Langerhans cell histiocytosis

Langerhans cell histiocytosis (LCH) is a poorly understood proliferative disease, with different patterns of clinical presentation. Currently it is classified according to the number and type of system involved and the degree of organ dysfunction. The aetiology of the disease remains uncertain, and in some cases the disease is polyclonal, suggesting a reactive condition. Many cytokines have been implicated in the pathogenesis of LCH. Different therapeutic approaches can be considered depending on the affected organ, including surgery, radiotherapy and chemotherapy. Long-term organ dysfunction may remain, despite disease control and/or eradication, making indefinite supportive treatment mandatory. Here we present a literature review on all of the aspects of the disease, treatment approaches and existing protocols, and finally an adult clinical case. Supported by an unrestricted educational grant from GlaxoSmithKline.     

Pathology of Langerhans cell histiocytosis

The spectrum of the histopathology of Langerhans cell histiocytosis was presented with special attention paid to the pathologic Langerhans cell as the diagnostic lesional cell. Features that distinguish this histiocyte from others are defined by electron microscopic demonstration of Birbeck granules and by immunohistochemical characteristics such as possession of antigenic determinant(s) that react with the monoclonal antibody T6. The relationship between Langerhans cells and the other histiocytes from which they are derived seems to be determined by events initiated by surface antigens reacting with specific antibodies. Immunohistochemical tests that are of value in diagnosing and classifying the various histiocytosis syndromes include those used to identify the S-100 antigen, T6 antigenic determinant(s), and peanut agglutinin binding sites. The use of a standard nomenclature and diagnostic criteria for the histiocytosis syndromes is encouraged as a step forward in progress to better understand and communicate about these puzzling disorders.     

Langerhans cell histiocytosis of the female genital tract

Langerhans cell histiocytosis (LCH) of the female genital tract is rare. Four new cases are reported, and there is a review of the 38 cases in the literature. This disease may involve the vulva, vagina, cervix, endometrium, and ovary. Four distinct patient groups, segregated on the basis of initial presentation and subsequent anatomic extent of disease, were categorized as follows: (1) "pure" genital LCH, (2) genital LCH with subsequent multi-organ involvement, (3) oral or cutaneous LCH with subsequent genital and multi-organ involvement, and (4) diabetes insipidus with subsequent genital and multi-organ disease. Although involvement of the genital tract can occur at any age, it is most common in young adulthood. Clinically, LCH may mimic either primary neoplasia or various inflammatory lesions; the major pathologic differential diagnosis is venereal and other inflammatory diseases. The pure genital form may have a distinct nosologic position in the spectrum of LCH similar to the "pure," self-limited cutaneous histiocytosis seen in infants. There is no correlation between histologic findings and the outcome of the genital lesions. There is also no correlation between clinical presentation and/or the extent of involvement and outcome of genital lesions; complete regression, partial improvement, persistent lesions, and recurrences were seen in all four groups of patients. The treatment of genital LCH is not well defined and is highly individualized. Therapy has included surgery, radiation, topical corticosteroids, topical nitrogen mustard, systemic chemotherapy, and combination therapy; mixed results were obtained with all treatment modalities. Although no modality has been shown to yield a superior outcome, complete surgical excision is advocated as initial therapy.     

骨骼朗格汉斯细胞增生症的治疗进展

朗格汉斯细胞增生症是以朗格汉斯细胞异常累积为特征的疾病,其发病原因尚不明确,发病率约为1∶1 500 000.患者以儿童为主,男性多见.根据朗格汉斯细胞增生症病灶累及部位及临床表现不同可分为嗜酸性肉芽肿,汗雪氏病（Hand-Schüller-Christian disease）及里斯氏病（Letterer-Siwe disease）.     

Hepatic Langerhans cell histiocytosis: A review

Hepatic Langerhans cell histiocytosis (LCH) is characterized by proliferation and accumulation of Langerhans cells in the liver, causing liver dysfunction or forming a mass lesion. The liver can be involved in isolation, or be affected along with other organs. A common clinical hepatic presentation is cholestasis with pruritis, fatigue and direct hyperbilirubinemia. In late stages, there may be hypoalbuminemia. Liver biopsy may be required for the diagnosis of hepatic LCH. Histologic finding may be diverse, including lobular Langerhans cell infiltrate with mixed inflammatory background, primary biliary cholangitis-like pattern, sclerosing cholangitis-like pattern, and even cirrhosis at later stages. Because of its non-specific injury patterns with broad differential diagnosis, establishing a diagnosis of hepatic LCH can be challenging. Hepatic LCH can easily be missed unless this diagnosis is considered at the time of biopsy interpretation. A definitive diagnosis relies on positive staining with CD1a and S100 antigen. Liver involvement is a high risk feature in LCH. The overall prognosis of hepatic LCH is poor. Treating at an early stage may improve the outcome. Systemic chemotherapy is the mainstay of treatment and liver transplantation may be offered. New molecular markers involved in pathogenesis of LCH are being explored with a potential for targeted therapy. However, further studies are needed to improve outcome.     

Cytogenetic abnormalities in Langerhans cell histiocytosis.

We present the cytogenetic investigations of five histiocytic tumour lesions from children. In four cases there was a confirmed diagnosis of Langerhans cell histiocytosis (LCH) and one case of histiocytosis that did not fulfil all the criteria for true LCH. All five cases showed cytogenetic abnormalities, including the first report of an abnormal clone in LCH. The clone showed a t(7;12)(q11.2;p13) translocation and was detected in only a small percentage of cells. This case and a further three also contained non-clonal abnormalities and an increase in chromosome breakage. The fifth case, the only one in which no acquired abnormalities were seen, had a constitutional paracentric inversion of chromosome 13q.     

骨朗格汉斯组织细胞增生症诊断难点分析

  目的  分析讨论骨朗格汉斯组织细胞增生症（bone Langerhans cell histiocytosis,BLCH）诊断中的难点及应对策略。  方法  回顾性分析上海市第一人民医院2014年1月至2020年12月期间诊断为B-LCH患者的临床、影像及病理资料,对诊断病例和未诊断病例进行逐例分析讨论。  结果  1）临床诊断率为7%（2/30）,难点在于缺乏诊断意识及临床特征特异性不足。患者年龄<14岁;好发于颅骨、脊柱等骨组织;局部疼痛,疾病进展相对缓慢;累及其他系统,如累及垂体引起尿崩症等,以及复发病例对诊断有提示意义。2）影像诊断率为27%（8/30）,难点在于影像表现的多样性导致该病与感染、偏良性病变、恶性病变均容易混淆。诊断时需仔细甄别影像特征,并密切结合临床综合分析,进一步行CT三维重建、MRI、PET-CT检查可提高该病的诊断率。3）病理初次、再次、三次诊断率分别为60%、33%、7%,难点在于当穿刺标本量少、大量炎症背景、肿瘤细胞特征不典型时会造成诊断困难。病理医生应多阅片,多结合临床,加强对该病的认识和诊断能力,当临床-影像有指向性意见时,可降低病理诊断难度和降低潜在的误诊、漏诊风险。  结论  B-LCH是一种发生于骨的罕见造血系统组织细胞类肿瘤,临床、影像、病理诊断均有难度,各科诊断医生需提高对该病的认识和诊断意识,采用临床-影像-病理等多学科联合诊疗方法对提高诊断准确率尤其重要。      

Langerhans cell histiocytosis: Current concepts and treatments

Langerhans cell histiocytosis (LCH) is a rare proliferative disorder of cells with the phenotype of activated Langerhans cells. The diagnosis of LCH is often delayed or missed. Many questions about LCH remain to be answered, including whether it is caused by a malignancy or by immune dysregulation. Data from the early 1990s showed that LCH consisted of an accumulation of monoclonal LCH cells, suggesting a neoplastic disorder. However, further investigations with current sophisticated techniques have not shown consistent genomic aberrations. Recent data which suggests a role for an IL-17A dependant pathway of dendritic cell fusion in LCH remains to be proven. The most recent data taken together swing the pendulum towards an immunologic aberration.     

Clinical and prognostic features of Langerhans cell histiocytosis in adults

Langerhans cell histiocytosis (LCH) is a rare disease characterized by clonal expansion of CD1a⁺CD207⁺ myeloid dendritic cells. The features of LCH are mainly described in children and remain poorly defined in adults; therefore, we conducted a nationwide survey to collect clinical data from 148 adult patients with LCH. The median age at diagnosis was 46.5 (range: 20–87) years with male predominance (60.8%). Among the 86 patients with detailed treatment information, 40 (46.5%) had single system LCH, whereas 46 (53.5%) had multisystem LCH. Moreover, 19 patients (22.1%) had an additional malignancy. BRAF V600E in plasma cell-free DNA was associated with a low overall survival (OS) rate and the risk of the pituitary gland and central nervous system involvement. At a median follow-up of 55 months from diagnosis, six patients (7.0%) had died, and the four patients with LCH-related death did not respond to initial chemotherapy. The OS probability at 5 years post-diagnosis was 90.6% (95% confidence interval: 79.8–95.8). Multivariate analysis showed that patients aged ≥60 years at diagnosis had a relatively poor prognosis. The probability of event-free survival at 5 years was 52.1% (95% confidence interval: 36.6–65.5), with 57 patients requiring chemotherapy. In this study, we first revealed the high rate of relapse after chemotherapy and mortality of poor responders in adults as well as children. Therefore, prospective therapeutic studies of adults with LCH using targeted therapies are needed to improve outcomes in adults with LCH.     

Treatment of Langerhans cell histiocytosis in children with etoposide.

Ten children with Langerhans cell histiocytosis (LCH) were treated with etoposide. For five patients, this was the initial diagnosis. The other five had failed to respond to previous therapies. Etoposide (100 mg/m2) was given intravenously twice a week for 4 weeks, followed by maintenance therapy every 2 to 4 weeks for 2 years. All 10 patients responded to etoposide, and 6 of them (60%) have been in complete remission for 3 to 36 months without any side effects. One patient relapsed with diabetes insipidus, one with a soft tissue mass, and two others developed multiple bone lesions. Chemotherapy with etoposide appears to be effective and safe for the treatment of children with systemic LCH.     

Treatment of recurrent Langerhans cell histiocytosis in children with 2-chlorodeoxyadenosine

The objective of this study was to evaluate the efficacy of 2-chlorodeoxyadenosine (2-CdA), a purine nucleoside analog, in treating recurrent Langerhans cell histiocytosis (LCH) in children. This study retrospectively analysed the clinical records of 13 patients who were seen in the department for recurrent LCH. These patients were treated consecutively with 2-CdA chemotherapy between July 1997 and May 2005. Median age at diagnosis was 4 years 7 months and median pre-treatment duration of disease was 16.4 months. Four children received 0.1 mg kg-1 per day for 7 days and nine patients 5 mg m-2 per day for 5 days, repeated every 21 days. The maximum number of courses of 2-CdA per patient was limited to six. Seventy-six courses of 2-CdA were administered without difficulty. All 13 patients (100%) had a clinical response documented by radiographic investigation. Nine patients did not require additional therapy and remain in complete remission (CR). Four remaining children are currently disease-free after receiving other therapy as irradiation (two cases) or maintenance chemotherapy (vinblastine, prednisone and 6-mercaptopurine) (one case) or chemotherapy (vinblastine) + irradiation (one child) ( Table I). Hematologic toxicity was minimal and no infectious complications were documented. Median follow-up after initiation of 2-CdA treatment was 4 years 3 months (range 7 months - 8 years 2 months). This experience confirms the reported efficacy of 2-CdA in the treatment of LCH. However, further studies are needed to determine the role of this agent in high-risk patient who did not achieve complete remission after 2-CdA administration.     

Clinico-biologic profile of Langerhans cell histiocytosis: a single institutional study

CONTEXT: Langerhans cell histiocytosis (LCH) is a rare atypical cellular disorder characterized by clonal proliferation of Langerhans cells leading to myriad clinical presentations and highly variable outcomes. There is a paucity of Indian studies on this subject. AIM: To present the experience of management of LCH at a single institution. SETTINGS AND DESIGN: This is a retrospective observational study of patients with LCH who presented at the Tata Memorial Hospital between January 1987 and December 2002. MATERIALS AND METHODS: Fifty-two patients with LCH were treated in the study period. Due to the long observation period and variability in diagnostic and therapeutic protocols, the patients were risk-stratified based on present criteria. The disease pattern, management approaches and treatment outcomes of patients were recorded. STATISTICAL ANALYSIS USED: Statistical analyses were done using Student's 't' test, test for proportion and survival estimates based on the Kaplan-Meier method. RESULTS: The median age at presentation was 3 years and more than 48% of the patients had Group I disease. Skeleton, skin and lymphoreticular system were the commonly involved organs. Majority (80%) required some form of therapy. The projected overall survival is 63% at 10 years and mean survival is 118 months. Seventeen percent of surviving patients developed long-term sequelae. CONCLUSIONS: The clinico-biologic profile of LCH patients in India is largely similar to international patterns except a higher incidence of lymphoreticular involvement. Majority of the patients respond favorably to therapy and have a good outcome, except a subset of Group I patients who warrant enrollment in clinical trials with innovative therapeutic strategies to improve outcome.     

Radiation therapy for diabetes insipidus caused by Langerhans cell histiocytosis.

Hypothalamic-pituitary radiation therapy has been the standard treatment for the diabetes insipidus of Langerhans cell histiocytosis. The goal of this study was to assess the role of radiation therapy in Langerhans cell histiocytosis-associated diabetes insipidus and to compare the results with nonirradiated controls. Forty-seven patients with pathologically confirmed Langerhans cell histiocytosis were diagnosed with diabetes insipidus between 1950 and 1989 and were treated at the Mayo Clinic. These patients were divided into two groups on the basis of treatment for the diabetes insipidus: The first group (radiation group) included 30 patients (28 of whom were evaluable for response) who received hypothalamic-pituitary radiation therapy, and the second group (control group) included 17 patients who did not. A partial response to treatment was defined as a reduction in vasopressin dosage or improvement in computed tomography (CT) or magnetic resonance imaging (MRI). A complete response was defined as no further need for vasopressin therapy or normalization of CT or MRI. End points analyzed included treatment response, patient characteristics, morbidity, dose-response relationship, and survival. Patient characteristics of the two groups were similar except for age and lung involvement, both of which were significantly less in the radiation group. Thirty-six percent of patients (10 of 28) in the radiation group responded to hypothalamic-pituitary radiation therapy (22% complete response and 14% partial response), whereas none in the control group responded. Five of the six complete responders were irradiated within 14 days of the diagnosis of diabetes insipidus. The mean dose used in the responding and nonresponding patients was 11.2 and 10 Gy, respectively. Three of five patients (60%) treated with more than 15 Gy responded compared to seven of 23 (30%) treated with less than 15 Gy. Eight of the 10 responders (80%), compared to 16 of 35 nonresponders (46%), were female. Only one in 20 patients with concomitant lung histiocytosis responded. Complications of therapy may include insufficiency in other hypothalamic-pituitary axes in the treated patients. Actuarial survivals at 5, 10, 20, and 40 years for the entire group were 80%, 78%, 75%, and 65%, respectively, with a median follow-up in living patients of 14.7 years.     

骨的Langerhans细胞组织细胞增生症8例临床病理分析

目的探讨骨的Langerhans细胞组织细胞增生症的临床病理学特征。方法对8例骨的Langer-hans细胞组织细胞增生症的临床资料和组织形态进行分析并采用免疫组织化学方法检测。年龄4～40岁,平均16岁。男5例,女3例。结果Langerhans细胞组织细胞增生症好发于青少年,组织学上由特征性的Langerhans细胞及嗜酸性粒细胞组成,免疫组织化学检测Langerhans细胞表达CD1a及S-100蛋白。结论Langerhans细胞组织细胞增生症是好发于骨的肿瘤性病变,发生在骨的Langerhans细胞组织细胞症要与慢性骨髓炎及恶性淋巴瘤相鉴别,该病治疗主要是手术刮除病灶及放疗,大多数患者预后良好。     

Langerhans cell histiocytosis in adults. Report from the International Registry of the Histiocyte Society

Langerhans cell histiocytosis (LCH), characterised by the infiltration of one or more organs by large mononuclear cells, can develop in persons of any age. Although the features of this disease are well described in children, they remain poorly defined in adults. From January 2000 to June 2001, 274 adults from 13 countries, with biopsy-proven adult LCH, were registered with the International Histiocyte Society Registry. Information was collected about clinical presentation, family history, associated conditions, cigarette smoking and treatment, to assist in future management decisions in patients aged 18 years and older. There were slightly more males than females (143:126), and the mean ages at the onset and diagnosis of disease were 33 years (standard deviation (S.D.) 15 years) and 35 years (S.D. 14 years), respectively. 2 patients had consanguineous parents, and 1 had a family history of LCH; 129 reported smoking (47.1%); 17 (6.2%) had been diagnosed with different types of cancer. Single-system LCH, found in 86 patients (31.4%), included isolated pulmonary involvement in 44 cases; 188 patients (68.6%) had multisystem disease; 81 (29.6%) had diabetes insipidus. Initial treatment consisted of vinblastine administered with or without steroids, to 82 patients (29.9%), including 9 who had received it with etoposide, which was the sole agent given to 19 patients. 236 patients were considered evaluable for survival. At a median follow-up of 28 months from diagnosis, 15 patients (6.4%) had died (death rate, 1.5/100 person years, 95% Confidence Interval (95% CI) 0.9-2.4). The probability of survival at 5 years postdiagnosis was 92.3% (95% CI 85.6-95.9) overall, 100% for patients with single-system disease (n=37), 87.8% (95% CI 54.9-97.2) for isolated pulmonary disease (n=34), and 91.7% (95% CI 83.6-95.9) for multisystem disease (n=163). Survival did not differ significantly among patients with multisystem disease, with or without liver or lung involvement) 5-year survival 93.6% (95% CI 84.7-97.4) versus 87.5% (95% CI 65.5-95.9), respectively; P value 0.1). LCH in adults is most often a multisystem disease with the highest mortality seen in patients with isolated pulmonary involvement. It should be included in the differential diagnosis of disseminated or localised disease of the bone, skin and mucosa, as well as the lung and the endocrine and central nervous system, regardless of the age of the patient. A prospective international therapeutic study is warranted.