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Role of CDKN2A deletion in grade 2/3 IDH-mutant astrocytomas: need for selective approach in resource-constrained
Shalini Suman1, Ravi Sharma2, Varidh Katiyar2
11Neuropathology Laboratory, and.
Objective:
The authors aimed to assess the frequency of homozygous CDKN2A deletion in isocitrate dehydrogenase (IDH)-mutant diffuse astrocytomas (grade 2/3) and to narrow down the clinicopathological indications in which the CDKN2A fluorescence in situ hybridization (FISH) assay is cost-effective in resource-constrained settings.
Methods:
IDH-mutant astrocytomas were analyzed for ATRX, p53, MIB1-LI, and p16 expression using immunohistochemistry. The FISH assay was used to evaluate CDKN2A deletion and 1p/19q codeletion. Survival outcomes were assessed according to the different molecular markers.
Results:
A total of 150 adult patients with IDH-mutant grade 2 (n = 95) and grade 3 (n = 55) astrocytomas (145 primary and 5 recurrent) were analyzed. Using a cutoff value of 30% for defining significant homozygous CDKN2A deletion, none of the grade 2 and 10.9% (6/55) of grade 3 astrocytomas showed this deletion (4 primary and 2 recurrent grade 3 tumors) and were reclassified as grade 4. This mutation was more frequent in recurrent (40%, 2/5) than primary (2.76%, 4/145) gliomas. Half (3/6, 50%) of the CDKN2A-deleted cases demonstrated poor outcomes; 2 of these cases experienced recurrence at 12 and 36 months after surgery, and 1 died at 5 months. The majority of CDKN2A-deleted cases showed marked cellularity (100%), pleomorphism (100%), brisk mitosis (83.3%), and tumor giant cell formation (83.4%). None of the cases with retained p16 expression harbored this deletion. Both overall survival (p = 0.039) and progression-free survival (p = 0.0045) were found to be worse in cases with p16 loss. Selectively performing CDKN2A FISH only in high-risk cases with histomorphological features of anaplasia, p16 loss, or recurrent tumors achieved a sensitivity and negative predictive value of 100%. This approach would have resulted in saving 41.1% of the original expenditure ($6900 US per 150 samples) and 27.6 person-minutes per sample without compromising the identification of deleted cases.
Conclusions:
Homozygous CDKN2A deletion is conspicuously absent in grade 2 and rare in primary grade 3 IDH-mutant astrocytomas. The authors propose that restricting use of the FISH assay to cases showing histomorphological features of anaplasia, p16 loss, or recurrent tumors will help this platform to be utilized in the most cost-effective manner in resource-constrained settings.
Insights
Homozygous CDKN2A deletion is rare in grade 2 and primary grade 3 IDH-mutant astrocytomas. Restricting CDKN2A fluorescence in situ hybridization (FISH) testing to high-risk cases improves cost-effectiveness in resource-limited settings.
Area of Science:
- Neuro-oncology
- Molecular Pathology
- Genetics
Background:
- Isocitrate dehydrogenase (IDH)-mutant diffuse astrocytomas are graded 2 or 3.
- CDKN2A deletion is a significant molecular marker in astrocytomas.
- Cost-effective diagnostic strategies are crucial in resource-constrained settings.
Purpose of the Study:
- To determine the frequency of homozygous CDKN2A deletion in IDH-mutant diffuse astrocytomas (grade 2/3).
- To identify clinicopathological indicators for cost-effective CDKN2A fluorescence in situ hybridization (FISH) assay use.
- To evaluate the impact of CDKN2A deletion on patient survival outcomes.
Main Methods:
- Analysis of 150 adult IDH-mutant astrocytomas (grade 2/3) using immunohistochemistry (ATRX, p53, MIB1-LI, p16) and FISH for CDKN2A deletion and 1p/19q codeletion.
- Assessment of survival outcomes based on molecular markers.
- Evaluation of cost-effectiveness of selective FISH testing.
Main Results:
- Homozygous CDKN2A deletion was absent in grade 2 and present in 10.9% of grade 3 astrocytomas, with higher frequency in recurrent tumors.
- CDKN2A deletion was associated with features of anaplasia and poorer survival outcomes (overall and progression-free survival).
- Selective FISH testing in high-risk cases (anaplasia features, p16 loss, recurrence) achieved 100% sensitivity and NPV, saving 41.1% of costs.
Conclusions:
- Homozygous CDKN2A deletion is infrequent in lower-grade IDH-mutant astrocytomas.
- Targeted CDKN2A FISH testing in specific high-risk patient groups enhances diagnostic efficiency and cost-effectiveness.
- This approach optimizes resource utilization in molecular diagnostics for astrocytomas.
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