Langerhans cell histiocytosis (LCH): Guidelines for diagnosis,clinical work‐up,and treatment for patients till the age of 18 years

These guidelines for the management of patients up to 18 years with Langerhans cell histiocytosis (LCH) have been set up by a group of experts involved in the Euro Histio Net project who participated in national or international studies and in peer reviewed publications. Existing guidelines were reviewed and changed where new evidence was available in the literature up to 2012. Data and publications have been ranked according to evidence based medicine and when there was a lack of published data, consensus between experts was sought. Guidelines for diagnosis, initial clinical work‐up, and treatment and long‐term follow‐up of LCH patients are presented. Pediatr Blood Cancer 2013;60:175–184. © 2012 The Authors. Pediatric Blood & Cancer, published by Wiley Periodicals, Inc.     

Langerhans cell histiocytosis in childhood: Results from the Italian cooperative AIEOP-CNR-H.X '83 study

Ninety patients with biopsy-proven Langerhans cell histiocytosis (LCH) were enrolled from June, 1983, to December, 1988, in the multicenter AIEOP-CNR-H.X. '83 study. They were divided into two groups: poor prognosis (PP), comprising 11 children with organ dysfunction (OD), and good prognosis (GP), made up of 79 patients without OD. Eighty-four patients were evaluable for treatment results. Among GP patients, 16 with a single lesion received only local treatment, while 59 entered a clinical trial of immunotherapy and/or monochemotherapy with vinblastine (VBL). Nonresponders, sequentially received doxorubicin (ADM) and then etoposide (VP16). PP patients were treated with 4 week cycles of vincristine, ADM, cyclophosphamide, and prednisone for nine courses. The overall survival was 92.8% (100% for GP patients and 45.5% for PP patients) at 48 months. The complete response (CR) rates for immunotherapy, VBL, ADM, and VP16 were 10%, 62.9%, 42.8%, and 88.2%, respectively. Two of the 11 PP patients had a CR (18.2%), while six died and three are still alive with recurrent disease. The overall incidence of disease-related disabilities was 47.7%, while that of diabetes insipidus was 20%. Monochemotherapy is probably adequate in GP patients, while more effective treatments are needed for PP patients. © 1993 Wiley-Liss, Inc.     

Langerhans cell histiocytosis in non‐twin siblings

Langerhans cell histiocytosis (LCH), which has unknown pathogenesis, can manifest as many kinds of signs and symptoms at any age. Although its genetic background has not been exactly identified, the familial clustering of this disease has been described in some reports. It is very uncommon, however, in siblings who are not monozygotic or dizygotic twins. Reported herein is a case of LCH in non‐twin siblings (younger sister and elder brother) who were diagnosed at 3.3 and 14.5 years of age, respectively, and successfully treated with chemotherapy, with BRAF V600E mutation status, and a brief review of the literature.     

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.     

Langerhans cell histiocytosis in the adult

A study of 47 well-documented patients with Langerhans cell histiocytosis (LCH) showed a slight female preponderance, with onset as late as the ninth decade. The skin was the commonest site of presentation, but pulmonary, and bone involvement was frequent. Patients with single-site disease did best. The worst prognosis was seen in the elderly or those with organ dysfunction. A high incidence of associated malignant disease was seen, which could precede, be coincidental with, or occur after a diagnosis of LCH. © 1996 Wiley-Liss, Inc.     

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.     

Reactivation and risk of sequelae in Langerhans cell histiocytosis

OBJECTIVE: To evaluate disease reactivation in patients with Langerhans cell histiocytosis (LCH) and its impact on adverse sequelae. MATERIALS AND METHODS: A retrospective evaluation of 300 patients diagnosed with LCH between 1987 and 2002 with complete response to initial treatment was performed. RESULTS: Mean age at diagnosis was 5.3 years. With a mean follow-up of 4.8 years, reactivation of the disease occurred in 29.7% (89/300) of the patients, with two or more reactivations in 34.8% (31/89) of those. Reactivation occurred in 17.4, 36.8, 46.5, and 53.5% of the patients with single-system unifocal disease (Group A: 161 patients), single-system multifocal disease (Group B: 53 patients), multi-system disease without (Group C: 58 patients), and with (Group D: 28 patients) risk-organ involvement, respectively. The differences between the incidence rates of Groups A and B (P < 0.0004), A and C (P < 0.0001), and A and D (P < 0.0001) were highly significant. The most common reactivation sites involved were bone, middle ear, and skin; reactivation was rare in risk organs (9.5%). The median time between initial complete response and the first reactivation episode was 1 year for Group A, 1.3 years for Group B, and 9 months for Groups C and D. Most reactivation episodes (88%) occurred within the first 2 years of follow-up. Adverse sequelae were recognized in 242/300 patients: 71% (49/69) of patients with and 25.4% (44/173) without reactivations developed these adverse sequelae (P < 0.0001), respectively. Sites most commonly showing sequelae were bone, middle ear, and hypothalamus (Diabetes Insipidus). CONCLUSIONS: Incidence of reactivation correlates with the stage of the disease at diagnosis. Incidence of sequelae correlates with the occurrence of reactivations.     

多系统累及朗格汉斯细胞组织细胞增生症治疗进展

朗格汉斯细胞组织细胞增生症(Langerhans cell histiocytosis,LCH)是一种罕见的树突细胞和网状细胞系统增生性疾病,目前分为单系统LCH(SS-LCH)和多系统LCH(MS–LCH)。MS-LCH的预后较差,及时有效地干预是患者存活的关键。目前有化学治疗、免疫治疗、造血干细胞移植治疗等多种治疗方案。文章就MS-LCH相关治疗方案的进展进行综述。     

Treatment of Langerhans cell histiocytosis with a modified risk‐adapted protocol—experience from a tertiary cancer institute in India

Background

Involvement of risk‐organs (RO+) in Langerhans cell histiocytosis (LCH) and inadequate early response identifies patients at high risk for relapse and mortality requiring intensive salvage therapy including stem cell transplant, adding cost and toxicity. To mitigate this, we used a standard induction, augmented with metronomic etoposide, and prolonged maintenance—similarly augmented for RO+, and retrospectively analyzed its impact.

Procedure

LCH patients from 2009 through 2014 were included. Patients received standard vinblastine and prednisolone therapy weekly till week 25 for RO+. Single site (SS) and multisystem (MS) without risk organ involvement (RO?) received 3‐weekly pulses from week 13 till week 25. Maintenance was 3‐weekly vinblastine and 5‐day prednisolone pulses, daily 6‐mercaptopurine (60 mg/m²) and weekly methotrexate (15 mg/m²) for 18 and 9 months for RO+ and MSRO?, respectively. RO+ also received oral etoposide (50 mg/m²) for 21 of every 28‐day cycle for the first year.

Results

Fifty consecutive patients were analyzed. Median age was 36 months (4–189 months). SS, MSRO?, and RO+ were 29 (58%), 12 (24%), and nine (18%), respectively. Four were lost to follow‐up and excluded from further evaluation. On response evaluation at week 6, 24 (52%) had no active disease (NAD), 17 (37%) had AD‐better (where AD is active disease), and one (2%) had AD‐worse. In RO+, eight (66.6%) had AD‐better and three (25%) had NAD. Forty‐five patients had NAD by week 12. Three patients relapsed. With median follow‐up of 39 months (8–84), 5‐year event free survival was 85.6% (RO? and SS), and 100% for RO+. One patient's death in remission from unrelated causes resulted in overall survival of 97%.

Conclusions

RO+LCH receiving oral etoposide augmented induction and maintenance had early and durable responses. Prolonging maintenance lowered reactivation rates in RO+ and RO?LCH, resulting in excellent survival.

     

Late manifestation of diabetes insipidus in “pure” cutaneous Langerhans cell histiocytosis

We report a case of congenital Langerhans cell histiocytosis (LCH), presenting with a generalized varicelliform rash in an otherwise well newborn. No signs of organ involvement were found on repeated skeletal radiography, abdominal ultrasonography and laboratory studies. A diagnosis of “pure cutaneous” LCH was established. Skin manifestation was unusually severe and recurred during the first 20 months of life, but responded well to combination chemotherapy (methylprednisone, vinblastine) while the child continued to thrive. At the age of 2 years the patient presented with acute onset diabetes insipidus due to infiltration of the hypothalomo-pituitary stalk region. He died for reasons unknown at the age of 28 months. Conclusion“Pure cutaneous” LCH, frequently also referred to as congenital self-healing LCH, is a variable disorder which may be complicated by late organ involvement. Close follow up and thorough diagnostic evaluation is therefore mandatory. Received: 25 September 1996 / Accepted: 21 October 1996     

朗格汉斯细胞组织细胞增生症治疗进展

目前朗格汉斯细胞组织细胞增生症(LCH)在治疗上采用分型、分级而分治的策略。研究表明,单系统病变(SS-LCH)的预后好,而伴危险器官受累的多系统病变(MS-LCH)及难治性/复发性病例(Re-LCH)预后差。随着化学疗法的进步,伴危险器官受累的MS-LCH 5年生存率已达80%以上,Re-LCH的治疗有效率达60%以上,Re-LCH可行造血干细胞移植以达到根治。     

Fifteen years of treatment with intravenous immunoglobulin in central nervous system Langerhans cell histiocytosis

Aim: There is currently no well‐accepted therapy for central nervous system Langerhans cell histiocytosis (CNS‐LCH), a neuroinflammatory disease clinically characterized by often progressive, neurological symptoms including ataxia, dysarthria, dysphagia, hypertonicity, intellectual impairment and behavioural abnormalities. We applied immunomodulative/anti‐inflammatory treatment on a patient with progressive CNS‐LCH disease. Method: Intravenous immunoglobulin (IVIG) was administered monthly for 15 years to a patient with severe, image‐verified neurodegenerative CNS‐LCH. Results: During the IVIG treatment, the neurological deterioration initially appeared to be haltered, but over time there was still some deterioration. Conclusions: IVIG may be beneficial in partly haltering CNS‐LCH neurodegeneration, but further studies are needed.