Astrocytoma IDH-mutant Grade 3
Astrocytoma IDH-mutant, Grade 3, refers to a type of brain tumor characterized by specific genetic mutations and a particular grade of malignancy.
Astrocytoma: Astrocytomas are tumors that arise from astrocytes, which are a type of glial cell in the brain. Glial cells provide support and nourishment to neurons. Astrocytomas are classified based on their grade, which reflects the degree of malignancy or aggressiveness.
IDH-mutant: This refers to a specific genetic mutation involving the isocitrate dehydrogenase (IDH) gene. Mutations in the IDH gene are commonly found in certain types of brain tumors, including astrocytomas. The presence of an IDH mutation is an important factor in classifying and treating these tumors.
WHO grade III: The World Health Organization (WHO) classifies astrocytomas into different grades based on their histological features and aggressiveness. Grade 3 astrocytomas are considered to be malignant or anaplastic. They show more abnormal cell characteristics and are faster-growing than lower-grade tumors but are not as aggressive as Grade 4 tumors.
The molecular and clinical heterogeneity among IDH mutant lower grade (WHO Grades II/III) astrocytomas have only rarely been investigated.
Yang et al. recruited 160 IDH mutant lower grade (WHO Grades II/III) astrocytomas, and examined PDGFRA amplification, CDKN2A deletion and CDK4 amplification by FISH analysis, TERT promoter mutation by Sanger sequencing and ATRX loss and p53 expression by immunohistochemistry. We identified PDGFRA amplification, CDKN2A homozygous deletion and CDK4 amplification in 18.8%, 15.0% and 18.1% of our cohort respectively, and these alterations occurred in a mutually exclusive fashion. PDGFRA amplification was associated with shorter PFS (P = 0.0003) and OS (P < 0.0001). In tumors without PDGFRA amplification, CDKN2A homozygous deletion or CDK4 amplification was associated with a shorter OS (P = 0.035). Tumors were divided into three risk groups based on the presence of molecular alterations: high risk (PDGFRA amplification), intermediate risk (CDKN2A deletion or CDK4 amplification) and low risk (neither CDKN2A deletion and CDK4 amplification nor PDGFRA amplification). These three risk groups were significantly different in overall survival with mean survivals of 40.5, 62.9 and 71.5 months. The high-risk group also demonstrated a shorter PFS compared to intermediate- (P = 0.036) and low-risk (P < 0.0001) groups. One limitation of this study is the relatively short follow-up period, a common confounding factor for studies on low-grade tumors. The data illustrate that IDH mutant lower grade astrocytomas is not a homogeneous group and should be molecularly stratified for risk 1)
Diagnosis
grade 3
anaplasia, significant mitotic activity
no necrosis or microvascular proliferation
CDKN2A/B homozygous deletion absent
typically has facilitated diffusion, with lower ADC values suggesting a higher grade
ADC values correlate with grade
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
Treatment
Grade 3 tumor, any resection — Immediate postoperative RT plus adjuvant chemotherapy is recommended in patients with newly diagnosed IDH-mutant grade 3 astrocytoma, regardless of the degree of resection or other risk factors
The evidence base for RT plus chemotherapy in patients with newly diagnosed IDH-mutant grade 3 astrocytoma consists of several key randomized trials showing that the addition of chemotherapy (either PCV or temozolomide) to RT improves survival over RT alone. All trials enrolled patients prior to the 2016 World Health Organization (WHO) revised classification and therefore included a mix of grade 3 tumors with variable 1p/19q codeletion and IDH mutation status. Although temozolomide and PCV have not been compared head-to-head in this setting, temozolomide is more convenient and less toxic, and its use is supported by randomized data in IDH-mutant grade 3 astrocytomas.
CATNON trial
●EORTC 26053 (CATNON trial) – Direct support for RT plus temozolomide in patients with IDH-mutant grade 3 astrocytoma is based on results of the EORTC 26053 CATNON trial.
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:
grade 2 and 3 (combined): 9.3 years
Rautajoki et al. analyzed matched IDH-mutant astrocytomas before and after progression to grade 4 from six patients (discovery cohort) with genome-wide sequencing, 21 additional patients with targeted sequencing, and 33 patients from Glioma Longitudinal AnalySiS cohort for validation. The Cancer Genome Atlas data from 595 diffuse gliomas provided supportive information. All patients in the discovery cohort received radiation, all but one underwent chemotherapy, and no patient received temozolomide (TMZ) before progression to grade 4 disease. One case in the discovery cohort exhibited a hypermutation signature associated with the inactivation of the MSH2 and DNMT3A genes. In other patients, the number of chromosomal rearrangements and deletions increased in grade 4 tumors. The cell cycle checkpoint gene CDKN2A, or less frequently RB1, was most commonly inactivated after receiving both chemo- and radiotherapy when compared to other treatment groups. Concomitant activating PDGFRA/MET alterations were detected in tumors that acquired a homozygous CDKN2A deletion. NRG3 gene was significantly downregulated and recurrently altered in progressed tumors. Its decreased expression was associated with poorer overall survival in both univariate and multivariate analysis. They also detected progression-related alterations in RAD51B and other DNA repair pathway genes associated with the promotion of error-prone DNA repair, potentially facilitating tumor progression. In our retrospective analysis of patient treatment and survival timelines (n = 75), the combination of postoperative radiation and chemotherapy (mainly TMZ) outperformed radiation, especially in the grade 3 tumor cohort, in which it was typically given after primary surgery. The results provide further insight into the contribution of treatment and genetic alterations in cell cycle, growth factor signaling, and DNA repair-related genes to tumor evolution and progression 2)
In summary, an IDH-mutant astrocytoma, Grade 3, is a moderately aggressive brain tumor with specific genetic features. Treatment options and prognosis can be influenced by factors such as the tumor's location, size, and the overall health of the patient. Management typically involves a combination of surgery, radiation therapy, and chemotherapy. It's important for individuals diagnosed with this type of tumor to work closely with a medical team specializing in neuro-oncology to develop an appropriate treatment plan.