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


Topic Completed: 13 September 2019

Revised: 13 September 2019

Copyright: 2019, PathologyOutlines.com, Inc.

PubMed Search: anaplastic astrocytoma IDH mutant [title]


John DeWitt, M.D., Ph.D.
Page views in 2019 to date: 1,200
Cite this page: Dewitt J. Anaplastic astrocytoma, IDH mutant. PathologyOutlines.com website. http://www.pathologyoutlines.com/topic/anaastroidhmutant.html. Accessed December 7th, 2019.
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
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
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
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
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
Board review question #1
Which is true about this brain lesion presenting in a 50 year old man?

  1. If R132H-IDH1 immunohistochemistry is negative, no further testing is necessary
  2. If R132H-IDH1 immunohistochemistry is positive, ATRX staining of tumor cells is expected to be lost
  3. If R132H-IDH1 immunohistochemistry is positive, ATRX staining of tumor cells is expected to be retained
  4. If R132H-IDH1 immunohistochemistry is positive, p53 staining of tumor cells is expected to be weak and scattered
  5. 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

Comment here
Board review 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?

  1. Microvascular proliferation
  2. Mitoses and pleomorphism in the absence of necrosis or microvascular proliferation
  3. Necrosis
  4. Necrosis and microvascular proliferation
  5. 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

Comment here
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