Langerhans cell histiocytosis in adultsReport from the International Registry of the Histiocyte Society

Abstract

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.

Introduction

The term Langerhans-cell histiocytosis (LCH), formerly known as histiocytosis X, encompasses a spectrum of diseases characterised by the proliferation and infiltration of organs by pathological Langerhans cells [1]. The clinical manifestations of the disease are largely related to the pattern of infiltration of the several organs and organ systems that may be involved, including bone, skin, hypothalamus, liver, lung and lymph nodes [2]. The term ‘eosinophilic granuloma’ [3] has been used in the past to indicate localised forms of the disease, whereas a number of terms have been used to indicate multisystem forms of the disease [4], including Abt-Letterer-Siwe 5, 6, 7 and Hand-Schuller-Christian 8, 9, 10 diseases.

The current classification developed by the Histiocyte Society provided uniform criteria for the diagnosis and clinical evaluation of patients with LCH. ‘Definitive diagnosis’ requires the finding of Birbeck granules in lesional cells by electron microscopy or demonstration of CD1a antigenic determinants on the surface of lesional cells; ‘diagnosis’ is justified when the lesion is characteristic by light microscopy and the lesional cells show the presence of two or more of the following features: positive stain for ATPase, S-100 protein, or alpha-d-mannosidase, or characteristic binding of peanut lectin in lesional cells; ‘presumptive diagnosis’ is warranted when findings, on study of conventionally stained biopsy material alone, are merely ‘consistent’ with those defined in the literature 11, 12.

The aetiology and pathogenesis of LCH remains largely undefined. Although LCH has been considered a sporadic disorder, some authors have recently reported a familial clustering in which a second affected relative was found in nearly 1% of cases, suggesting a familial predisposition [13]. Furthermore, chromosomal instability has been identified as a frequent abnormality in peripheral blood lymphocytes from patients with LCH [14]. Whether this abnormality represents the result of a constitutional predisposing factor or perhaps a hallmark of an environmental event associated with development of LCH remains to be assessed [15].

Experience in randomised trials conducted by the Histiocyte Society in children has led to the identification of the diagnostic features of LCH [16] and of the factors that influence the response to therapy [17]. LCH may be diagnosed at any age, from birth to those aged over 80 years 18, 19. Children with multisystem disease present at a median age of 18 months. Although a younger age at presentation has often been linked to a higher probability of disease reactivation and dissemination, resulting in a worse prognosis [20], the LCH-II trial demonstrated that age is not an independent prognostic factor in childhood LCH [17].

Reports of studies of adults with LCH have been available for many years, but the lack of large series or of prospective trials has impeded the acquisition of knowledge of the disease in this age group. Some of the reported series may have inherent biases in their demographics and treatments because of the types of centres they originate from.

To address this issue, the Histiocyte Society established a registry for LCH in adults. We report here, the preliminary results of an analysis of the first 274 cases collected in this registry.