Multisystemic Pediatric Langerhans cell histiocytosis: a comprehensive clinico-pathological and BRAF V600E mutation study at autopsy

Abstract

Langerhans cell histiocytosis (LCH), a disorder of antigen-presenting cells, is the commonest disorder of the mononuclear phagocytic system. Diagnosis is always challenging due to heterogeneous clinical presentation. However, with the evolution and better understanding of its biology, many of these children are being diagnosed early and offered appropriate therapy. Despite these advances, in developing countries, an early diagnosis is still challenging due to resource constraints for specialized tests. As a result, many patients succumb to their disease. Autopsy data on LCH is notably lacking in the literature. We sought to analyze the clinical (including mutational) and morphologic features at autopsy in six proven cases of LCH. This study includes a detailed clinico-pathological and mutational analysis of 6 proven cases of LCH. Presence of BRAF V600E mutation was assessed by both Real Time PCR and Sanger sequencing. A varied spectrum of organ involvement was noted with some rare and novel morphological findings, like nodular bronchiolocentric infiltration of LCH cells, lymphovascular emboli of LCH cells, and paucity of eosinophils within the infiltrate; these features have not been described earlier. Surprisingly, all cases were negative for BRAF V600E mutation on both RQ-PCR and Sanger sequencing. The present study is perhaps the first autopsy series on LCH. This extensive autopsy analysis represents a correlation of pathological features with clinical symptoms which provides clues for a timely diagnosis and appropriate therapeutic intervention. Also, our findings hint at the low frequency of BRAF V600E mutation in our LCH patients.

Educational Case: Langerhans cell histiocytosis

“… 39 Given that mutations in the genes BRAF , TP53 , and KRAS are oncogenic in other disease processes and since around 60% of LCH cases have the BRAF V600E mutation, LCH is now characterized as a neoplastic disorder. 25 , 40 , 41 Additionally, the remaining 40% of LCH cases typically have other mutations in BRAF or different parts of the signaling pathway. 40 Response to BRAF V600E or MEK1 (signaling protein downstream of BRAF) targeted therapy further supports LCH as a myeloid neoplasm.…”

Impact of molecular status on clinical management in children with histiocytosis treated according to POL HISTIO project

“…In LCH, BRAF V600E is the most frequently detected mutation, followed by MAP2K1 alterations [1,2,5,7,8]. The occurrence of mutations seems to cause a more severe course and resistance to conventional chemotherapy, with potentially higher mortality and severe secondary conditions such as neurodegenerative disease (ND) or sclerosing cholangitis (SC) with consequent liver cirrhosis [7,[9][10][11][12].…”