Astrocytoma, IDH-mutant

Astrocytoma, IDH-mutant tumors are 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.

Terminology

The 5^th 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 ¹⁹. 

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 codeletion, 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 ¹³. Although gemistocytic astrocytoma are also no longer recognized as distinct entities, gemistocytic tissue pattern remains a histological feature ¹⁹. 

Epidemiology

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.

Clinical presentation

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.

Pathology

Adult-type 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 what was previously known as protoplasmic astrocytomas. 

The occasional occurrence of gemistocytes in a diffuse astrocytoma does not justify the diagnosis of what was previously known as a gemistocytic astrocytoma, which tended 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, diffuse 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. Moreover, the genetic status of these tumors is more reflective of their subtypes than the histologic grading (please refer to isocitrate dehydrogenase (IDH) for a broad discussion on this topic) ¹¹.  

Grading

The grading of astrocytoma, IDH-mutant is based on histological features, as well as incorporating molecular markers (introduced in the 5^th edition (2021) WHO classification of CNS tumors) ¹⁹. 

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

Radiographic features

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.

CT

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 tumors with gemistocytic differentiation can demonstrate wispy enhancement.

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

MRI

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 incompletely 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 the 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 = 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

• SWI

  • the presence of artifacts is usually due to neoangiogenesis and microhemorrhage rather than calcification, reflecting microvascular proliferation. If present, grade 4 should be suspected ²²

• 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 a 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-CT

• has FDG uptake similar to the normal white matter

• FDG,18-F-choline and 11C-choline PET is useful for biopsy targeting the most hypermetabolic areas that are most likely the highest grade component

Treatment and prognosis

Treatment

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. 

Similarly, there is evidence that resection of low-grade tumors is of benefit and that total resection of the T2 signal abnormality, or even "supramaximal resection" (resection of the normal-appearing brain beyond the margins of T2 signal abnormality) confers survival benefits ²⁰. The extent of resection that is achievable will, however, depend on the location of the tumor and how circumscribed its margins are.

Vorasidenib, an IDH1 and IDH2 inhibitor that is administered orally and can penetrate the blood brain barrier, has been shown to significantly prolong progression-free survival (27.7 months vs 11.1 months) ²¹.

Prognosis

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

* NB: It is almost certain 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.

Differential diagnosis

Possible imaging differential considerations include:

• glioblastoma

  • may be indistinguishable from grade 4 astrocytoma, IDH-mutant

  • tends to be in older patients

  • tends to have a less sizable non-enhancing component

• infarction: major vascular territory

• cerebritis/encephalitis: herpes simplex encephalitis, ADEM

• cortical based tumors: oligodendroglioma, angiocentric glioma