Long-term outcome and prognosis of mixed histiocytosis (Erdheim-Chester disease and Langerhans Cell Histiocytosis)

Francesco Pegoraro^{1

2

3}, Matthias Papo¹, Fleur Cohen-Aubart¹, Francesco Peyronel^{3

4}, Gianmarco Lugli⁵, Irene Trambusti^{2

6}, Gildas Baulier⁷, Mathilde de Menthon⁸, Tanguy Le Scornet⁹, Eric Oziol¹⁰, Nicole Ferreira-Maldent¹¹, Olivier Hermine¹², Benoit Faucher¹³, Dirk Koschel¹⁴, Nicole Straetmans¹⁵, Noémie Abisror¹⁶, Benjamin Terrier¹⁷, François Lifermann¹⁸, Jerome Razanamahery¹⁹, Yves Allenbach²⁰, Jeremy Keraen²¹, Sophie Bulifon^{22

23

24}, Baptiste Hervier²⁵, Annamaria Buccoliero²⁶, Frederic Charlotte²⁷, Quentin Monzani²⁸, Samia Boussouar²⁹, Natalia Shor³⁰, Annalisa Tondo², Stephane Barete³¹, Ahmed Idbaih³², Abdellatif Tazi^{33

34

35}, Elena Sieni², Zahir Amoura¹, Jean-François Emile³⁶, Augusto Vaglio^{4

37}, Julien Haroche¹

Affiliations

¹ Sorbonne University, Internal Medicine Department 2, Institut E3M, French Reference Centre for Histiocytosis, Pitié-Salpȇtrière Hospital, CIMI INSERM-UMRS 1135, Assistance Publique-Hôpitaux de Paris, Paris, France.
² Hematology and Oncology Department, Meyer Children's Hospital IRCCS, Florence, Italy.
³ Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy.
⁴ Nephrology and Dialysis Unit, Meyer Children's Hospital IRCCS, Florence, Italy.
⁵ Rare Disease Center, Meyer Children's Hospital IRCCS, Florence, Italy.
⁶ Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.
⁷ Internal Medicine and Clinical Immunology Department, Périgueux University Hospital, Périgueux, France.
⁸ Paris-Saclay University, Internal Medicine and Clinical Immunology Department, Bicetre Hospital, Assistance Publique - Hôpitaux de Paris, Le Kremlin Bicêtre, France.
⁹ Internal Medicine Department, Hotel Dieu, Nantes University Hospital, Nantes, France.
¹⁰ Internal Medicine Department, Béziers Hospital, Béziers, France.
¹¹ Internal Medicine Department, University Hospital of Tours, Tours, France.
¹² Hematology Department, Hôpital Necker - Enfants Malades, Assistance Publique-Hôpitaux de Paris, Paris, France.
¹³ Internal Medicine Department, La Timone Hospital, Assistance Publique-Hôpitaux de Marseille, Marseille, France.
¹⁴ Internal Medicine and Pneumology Department, Fachkrankenhaus Coswig, Lung Center, Coswig and Medical Department I, Division of Pneumology, University Hospital Carl Gustav Carus, TU Dresden, Dresden, Germany.
¹⁵ Hematology Department, University Hospital Saint-Luc, Brussels, Belgium.
¹⁶ Internal Medicine Department, Saint Antoine Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.
¹⁷ Internal Medicine Department, Referral Center for Rare Autoimmune and Systemic Diseases, Cochin Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.
¹⁸ Internal Medicine Department, Dax University Hospital, Dax, France.
¹⁹ Internal Medicine and Clinical Immunology Department, Dijon University Hospital, Dijon, France.
²⁰ Internal Medicine Department, Sorbonne University, INSERM UMRS 974, Pitié-Salpêtrière Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.
²¹ Internal Medicine and Immunology Department, Cornouaille Hospital Center, Quimper, France.
²² Paris-Saclay University, Faculty of Medicine, Le Kremlin-Bicêtre, France.
²³ INSERM UMR_S 999, Le Kremlin-Bicêtre, France.
²⁴ Respiratory and Intensive Care Medicine Department, Pulmonary Hypertension National Referral Center, Bicêtre Hospital, Assistance Publique-Hôpitaux de Paris, Le Kremlin-Bicêtre, France.
²⁵ Internal Medicine Department, Saint Louis Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.
²⁶ Pathology Department, Meyer Children's Hospital IRCCS, Florence, Italy.
²⁷ Pathology Department, Pitié-Salpêtrière Hospital, Sorbonne University, Assistance Publique-Hôpitaux de Paris, Paris, France.
²⁸ Polyvalent and Oncologic Radiology Department-Musculoskeletal Unit, Pitié-Salpêtrière Hospital, Paris, France.
²⁹ Cardiovascular and Thoracic Imaging Unit, Pitié-Salpêtrière Hospital, Assistance Publique-Hôpitaux de Paris, Institute of Cardiometabolism and Nutrition (ICAN), Paris, France.
³⁰ Neuro-Radiology Department, Pitié-Salpêtrière Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.
³¹ Sorbonne University, Dermatology Unit, Pitié-Salpêtrière Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.
³² Sorbonne University, Neuro-Oncology Department, Paris Brain Institute - ICM, Inserm, CNRS, Pitié-Salpêtrière Hospital, DMU Neurosciences, Assistance Publique-Hôpitaux de Paris, Paris, France.
³³ UFR de Médecine, Paris Cité University, Paris, France.
³⁴ INSERM UMR 976 Saint Louis Research Institute, Paris, France.
³⁵ Pneumology Department, Saint Louis Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.
³⁶ EA4340 BECCOH, Versailles SQY University, Pathology Department, Ambroise Paré Hospital, Assistance Publique-Hôpitaux de Paris, Boulogne, France.
³⁷ Department of Biomedical, Experimental and Clinical Sciences "Mario Serio", University of Florence, Florence, Italy.

PMID: 38841707
PMCID: PMC11152896
DOI: 10.1016/j.eclinm.2024.102658

Long-term outcome and prognosis of mixed histiocytosis (Erdheim-Chester disease and Langerhans Cell Histiocytosis)

Francesco Pegoraro et al. EClinicalMedicine. 2024.

. 2024 May 27:73:102658.

doi: 10.1016/j.eclinm.2024.102658. eCollection 2024 Jul.

Authors

Affiliations

¹ Sorbonne University, Internal Medicine Department 2, Institut E3M, French Reference Centre for Histiocytosis, Pitié-Salpȇtrière Hospital, CIMI INSERM-UMRS 1135, Assistance Publique-Hôpitaux de Paris, Paris, France.
² Hematology and Oncology Department, Meyer Children's Hospital IRCCS, Florence, Italy.
³ Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy.
⁴ Nephrology and Dialysis Unit, Meyer Children's Hospital IRCCS, Florence, Italy.
⁵ Rare Disease Center, Meyer Children's Hospital IRCCS, Florence, Italy.
⁶ Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.
⁷ Internal Medicine and Clinical Immunology Department, Périgueux University Hospital, Périgueux, France.
⁸ Paris-Saclay University, Internal Medicine and Clinical Immunology Department, Bicetre Hospital, Assistance Publique - Hôpitaux de Paris, Le Kremlin Bicêtre, France.
⁹ Internal Medicine Department, Hotel Dieu, Nantes University Hospital, Nantes, France.
¹⁰ Internal Medicine Department, Béziers Hospital, Béziers, France.
¹¹ Internal Medicine Department, University Hospital of Tours, Tours, France.
¹² Hematology Department, Hôpital Necker - Enfants Malades, Assistance Publique-Hôpitaux de Paris, Paris, France.
¹³ Internal Medicine Department, La Timone Hospital, Assistance Publique-Hôpitaux de Marseille, Marseille, France.
¹⁴ Internal Medicine and Pneumology Department, Fachkrankenhaus Coswig, Lung Center, Coswig and Medical Department I, Division of Pneumology, University Hospital Carl Gustav Carus, TU Dresden, Dresden, Germany.
¹⁵ Hematology Department, University Hospital Saint-Luc, Brussels, Belgium.
¹⁶ Internal Medicine Department, Saint Antoine Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.
¹⁷ Internal Medicine Department, Referral Center for Rare Autoimmune and Systemic Diseases, Cochin Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.
¹⁸ Internal Medicine Department, Dax University Hospital, Dax, France.
¹⁹ Internal Medicine and Clinical Immunology Department, Dijon University Hospital, Dijon, France.
²⁰ Internal Medicine Department, Sorbonne University, INSERM UMRS 974, Pitié-Salpêtrière Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.
²¹ Internal Medicine and Immunology Department, Cornouaille Hospital Center, Quimper, France.
²² Paris-Saclay University, Faculty of Medicine, Le Kremlin-Bicêtre, France.
²³ INSERM UMR_S 999, Le Kremlin-Bicêtre, France.
²⁴ Respiratory and Intensive Care Medicine Department, Pulmonary Hypertension National Referral Center, Bicêtre Hospital, Assistance Publique-Hôpitaux de Paris, Le Kremlin-Bicêtre, France.
²⁵ Internal Medicine Department, Saint Louis Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.
²⁶ Pathology Department, Meyer Children's Hospital IRCCS, Florence, Italy.
²⁷ Pathology Department, Pitié-Salpêtrière Hospital, Sorbonne University, Assistance Publique-Hôpitaux de Paris, Paris, France.
²⁸ Polyvalent and Oncologic Radiology Department-Musculoskeletal Unit, Pitié-Salpêtrière Hospital, Paris, France.
²⁹ Cardiovascular and Thoracic Imaging Unit, Pitié-Salpêtrière Hospital, Assistance Publique-Hôpitaux de Paris, Institute of Cardiometabolism and Nutrition (ICAN), Paris, France.
³⁰ Neuro-Radiology Department, Pitié-Salpêtrière Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.
³¹ Sorbonne University, Dermatology Unit, Pitié-Salpêtrière Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.
³² Sorbonne University, Neuro-Oncology Department, Paris Brain Institute - ICM, Inserm, CNRS, Pitié-Salpêtrière Hospital, DMU Neurosciences, Assistance Publique-Hôpitaux de Paris, Paris, France.
³³ UFR de Médecine, Paris Cité University, Paris, France.
³⁴ INSERM UMR 976 Saint Louis Research Institute, Paris, France.
³⁵ Pneumology Department, Saint Louis Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.
³⁶ EA4340 BECCOH, Versailles SQY University, Pathology Department, Ambroise Paré Hospital, Assistance Publique-Hôpitaux de Paris, Boulogne, France.
³⁷ Department of Biomedical, Experimental and Clinical Sciences "Mario Serio", University of Florence, Florence, Italy.

PMID: 38841707
PMCID: PMC11152896
DOI: 10.1016/j.eclinm.2024.102658

Abstract

Background: Erdheim-Chester disease (ECD) is a rare histiocytosis that may overlap with Langerhans Cell Histiocytosis (LCH). This "mixed" entity is poorly characterized. We here investigated the clinical phenotype, outcome, and prognostic factors of a large cohort of patients with mixed ECD-LCH.

Methods: This retrospective study was performed at two referral centers in France and Italy (Pitié-Salpêtrière Hospital, Paris; Meyer Children's Hospital, Florence). We included children and adults with ECD diagnosed in 2000-2022 who had biopsy-proven LCH, available data on clinical presentation, treatment and outcome, and a minimum follow-up of one year. Outcomes included differences in clinical presentation and survival between mixed ECD-LCH and isolated ECD; we also investigated response to treatments and predictors of survival in the mixed cohort. Survival was analyzed using the Kaplan-Maier method and differences in survival with the long-rank test. Cox regression models were used to evaluate the potential impact of age and gender on survival and to identify predictors of non-response and survival.

Findings: Out of a cohort of 502 ECD patients, 69 (14%) had mixed ECD-LCH. Compared to isolated ECD, mixed ECD-LCH occurred more frequently in females (51 vs. 26%, p < 0.001) and in patients with multisystem disease (≥4 sites). Mixed ECD-LCH more frequently involved long bones (91 vs. 79%, p = 0.014), central nervous system (51 vs. 34%, p = 0.007), facial/orbit (52 vs. 38%, p = 0.031), lungs (43 vs. 28%, p = 0.009), hypothalamic/pituitary axis (51 vs. 26%, p < 0.001), skin (61 vs. 29%, p < 0.001), and lymph nodes (15 vs. 7%, p = 0.028); the BRAF^V600E mutation was also more frequent in mixed ECD-LCH (81 vs. 59%, p < 0.001). Targeted treatments (BRAF and/or MEK inhibitors) induced response more frequently than conventional therapies (interferon-α, chemotherapy), either as first-line (77 vs. 29%, p < 0.001) or as any line (75 vs. 24%, p < 0.001). After a median follow-up of 71 months, 24 patients (35%) died. Survival probability was comparable between ECD alone and mixed ECD-LCH (log-rank p = 0.948). At multivariable analysis, age at diagnosis (HR 1.052, 95% CI 1.008-1.096), associated hematologic conditions (HR 3.030, 95% CI 1.040-8.827), and treatment failure (HR 9.736, 95% CI 2.919-32.481) were associated with an increased risk of death, while lytic bone lesions with a lower risk (HR 0.116, 95% CI 0.031-0.432).

Interpretation: Mixed ECD-LCH is a multisystem disease driven by the BRAF^V600E mutation and targeted treatments are effective. Age at diagnosis, bone lesion patterns, associated hematologic conditions, and treatment failure are the main predictors of death in mixed ECD-LCH.

Funding: None.

Keywords: BRAF; Erdheim-Chester disease; Histiocytosis; Langerhans; Mixed histiocytosis; Pediatric histiocytosis.

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Conflict of interest statement

AI reports research grants from Transgene, Sanofi, and Nutritheragene; consulting fees from Novocure, LeoPharma, Polytone Laser, and Novartis; honoraria from Novocure and Neurologies; travel funding from LeoPharma, Novocure, and Carthera. BT report consulting fees and honoraria from GSK, AstraZeneca, CSL Vifor, Boehringer Ingelheim, and Novartis; advisory board activity for Amgen.

Figures

**Fig. 1**
Typical imaging and pathology findings in mixed ECD-LCH. A. Brain MRI gadolinium-enhanced T1 FAT SAT reveals orbital fat histiocytic infiltration (arrows), pachymeningeal involvement (arrowhead), and right premaxillary involvement (asterisk). B. Brain MRI T2 FLAIR sequence showing degenerative changes with symmetrically increased signal intensity within the cerebellar parenchyma. C. Axial abdominal contrast-enhanced CT scan showing periaortic and bilateral perinephric infiltrates (“hairy kidneys”, arrow). D. Axial thin-section CT scan of the lungs showing multiple cysts and nodules in the upper lobes. E. Axial arterial contrast-enhanced CT scan showing circumferential periaortic infiltration (arrow). F. 99 mTC bone scan demonstrating multiple areas of abnormally increased uptake including a symmetric uptake in the femurs, tibia, knees, and ankles. Other locations in the appendicular skeleton show mild uptake. Left: anterior view; right: posterior view. **G, H**. Humeral X-ray (G) and CT-scan (H) showing a lytic lesion with periosteal reaction (arrow); osteosclerosis and cortical thickening are present on the lower half of the humeral diaphysis (empty arrows). I. Brown and purplish papules with crusted lesions in the breast folds and upper abdomen. J. Xanthelasma-like lesions of the eyelids. K. H&E staining of mixed ECD-LCH bone involvement, showing large histiocytes with abundant clear cytoplasm and smaller histiocytes with eosinophilic cytoplasm (200×) **L, N**. Low (L, 40×), and high (N, 400×) magnification of the same biopsy showing infiltration by CD1a + LCH cells. M. The same sample stained with CD68+ showing a strong positivity of the foamy ECD cells (200×).

**Fig. 2**
Kaplan–Meier estimates of survival of patients with mixed ECD-LCH *vs.* patients with ECD alone. A. Mixed ECD-LCH *vs.* the whole cohort of isolated ECD (424 patients); B. Mixed ECD-LCH *vs.* an age- and gender-matched cohort of 138 patients with isolated ECD (1:2 ratio). *Abbreviations used in the figure*: ECD, Erdheim-Chester Disease; LCH, Langerhans Cell Histiocytosis.

**Fig. 3**
Heat-map of clinical characteristics of patients with ECD, mixed ECD-LCH, and LCH. *Abbreviations used in the figure*: ECD, Erdheim-Chester Disease; LCH, Langerhans Cell Histiocytosis; CNS, central nervous system. ∗Data on patients with LCH are extracted from two recent cohort studies on LCH (DOIs: 10.1111/cas.15879; 10.1182/bloodadvances.2023010706).

See this image and copyright information in PMC

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Long-term outcome and prognosis of mixed histiocytosis (Erdheim-Chester disease and Langerhans Cell Histiocytosis)

Affiliations

Long-term outcome and prognosis of mixed histiocytosis (Erdheim-Chester disease and Langerhans Cell Histiocytosis)

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

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Research Materials