Long-term follow-up of Langerhans cell histiocytosis: 39 years' experience at a single centre

AIM: To evaluate the long-term outcome of Langerhans cell histiocytosis (LCH) in children. METHODS: We re-evaluated all children (<15 y old at diagnosis) treated at our unit in 1962-1989. Histopathology specimens were reviewed and verified for 49 patients. Forty patients underwent physical examination and laboratory tests, and 38 were subjected to imaging, at a median time of 16 y (range 5.5-33.5) after diagnosis. RESULTS: Altogether, 5/49 (10%) children died, all with multi-system disease and age <2 y at diagnosis. Age at diagnosis (p=0.001) and survival (p=0.014) for the 22 children with multi-system disease was significantly lower compared with the 27 children with single-system disease. The term "maximal extent of disease" was introduced since reactivation of LCH often tends to involve additional organs not previously affected by the disease. At follow-up, late sequelae had developed in 17/40 (42%) patients, including diabetes insipidus in 6/40 (15%), CNS complications in at least 4/40 (10%) (3/16, 19%, of multi-system patients) and late-stage pulmonary disease in 4/38 (11%). Seven out of 21 (33%) of the patients with multi-system disease were alive and healthy without sequelae at follow-up, as compared to 16/24 (67%) of those with single-system disease (p=0.026). Of 14 individuals 25 y at follow-up, senior high school had been completed in 7/9 (78%) with single-system and 1/5 (20%) with multi-system disease (at maximal disease extent) (p=0.091). CONCLUSION: Multi-system LCH is associated not only with increased mortality but also pronounced propensity for severe late sequelae; 51% of the patients (multi-system=33%, single-system=67%) were alive without sequelae at follow-up. Among multi-system patients, at least 19% suffered CNS sequelae.     

LANGERHANS CELL HISTIOCYTOSIS: Retrospective Evaluation of 123 Patients at a Single Institution

The aim of this study was to retrospectively evaluate clinical characteristics at diagnosis and outcome of patients with Langerhans cell histiocytosis (LCH). From October 1987 to March 1996, 133 patients with confirmed LCH were admitted to Hospital JP Garrahan in Buenos Aires (123 evaluable). Median age was 5 years (range 15 days to 18 years). Initial organ involvement included bone 114 patients, ear 34, skin 30, liver 18, lung 14, lymph nodes 14, spleen 12, diabetes insipidus 9, and bone marrow 2. Nineteen patients had organ dysfunction, pulmonary 14, hematological 14, and hepatic 12. Two groups were defined: Group A included patients with single system disease (unior multifocal) and group B multisystem (with or without organ dysfunction). In group A (n = 82), 24 patients were treated with chemotherapy (prednisone and vinblastine), 21 with surgery, 15 received radiotherapy, and 22 were only observed. Patients of group B ( n = 41) were treated with chemotherapy consisting of prednisone and vinblastine, DALHX 83, or LCH1-based chemotherapy. At a median follow-up of 3 years (range 1 month-8 5/12 years) 93% of patients of group A and 39% of group B survive free of reactivation. In group B, 22% had a reactivation and 39% died of progressive disease. Sequelae were detected in 35 patients (28%), which included diabetes insipidus in 17, hearing loss in 13, bony sequelae in 11, sclerosing cholangitis in 6, and lung fibrosis with bullae in 6. Two patients had a subsequent malignant disease. A total of 17 (14%) patients died and 16 of them belonged to the group B: 13 died of progressive disease, 2 due to sclerosing cholangitis (with sepsis in one case and encephalitis in the other one), 1 with progressive disease and associated myelofibrosis, and 1 patient of group A with active disease and brain stem tumor. Patients who had organ dysfunction had a reactivation free survival of 32%. All these patients survived with sequelae. Logistic regression analysis showed that organ dysfunction and hematological involvement had significant predictive values in relation to death. Patients of group A had an excellent survival rate, whereas in those of group B a high mortality was found, especially in the subgroup of patients with organ dysfunction. Lahey's criteria should be revised. Sequelae were also more common in this group.     

LANGERHANS CELL HISTIOCYTOSIS: Retrospective Evaluation of 123 Patients at a Single Institution

The aim of this study was to retrospectively evaluate clinical characteristics at diagnosis and outcome of patients with Langerhans cell histiocytosis (LCH). From October 1987 to March 1996, 133 patients with confirmed LCH were admitted to Hospital JP Garrahan in Buenos Aires (123 evaluable). Median age was 5 years (range 15 days to 18 years). Initial organ involvement included bone 114 patients, ear 34, skin 30, liver 18, lung 14, lymph nodes 14, spleen 12, diabetes insipidus 9, and bone marrow 2. Nineteen patients had organ dysfunction, pulmonary 14, hematological 14, and hepatic 12. Two groups were defined: Group A included patients with single system disease (unior multifocal) and group B multisystem (with or without organ dysfunction). In group A (n = 82), 24 patients were treated with chemotherapy (prednisone and vinblastine), 21 with surgery, 15 received radiotherapy, and 22 were only observed. Patients of group B ( n = 41) were treated with chemotherapy consisting of prednisone and vinblastine, DALHX 83, or LCH1-based chemotherapy. At a median follow-up of 3 years (range 1 month-8 5/12 years) 93% of patients of group A and 39% of group B survive free of reactivation. In group B, 22% had a reactivation and 39% died of progressive disease. Sequelae were detected in 35 patients (28%), which included diabetes insipidus in 17, hearing loss in 13, bony sequelae in 11, sclerosing cholangitis in 6, and lung fibrosis with bullae in 6. Two patients had a subsequent malignant disease. A total of 17 (14%) patients died and 16 of them belonged to the group B: 13 died of progressive disease, 2 due to sclerosing cholangitis (with sepsis in one case and encephalitis in the other one), 1 with progressive disease and associated myelofibrosis, and 1 patient of group A with active disease and brain stem tumor. Patients who had organ dysfunction had a reactivation free survival of 32%. All these patients survived with sequelae. Logistic regression analysis showed that organ dysfunction and hematological involvement had significant predictive values in relation to death. Patients of group A had an excellent survival rate, whereas in those of group B a high mortality was found, especially in the subgroup of patients with organ dysfunction. Lahey's criteria should be revised. Sequelae were also more common in this group.     

Pulmonary abnormalities at long-term follow-up of patients with Langerhans cell histiocytosis

BACKGROUND: In Langerhans cell histiocytosis (LCH) pulmonary involvement, which is often initially asymptomatic, may contribute to significant morbidity and mortality. To determine the long-term prognosis, a cross-sectional study was undertaken. PROCEDURE: Forty-one patients with > or = 5 years follow-up after the diagnosis of LCH were interviewed and underwent physical examination, blood tests, a chest X-ray and a high-resolution CT (HRCT) of the lungs. All patients included had been referred to the Department of Pediatrics at the Karolinska Hospital in Stockholm between July 1962 and February 1990 (median follow-up 16 years). Biopsies from all patients were reviewed and confirmed to be consistent with LCH. Information on previous clinical features including treatment and the results of chest X-rays were also collected for risk factor analysis. RESULTS: Radiographic abnormalities of the lungs (cysts and/or emphysema), found in 10/41 (24%) at follow-up, were classified into five groups according to the extent of the cysts. These patients had more often suffered from multisystem than from single-system disease (P = 0.01), were significantly older at diagnosis (P < 0.001), and had been more heavily treated with chemotherapy and/or radiotherapy. They were also more frequently smokers (P < 0.0001) and 7/10 (70%) had suffered lung involvement at diagnosis. At the time of diagnosis of the pulmonary involvement, 4/10 (40%) patients had respiratory symptoms, but only 2/10 (20%) had symptoms at follow-up. CONCLUSIONS: Ten (24%) of the 41 patients had abnormal findings on radiological examination of the lungs at long-term follow-up and seven are or had been smokers. It is of great importance that patients with LCH be informed about smoking-related pulmonary morbidity. Prolonged monitoring of the lungs for smokers and patients with known pulmonary involvement is recommended.     

A randomized trial of treatment for multisystem Langerhans' cell histiocytosis

OBJECTIVE: To compare 2 active agents, vinblastine and etoposide, in the treatment of multisystem Langerhans' cell histiocytosis (LCH) in an international randomized study. STUDY DESIGN: One hundred forty-three untreated patients were randomly assigned to receive 24 weeks of vinblastine (6 mg/m(2), given intravenously every week) or etoposide (150 mg/m(2)/d, given intravenously for 3 days every 3 weeks), and a single initial dose of corticosteroids. RESULTS: Vinblastine and etoposide were equivalent (P > or = .2) in all respects: response at week 6 (57% and 49%); response at the last evaluation (58% and 69%); toxicity (47% and 58%); and probability of survival (76% and 83%) [corrected], of disease reactivation (61% and 55%), and of developing permanent consequences (39% and 51%) including diabetes insipidus (22% and 23%). LCH reactivations were usually mild, as was toxicity. All children > or = 2 years old without risk organ involvement (liver, lungs, hematopoietic system, or spleen) survived. With such involvement, lack of rapid (within 6 weeks) response was identified as a new prognostic indicator, predicting a high (66%) mortality rate. CONCLUSIONS: Vinblastine and etoposide, with one dose of corticosteroids, are equally effective treatments for multisystem LCH, but patients who do not respond within 6 weeks are at increased risk for treatment failure and may require different therapy.     

Langerhans cell histiocytosis in neonates

BACKGROUND: To study the incidence, clinical patterns, course, and outcome of neonatal Langerhans cell histiocytosis (LCH). PROCEDURE: Retrospective analysis of the data of the Austrian/German/Swiss/Netherlands LCH Study Group. The incidence of neonatal LCH was estimated with the data from the population-based German Childhood Cancer Registry. RESULTS: The estimated incidence of neonatal LCH (LCH diagnosed within 28 days after birth) in the population-based registry was 1-2/1,000,000. In 61/1,069 trial patients (6%), the first disease manifestations were observed in the neonatal period. However, in only 20 of them, the diagnosis was established within this period. There was a preponderance of multisystem (MS)-LCH 36/61 (59%). Cutaneous changes were the most common initial manifestation in both, single-system (SS)-LCH (92%), and MS-LCH (86%). In 72% of the MS-LCH patients, risk organs (ROs) were involved at diagnosis as well. The probability of survival at 5 years was 94% in SS-LCH and 57% in MS-LCH, which is significantly lower than in older age groups. CONCLUSIONS: In contrast to the available literature, neonatal LCH is characterized by a clear predominance of MS-LCH. Cutaneous changes are the most common initial manifestation in neonates with both SS-LCH and MS-LCH. Prompt evaluation of disease extent upon diagnosis is mandatory for risk-adapted treatment. The disease course is unpredictable upon diagnosis. Close monitoring for disease progression is mandatory if isolated cutaneous LCH is managed by the "wait and see" approach. Neonates with MS-LCH, especially those with RO involvement at diagnosis, have less favorable prognosis compared to infants and older children, and need systemic therapy.     

Elevated erythrocyte sedimentation rate and thrombocytosis as possible indicators of active disease in Langerhans''cell histiocytosis

Langerhans' cell histiocytosis (LCH) is a disease with an unpredictable course and unpredictable reactivations. Since active disease may cause life-long sequelae, early detection of reactivation is important. The usefulness of erythrocyte sedimentation rate (ESR) and thrombocytosis as indicators of disease activity in patients with LCH were examined. The mean values for ESR and platelet count for each quarter of a year were compiled. The means of all the ESR estimates (n=76) during each quarter of a year with active disease was 21 mm h^-1, with intermediate disease activity 11 mm h^-1 and with resolution 7 mm h^-1. The corresponding platelet count estimates (n = 139) were 433 × 109 l^-1, 365 × 109 l^-1 and 304 × 109 l^-1, respectively. In conclusion, elevated ESR and platelet count may be clinically valuable indicators of disease activity in LCH.     

儿童朗格罕细胞组织细胞增生症BRAFV600E突变对预后的影响

目的 探讨BRAFV600E突变在儿童朗格罕细胞组织细胞增生症（LCH）中的预后意义以及影响儿童LCH的预后因素。方法 回顾性纳入首都医科大学附属北京儿童医院2016年1月1日至2017年12月31日收治的初治LCH患儿,采用数字PCR方法检测患儿病灶组织中的BRAFV600E突变,分析突变与临床特征和预后的相关性,影响预后的因素。结果 140例LCH患儿纳入研究,诊断时中位年龄为2.2（0.1~15.7）岁,男89例（63.6%）,女51例。临床分型为单系统（SS）60例（42.9%）,多系统无危险器官受累（MS RO－）47例（33.6%）,多系统有危险器官受累（MS RO+）33例（23.6%）。中位随访时间34.1（0.9~50.7）月,随访期内70例（50.0%）出现进展或复发,12例（9.6%）出现持续性后遗症,死亡3例（2.1%）。总体3年无进展生存率（PFS）、无事件生存率（EFS）和总生存率（OS）分别为（48.9±4.5）%、（46.6±4.4）%和（97.8±1.2）%。①儿童LCH中BRAFV600E突变阳性率67.1%（94/140）。②BRAFV600E突变与患儿临床分型明显相关,突变阳性率MS RO+患儿（90.9%）高于MS RO－患儿（53.2%）或SS患儿（65.0%）（P=0.001）;皮肤受累患儿中突变阳性率（77.8%）高于非皮肤受累的患儿（P=0.042）;③BRAFV600E突变阳性患儿进展/复发率（57.4%）高于突变阴性患儿（34.8%）,P=0.019。3种临床分型中突变阳性和阴性患儿的预后差异均无统计学意义。④多因素分析结果表明,危险器官受累是影响LCH患儿PFS的独立预后因素（HR=2.702,P=0.003）,垂体受累（HR=3.582,P<0.001）、危险器官（HR=2.321,P=0.008）和耳部受累（HR=2.093,P=0.013）是EFS的独立预后因素。结论 LCH患儿BRAFV600E突变与危险器官受累密切相关,突变阳性患儿的进展/复发率高于突变阴性患儿,BRAFV600E不是儿童LCH的独立预后因素。     

Whole-body MRI of Langerhans cell histiocytosis: comparison with radiography and bone scintigraphy

Background In Langerhans cell histiocytosis (LCH) evaluation of the extent of disease is one of the major predictors of patient outcome. Historically this is undertaken using plain radiography and bone scintigraphy. Recently, whole-body (WB) MRI has been reported to be useful in detecting skeletal and extraskeletal metastases in both adults and children. Objective To evaluate the usefulness of WB MRI in patients with LCH in comparison with plain radiography and bone scintigraphy. Materials and methods In nine children (1–7 years of age; mean 3.3 years) who had a pathological diagnosis of LCH and had either plain radiography or bone scintigraphy for comparison, 43 WB MR examinations were performed. Skeletal and extraskeletal lesions of the disease on WB MRI were compared with those on plain radiography and bone scintigraphy. Results LCH showed unifocal single-system involvement in one patient, multifocal single-system involvement in three, and multifocal multisystem disease in five. WB MRI identified additional skeletal lesions in three (38%) of eight patients, compared with plain radiography, and in two (25%) of eight, compared with bone scintigraphy. WB MRI detected extraskeletal lesions of the disease in five (56%) of the nine patients exclusively, except for one patient whose lung lesions were also detected on plain radiography. In two patients, treatment was changed according to WB MRI findings. Conclusion WB MRI is a useful initial and follow-up diagnostic method to assess the extent of LCH because WB MRI not only identifies more skeletal lesions of the disease than do plain radiography and bone scintigraphy, but also detects extraskeletal lesions of the disease.     

Incidence and survival of childhood Langerhans cell histiocytosis in Northwest England from 1954 to 1998

BACKGROUND: Langerhans cell histiocytosis (LCH) is a rare proliferative disorder of pathological Langerhans cells, for which the aetiology and pathogenesis remain largely unknown. PROCEDURE: Information on the 101 children with LCH registered with the population-based Manchester Children's Tumour Registry (MCTR) between 1954 and 1998 was extracted from the records of the MCTR. This included age, sex, date of diagnosis, systems affected at diagnosis and follow-up. RESULTS: The overall incidence rate for LCH was 2.6 cases per million child years. In those under 1 year of age the incidence rate was 9.0 cases per million child years, compared to 0.7 cases per million in those aged 10-14 years (P < 0.0001 for age trend). There was no evidence of seasonal variation in presentation by month of birth or first symptom. Bone was the most common site of disease involvement (67% of cases), followed by skin (37%) and soft tissue (22%). The overall survival rate has improved over time, from 57% in 1954-1968 to 74% in 1985-1998. Ninety percent of deaths were due to disease progression, the remainder were due to complications of intensive therapy. The site of LCH lesions and extent of disease present at diagnosis strongly predicted survival outcome. Patients with initial liver involvement had a 5-year survival rate of 25% compared with 93% for those with bone lesions alone at diagnosis. CONCLUSIONS: Incidence rates varied significantly by age at diagnosis, and have been stable over time. Survival has improved considerably over time, but varies strongly by age and systems affected at diagnosis.     

Risk factors for diabetes insipidus in langerhans cell histiocytosis

BACKGROUND: Diabetes insipidus (DI) is the most frequent central nervous system (CNS)-related permanent consequence in Langerhans cell histiocytosis (LCH), which mostly requires life-long hormone replacement therapy. In an attempt to define the population at risk for DI, 1,741 patients with LCH registered on the trials DALHX 83 and DALHX 90, LCH I and LCH II were studied. RESULTS: Overall 212 of 1,741 patients (12%) was reported to have DI. In 102 of 1,741 patients (6%) DI was present at diagnosis of LCH. One thousand one hundred eighty three of 1,539 patients without DI at diagnosis had follow up information. One hundred ten of these (9%) later developed DI. The risk of developing DI was 20% at 15 years after diagnosis. Multisystem disease patients at diagnosis carried a 4.6-fold risk for DI compared to single system patients. Craniofacial lesions, in particular in the "ear," "eye," and oral region were associated with a significantly increased risk for DI (relative hazard rate, RHR 1.7), independent of the extent of disease. No influence of the duration of therapy could be determined, but the duration of initial disease activity (RHR 1.5) and the occurrence of reactivations (RHR 3.5) significantly increased the risk for DI. CONCLUSIONS: Patients with multisystem disease and craniofacial involvement at diagnosis, in particular of the "ear," "eye," and the oral region carry a significantly increased risk to develop DI during their course. This risk is augmented when the disease remains active for a longer period or reactivates.     

Predictors of outcome in children with Langerhans cell histiocytosis

BACKGROUND: Our goal was to examine the clinical course of patients with Langerhans cell histiocytosis (LCH), with a special emphasis on bone disease and to attempt to identify and examine the factors that may predict reactivation and overall prognosis. PROCEDURE: We conducted a retrospective chart review of 132 consecutive pediatric patients treated at Children's Hospital Los Angeles for LCH from 1984 to 2001. RESULTS: The risk for reactivation after initial management is significantly higher for patients with multiple bone and those with multiple organ involvement as compared with patients who had a single bone lesion (hazard ratios are 7.1 and 11.6). Patients younger than 1 year in the multiple organ group have an increased risk of death at 2 years when compared with the older patients in that group (hazard ration = 6.2, P = 0.022). Endocrine abnormalities were seen in 20% and 7.5% of patients with or without skull lesions respectively. CONCLUSIONS: Patients with LCH involving only the bones have a significantly better outcome than those with other organ involvement. Patients with multiple organ involvement who are less than 1 year of age are at high risk of death and should be approached more aggressively upfront.     

Use of indomethacin in Langerhans cell histiocytosis

BACKGROUND: Because prostaglandin (PG) E2 has been identified in the bone lesions of Langerhans cell histiocytosis (LCH), we speculated that indomethacin, a potent PG inhibitor, may be useful in patients with symptomatic LCH involving the bony skeleton. PROCEDURE: We used indomethacin to treat patients in whom we wanted to avoid steroids or chemotherapy, or in whom these treatments did not provide complete symptom relief. Ten children with bony LCH between 1984 and 1995 were treated; six had single-system bone disease and four had multisystem disease involving the bony skeleton and other organs. RESULTS: The dose of indomethacin ranged from 1 to 2.5 mg/kg/day (9-200 mg/day) in divided doses and was given for 1-16 weeks (mean, 6 weeks). Eight patients had a complete response to treatment, defined as complete resolution of symptoms for 4 weeks. One patient was withdrawn from treatment because of concern regarding the potential of indomethacin to induce seizures and a second patient, with suppurative skin lesions overlying a lytic skull defect, did not respond. CONCLUSIONS: Indomethacin is a useful therapy for LCH involving the bony skeleton and may have a role as first-line treatment in single-system bone disease. Whether it has a specific role in slowing disease progression or merely acts as an analgesic has not yet been established.     

Permanent consequences in Langerhans cell histiocytosis patients: a pilot study from the Histiocyte Society-Late Effects Study Group

BACKGROUND: Permanent consequences (PC) are often described among subjects with Langerhans cell histiocytosis (LCH) but data on the real incidence are scarce. Within the Histiocyte Society (HS), and in order to design a definitive late effects study, a retrospective survey was organized to describe the prevalence of PC among long-term survivors of LCH. METHODS: Nine institutions contributed with their LCH patients having a minimum follow-up of 3 years. Information was collected on their disease-history, and on type and date of onset of any PC. Because of the retrospective type of this study, it was accepted that each institution might have used different criteria to assess PC. RESULTS: One hundred eighty-two subjects were registered and in 95 (52%) at least 1 PC was reported. For some specific PC (e.g., anterior pituitary dysfunction) information was too scarce to provide reliable data. PC were more frequent among subjects with multisystem (MS) disease (71%), compared to those with single system (SS) disease (24%); P < 0.0001. The most frequently reported PC were diabetes insipidus (DI) (24%) orthopedic abnormalities (20%), hearing loss (13%), and neurological consequences (11.0%). Analysis of cumulative risk showed that some types of PC may become manifest more than 10 years from diagnosis. CONCLUSIONS: This survey on selected cases of LCH survivors has confirmed that late sequels are frequent, and that they are even more common among those with MS LCH. Our findings highlight the need for long-term and patient-oriented follow-up in children with LCH.     

p53 expression in biopsies from children with Langerhans cell histiocytosis

PURPOSE: Langerhans cell histiocytosis (LCH) is a rare pediatric and adult disease causing skin rashes, osteolytic bone lesions, tumorous growth in various organs, and in some patients, organ dysfunction. The cause of the disease is obscure, and it is not yet understood why some patients develop single-system lesions only without relapse, whereas others develop fatal multiorgan disease. The expression of p53 tumor suppressor gene product detected immunohistochemically can be used as a guideline to alterations in DNA repair control and apoptosis. The authors have chosen to analyze p53 expression in biopsies from children with LCH and correlate it with clinical manifestation and outcome in a broad range of organs. PATIENTS AND METHODS: The study was performed on 50 specimens from 32 children (19 boys and 13 girls), median age 3 1/4 years, range 5 months to 12 1/3 years with a definite diagnosis of LCH based on CD1a positivity. The slides were stained with p53 antibody and semiquantitatively evaluated using a grading system from 1 to 5 as an estimate for 0% to 20%, 20% to 40%, 40% to 60%, 60% to 80%, and 80% to 100% p53-positive for pathologic Langerhans cells (pLC), respectively. RESULTS: The p53 protein was expressed in various degrees in pLC in all lesions. The degree of p53 expression could not be correlated to either clinical manifestation or outcome. CONCLUSIONS: An increased expression of p53 in pLC indicates an altered DNA repair control with or without abnormal control of apoptosis.     

Serum levels of interleukin-1 receptor antagonist and tumor necrosis factor-alpha are elevated in children with Langerhans cell histiocytosis

PURPOSE: Langerhans cell histiocytosis (LCH) is a rare disease with variable prognosis in which lesions and clinical features suggest that pro- and anti-inflammatory cytokines may be involved in its pathogenesis. The authors wished to evaluate whether serum levels of interleukin-1 receptor agonist (IL-1Ra) and tumor necrosis factor-alpha (TNF-alpha) are elevated in children with LCH and decrease after chemotherapy. PATIENTS AND METHODS: Circulating levels of IL-1Ra and TNF-alpha were measured in 23 and 8 children with LCH, respectively, and 7 pediatric controls using commercially available ELISA kits. All patients fulfilled the Histiocyte Society LCH Protocols criteria for diagnosis, stratification, and treatment. RESULTS: Pretreatment concentrations of IL-1Ra and TNF-alpha were found to be significantly elevated in patients with LCH compared with controls. Among LCH substages, a significant difference in IL-1Ra values was observed between individuals with single-system single-site disease vs. multisystem disease with risk-organ dysfunction. In all eight patients evaluated, IL-1Ra levels decreased after 6 weeks of chemotherapy. Lower values of TNF were observed in three patients after treatment. A positive and significant correlation between IL-1Ra and TNF serum concentrations was found. CONCLUSIONS: Patients with LCH have elevated levels of IL-1Ra and TNF, which decrease after chemotherapy.     

Pattern and course of single-system disease in Langerhans cell histiocytosis data from the DAL-HX 83- and 90-study

BACKGROUND: Single-system (SS) disease is the most common presentation in Langerhans cell histiocytosis (LCH) with a heterogenous clinical picture and course. Mostly bone and rarely skin or lymph nodes are involved. PROCEDURE: One hundred and seventy patients with SS-LCH were registered in the DAL-HX 83/90 studies. They were diagnosed according to uniform diagnostic criteria and followed by a standardised schedule. RESULTS: Single bone lesions were most common (68%), followed by multiple bone lesions (19%), isolated skin disease (11%), and isolated lymph node involvement (4 patients). In the detection of bone lesions radiographic skeletal survey proved to be superior to bone scan (97% vs. 82%). Treatment comprised surgery, irradiation and local instillation of steroids, and standardised chemotherapy for multifocal bone disease. After initial therapy 81% of the patients remained disease free. Reactivations restricted to the skeleton occurred in 18% of both unifocal and multifocal bone disease. Two skin patients had a chronic course. Fatality occurred only in one infant with skin disease who progressed to multi-system disease. Twenty-five percent of all patients developed permanent consequences, which were already present at diagnosis in about half of these patients and comprised mainly orthopedic problems related to lesional sites. Diabetes insipidus occurred in 3% and anterior pituitary dysfunction in 2% of the patients. CONCLUSIONS: The course in SS%LCH was benign. In bone disease reactivations remained restricted to the skeleton and did not influence survival. However, reactivations had an impact on morbidity, as permanent consequences were mostly related to the site of disease activity. Med Pediatr Oncol 2001;37:108-114.     

Central nervous system-related permanent consequences in patients with Langerhans cell histiocytosis

BACKGROUND: Permanent consequences in Langerhans cell histiocytosis (LCH) are irreversible late sequelae related to the disease that may severely impair the quality of life of survivors. The frequency and pattern of permanent consequences affecting the central nervous system (CNS) remains to be determined. PROCEDURE: In this single center study, 25 LCH patients observed for a median time of 10 years 3 months underwent a uniform thorough follow-up program including neuropsychological testing and electrophysiological evaluation. RESULTS: Overall permanent consequences were seen in 9 of 25 patients. Intracranial abnormalities were the most frequent including diabetes insipidus (DI) in seven patients, anterior pituitary deficiencies in five patients, and neurodegenerative CNS disease in five patients. No patient had overt neurological symptoms upon neurological evaluation, but psychological testing revealed subtle deficits in short-term auditory memory (STAM) in 14 patients. Brain stem evoked potentials showed abnormalities in four of nine tested patients, all of these four had neurodegeneration on MRI. CONCLUSION: Psychoneuroendocrine sequelae were found in an unexpectedly high number of patients in this single center study. Long-term follow-up focusing on such sequelae are important in LCH survivors, in order to detect early deficits, to monitor the evolution of the disease, and to provide specific support.     

Cholestasis, sclerosing cholangitis, and liver transplantation in Langerhans cell Histiocytosis

OBJECTIVE: To analyze features and outcomes of cholestasis, sclerosing cholangitis (SC), and liver transplantation (LTx) in patients with Langerhans cell Histiocytosis (LCH) between October 1987 and June 1999. STUDY DESIGN: Of 182 cases with LCH, 36 had hepatic involvement and 12 of those presented with cholestasis. These 12 were the focus of our study. Their median age was 23 months (range: 3-36). Hepatomegaly or hepatosplenomegaly was found in 11 of the 12; elevations of alkaline phosphatase, transaminases, gamma glutamyl transpeptidase (GGT), and less frequently direct bilirubin were detected. Sonography, liver biopsy, and cholangiography were consistent with the diagnosis of SC in 11 patients. None of the biopsies revealed Langerhans cells (LC). Frequently associated lesions of skin, bone, and ear were noted. Early patients were treated with Vinblastine/prednisone for 8 weeks, later patients with the LCH I and LCH II protocols of the Histiocyte Society (HS). RESULTS: Median follow-up was 28 months (range: 10-86). Three patients improved and remained without signs of progressive SC at 27, 32, and 86 months. Nine had progressive liver sequelae resistant to chemotherapy. Of these nine, five received LTx, three died before LTx with progressive SC, and one awaits LTx. Three LTx patients survive without disease reactivation 14, 25, and 37 months post-transplant. Two patients died less than one month after LTx, due to renal failure and sepsis in the first patient and bowel volvulus with perforation followed by sepsis in the second one. CONCLUSIONS: SC is a frequent and usually progressive sequela of multisystem LCH in our institution. LTx has become the treatment of choice for the majority of patients and should be considered early in cases with severe hepatic involvement.     

Response to subcutaneous therapy with mistletoe in recurrent multisystem Langerhans cell histiocytosis

We report a case of histologically proven multisystem (MS) Langerhans cell histiocytosis (LCH) with recurrent disease reactivations after systemic chemotherapy. Through the use of subcutaneous therapy with mistletoe (MT), an inactive disease state was achieved.