BRAF Fusions in Histiocytic Disorders: Frequency and Clinical Characteristics

Background: Activation of extracellular-signal regulated kinase (ERK) is almost universal in histiocytic disorders and is driven by genomic alterations in the mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinases (PI3K) pathways. While BRAFV600E mutations are well described in histiocytic disorders, less is known about BRAF fusions. The goal of our study is to describe the frequency and clinical characteristics of patients harboring BRAF fusions. Methods: We included patients with a diagnosis of histiocytic disorder seen at our institution from November 2016-June 2021. Only those who had adequate BRAF testing were included. The following were considered adequate BRAF testing: 1) unequivocally positive BRAF V600E immunostain with or without molecular confirmation; 2) successful multigene next generation sequencing (mostly Tempus â or FoundationOne â) if BRAF V600Eimmunostain was equivocal or negative. We also searched the literature for similar cases and compared BRAF fusions found in histiocytic disorders to those found in solid tumors and other hematologic conditions. Results: One hundred and twenty-six patients were included in this study. BRAF fusions were detected in 7 (6%) patients. The median follow-up for these patients was 1.4 years (95% CI: 0.4-not reached). The frequency according to disease subtypes is as follows: Erdheim-Chester disease (ECD; 2/46 [4%]), Langerhans cell histiocytosis (LCH; 1/41 [2%]), adult or juvenile xanthogranuloma (AXG/JXG; 4/7 [57%]), and histiocytic or Langerhans cell sarcoma (HS/LCS; 0/9 [0%]). The median age at diagnosis for our study cohort was 34 years (range, 7-81 years) and 5 were females. The clinical characteristics and nature of BRAF fusions of our 7 patients plus additional 13 cases from the literature are shown in Table 1. For the final cohort of 20 patients with BRAF-fusions, the median age was 16 years (range, 0.5-81 years) and most (56%) were females. The distribution by histiocytic subtypes is as follows: AXG/JXG (45%), LCH (40%), ECD (10%), HS/LCS (5%). Two patients received cobimetinib as frontline treatment in our cohort and achieved partial responses. Of these two patients, one completed 12 cycles (12 months) of cobimetinib and had a sustained PR while the other patient received 2 cycles before having to hold therapy due to intolerable adverse effects despite dose reduction. From literature review, another patient (LR-12) received cobimetinib as second line treatment and achieved complete response. We found 15 unique BRAF gene fusions with 4 being recurrent. Except for AGAP3-BRAF, none of these BRAF fusions in histiocytosis has been reported in solid tumors or hematologic conditions to date. Conclusions: BRAF gene fusions occur rarely (<5%) in histiocytic disorders. The only exception is AXG/JXG where more than half of the patients harbor BRAF gene fusions. These gene fusions are mostly distinct to histiocytosis and not found in solid tumors or other hematologic conditions. Figure 1 Figure 1. Disclosures Bennani: Purdue Pharma: Other: Advisory Board; Daichii Sankyo Inc: Other: Advisory Board; Kyowa Kirin: Other: Advisory Board; Vividion: Other: Advisory Board; Kymera: Other: Advisory Board; Verastem: Other: Advisory Board.

Symmetrisches juveniles Riesenxanthogranulom vom Plaque-Typ im Gesicht: Fallbericht und Literaturübersicht

Das juvenile Xanthogranulom (JXG) ist die häufigste Form der Non-Langerhans-Zell-Histiozytose. Es handelt sich um einen seltenen, angeborenen oder im späteren Alter auftretenden gutartigen Tumor. Die klassische Form des JXG ist durch rötlich-gelbe benigne Papeln oder Knötchen mit Prädilektion am Kopf, Hals und Rumpf gekennzeichnet, doch können auch den Extremitäten oder extrakutanen Stellen Läsionen auftreten. In den meisten Fällen findet sich nur eine solitäre Läsion, allerdings können auch multiple Papeln oder Knötchen vorliegen. Sonderformen sind unter anderem das gemischte, riesige, subkutane, eruptive, gruppierte und plaqueartige JXG, und das JXG wurde überdies mit systemischen Erkrankungen in Verbindung gebracht. Die Diagnose wird im Wesentlichen auf Grundlage des klinischen Erscheinungsbildes gestellt und in der Regel durch die histologische Untersuchung bestätigt. In der vorliegenden Arbeit berichten wir über einen sehr seltenen Fall eines symmetrischen juvenilen Riesenxanthogranuloms vom Plaque-Typ im Gesicht (symmetrical giant facial plaque-type juvenile xanthogranuloma, SGFP-JXG); außerdem nehmen wir einen Vergleich mit der klassischen Form des JXG sowie JXG-Varianten vor und diskutieren die Differentialdiagnosen. Vorgestellt wurde uns ein 4-jähriges Mädchen kaukasischer Abstammung mit plaqueartigen Läsionen auf beiden Wangen, die aus gelblichen konfluierenden Papeln bestanden. Die histologische Untersuchung zeigte eine histiozytäre Läsion mit Bildung von Touton-Riesenzellen, und die immunhistochemischen Ergebnisse bestätigten die Diagnose SGFP-JXG. Im Vergleich zum klassischen JXG tritt das SGFP-JXG in manchen Fällen später auf, und die spontane Abheilung kann länger dauern. Begleiterkrankungen und eine systemische Beteiligung wurden nicht festgestellt. Die histopathologische Untersuchung ist erforderlich, um diese Form des JXG von anderen Histiozytosen abzugrenzen. Unseres Wissens wurden bisher nur vier Fälle von SGFP-JXG in der Literatur beschrieben.

A Rare Case of Juvenile Xanthogranuloma in 8 Months Old Baby with Dyslipidemia

Background: Juvenile xanthogranuloma (JXG) is a non-Langerhans cell histiocytosis disease of childhood. But due to rarity of non Langerhans cell hystiosis itself, the exact prevalence of juvenile xanthogranuloma remain unknown with only a few epidemiological journal ever published. Juvenile xanthogranuloma usually wihout lipid abnormality and systemic involvement. But association between JXG and lipid abnormalities is still not well understood. We describe a patient with multiple cutaneous JXG who also developed hyperlipidemia. Case: A case of a 8 months-old baby patient with juvenile xanthogranuloma is reported. Patient parents noticed yellowish dots on child’s face since six months ago, and it was gradually increase in size and number, and spread to trunks, upper and lower limb since 2 months ago. Patients got formula milk since 7 months ago. Patients father has uncontrolled hypercholesterolemia, and grandparents had controlled dyslipidemia. Dermatological state showed yellowish plaque and papule on the face, trunk, lower limb, and upper limb. Dermoscopy show yellowish papule with sun setting appearance and branched and linear vessel on orange yellow background. Laboratory finding showed elevated lipid serum. Foam cell and Touton giant cell is found on histopathology examination. Discussion: The presented case demonstrates that skin lesions in patients with diagnosed JXG may have a variable clinical presentation, ranging from single to diffuse skin lesions, also present from the birth to childhood. The diagnosis requires histopathological confirmation to avoid misdiagnosis of malignant disease. Association between JXG and lipid abnormalities remain unknown, with most of the patient show normal lipid serum. Majority of patients presenting lesions limited to the skin requires only a strict dermatological observation.