Inadequate Test Sensitivity

Molecular assays generally do not achieve 100% analytical sensitivity, so a false-negative result must always be considered. SBA will not detect clonal B-cell populations representing less than 3% to 5% of total nucleated cells in a fresh or frozen sample. Standard IGH PCR of fresh or frozen tissue is slightly more sensitive than SBA, detecting one clonal cell in 102 to 103 normal cells. IGH PCR sensitivity in paraffin-embedded tissue is much lower, sometimes as low as 40% to 60%, and is highly subject to the conditions used for tissue fixation and processing. Surprisingly, many laboratories performing IGH PCR for clinical purposes today do not know the sensitivity level of their tests. It is imperative that every assay for IGH clonal-ity include appropriate sensitivity controls, and it is essential to know the necessary level of sensitivity for the target of interest in each case. A test sensitivity of one positive cell in 20 normal cells (5%) is adequate for diagnostic or prognostic testing of almost all BCL, but there is no rationale for performing SBA or standard IGH PCR for MRD detection when the assay sensitivity is 5%. The minimal sensitivity for a test offered for MRD detection should be one positive cell in 104 normal cells, and a sensitivity of one positive cell in 105 to 106 normal cells is achievable and desirable for some assays. It is important to remember the difference in sensitivity of the IGH AgR and IGH/BCL2 PCR assays; in most laboratories, the IGH AgR assay has a much lower sensitivity than the IGH/BCL2 assay, which may lead to discrepant results when both tests are performed for the same case.

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