Genotyping Assay Accelerates Diagnosis of Primary CNS Lymphoma, Detects Other Hematologic Malignancies
Key findings
- A review of 159 consecutive patients who were eventually diagnosed with primary central nervous system lymphoma (PCNSL) showed the median time to diagnosis was 10 days (range, 0–617) and 96% required at least one neurosurgical biopsy
- Massachusetts General Hospital researchers created a quantitative polymerase chain reaction–based assay to detect mutations found in PCNSL and glioma, including the MYD88 L265P, TERT promoter, IDH1/2, H3F3A and BRAF mutations that could provide results with 80 minutes of performing a lumbar puncture
- In an analysis of 86 archived specimens, the assay, dubbed Targeted Rapid Sequencing (TetRS), detected the MYD88 L265P mutation with 100% sensitivity and specificity and allowed for detection of hematologic malignancies with 58% sensitivity and 100% specificity
- When TetRS was optimized to report results within 80 minutes, it was 100% concordant with clinical molecular testing in detecting MYD88 L265P in 32 CSF samples, and in 132 specimens it detected hallmark mutations of CNS neoplasms with 66% sensitivity and 100% specificity
- Incorporating this rapid, targeted approach to genotyping into diagnostic workflows may reduce delays in diagnosis of CNS lymphoma, the need for neurosurgical biopsy and delays in treatment initiation
Diagnosis of primary central nervous system lymphoma (PCNSL) frequently requires neurosurgical biopsy because other malignancies have similar radiographic appearance and cerebrospinal fluid (CSF) studies can have low yield.
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Ganesh M. Shankar, MD, PhD, assistant professor and neurosurgeon in the Department of Neurosurgery at Massachusetts General Hospital, Bob S. Carter, MD, PhD, chief of the Department of Neurosurgery, and colleagues have created a quantitative polymerase chain reaction–based assay that facilitates diagnosis of PCNSL from CSF and can also detect other hematologic malignancies. In Blood, they report the scope of the problem in diagnosing PCNSL and the benefits of the new platform that can be applied to CSF, blood or solid tumor specimens, which they call Targeted Rapid Sequencing (TetRS).
Previous Diagnostic Workflow
To characterize the existing challenge in diagnosing PCNSL, the researchers analyzed the clinical courses of 159 consecutive patients diagnosed with PCNSL between 2010 and 2019:
- The median time to diagnosis was 10 days (range, 0–617; IRQ, 7–17 days)
- PCNSL was not included as a potential diagnosis in the initial evaluation of 27 patients (17%)
- Patients who underwent CSF sampling as the first procedure, rather than biopsy, required one to five more procedures before the diagnosis was established
- 96% of patients required at least one neurosurgical biopsy to establish the diagnosis
Genotyping Assay
TetRS was engineered to detect mutations often found in PCNSL and glioma, including MYD88, TERT promoter, IDH1/2, H3F3A and BRAF mutations. In an analysis of 86 archived specimens, TetRS detected the MYD88 L265P mutation with 100% sensitivity and specificity, allowing identification of hematologic malignancies including PCNSL with 58% sensitivity and 100% specificity.
TetRS was then optimized to report results within 80 minutes:
- In 32 CSF specimens, detection of the MYD88 L265P mutation was 100% concordant with available clinical molecular testing
- Across 132 CSF and plasma specimens from 117 patients, TetRS detected hallmark mutations of hematologic malignancies with 66% sensitivity and 100% specificity
Reducing Delays
Because TetRS can detect clinically relevant mutations rapidly from CSF, incorporating it into diagnostic workflows may reduce delays in diagnosis, the need for neurosurgical biopsy and delays in treatment initiation. Targeted genotyping might also guide cost-effective selection of next-generation sequencing panels, molecular assays and assignment to clinical trials.
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