)
Chemotherapy (temozolomide) or radiation therapy

Gross description

Typically invade surrounding brain without overt tissue destruction
Expand native structures and can give a mass-like appearance on cut section
Areas of granularity or softening may be present

Frozen section description

Smear done at the time of frozen section will show astrocytic appearing tumor cells with oblong irregular nuclei with varying degrees of atypia and glial processes
High grade nuclear features and mitotic activity may be observed at frozen section but necrosis or microvascular proliferation (features of glioblastoma) should not be present

Frozen section images

Contributed by John DeWitt, M.D., Ph.D.

Anaplastic astrocytoma, IDH mutant H&E smear

Microscopic (histologic) description

Diffusely infiltrating tumor cells with oval to elongated astrocytic nuclei and varying appearance of tumor cytoplasm and fibrillar glial processes
Defined increased mitotic activity, cellularity and nuclear atypia compared to that of diffuse astrocytoma, IDH mutant, WHO grade II
In small biopsy specimens the presence of one mitosis may be sufficient for the diagnosis, while the presence of a few mitotic figures in a large resection would not be sufficient for an anaplastic designation
Necrosis and microvascular proliferation will be absent (Bailey: A Classification of the Tumors of the Glioma Group on a Histo-Genetic Basis with a Correlated Study of Prognosis, 1928)

Microscopic (histologic) images

Contributed by John DeWitt, M.D., Ph.D.

Pleomorphic hypercellular astrocytic appearance

Mitotically active

Gemistocytic histology

R132H-IDH1

ATRX

p53

Ki67

Positive stains

Negative stains

ATRX (should be retained in tumor vasculature as internal positive control)
Keratins (although cocktails may show cross reactivity)

Molecular / cytogenetics description

IDH1 or IDH2 mutation necessary for the diagnosis, with R132H-IDH1 variant seen in > 90% of cases (Acta Neuropathol 2009;118:469)
Tumors negative for R132H-IDH1 immunohistochemistry require IDH1 / 2 sequencing to determine IDH status (Neuro Oncol 2017;19:1640)
p53 mutation and ATRX promoter mutation nearly always present (typically absent in oligodendroglioma, IDH mutant and 1p19q codeleted (N Engl J Med 2015;372:2481)

Sample pathology report

Brain, frontal lobe mass, resection:
- Integrated diagnosis: Anaplastic astrocytoma, IDH mutant, WHO grade III (see comment)
- Histological diagnosis: Anaplastic astrocytoma
- WHO (histological) grade: III of IV
- Molecular information:
  - IDH: Positive (R132H-IDH1 immunohistochemistry, consistent with mutant)
  - ATRX: Nuclear expression retained (immunohistochemistry; consistent with wildtype)
  - p53: Positive (immunohistochemistry; consistent with mutant)
- Comment: The specimen consists of brain infiltrated by hyperchromatic and moderately pleomorphic astrocytic tumor cells. Scattered mitoses are present. Necrosis and vascular proliferation are not seen.

Differential diagnosis

Anaplastic astrocytoma, IDH wildtype: anaplastic astrocytoma lacking IDH mutation; negative R132H-IDH1 immunohistochemistry is insufficient for this diagnosis as IDH1 / 2 sequencing must be performed for a wildtype diagnosis
Anaplastic astrocytoma, NOS: when the tumor shows classical anaplastic astrocytoma histology but molecular studies to confirm IDH mutation are lacking, or are inconclusive
Diffuse astrocytoma, IDH mutant: when significant anaplasia and proliferative activity are lacking in an IDH mutant astrocytic tumor
Glioblastoma, IDH mutant: IDH mutant astrocytoma with necrosis or microvascular proliferation in addition to the anaplasia and proliferative activity of anaplastic astrocytoma, IDH mutant
Reactive gliosis: typically not as difficult to distinguish as in diffuse astrocytoma, as the cellularity, anaplasia and proliferative activity of anaplastic astrocytoma, IDH mutant are lacking

Additional references

Acta Neuropathol 2016;131:803

Board review style question #1

Which is true about this brain lesion presenting in a 50 year old man?

If R132H-IDH1 immunohistochemistry is negative, no further testing is necessary
If R132H-IDH1 immunohistochemistry is positive, ATRX staining of tumor cells is expected to be lost
If R132H-IDH1 immunohistochemistry is positive, ATRX staining of tumor cells is expected to be retained
If R132H-IDH1 immunohistochemistry is positive, p53 staining of tumor cells is expected to be weak and scattered
If R132H-IDH1 immunohistochemistry is positive, patient survival is similar to glioblastoma, IDH wildtype

Board review answer #1

B. If R132H-IDH1 immunohistochemistry is positive, ATRX staining of tumor cells is expected to be lost

Reference: CNS tumor - Anaplastic astrocytoma, IDH mutant

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Board review style question #2

You are working up a diffusely infiltrating glial tumor and find tumor cells are positive for R132H-IDH1 and have lost ATRX. Which histologic features should be present for a diagnosis of anaplastic astrocytoma, IDH mutant?

Microvascular proliferation
Mitoses and pleomorphism in the absence of necrosis or microvascular proliferation
Necrosis
Necrosis and microvascular proliferation
Round cells with perinuclear halos

Board review answer #2

B. Mitoses and pleomorphism in the absence of necrosis or microvascular proliferation

Reference: CNS tumor - Anaplastic astrocytoma, IDH mutant

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