A nationwide team of scientists, led by researchers at Baylor College of Medicine, Texas Children’s Hospital, and UPMC Children’s Hospital of Pittsburgh has proposed a major revision to how Langerhans cell histiocytosis (LCH), a myeloid-derived dendritic cell disorder, is diagnosed and treated after analyzing patients with LCH for several years.[1][2][3]
LCH is a rare disease* that is characterized by the abnormal growth of immune cells called Langerhans cells which are a type of dendric cell.
While these cells normally help regulate the immune system, individuals with LCH have a mutation in genes, including mutation of the BRAF, MAP2K1, RAS, and ARAF genes, that control how dendric cells function. This mutation results in an abnormal accumulation of cells of the mononuclear phagocytic system and the formation of tumors** in one or more organs. Some patients also develop LCH-associated neurodegeneration, which is caused by inflammatory LCH cells that migrate to the brain, eventually leading to problems with certain brain functions, especially related to fine motor movement. [3][4]
Studies show that the survival for patients without organ dysfunction is excellent, however, mortality rates for patients with organ dysfunction may only reach 20%. And despite progress made in the treatment of patients diagnosed with LCH, disease reactivation rates remain above 30%, and standard second-line treatment needs still to be established. [3]
Overall, the long-term effects of LCH, including neuroendocrine dysfunction and neurodegeneration, represent a major medical challenge for survivors.[3]
Redefining diagnosis and treatment
The work that led to the proposed revisions of the diagnostic staging of pediatric LCH pathogenesis in which the persistence of disease reservoir and cell of origin determine the extent of disease and clinical risks was supported by the National Institutes of Health, Department of Defense, St. Baldrick’s Foundation, the Leukemia and Lymphoma Society, HistioCure Foundation, and the Sauer Family Histiocytosis Program, and published in the journal Blood on April 1, 2025.[1]
“The proposed revisions are the culmination of more than a decade of work and would not have been possible without collaboration in clinical trials and translational research between scientists, patients, and families. The findings from this study identify genetic changes in a type of precursor blood cell that predict a much higher chance of treatment failure and risk of developing LCH-associated neurodegeneration,” noted Carl E. Allen, MD, Ph.D., co-corresponding author, co-director of the Pediatric Cancer Program at the Dan L Duncan Comprehensive Cancer Center at Baylor and co-director of the Histiocytosis Program at Texas Children’s Cancer and Hematology Center.
“Contemporary staging approaches were developed at a time when the nature of LCH as a cancer was debated, mutations in tumors had not been discovered and advanced PET-CT imaging scans were not routinely used. Currently, all patients with systemic LCH receive the same chemotherapy that ultimately cures fewer than half and has little effect on LCH-associated neurodegeneration,” Allen added.
Missing mutated precursor cells
“Another major finding from our study is that mutated precursor cells hiding in the bone marrow of certain LCH patients can be missed with standard histology and reported as ‘normal.’
When LCH patients undergo bone marrow analysis, molecular studies are required to identify these rare disease cells, which may not be recognized as LCH by traditional staining methods,” explained Jennifer Picarsic, MD, chief and chair of Pediatric Pathology at UPMC Children’s Hospital of Pittsburgh.
Study
The study enrolled 385 children and adolescents with LCH from 2006 to 2023 and followed them for a median of four years. Researchers correlated patient outcomes with the extent of LCH at diagnosis, tumor genotype, and presence of the BRAFV600E mutation in blood and bone marrow cells pre-therapy.
The outcome of the study supports a major revision for pediatric LCH diagnostic staging that considers the underlying drivers of disease.
“In the study, we found that patients who present with a reservoir of precursor disease cells with the most common BRAFV600E mutation in bone marrow and blood are at the highest risk of treatment failure and LCH-associated neurodegeneration,” Allen added.
Myeloid cells, a type of white blood cell, originate in the bone marrow and circulate ‘peripherally’ in the blood; the same is true for mutant myeloid LCH precursors.
“These novel mechanistic insights and sensitive molecular testing strategies create possibilities for risk-stratification regimens that can be better tailored to individual patients,” Allen explained.
The study highlights how modern imaging and sensitive, updated molecular diagnostics offer an opportunity to improve risk stratification for pediatric LCH.
“This study, which includes a 15-year longitudinal cohort with correlative biology, is unprecedented. It has both an immediate impact and future implications for the care of these patients,” explained contributing author Donald Williams (Will) Parsons. MD. PhD, professor of pediatrics at Baylor and interim director of the Texas Children’s Cancer and Hematology Center.
“This study builds on long-standing NIH-funded research collaborations with Miriam Merad, MD, PhD and her team at Icahn School of Medicine at Mount Sinai that have investigated causes of LCH to improve therapies and outcomes for patients.”
The scientists believe that the advances in a better understanding of LCH will help in understanding the biology, diagnosis, and treatment options of other histiocytic diseases.
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Note: * The disease affects both children and adults, with peak incidence occurring in children between 5 and 10 years old. The incidence in children is approximately five per million, and in adults, approximately half that.
** According to the Nationa Cancer Institute (NCI), it is not known whether LCH is a form of cancer or a cancer-like disease.
Reference
[1] Howard Lin, Akanksha Batajoo, Erin Peckham-Gregory, Daniel Zinn, Olive S Eckstein, Nader K El-Mallawany, Nitya Gulati, Zachary Prudowsky, Brooks P. Scull, Jessica Velazquez, Harshal A Abhyankar, Stephen J Simko, Daria Vakula, Ryan Fleischmann, Vivekanudeep Karri, John Hicks, Kevin E. Fisher, Choladda V. Curry, Angshumoy Roy, Deborah E Schiff, Kenneth Heym, Michael E Scheurer, Donald Williams Parsons, Miriam Merad, Tsz-Kwong Man, Kenneth L McClain, Jennifer Picarsic, Carl E Allen; Diagnostic BRAFV600E blood predicts treatment failure and neurodegeneration and redefines paradigms of pediatric LCH. Blood 2025; blood.2024026671. doi: https://doi.org/10.1182/blood.2024026671
[2] Rodriguez-Galindo C, Allen CE. Langerhans cell histiocytosis. Blood. 2020 Apr 16;135(16):1319-1331. doi: 10.1182/blood.2019000934. PMID: 32106306.
[3] Rodriguez-Galindo C. Clinical features and treatment of Langerhans cell histiocytosis. Acta Paediatr. 2021 Nov;110(11):2892-2902. doi: 10.1111/apa.16014. Epub 2021 Jul 7. PMID: 34192374.
[4] Langerhans Cell Histiocytosis Treatment (PDQ®)–Health Professional Version. National Cancer Institute (NCI). Online. Last accessed on April 1, 2025.
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