Langerhans cell histiocytosis (LCH) is a rare disorder with diverse clinical presentations and prognosis [1, 2]. Patients with localized disease need minimum or even no treatment, whereas patients with multi-organ involvement, more frequently young children, might benefit from cytotoxic drugs and steroids [1-3].

Disease activity is currently assessed using the Scoring System of the Histiocyte Society Protocol LCH III [4]. This assessment system is semi-quantitative, with the following 4 categories: non-active disease, active disease-better, active disease-stable, and active disease-worse. The main drawback is that, by definition, each assessment is based on a comparison of the situation before and after therapy (or a 6-week interval) and is, in part, subjective. Donadieu et al. [5] developed a new quantitative scoring system for LCH disease activity at diagnosis as an objective tool for therapeutic decision-making. This scoring system also had some limitations; the authors did not evaluate the involvements of risk organs in the endocrine system or the central nervous system (CNS) and leukocytopenia. Furthermore, pulmonary function tests are not easy to perform in individuals less than 5 years of age, but this test was included in their study as an important tool.

To treat LCH appropriately, it is essential to investigate disease activity and choose the optimal treatment options. In this study, our aim was to develop a new quantitative scoring system for LCH disease activity at diagnosis that is easy to apply to patients and can help therapeutic decision-making in the context of the wide spectrum of clinical features of LCH.

LCH has a variable clinical spectrum, and the course of the disease is unpredictable, varying from spontaneous regression and resolution to rapid progression and death or recurrence [1-3]. Patients with localized disease generally have a good prognosis and need minimal or even no treatment. Bone involvement with or without other associated sites is the most common manifestation of LCH and has been observed in 80-100% of cases [7]. The bones most frequently involved in LCH patients, in a study of 503 osseous lesions, were the skull (27%), femur (13%), mandible/maxilla (11%), pelvis (10%), vertebral bodies (8%), ribs (8%), humerus (5%), and tibia (3%) [8]. The prognosis is dependent on the number of organs involved, as well as the presence of organ dysfunction, and to a lesser degree, the age of the patient at the onset of the disease [1-3]. Involvement of the spleen, lung, liver, or hematopoietic system also contributes to a poor prognosis [1]. In one large study of 101 children with LCH, the overall survival rate for all was 79% at 1 year, 74% at 3 years, and 71% at 5 years; however, in patients with liver or spleen involvement, the 1-year survival was 33% and 5-year survival was just 25% [9].

More detailed clinical information will help delineate the different entities of LCH clearly and may facilitate the development of an advanced classification system as a basis for selecting the appropriate therapeutic approach. Therefore, factors influencing the outcome of LCH must be identified to prevent or facilitate the treatment of disease progression and relapse. A quantitative disease activity score can help therapeutic decision-making, especially in complex situations such as multi-organ involvement. We developed a new quantitative scoring system for LCH disease activity, which is easy to practice and can help therapeutic decision-making in this disease. It may also serve to standardize the management of patients with very severe forms of LCH, who need more effective treatments.

According to our new clinical score, most of the patients were assigned scores of 1 and 2 (75.9%). The patients with low scores (1-2) did not have life-threatening disease, and the reactivation rate was lower in this group than in the higher score groups (Fig. 3). Most of the patients in this group were diagnosed with single or multiple bone involvement. Of these patients, only 55.4% received systemic chemotherapy, and 4.0% of the patients had a worse response at the 6-week evaluation. On the basis of these data, the treatment plan of these patients has to be simplified, and more attention may be needed to prevent functional sequelae. All the patients with moderate scores (3-6) received chemotherapy, and none of them showed progression at the 6-week evaluation. This group of patients showed reactivation-free survival rates comparable to the lower score group (1-2) (86.5% vs. 77.9%). Patients with high scores (>6) showed a poor short-term outlook: 36.3% of the patients progressed at 6 weeks and the reactivation-free survival rate was 45.5%. These results are much worse than for other groups. Such patients may therefore qualify for aggressive chemotherapy or even stem cell transplantation (Table 2, 3).

Comparing our scoring system with that of Donadieu et al. [5], their scoring system does not take bone involvement into account, even though this is the most frequent manifestation. In addition, only bone pain was taken into account, and this is a subjective symptom and responds very rapidly to various treatments, including non-steroidal anti-inflammatory drugs. Radiological outcome was poorly characterized and was not used to assess disease activity or progression. Further, the score did not evaluate endocrine or neurological sequelae. Our new clinical scoring system accounts for all these factors and uses a simplified protocol.

The etiology and pathogenesis of LCH have remained an enigma [10-12]. The mechanisms of LCH cell development are still not completely understood. However, several mechanisms might play important roles, including multiple chromosomal alterations that have been found in LCH cells [13-15], and clonal proliferation of LCH cells [16-19]. Although definitive and consistent molecular events leading to clonal proliferation are unclear, high levels of cytokines are secreted by LCH cells, as well as by bystander cells in LCH lesions [20-22]. These cytokines could contribute to the proliferation and differentiation of LCH cell progenitors and could play a role in preventing LCH cells from maturing. The clinical course of LCH is quite variable, and we divided the LCH patients into 3 groups according to the new clinical scores. With this classification, we observed differences in clinical courses and outcomes among these 3 groups. Roughly, most of the patients with scores 1 and 2 have single system disease, especially bone involvement, and those with scores 3-5 have multisystem disease, without risk organ involvement, whereas patients with scores >6 have multisystem disease, with risk organ involvement. We pinpoint correlations between the clinical variability and different pathogeneses, albeit with caution.

The major limitation of this scoring system is that it has been applied to only a small patient dataset, in a retrospective fashion. In particular, a precise evaluation of late sequelae was not possible. We stress that it needs to be validated prospectively in larger patient populations. Future studies on the biology of LCH should enable us to better understand the pathology and mechanisms responsible for the development of LCH and its variable clinical course.

Despite these limitations, our new clinical score has the merit of being able to quantify LCH disease activity at diagnosis. We expect that this new clinical score can help therapeutic decision-making and formulation of improved follow-up plans in this variable disease. It may also serve to standardize the treatment of patients with severe forms of LCH, who need more intensive treatments.

The clinical score distribution at initial diagnosis. Scores between 1 and 2 were assigned to 75.9% (N=101) of cases, between 3 and 6 to 15.8% (N=21), and more than 6 to 8.3% (N=11). The number of patients with a score of 1 or 2 was significantly higher than the other groups.

The age distribution of 3 clinical score categories. In the group with scores of 1 or 2, the number of patients who were less than 2 years of age was higher than in the group with scores higher than 3. However, this difference did not reach statistical significance.

The curve of reactivation free survival rate. The reactivation-free survival curves during follow-up in the high score group (>6) was significantly lower than in groups with lower scores.

Table 1 New clinical scores of Langerhans cell histiocytosis at diagnosis.

Table 2 Therapeutic approach according to the new clinical scores.

Table 3 Treatment response at 6 weeks according to the new clinical scores.

Table 4 Late sequelae according to the new clinical scores.