Langerhans cell histiocytosis: pragmatic empirism on the road to rational cure

Abstract

Langerhans cell histiocytosis (LCH) is a rare disease characterized by the accumulation of clonal dendritic cells in different organs. Most recent findings (e.g., activating BRAF mutations) favor the hypothesis that LCH may represent a neoplasm with varying behavior, but the ultimate pathogenesis remains to be uncovered. In view of the gaps in the basic understanding of the disease, its clinical management foots on empirical knowledge and is pragmatically oriented. Some of the current guidelines for clinical and radiological evaluation are based on outdated knowledge and therefore appropriately designed prospective studies are urgently needed. Furthermore, there is a need for biological markers, for disease activity and treatment-response assessment. The upcoming prospective clinical trial of the Histiocyte Society, LCH-IV, is expected to address the most burning issues concerning optimal patient management.

Keywords::

• Langerhans cell histiocytosis
• prognosis
• risk groups
• sequelae
• treatment

Langerhans cell histiocytosis (LCH) is a rare disease characterized by accumulation of clonal dendritic cells in lesional tissue. Different names (e.g., Hand–Schüller–Christian disease, Letterer–Siwe disease, eosinophilic granuloma, histiocytosis X) have been used for its designation since the first description over more than a century ago. Due to phenotypic similarity between the lesional cells and the normal Langerhans cells of the epidermis, the disease was renamed LCH in the late 1970s. Recent research suggests that the cell of origin may be a myeloid precursor rather than the Langerhans cell itself [1,2]; thus challenging the appropriateness of the term LCH. The progress on basic aspects of the disease has been hampered for decades by a number of obstacles (disease rarity, small-sized tissue samples, composite content of the lesions and inability to culture lesional cells). Two major hypotheses on the pathobiology of LCH are neoplastic clonal evolution of dendritic cells versus immune-mediated inflammatory interplay between antigen-presenting cells and regulatory lymphocytes. The pros and cons for both hypotheses have fed the scientific controversy and directed the clinical management of LCH since the 1960s; yet the disease cause still remains unknown. Interested readers are referred with this respect to a recent comprehensive review [3]. The most recent findings (e.g., activating BRAF mutations) favor the hypothesis that LCH may represent neoplastic proliferation [3,4], but do not give clue why the disease is self-limited in some patients or why biopsy or intralesional curettage are sufficient to cure isolated bone lesions.

Despite expanding knowledge on basic aspects of LCH, the disease with its broad variety of clinical presentations and unpredictable course still poses problems for both scientists and clinicians. In the absence of exact knowledge on the cause and pathobiology, the search for biological markers, prognostic predictors and optimization of empirically established drug combinations aims to address the clinical needs of patients with LCH.

In a recent issue of the Expert Opinion on Pharmacotherapy, Donadieu et al. [5] provided a thorough critical review on current diagnostic criteria, prognostic prediction and clinical management of LCH.

A LCH Working Group of the Histiocyte Society introduced robust diagnostic criteria in 1987, the revision of which is still in use [6]. Current developments allow laborious electron microscopy (earlier used for search of intracytoplasmic Birbeck granule) to be replaced by immune histochemistry (CD207 staining for Langerin), thus facilitating the diagnostic process. Nevertheless, carefully scrutinizing medical history and imaging findings are still important in the diagnostic process of LCH. Based on their rich experience, Donadieu et al. [5] provided exhaustive lists of possible differential diagnoses depending on involved organs system and localization of the lesions. Those would be of great help as a reference for physicians facing LCH.

Available clinical experience suggests that treatment of LCH has to be tailored to disease extent and severity [7]. Thus, a careful evaluation of disease extent at diagnosis is critical for therapeutic decision making. A stepwise approach including a set of obligatory investigations and a set of investigations for specific indications was adopted in the late 1980s [8]. In their recent paper, Donadieu et al. [5] provided a critical review on the current recommendations for patient evaluation from the point of view of the principles of parsimony and exhaustivity. Particularly, they revealed weakness of the evidence on which the recommendations for visualization of skeletal lesions in LCH are based. Prospective studies targeting optimal imaging of LCH lesions are obviously needed, as the current recommendations are based on outdated empiric clinical experience. The value, and above all, the clinical implications of whole-body magnetic resonance imaging (MRI) and positron emission tomography (PET) in LCH are still ill-defined. The authors suggest a uniform protocol for MRI of the brain based on still unpublished international expert consensus, which would allow optimal assessment of the commonly affected hypothalamic-pituitary axis and appropriate characterization of the typical neurodegenerative lesions. An existing gap is the lack of MRI-based criteria for judgment of severity and dynamic changes of the cerebral lesions (e.g., changes due to the natural course or applied treatment), and this issue is also worth a prospective study. Another urgent need is a prospective correlation of brain MRI findings to the findings of standardized tools for clinical neurologic assessment (e.g., International Cooperative Ataxia Rating Scale (ICARS) and Expanded Disability Status Scale (EDSS)) [9,10]. All these open questions will be addressed in the upcoming LCH-IV trial of the Histiocyte Society. The role of computed tomography (CT) in assessing severity and treatment response of pulmonary LCH is another still unsolved issue waiting for appropriate prospective assessment.

The current classification of the Histiocyte Society arbitrarily categorizes LCH into single-system (SS-LCH; involvement of a single organ system) and multisystem disease (MS-LCH; involvement of two or more organ systems). Donadieu et al. provided additional definitions for organ involvement by LCH based on objective findings [5]. They critically evaluated the concept of ‘risk organs' in LCH and suggested excluding lungs from the current definition, a proposal supported also by a recent paper of Ronceray et al. [11]

Besides involvement of risk organs at initial presentation, early response to standard treatment appears to be another reliable predictor of prognosis in patients with MS-LCH [12]. Donadieu et al. revealed the limitations of the current semi-quantitative system for assessment of disease state and response to treatment [13]; the authors promoted their previously published original score system for disease activity [14]. A more objective dynamic disease activity assessment is obviously needed, and the disease activity score developed by the French LCH Study Group comes to close this gap. Its applicability in an international setting is also going to be prospectively evaluated in the above-mentioned LCH-IV trial.

Since its first description, LCH has been exposed to a wide range of therapeutic approaches, reflecting the changing understanding of the disease process [7]. Although the series described in earlier reports varied greatly with respect to diagnostic criteria and disease extent, some general principles have emerged from those observations. It is generally agreed that patients with single-system disease (usually bone, skin or lymph node) have a good prognosis with a high chance of spontaneous healing and favorable outcome [15,16]. It is well established that LCH presenting with multiple bone lesions at diagnosis remains confined to the skeleton during the course of the disease, and rarely extends to other organs. Therefore, a conservative approach is advocated for localized LCH.

In severely affected children (age under 2 years, multisystem involvement and organ dysfunction), systemic treatment (mostly combination of steroids and cytostatics) has reduced disease-related mortality. However, about 10 – 20% of these patients die. In their recent paper, Donadieu et al. [5] provided a comprehensive synthesis of the findings and the lessons drawn from the prospective clinical trials of the Histiocyte Society (LCH I-III). Based on the cumulative evidence of the literature, an initial 6-week course of prednisolone (40 mg/m²/day orally for 4 weeks and tapering over 2 weeks) and vinblastine (6 mg/m² weekly intravenous bolus) is currently the accepted standard initial regimen for patients with multisystem LCH [7,17]. Further treatment, its intensity and duration, depends on the achieved response. The possible scenarios are covered in detail elsewhere [7]. Treatment on disease reactivation deserves special attention. In the past, LCH reactivations have been treated exclusively at the discretion of the individual physicians and no controlled studies have been conducted to date. At reactivation, LCH is confined in most cases to non-risk organs (skin, skeleton, hypophysis) and does not considerably influence survival [18]. Disease reactivations, however, are associated with acute morbidity and increase the risk of permanent consequences. Thus, end points of any future prospective trial on treating reactivations of LCH have to focus on prevention of subsequent reactivations and permanent sequelae instead of response of the active disease lesions. There is still an urgent need to address the controversies in the treatment of some special disease presentations of LCH. Two good examples are new-onset diabetes insipidus and ‘neurodegeneration-like' CNS-LCH [19,20]. The latter, albeit rare, can be extremely debilitating and even fatal.

Progress in treatment of LCH can be achieved only by broad cooperation in large international prospective studies. The recent paper by Donadieu et al. [5], offers an excellent guidance for standard treatment of patients, who for different reasons are treated outside of clinical trials. There is a hope that most of the controversies pointed out by the authors in their critical review on the current practices of diagnosis, evaluation and treatment of patients with LCH will be appropriately addressed in the upcoming LCH-IV trial. This ambitious project of the Histiocyte Society, expected to be launched in mid-2012, consists of five interventional and two observational strata covering relevant aspects throughout the clinical spectrum of LCH. Nearly 20 national groups have declared interest in joining the trial, and there is great hope for high-quality clinical evidence in the nearest future.

Declaration of interest

The author states no conflict of interest and has received no payment in preparation of this manuscript.