Hypothalamo-Pituitary Abnormalities in Adult Patients with Langerhans Cell Histiocytosis: Clinical, Endocrinological, and Radiological Features and Response to Treatment

Abstract

Langerhans cell histiocytosis (LCH) is a rare disorder in which granulomatous deposits occur at multiple sites within the body, but which often involves the hypothalamo-pituitary axis (HPA). Although diabetes insipidus (DI) is a well recognized complication, the frequency of anterior pituitary and other nonendocrine hypothalamic (NEH) involvement has not been well defined, particularly in adult patients with the disease. We have evaluated the frequency and progression of LCH-related anterior pituitary and other NEH dysfunction and their responses to treatment in 12 adult patients with histologically proven LCH and DI. They were followed up for a median of 11.5 yr (range, 3-28 yr) after the diagnosis of DI was made. Study evaluations comprised clinical (including formal psychometric assessment where appropriate), basal and dynamic pituitary function tests, and radiology with computed tomography and/or magnetic resonance imaging scanning. Eleven patients received systemic treatment, and 5 patients received external beam radiotherapy confined to the HPA. The median age at diagnosis of DI was 34 yr (range, 2-47 yr); DI was the presenting symptom in four patients, whereas the remaining eight each developed DI 1-20 yr (median, 2 yr) after the diagnosis of LCH. Eight patients developed one or more anterior pituitary hormonal deficiencies at a median of 4.5 yr (range, 2-22 yr) after the diagnosis of DI: GH deficiency developed in eight patients (median, 2 yr; range, 2-22 yr), FSH-LH deficiency in 7 patients (median, 7 yr; range, 2-22 yr), and TSH and ACTH deficiency in five patients (median, 10 yr; range, 3-16 and 3-19 yr), respectively; five patients developed panhypopituitarism. In addition, seven patients with anterior pituitary dysfunction also developed symptoms of other NEH dysfunctions at a median of 10 yr (range, 1-23 yr): five morbid obesity (body mass index, >35), five short term memory deficits, four sleeping disorders, two disorders of thermoregulation, and one adipsia. All patients developed disease outside of the hypothalamus during the course of the study, and no fluctuation of disease activity in the HPA region was noted. Radiological examination of the HPA was abnormal in each of the eight patients with anterior pituitary involvement and in the seven patients with NEH dysfunction (one or more abnormalities): seven had thickening of the infundibulum, and one had hypothalamic and thalamic signal changes. All patients who had a magnetic resonance imaging scan had absence of the bright spot of the posterior pituitary on the T1-weighted sequences, and in four patients with DI and normal anterior pituitary function this was the only abnormality. The five patients who received radiotherapy to the HPA achieved a partial or complete radiological response, and there was no evidence of tumor progression in this region. No form of therapy, including chemotherapy, improved any established hormonal deficiencies or symptoms of NEH. In summary, in our adult patients with hypothalamic LCH and DI, anterior pituitary hormo...

Neurodegeneration in the course of Langerhans cell histiocytosis

“…Although DI may predate the diagnosis of LCH it usually develops within 1 year from diagnosis [7]. In our patient, the delay by 19 years between the occurrence of DI and diagnosis of LCH was particularly striking, and supports the hypothesis that LCH in adults runs a relatively indolent course [8].…”

Langerhans cell histiocytosis and pituitary function

“…Anterior pituitary hormonal deficiencies and DI persisted during the follow-up period irrespective of the treatment administered, except in one patient in whom hypogonadism resolved [9]. The results of the present study confirm previous findings and highlight the importance of assessing and following up pituitary function in patients with multisystem LCH and DI or abnormal hypothalamic-pituitary region imaging [7,8,10]. Anterior pituitary hormonal deficiencies should be diagnosed early and treated appropriately as they can affect quality of life and can also be life threatening.…”

“…Unfortunately, that study did not provide information regarding the involvement of the anterior pituitary gland and its function, although a previous retrospective study in a pediatric population had indicated that anterior pituitary deficiency is common in patients with DI [6]. It was only after a retrospective study which evaluated 12 adult patients with LCH, who presented either with DI or developed DI during the course of the disease, assessed regularly using a consistent investigational protocol of pituitary function that the evolution of anterior pituitary hormonal deficiency and associated implications became apparent [7]. Since then, a number of studies, mainly including relatively small number of patients, have provided more information on the evolution of pituitary dysfunction in patients with LCH along with the morphological changes that involve the hypothalamic-pituitary region [6,8].…”

“…The recently published recommendations from the Euro-Histio-Net recognize the high prevalence of anterior pituitary dysfunction (approximately 20 %) in patients with LCH and propose a specific investigational and follow-up protocol [1]. Anterior pituitary dysfunction although not invariably associated with abnormal hypothalamic-pituitary region imaging, it is almost always encountered in patients with multisystem disease who have DI and hypothalamic-pituitary pathology on magnetic resonance (MR) imaging [4,7,8]. Growth hormone deficiency is the most frequent disease-related anterior pituitary deficiency found in up to 50 % of patients, followed by gonadotrophin deficiency, whereas adrenocorticotrophin (ACTH) and thyreotrophin (TSH) are relatively less common; moderately elevated prolactin (PRL) levels are less commonly found and are attributed to pituitary stalk involvement [1,4].…”

An Unusual Intracranial Inflammatory Process of Unknown Origin

“…In HPA involvement, central diabetes insipidus (CDI) arises in up to 50% of cases, 1 and anterior pituitary hormone deficiencies in 20%. 2 CDI is rare and characterised by polyuria, polydipsia and hypotonic urine due to antidiuretic hormone deficiency and, whilst LCH is a cause, it is by no means the most common cause. 3,4 Conversely, the latter pattern presents with a mixture of ataxia, nystagmus, dysarthria, spastic tetraparesis, pseudobulbar palsy or cognitive/behavioural alterations 5 -the first two and latter symptoms were seen in our patient but not CDI.…”