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Accurate detection of BRAF p.V600E mutations in challenging melanoma specimens requires stringent immunohistochemistry scoring criteria or sensitive molecular assays. | LitMetric

AI Article Synopsis

  • BRAF mutation testing is essential for melanoma patients before starting BRAF inhibitor therapy, with molecular testing being the preferred method; however, BRAF immunohistochemistry (IHC) may provide similar results under certain conditions.* -
  • A study involving 122 melanoma samples highlighted that varying sample attributes, such as high melanin pigmentation and metastasis, often led to discrepancies in IHC scoring among pathologists, but using stringent scoring criteria improved agreement and reliability.* -
  • While molecular BRAF testing is more sensitive for detecting mutations in difficult cases, implementing careful IHC scoring methods can yield high specificity and positive predictive value, particularly for the BRAF V600E mutation.*

Article Abstract

Malignant melanoma patients require BRAF mutation testing prior to initiating BRAF inhibitor therapy. Molecular testing remains the diagnostic gold standard, but recent work suggests that BRAF immunohistochemistry (IHC) confers comparable results. Sample attributes and scoring criteria that may affect BRAF IHC interpretation, however, are poorly defined. We investigated formalin-fixed, paraffin-embedded samples with variable challenging interpretative attributes: metastases, core needle biopsies, sample tissues less than 60 mm(2), samples with greater than 50% necrosis, and/or samples with greater than 10% melanin pigmentation. Three pathologists independently scored 122 BRAF V600E IHC-labeled melanoma samples for percentage (0%-100%) of staining intensity (0-3+). Interscorer BRAF IHC discrepancies were resolved by consensus review. Lenient (≥1+, >0%) and stringent (≥2+, ≥10%) IHC scoring criteria were compared to BRAF V600 mutation (cobas) results (n = 118). Specimens with greater than 10% melanin pigmentation and metastatic samples produced the majority of interobserver IHC and IHC/cobas scoring discrepancies. Consensus review using stringent scoring criteria decreased the number of discrepant results, yielded very good interobserver reproducibility, and improved specificity and positive predictive value for BRAF p.V600E detection. BRAF p.V600K mutations accounted for 57.1% of false-negative IHC results when stringent, consensus criteria scoring were used. The cobas test detected 75.0% (8/12) of BRAF IHC-negative BRAF p.V600K mutations confirmed by next-generation sequencing. Molecular BRAF testing is the preferred screening test for BRAF inhibitor therapy eligibility because of superior sensitivity in challenging interpretative melanoma specimens. However, BRAF V600E IHC has excellent specificity and positive predictive value when stringent, consensus scoring criteria are implemented. To decrease IHC scoring discrepancies, pathologists should interpret metastatic and pigmented samples with caution.

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Source
http://dx.doi.org/10.1016/j.humpath.2014.07.014DOI Listing

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