Cluster analysis reveals the clinical spectrum of Erdheim-Chester disease.

Michelangelo Tesi, Roei D Mazor, Antoine Néel, Tanguy Le Scornet, Emmanuel Ledoult, Achille Aouba, Noemie Gensous, Mathilde de Menthon, Radjiv Goulabchand, Jerome Razanamahery, Kevin O'Brien, Juvianee I Estrada-Veras, Matthias Papo, Paul Milne, Francesco Catamerò, Francesco Pegoraro, Matthew Collin, Lorenzo Dagna, Corrado Campochiaro, Augusto Vaglio, Fleur Cohen-Aubart, Matthew J Koster, Gaurav Goyal, Ronald S Go, Zahir Amoura, Julien Haroche, Francesco Peyronel, Jean-François Emile, Ahmed Idbaih, Samia Boussouar, Eli L Diamond

Journal: Leukemia 2025;39(8):1987-1996

PMID: 40437172

Full Text on Nature Publishing Group View on PubMed

Abstract

Erdheim-Chester disease (ECD) is a clonal-inflammatory neoplasm driven by mutations in MAPK pathway proto-oncogenes, such as BRAF. Clinical manifestations are protean, affecting virtually every system. This cohort study analyzed 661 patients with ECD to classify them based on clinical features and mutational profiles using unsupervised clustering. Nineteen clinical and mutational variables were subjected to hierarchical clustering combined with k-means. A three-cluster model emerged as the most stable. Most patients were classified according to key features, namely BRAF mutation, and large-vessel, heart, and perirenal involvement. The "Widespread Disease" (WID) cluster (320 patients, 49%) was associated with the presence of the key features and the "Limited Disease" (LIM) cluster (282 patients, 42%) was associated with their absence. The "MAP2K1-RDD" cluster (MAP) was assigned 59 patients (9%), based on MAP2K1 mutation and/or overlapping Rosai-Dorfman-Destombes disease (RDD). Survival analysis revealed worse outcomes for WID compared to LIM (hazard ratio 1.54, 95% CI 1.09-2.17), while no significant survival difference was found for MAP. The identification of these clusters, based on mutational profiles, organ involvement and overlapping conditions, offers a data-driven validation of established clinical observations. These findings substantiate the role of the somatic mutation type in shaping the ECD phenotype.

Address: Nephrology and Dialysis Unit, Meyer Children's Hospital IRCCS, Firenze, Italy.; Department of Experimental and Clinical Medicine, University of Firenze, Firenze, Italy.; Department of Hematology and Oncology, Meyer Children's Hospital IRCCS, Firenze, Italy.; Nephrology, Dialysis and Transplant Unit, Careggi University Hospital, Florence, Italy.; Pathology Department, Ambroise-Paré Hospital, Boulogne, France.; Department of Health Sciences, University of Firenze, Firenze, Italy.; Rheumatology, Mayo Clinic, Rochester, MN, USA.; Hematology-Oncology, University of Alabama at Birmingham, Birmingham, AL, USA.; Haematology, Newcastle Upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK.; Institut de Cardiométabolisme et Nutrition (ICAN), Service de Radiologie, Assistance Publique-Hôpitaux de Paris, Hôpital Pitié-Salpêtrière, Paris, France.; Departement of Internal Medicine, Center of reference of Histiocytosis, Hôpital Pitié-Salpêtrière, Sorbonne University, APHP, Paris, France.; Pediatrics and Medical Genetics, NIH, Bethesda, MD, USA.; Department of Internal Medicine and Clinical Immunology, Dijon University Hospital, Dijon, France.; Desbrest Institute of Epidemiology and Public Health, University of Montpellier and INSERM, Montpellier, France.; Sorbonne Université, AP-HP, Institut du Cerveau - Paris Brain Institute - ICM, Inserm, CNRS, Hôpitaux Universitaires La Pitié Salpêtrière - Charles Foix, DMU Neurosciences, Service de Neuro-Oncologie-Institut de Neurologie, Paris, France.; Paris-Saclay University, Internal Medicine and Clinical Immunology Department, Bicetre Hospital, Assistance Publique - Hôpitaux de Paris, Le Kremlin Bicêtre, France.; Department of Internal Medicine and Clinical Immunology, CHU Bordeaux, Hôpital Saint-André, Bordeaux, France.; Department of Internal Medicine, University Hospital Centre Caen, Caen, Basse-Normandie, France.; U1286-INFINITE-Institute for Translational Research in Inflammation, INSERM, Université de Lille, CHU Lille, Lille, France.; Internal Medicine Department, Hotel Dieu, Nantes University Hospital, Nantes, France.; CEREMAST, the Department of Internal Medicine, Hôtel-Dieu University Hospital, Nantes, France.; Division of Hematology, Mayo Clinic, Rochester, MN, USA.; Institute of Hematology, Assuta Medical Center, Tel Aviv, Israel.; Unit of Immunology, Rheumatology, Allergy and Rare Diseases, IRCCS San Raffaele Hospital, Vita-Salute San Raffaele University, Milano, Italy.; Neuro-oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.; Nephrology and Dialysis Unit, Meyer Children's Hospital IRCCS, Firenze, Italy. [email protected].; Department of Biomedical, Experimental and Clinical Sciences "Mario Serio", University of Firenze, Firenze, Italy. [email protected].

DOI: 10.1038/s41375-025-02656-w

Link outs

Free resources

Miscellaneous:

https://assays.cancer.gov/CPTAC-808

Research Materials:

https://antibodies.cancer.gov/detail/CPTC-BRAF-6

Subscription / membership required

Full Text Sources:

https://doi.org/10.1038/s41375-025-02656-w

MeSH Terms: Humans, Erdheim-Chester Disease, Male, Female, Middle Aged, Cluster Analysis, Mutation, Adult, Proto-Oncogene Proteins B-raf, Aged, Prognosis, Young Adult, MAP Kinase Kinase 1, Adolescent, Follow-Up Studies, Cohort Studies