Astrocytoma, IDH-mutant

Last revised by Dr Payam Riahi on 05 Nov 2021

Astrocytoma, IDH mutant tumors are as WHO CNS grade 2, 3 or 4 tumors of the brain found in adults. They are diffuse infiltrating astrocytic tumors where there is no identifiable border between the tumor and normal brain tissue, even though the borders may appear relatively well-marginated on imaging.

The 5th edition (2021) update to the WHO classification of CNS tumors has substantially changed the classification of astrocytic tumors, building upon the prior (2016) edition that started to define tumors based on molecular characteristics. 

What would previously in most instances have been known as a diffuse astrocytoma or anaplastic astrocytoma or secondary glioblastoma now all come under the one diagnosis, based on the presence of IDH mutation and the demonstrated absence of 1p19q co-deletion, which if present would make the diagnosis of an oligodendroglioma 16

These IDH-mutant astrocytomas are now graded 2, 3 or 4 based on histological and molecular features, but importantly a grade 4 tumor is no longer a glioblastoma, but rather just an astrocytoma, IDH mutant WHO CNS grade 4 16

Glioblastoma is now considered a separate entity and distinct and must be IDH-wildtype, and is therefore discussed separately. 

Importantly, the diagnosis of astrocytoma, IDH mutant is an adult-type diagnosis, distinct from a variety of other pediatric-type diffuse astrocytomas (see astrocytic tumors).

The terms fibrillary astrocytoma and protoplasmic astrocytomas are no longer recognized as separate entities 13Gemistocytic astrocytoma remains a distinct subtype,

IDH-mutant adult-type astrocytomas are typically diagnosed in young adults median age of 36 years for grades 2 and 3 (combined), and 38 years for grade 4) 17. This is substantially younger than glioblastoma IDH wildtype tumors (median 50-60 years of age) 17

There is a substantially higher incidence in men of all ages and of all grades tumor  (M:F ~1.5) 1,17.

The most common presenting feature (~40% of cases) is a seizure. This is particularly the case in adults. Headaches are often also present. Depending on the size of the lesion and its location, other features may be present, such as hydrocephalus and focal neurological dysfunction, including personality changes.

Adult-type diffuse astrocytomas are predominantly composed of a microcystic tumor matrix within which are embedded fibrillary neoplastic astrocytes with mild nuclear atypia and a low cellular density. Often microcystic spaces containing mucinous fluid are present, a typical finding in what was previously known as fibrillary astrocytomas, but even more characteristic and pronounced in protoplasmic astrocytomas

The occasional occurrence of gemistocytes in a diffuse astrocytoma does not justify the diagnosis of gemistocytic astrocytoma. Gemistocytic astrocytomas tend to progress more rapidly to higher-grade tumors.

Mitoses, microvascular proliferation and necrosis are absent (if present they suggest a high-grade tumor). Like all tumors derived from astrocytes, fibrillary astrocytomas stain with glial fibrillary acid protein (gFAP) 2-3.

It is well recognized that pathological classification has a high interobserver variation and thus imperfectly predicts clinical outcomes 11. More recent studies have shown that the genetic status of these tumors is more reflective of their subtypes than the histologic grading (please refer on isocitrate dehydrogenase (IDH) for a broad discussion on this topic) 11.  

The grading of astrocytoma, IDH mutant is based on histological features, as well incorporating molecular markers (introduced in the 5th edition (2021) WHO classification of CNS tumors). 

  1. grade 2
    • well-differentiated, low mitotic activity
    • no necrosis or microvascular proliferation
    • CDKN2A/B homozygous deletion absent
  2. grade 3
    • anaplasia, significant mitotic activity
    • no necrosis or microvascular proliferation
    • CDKN2A/B homozygous deletion absent
  3. grade 4
    • necrosis, and/or
    • microvascular proliferation, and/or
    • CDKN2A/B homozygous deletion

MRI is the modality of choice for characterizing these lesions, and in the case of smaller tumors, they may be subtle and difficult to see on CT, especially as they tend not to enhance.

Typically low-grade infiltrating astrocytomas appear as isodense or hypodense regions of positive mass effect, often without any enhancement (in fact, the presence of enhancement would suggest higher grade tumors), although gemistocytic astrocytomas particularly can demonstrate wispy enhancement.

Cystic or fluid attenuation components are also encountered, particularly in tumors with a gemistocytic component of "protoplasmic" component. 

Reported signal characteristics include:

  • T1
    • isointense to hypointense compared to white matter
    • usually confined to the white matter and causes expansion of the adjacent cortex
  • T2/FLAIR 
    • mass-like hyperintense signal that suppresses on FLAIR: T2-FLAIR mismatch sign
    • always follow the white matter distribution and cause expansion of the surrounding cortex
    • cortex can also be involved in late cases in comparison to oligodendroglioma, which is a cortical-based tumor from the start
    • the "microcystic changes" along the lines of spread of the infiltrative astrocytoma is a unique behavior for the infiltrative astrocytoma; however, it is only appreciated in a small number of cases
    • high T2 signal is not related to cellularity or cellular atypia, but rather to edema, demyelination, and other degenerative change 10
  • DWI/ADC
    • typically has facilitated diffusion, with lower ADC values suggesting a higher grade
    • ADC values correlate with grade 15
      • grade 4 /GBM = 745 ± 135 x 10-6 mm2/s
      • grade 3 = 1067 ± 276 x 10-6 mm2/s
      • grade 2 = 1273 ± 293 x 10-6 mm2/s
  • T1 C+ (Gd)
    • no enhancement in grade 2 tumors
    • solid areas of enhancement +/- necrosis suggest higher grade
  • MR spectroscopy
    • typically will show elevated choline peak, low NAA peak, elevated choline:creatine ratio
    • elevated myo-inositol and myo-inositol/creatine ratio
    • there is lack of the lactate peak seen at 1:33
    • the lactate peak represents the necrosis seen in grade 4 tumors
  • MR perfusion
    • relative cerebral blood volume (rCBV) will depend on the grade
      • grade 2: no elevation
      • grade 4: usually elevated especially in enhancing components
  • PET
    • has FDG uptake similar to the normal white matter
    • FDG,18-F-choline and 11C-choline PET are useful for biopsy targeting the most hypermetabolic areas that is most likely the highest grade component

Treatment depends on clinical presentation, tumor grade, as well as tumor size and location.

Historically low-grade tumors were managed as follows:

  • biopsy to confirm the diagnosis and observe
  • surgical resection if feasible
  • usually radiotherapy at the time of recurrence or progression

In contrast, high-grade tumors have maximal safe resection followed by concurrent chemoradiotherapy (Stupp protocol).

There is an increasing body of evidence that suggests that concurrent chemoradiotherapy, usually reserved for tumors that progressed to higher grades, may be of benefit in lower grade tumors also. 

Care must be taken when reviewing survival data as the classification system used (WHO 2007 vs 2016 vs 2021) will dramatically affect the results. 

The 5-year survival for adult-type astrocytoma IDH-mutant varies by grade 18

  • grade 2 and 3 (combined): 9.3 years *
  • grade 4: 3.6 years

Note: * It is very likely that grade 2 tumors do somewhat better and grade 3 do somewhat worse, although little data on this exists on strictly molecular-based diagnosis (post-2016) 18

Possible imaging differential considerations include:

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Cases and figures

  • Figure 1: Diffuse glioma classification (WHO 5th Edition, 2021)
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  • Case 1: diffuse astrocytoma NOS
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  • Case 2: IDH-mutant (gemistocytic)
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  • Case 3: diffuse astrocytoma NOS
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  • Case 4: basal ganglionic diffuse infiltration
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  • Case 6: low grade glioma
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  • Case 7
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  • Case 8
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  • Case 9: diffuse astrocytoma NOS
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  • Case 10: diffuse astrocytoma IDH-1 mutant
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  • Case 11: IDH-1 mutant
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