BRAF testing modalities in histiocytic disorders: Comparative analysis and proposed testing algorithm

Author:

Acosta-Medina Aldo A1ORCID,Abeykoon Jithma P2ORCID,Go Ronald S2ORCID,Goyal Gaurav3ORCID,Ravindran Aishwarya4ORCID,Schram Susan M2,Rech Karen L5ORCID

Affiliation:

1. Department of Internal Medicine , Mayo Clinic, Rochester, MN , US

2. Division of Hematology , Mayo Clinic, Rochester, MN , US

3. Division of Hematology-Oncology and University of Alabama at Birmingham , Birmingham, AL , US

4. Division of Laboratory Medicine, University of Alabama at Birmingham , Birmingham, AL , US

5. Department of Laboratory Medicine and Pathology, Mayo Clinic , Rochester, MN , US

Abstract

Abstract Objectives Understanding of histiocytic disorders has been revolutionized by demonstration of mitogen-activated protein kinase (MAPK) pathway mutations, most commonly BRAFV600E. The optimal testing strategy to assess BRAFV600E is unknown. We aimed to compare performance of testing modalities, to propose a framework for evaluation of BRAFV600E mutation status in histiocytic disorders. Methods We retrospectively reviewed patients with histiocytic disorders and BRAF mutation testing on a lesional tissue specimen. Results In 120 patients, BRAF assessment included immunohistochemistry (IHC) in 97 (80.2%), polymerase chain reaction (PCR) in 35 (28.9%), and next-generation sequencing (NGS) in 62 (51.2%). Forty-five underwent both NGS and IHC. With NGS as the gold standard, the sensitivity and specificity of IHC were 82.4% and 96.4%. Three false negatives were observed in biopsy specimens with low BRAFV600E variant allele frequency or decalcified tissue. One false-positive IHC was observed in a lung biopsy specimen, likely due to antibody cross-reactivity with respiratory cilia. Among 14 with successful NGS and PCR, a single discordance was observed. Two PCR-to-IHC discrepancies were observed, including one other false-positive IHC. Conclusions Immunohistochemistry was highly specific for detection of BRAFV600E. Main caveats were false negatives and lack of detection of non-BRAFV600E mutations. We propose the use of IHC as initial screening in general practice with reflex molecular testing if negative.

Funder

University of Iowa

Publisher

Oxford University Press (OUP)

Subject

General Medicine

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