Langerhans cell histiocytosis (LCH) is a disease originating from abnormal proliferation of CD1a+/CD207+ myeloid dendritic cells and characterized by activation of the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) signaling pathway [1, 2]. For almost 60%–70% of patients, the somatic activating mutation in the proto-oncogene for the serine/threonine-protein kinase B-Raf or
The incidence of LCH among patients aged <15 years was 4–10 per million people in Western populations [6, 7], which is consistent with the <6 per million people annually in Thailand [8]. The childhood cancer registries covered approximately 22% of the Thai population. Fifty percent of those registered were in Bangkok [9]. Phramongkutklao Hospital, a tertiary referral center for childhood cancer in Bangkok, Thailand, constitutes 5%–10% of childhood cancer care in Bangkok. Therefore, there are 1–2 patients newly diagnosed with LCH annually at our institute.
Etiology and risk factors for developing LCH are unclear [10]. Population-based cancer studies have observed a higher incidence in Hispanic, but lower in Black populations, densely-populated countries, and among those with low educational status [6].
LCH has a wide range of symptoms from self-resolution to disseminated disease. Various clinical manifestations have a systemic involvement [11] and all organs can be affected in any age group. Bone is the most affected system and presents in approximately 80% of patients [12]. However, head-to-toe organ involvement can be influenced by the disease [13]. Therefore, prompt and comprehensive evaluation is needed to provide accurate diagnosis and avoid delayed treatment.
Histopathology with positive cluster of differentiation antigen (CD) 1a or CD 207 (Langerin) staining lesional cells, or both, are required to diagnose LCH. Currently, there is no specific laboratory marker or imaging to diagnose LCH. However, radiological diagnosis is mandatory to obtain diagnosis before providing a tissue diagnosis. A radiograph of the skull or Tc-99m bone imaging, or both, are evaluated in patients suspected with LCH, in particular, those presenting with bone lesions. Brain magnetic resonance imaging (MRI) was evaluated in patients presented with diabetes insipidus (DI) [11]. Currently, fluorodeoxyglucose F18 (FDG) positron emission tomography (PET)-computed tomography (CT) is established as an investigation of choice for LCH patients [14].
The standard treatment of LCH is adapted by group-system involvement of the disease [15]. Patients with involvement of a single system (SS) can often be treated with surgery or local therapy, and even spontaneous regression has occurred under close monitoring [16]. For multisystem (MS) involvement, a challenge exists to achieve disease remission, especially for risk-organ involvement (RO+), for which an intensified chemotherapy (CMT) regimen would be warranted and still carries a dismal prognosis [17]. However, groups without organ of risk involvement (RO−) have responded well to prolonged low dose CMT and yet can experience disease reactivation [18]. Similarly, it often ensues with SS multifocal bone (MFB) [19].
To date, few studies conducted in Asian countries have reported the clinical characteristics and outcomes of LCH. Most studies were from China [20, 21]. However, LCH treatment regimens mostly based on studies from Japan [22, 23], have been well documented and have been tolerable for patients in Thailand. Due to the rarity of LCH the clinical characteristics, management, treatment regimens, and outcomes of disease have not been explored fully in pediatric populations. Therefore, the present study of LCH explicitly in Thai children is warranted.
The present study aimed to identify clinical characteristics, investigations, treatment regimens, and outcomes of pediatric LCH in Phramongkutklao Hospital. The results of this study should provide better comprehension of the LCH situation and further facilitate treatment plans, which might apply to our institution and be applied throughout Thailand, and possibly by ASEAN neighbors.
We conducted a 20-year retrospective review of the medical records of 14 pediatric patients diagnosed with LCH from birth to 21 years old from January 1, 1997 to December 31, 2016. This study was approved by the Ethics Committee and Institutional Review Board of Phramongkutklao Hospital and Phramongkutklao College of Medicine, Bangkok, Thailand, (approval No. IRBRTA 111/2562) and was conducted in accordance with the principles of the Declaration of Helsinki, the guidance of the Council for International Organizations of Medical Sciences (CIOMS), and International Council on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) and good clinical practice (GCP). This observational study has been registered with the Thai Clinical Trials Registry (TCTR
For all patients, demographic data, imaging studies, type of treatment, and treatment outcomes were also reviewed.
Patients were classified according to the Histiocyte Society LCH-IV guidelines [24], which consider the number of system involvements, number of lesions, site of involvement, and whether the disease involves a “risk-organ” (the hematopoietic system, liver, or spleen) [10]. The 5 classifications are bullet pointed below.
SS: one system involvement and RO−
SS, unifocal: one system involvement with one lesion SS, multifocal: one system involvement with at least two lesions MFB, bone involvement only with at least two lesions
MS: more than two systems involved
MS, RO− or low risk: more than two systems RO− MS and RO+ or high risk: more than two systems with at least one organ of risk involvement or any organ of risk involvement, regardless of the number of organs involved
Remission of disease was defined as resolution of all signs and symptoms. Progressive disease was defined as progression of signs or symptoms and/or appearance of new lesions. Reactivation was defined as the reappearance of signs and symptoms of active disease after either complete disease resolution or a period of disease control that persisted for >3 months on maintenance therapy.
Patients were treated as per institutional protocols based on the oncologists’ expertise. CMT regimens were mainly based on International Collaborative Treatment Protocol for Children and Adolescents with LCH included LCH-III study (vinblastine [VBL], prednisolone (Pred), 6-mercaptopurine [6-MP], and methotrexate [MTX]) [18], LCH-IV study (frontline with VBL, Pred and 6-MP, and salvage regimens) [24], DAL-Hx83 protocol (VBL, etoposide, 6-MP, MTX, and Pred) [25, 26], and individualized treatment protocols such as cyclophosphamide (CTX), vincristine (VCR), cytosine arabinoside (Ara-C), and Pred.
Clinical characteristics, imaging studies, and treatments were calculated as descriptive statistics with mean and standard deviation or as median (range) for continuous variables, and frequency and percentage for categorical variables. Survival was calculated using a Kaplan–Meier method and comparing using a Cox proportional hazard model. Statistical analysis was performed using STATA/MP (version 12; STATA Corp.) with
Patient characteristics included age, sex, DI, and organ system involvement; these were analyzed for 14 patients who all met eligible criteria and whose data were included in the study (
Patient demographic and clinical characteristics
Age at diagnosis (years) | |
Median (range) | 2.5 (0.25–15.6) |
Mean ± SD | 5.1 ± 4.8 |
Sex | |
Female | 11 (79) |
Male | 3 (21) |
DI at diagnosis | 2 (14) |
System involvement | |
SS | 6 (43) |
Skin only | 1 (17) |
Single bone | 3 (50) |
MFB | 2 (33) |
MS | 8 (57) |
Low risk | 3 (38) |
High risk | 5 (63) |
Follow-up (years) | |
Median (range) | 6.8 (0.5–16.2) |
Mean ± SD | 6.9 ± 5.7 |
DI, diabetes insipidus; MFB, multifocal bone; MS, multisystem; SS, single system.
Characteristics and outcomes of patients with LCH (n = 14)
1.7 | Female | MS | Skin, bone | Liver, spleen, hematopoietic | No | CMT | Ara-C, Pred | Progressive | DWD | 1 | |
0.25 | Female | MS | Lung, bone | Liver, spleen, hematopoietic | No | CMT | DAL-Hx83 | Remission | ANED | 16 | |
1.2 | Female | MS | Bone, LN | Liver, spleen | No | CMT | LCH-III | Reactivation MFB | AWD | 8.6 | |
15.6 | Male | MS | Lung, MFB (vertebrae) | Liver, spleen | No | CMT | LCH-IV | Reactivation | AWD | 2.7 | |
1.3 | Female | MS | Skin, bone | Liver, spleen, hematopoietic | No | CMT | LCH-IV | Progressive | DWD | 0.6 | |
9 | Female | SS | Bone | – | No | RT, CMT | CTX, VCR, Pred | Remission | ANED | 12 | |
0.5 | Female | SS | Skin | – | No | Observation | – | Remission | ANED | 12 | |
3 | Female | SS | Bone (CNS risk) | – | No | Curettage, CMT | LCH-III | Remission | ANED | 15 | |
8 | Female | MS | MFB, pituitary | – | Yes | CMT | LCH-III | Remission | ANED | 3 | |
7 | Female | SS | Bone | – | No | Surgery | – | Remission | ANED | 1 | |
10 | Male | SS | MFB | – | No | CMT | LCH-III | Remission | ANED | 6 | |
2 | Female | MS | Skin, pituitary, bone | – | Yes | CMT | LCH-III | Remission | ANED | 9 | |
10.25 | Male | MS | Bone (vertebrae), LN | – | No | Surgery, CMT | LCH-III | Remission | ANED | 8 | |
1.4 | Female | SS | MFB | – | No | CMT | LCH-IV | Remission | ANED | 0.5 |
ANED, alive with no evidence of disease; Ara-C, cytosine arabinoside; AWD, alive with disease; CMT, chemotherapy; CNS, central nervous system; CTX, cyclophosphamide; DI, diabetes insipidus; DWD, died with disease; LCH, Langerhans cell histiocytosis; LN, lymph nodes; MFB, multifocal bone; MS, multisystem; Pred, prednisolone; RT, radiation; SS, single-system; VBL, vinblastine; VCR, vincristine.
Characteristics of patients with RO+ are shown in
MS “risk” LCH (RO+ MS-LCH) characteristics of 5 patients
1.7 | Female | TP 4.8 Alb |
Liver, spleen, hematopoietic | Skin, bone | Ara-C, Pred | Progressive | DWD | 1 | Not done | |
0.25 | Female | TP 8 Alb |
Liver, spleen, hematopoietic | Lung, bone | DAL-Hx83: VBL, VP-16, 6-MP, MTX, Pred | Remission | ANED | 16 | Not done | |
1.2 | Female | – | Liver, spleen | Bone, LN | LCH-III (High risk): MTX, VBL, Pred, 6-MP | Reactivation MFB | AWD | 8.6 | Not done | |
15.6 | Male | – | Liver, spleen | Lung, bone (special site) | LCH-IV adapted: (High risk): VBL, Pred, 6-MP | Reactivation | AWD | 2.7 | Negative | |
1.3 | Female | TP 6.27 |
Liver, spleen, hematopoietic | Skin, bone | LCH-IV adapted: (High risk): VBL, Pred, 6-MP | Progressive | DWD | 0.6 | Positive |
6-MP, 6-mercaptopurine; ANED, alive with no evidence of disease; Alb, albumin; ALP, alkaline phosphatase; ALT, alanine aminotransferase; Ara-C, cytosine arabinoside; AST, aspartate aminotransferase; AWD, alive with disease; CMT, chemotherapy; DB, direct bilirubin; DWD, died with disease; LCH, Langerhans cell histiocytosis; LFT, liver function test; LN, lymph nodes; MFB, multifocal bone; MS, multisystem; MTX, methotrexate; Pred, prednisolone; RO+, risk-organ involvement; TB, total bilirubin; TP, total protein; VBL, vinblastine; VP-16, etoposide.
Eleven of 14 patients (79%) showed an osteolytic lesion of the skull or widening of the sella turcica as observed from the skull radiograph (
Radiology of patients with LCH (n = 14)
Normal | 3 (21) |
Abnormal | 11 (79) |
8 (73) | |
Normal | 1 (13) |
Abnormal | 7 (88) |
3 (27) | |
Done | 9 (64) |
Not done | 5 (36) |
Done | 4 (29) |
Not done | 10 (71) |
CT, computed tomography; FDG, fluorodeoxyglucose; LCH, Langer-hans cell histiocytosis; MR, magnetic resonance; PET, positron emission tomography.
Subsequently, a Tc-99m bone imaging was conducted for 9 patients (64%), demonstrating abnormal uptake in 8 (89%). One patient showed normal uptake on Tc-99m bone imaging with multiple osteolytic lesions from the whole-body skeletal survey.
FDG-PET-CT was performed for 4 patients (29%) and demonstrated FDG-avid lesions. Three of 4 patients received both Tc-99m bone and FDG-PET-CT imaging, which had parallel positive results. Only 1 patient underwent FDG-PET-CT imaging and a whole-body skeletal survey without Tc-99m bone imaging, and both types of imaging showed abnormal results.
Surgery was performed for 3 (21%) patients (
Treatment and outcomes of patients with LCH (n = 14)
3 (21) | |
Curettage | 1 (33) |
Partial resection | 2 (67) |
12 (86) | |
4 (33) | |
Single bone | 2 (50) |
MFB | 2 (50) |
8 (67) | |
Low risk | 3 (38) |
High risk | 5 (62) |
1 (7) | |
Remission | 10 (71) |
Reactivation/progressive | 4 (29) |
On therapy | 3 (75) |
Off therapy | 1 (25) |
ANED | 10 (72) |
AWD | 2 (14) |
DWD | 2 (14) |
ANED, alive with no evidence of disease; AWD, alive with disease; CMT, chemotherapy; DWD, died with disease; LCH, Langerhans cell histiocytosis; MFB, multifocal bone; MS, multisystem; RT, radiation therapy.
Twelve patients (86%) received CMT. One patient with single bone involvement presented a gingival mass with a diagnosis in 1997, and received CMT consisting of CTX, VCR, and Pred with concurrent radiotherapy. Nine patients (75%) received VBL-containing CMT (
Ten of 14 (71%) patients experienced disease remission and remained alive with no evidence of disease (ANED). Four (29%) patients with RO+ complicated with progressive or reactivation of disease. Two (14%) patients with disease reactivation survived with the disease after treatment. However, 2 (14%) patients had refractory disease and eventually died with the disease (
Five-year event-free survival (EFS) for patients with SS-LCH tended to be better than MS-LCH (100% vs. 50%,
In the present study, we describe the clinical characteristics, imaging modalities, treatment regimens, and outcomes for children with LCH in a large tertiary care center for pediatric oncology in Bangkok, Thailand over a 20-year period. The incidence of LCH is approximately <6 per million persons per year in Thailand [8]. This is consistent with other countries in Asia with 3 patients per year [27] and 5–9 per million persons per year in Europe [28]. During the 20-year period of the study to the end of 2016, we found only 14 LCH patients, due to the rarity of disease. Only 14% of patients had DI, consistent with a related report of from 2% to 25% of patients with LCH in developed countries [12, 29]. However, 2 patients with LCH presenting with DI had been classified as RO− MS-LCH and 1 of these experienced MFB involvement. A related report by Imashuku et al. [19] showed MS-LCH with MFB was associated with a significantly higher incidence of DI.
The most common organ involvements for LCH are bone [12] and skin [30]. Therefore, plain X-ray radiographs [31, 32], skeletal surveys, and Tc-99m bone imaging [33] are crucial modalities and investigations of choice for patients with LCH to explore systematic involvement of the disease. We found that almost 80% of patients with LCH had been diagnosed after plain X-ray radiographs of the skull. In addition, we found Tc-99m bone imaging showed abnormal results in almost 90% of patients, and 100% for FDG-PET-CT. Tc-99m bone imaging is currently substituted by FDG-PET-CT scan [34] because it is more highly sensitive for detecting positive lesions with a very low false-positive rate among patients with LCH [14].
Interestingly, patient No. 4 with RO+ MS-LCH was 15 years old at diagnosis. He had liver, spleen, lung, vertebral, and multiple bone involvement indicated by CT and MRI. As the age is uncommon for LCH and CT/MRI was unable to distinguish active LCH lesions and other causes, FDG-PET-CT was also performed. The result showed hypermetabolic activities in active lesions, which were not clearly indicated by MRI or CT (
Treatment of LCH is tailored by organ system involvement. SS-LCH would be cured by local treatment such as curettage or surgery [35]. Low-intensity CMT in MFB SS-LCH [36] and RO− MS-LCH [18] have shown excellent outcomes. By contrast, disease remission and prognosis of RO+ MS-LCH is still unsatisfactory even using high-intensity therapy and prolonged therapy regimens [18].
The outcome of pediatric LCH in Thailand is consistent with that in developed countries in the Asia–Pacific such as Taiwan. Five-year EFS was 100% in SS-LCH for both countries. However, 5-year EFS of MS-LCH was lower in Thailand (50%) than it was in Taiwan (85.7%) [27]. Outcomes for RO+ MS-LCH are inferior to RO− MS-LCH and SS-LCH [18] especially correlated with the number of RO+. Hematopoietic involvement was associated with a worse prognosis in RO+ [37]. From our present study, patients with MS-LCH having 2 RO+; liver and spleen involvement (patient Nos. 3 and 4;
Historical treatments such as the DAL-Hx83 protocol, conducted between 1983 and 1991 in Europe, were an effective regimen especially for RO+ MS-LCH due to its high intensity [25, 26]. Currently, standard treatment of RO+ MS-LCH for Thai children has been adapted from the Histiocyte Society LCH studies. However, the survival rate for RO+ MS-LCH in our present study was approximately 20% by comparison with 84% in the LCH-III study [12, 18]. This might be the result of the small number of 5 patients in our study compared with the 285 patients in the LCH-III study as well as limited resources for complex supportive care in patients receiving high-intensity CMTs with vital organ damage in RO+ MS-LCH.
Disease reactivation is common in patients with LCH patients. Patients with MFB disease reactivation usually respond well to second-line therapy including oral 6-MP and MTX [15] as did patient No. 3 (
To our knowledge, this study is the first to record the clinical characteristics and outcomes of LCH in Thailand over 20 years. Considering the rarity of disease, variety of clinical presentations, and serious comorbidities in RO+ MS-LCH, it is our opinion that a uniformed CMT protocol and centralized care by disease-specific professionals would facilitate an optimal standard of care that would result in better outcomes.
This was a retrospective study in which some data was unavailable and might not represent the entire patient population of our institute. Moreover, the study duration was short for some patients. Patients who had not been followed at the Division of Hematology–Oncology, such as those with skin-only LCH, who were treated at the Dermatology Department, were not included in the study. These might have an effect on outcomes for the small sample size. A multicenter prospective study would improve the power and quality of data, which would more truly represent the LCH disease situation in Thailand.
LCH is a rare disease with some patients having DI. FDG-PET-CT is considered as an investigation of choice and has greater accuracy than conventional plain radiographs and Tc-99m bone imaging to detect sites of active disease and for disease monitoring after treatment. SS-LCH and RO− MS-LCH have been successfully treated using local treatment or low-intensity CMT. However, patients with RO+ MS-LCH have often encountered disease reactivation or progressive disease with a dismal prognosis. Hematopoietic system and organ of risk involvement were associated with worse prognosis. Hypoalbuminemia and conjugated hyperbilirubinemia may predict a greater mortality in RO+ MS-LCH.