Diagnosis and treatment of Langerhans cell histiocytosis in adults

Introduction

Langerhans cell histiocytosis (LCH) is a rare hematologic disorder that affects patients of all ages. While most of our current understanding of LCH comes from studies of pediatric patients, data on adult cases remain limited. The discovery of the BRAF^V600E mutation in approximately 50% of LCH samples established LCH as a neoplastic disease, and subsequent research has identified additional activating mutations in the mitogen-activated protein kinase (MAPK) pathway. Recent advances in our understanding of the disease’s pathogenesis and treatment, combined with its rarity, have highlighted the need for comprehensive guidelines for diagnosing and treating LCH in adults (Figure 1).

Figure 1.

Suggested diagnosis and treatment algorithm for newly diagnosed LCH in adults

Clinical features of LCH in adults

The clinical manifestations and disease progression of LCH exhibit remarkable heterogeneity, encompassing a spectrum from localized single-system disease with isolated involvement (SS-s) to multiple sites within a single system (SS-m) and potentially progressing to multisystem (MS) disease with severe organ dysfunction. In adult patients, the predominant sites of involvement include the pulmonary system, skeletal structures, and the pituitary gland.¹

Pulmonary manifestations: pulmonary LCH can manifest either as a component of MS disease or as isolated single-system pulmonary involvement (SS-p). Tobacco use has been identified as a significant etiologic factor in pulmonary LCH, particularly in SS-p cases. The clinical presentation may include dyspnea, chest pain, chronic cough, or spontaneous pneumothorax. High-resolution computed tomography (HRCT) typically reveals characteristic patterns, including cystic changes, nodular lesions, ground-glass opacities, emphysematous changes, reticular patterns, honeycomb formation, or pneumothorax. Notably, the majority of pulmonary lesions demonstrate minimal to no hypermetabolic activity on ¹⁸F-FDG positron emission tomography (PET).

Skeletal manifestations: patients typically present with skeletal pain, and diagnostic imaging reveals characteristic osteolytic lesions detectable through radiography or CT. ¹⁸F-FDG PET demonstrates high sensitivity in detecting osseous involvement.

Pituitary manifestations: central diabetes insipidus constitutes the primary clinical presentation in patients with pituitary involvement. ¹⁸F-FDG PET findings are variable, ranging from hypermetabolic lesions to normal metabolic activity.

Hepatic manifestations: liver involvement in adult patients with LCH is frequently asymptomatic. Laboratory investigations typically reveal elevated alkaline phosphatase (ALP) and γ-glutamyl transpeptidase (GGT) levels as the primary biochemical abnormalities. Hyperbilirubinemia generally manifests in advanced disease stages. Notably, approximately two-thirds of patients exhibit no hypermetabolic hepatic lesions on ¹⁸F-FDG PET at initial diagnosis.

Diagnosis of LCH in adults

The definitive diagnosis of LCH requires comprehensive histopathologic examination of lesional tissue. Tissue biopsy acquisition is essential for not only diagnostic confirmation but also molecular analysis, which may guide therapeutic decision-making. Histologically, the characteristic LCH infiltrate demonstrates aggregates of intermediate-sized cells with reniform nuclei, dispersed chromatin, and abundant eosinophilic cytoplasm. The immunophenotypic profile of LCH is characterized by positive expression of CD68, S100, surface CD1a, cytoplasmic langerin (CD207), and cyclin D1.

Evaluation and classification of LCH in adults

For all patients with confirmed LCH, we recommend a comprehensive baseline assessment including complete blood count, hepatorenal function tests, C-reactive protein, and ¹⁸F-FDG PET/CT imaging from skull vertex to pedal extremities to determine the extent of organ involvement. In cases of suspected pulmonary, hepatic, or pituitary involvement, HRCT or MRI of the respective organs should be performed.

Next-generation sequencing (NGS) of lesional tissue is recommended for molecular characterization, with essential gene targets encompassing BRAF, MAP2K1, ARAF, KRAS, NRAS, PIK3CA, and other genes involved in the MAPK-ERK and PI3K-AKT-mTOR signaling pathways. For cases with limited tissue availability, analysis of cell-free DNA from peripheral blood presents a viable alternative. Additionally, BRAF-V600E mutation-specific immunostaining using the VE1 antibody may serve as an alternative diagnostic approach when tissue quantity is insufficient for NGS analysis.

Disease classification

Patient stratification is based on the extent of organ or system involvement, comprising four distinct categories.

• (1)Unifocal disease (SS-s): characterized by a single lesion within one system or organ.
• (2)SS-p: isolated pulmonary involvement.
• (3)SS-m: multiple lesions confined to one system.
• (4)MS: involvement of multiple organ systems.

Risk-organ assessment criteria

Risk-organ involvement is defined by the following parameters.

• (1)Hepatic involvement: hepatomegaly extending >3 cm below the costal margin, hyperbilirubinemia, elevated GGT and/or ALP >1.5 times the upper limit of normal, or FDG-avid lesions on PET/CT.
• (2)Splenic involvement: splenomegaly extending >2 cm below the costal margin or FDG-avid lesions on PET/CT.
• (3)Hematopoietic system involvement: histologically confirmed bone marrow involvement accompanied by either anemia (hemoglobin < 100 g/L), leukopenia (white blood cell count < 4.0 × 10⁹/L), or thrombocytopenia (platelets < 100 × 10⁹/L).

Treatment of LCH in adults

Unifocal LCH

In adult patients, unifocal LCH frequently demonstrates a favorable prognosis with curative potential, and localized therapeutic interventions often suffice. Surgical excision may be the preferred therapeutic approach, contingent upon anatomical location and accessibility. Notably, spontaneous disease remission has been observed following diagnostic biopsy in cases where symptomatic improvement occurs rapidly. For patients who are not surgical candidates, radiation therapy (typically administered at doses of approximately 20 Gy) can achieve excellent and sustained therapeutic responses. However, unifocal disease involving anatomically challenging locations (such as hepatic lesions) that preclude effective local intervention generally necessitates systemic therapeutic approaches analogous to those employed in MS disease.

Single-system pulmonary LCH

In all cases of pulmonary LCH, smoking cessation is a fundamental therapeutic requirement. Complete disease remission may be achieved through smoking cessation alone in select patients. For those who fail to demonstrate at least partial remission following 3–6 months of smoking abstinence, systemic therapeutic intervention should be considered. Several systemic treatment modalities have demonstrated efficacy in pulmonary LCH,² including cladribine, combination therapy with methotrexate and cytarabine, and targeted agents (BRAF or MEK inhibitors), with documented improvements in pulmonary function.

Multifocal and MS LCH

Multifocal and MS without risk-organ involvement

The clinical evidence base for adult LCH comprises only four prospective trials to date. The landmark study, which remains the largest, evaluated combination therapy with methotrexate and cytarabine, demonstrating an impressive response rate of 88% and a 6-year event-free survival (EFS) rate of 55.2%.³ This study identified risk-organ involvement as a significant negative prognostic indicator. Monotherapy regimens utilizing either cladribine or cytarabine have also exhibited promising response rates, although long-term follow-up data remain limited.⁴ The most recent prospective trial investigated denosumab monotherapy, achieving an 80% response rate, though the study’s small sample size (n = 10) limits definitive conclusions.

Based on these data, our therapeutic recommendations for patients with multifocal or MS disease without risk-organ involvement include combination therapy with methotrexate plus cytarabine or monotherapy with either cladribine or cytarabine. For patients who are not candidates for systemic chemotherapy, particularly those with predominant bone involvement, denosumab monotherapy represents a viable alternative.

MS with risk-organ involvement

Adult patients with MS LCH involving risk organs demonstrate poor outcomes across multiple studies.^1,3 The optimal therapeutic approach for this high-risk population remains undefined due to the absence of prospective clinical trials specifically addressing this cohort. One notable prospective study evaluated the combination of thalidomide, cyclophosphamide, and dexamethasone in relapsed or refractory adult LCH, demonstrating comparable EFS rates regardless of risk-organ involvement.⁵ Evidence from pediatric populations has provided valuable insights into novel therapeutic approaches. A significant study investigated the combination of vemurafenib with cytosine-arabinoside and 2′-chlorodeoxyadenosine (2-CdA) in 19 pediatric patients harboring BRAF^V600E mutations, achieving a 2-year reactivation/progression-free survival rate of 76.9% in patients with risk-organ involvement. Additionally, treatment with dabrafenib and/or trametinib demonstrated an impressive 94% response rate in a cohort of 26 patients with LCH (median age: 1.9 years, range: 0.2–45 years). However, all patients with MS disease experienced disease recurrence following discontinuation of targeted therapy.

Based on current evidence, we strongly advocate for clinical trial participation whenever feasible for patients with risk-organ involvement. For patients unable to access clinical trials, we recommend combination therapy incorporating target therapy (BRAF inhibitors for patients harboring BRAF^V600E mutations and MEK inhibitors for those with alternative MAPK pathway mutations) or immunomodulatory drugs (IMiDs) with conventional chemotherapy.

Response assessment and monitoring

For patients presenting with hypermetabolic lesions on ¹⁸F-FDG PET/CT at initial diagnosis, the first therapeutic response assessment should be conducted within a 3-to-6-month time frame, with the specific interval determined by the therapeutic modality employed. In certain cases, organ-specific imaging modalities, such as HRCT or MRI, may be warranted for comprehensive response evaluation. PERCIST 1.0 (PET response criteria in solid tumors) represents the predominant response assessment criteria for adult LCH utilizing PET/CT, wherein a response is quantified through changes in standardized uptake values of the lesions. The whole-body imaging capability of PET/CT, coupled with standardized response criteria across diverse organ involvement patterns, demonstrates particular utility in response assessment for MS disease. For patients with disease not amenable to PET/CT evaluation, RECIST 1.1 may be employed in conjunction with clinical manifestations, physical examination findings, and laboratory parameters. Following the achievement of at least a partial response and disease stabilization, the frequency of subsequent imaging surveillance may be tailored to individual patient characteristics. It is crucial to note that endocrinopathies affecting the pituitary gland may persist despite LCH-directed therapy, necessitating ongoing monitoring of hormonal parameters and maintenance of appropriate hormone replacement therapy.

Prognosis

The overall prognosis for LCH is favorable, with 5-year overall survival rates exceeding 90%. However, prognostic stratification reveals that patients presenting with risk-organ involvement or harboring BRAF insertion or deletion (indel) mutations demonstrate less favorable clinical outcomes. With the advent of novel therapeutic modalities and consequent improvement in survival rates among adult patients, comprehensive long-term surveillance has become imperative. This surveillance should encompass monitoring for emerging morbidities and the development of secondary malignancies, with particular attention to hematological neoplasms, which may contribute to premature mortality.

Funding and acknowledgments

This study was supported by the National Natural Science Foundation of China (grant no. 82370179), the Beijing Natural Science Haidian Frontier Foundation (L222081), National High Level Hospital Clinical Research Funding (2025-PUMCH-D-003, 2022-PUMCH-B-070), and the Peking Union Medical College Hospital Talent Cultivation Program (category C, UBJ10707). The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Declaration of interests

The authors declare no competing interests.

Published Online: May 15, 2025