RESUMO
In this retrospective study, BRAF mutation status did not correlate with disease extent or (event-free) survival in 156 adults with Langerhans cell histiocytosis. BRAFV600E was associated with an increased incidence of second malignancies, often comprising hematological cancers, which may be clonally related.
Assuntos
Histiocitose de Células de Langerhans , Segunda Neoplasia Primária , Humanos , Adulto , Segunda Neoplasia Primária/epidemiologia , Segunda Neoplasia Primária/genética , Proteínas Proto-Oncogênicas B-raf/genética , Estudos Retrospectivos , Incidência , Histiocitose de Células de Langerhans/epidemiologia , Histiocitose de Células de Langerhans/genética , Histiocitose de Células de Langerhans/patologia , MutaçãoRESUMO
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.
