Hypothalamo-pituitary abnormalities in adult patients with langerhans cellhistiocytosis: Clinical, endocrinological, and radiological features and response to treatment

Langerhans cell histiocytosis (LGH) is a rare disorder in which granulomato us deposits occur at multiple sites within the body, but which often involv es the hypothalamo-pituitary axis (HPA). Although diabetes insipidus (DI) i s a well recognized complication, the frequency of anterior pituitary and o ther nonendocrine hypothalamic (NEH) involvement has not been well defined, particularly in adult patients with the disease. We have evaluated the fre quency and progression of LCH-related anterior pituitary and other NEH dysf unction and their responses to treatment in 12 adult patients with histolog ically proven LCH and DI. They were followed up for a median of 11.5 yr (ra nge, 3-28 yr) after the diagnosis of DI was made. Study evaluations compris ed clinical (including formal psychometric assessment where appropriate), b asal and dynamic pituitary function tests, and radiology with computed toma graphy and/or magnetic resonance imaging scanning. Eleven patients received systemic treatment, and 5 patients received external beam radiotherapy con fined to the HPA. The median age at diagnosis of DI was 34 yr (range, 2-47 yr); DI was the pr esenting symptom in four patients, whereas the remaining eight each develop ed DI 1-20 yr (median, 2 yr) after the diagnosis of LCH. Eight patients dev eloped 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 pa tients (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 patie nts 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 disorde rs of thermoregulation, and one adipsia. Al patients developed disease outs ide of the hypothalamus during the course of the study, and no fluctuation of disease activity in the HPA region was noted. Radiological examination o f the HPA was abnormal in each of the eight patients with anterior pituitar y involvement and in the seven patients with NEH dysfunction tone or more a bnormalities seven had thickening of the infundibulum, and one had hypothal amic 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 TL-weighted sequences, and in four patients with DI and normal anterior pituitary function this was the only abnormality. The five patients who re ceived radiotherapy to the HPA achieved a partial or complete radiolagical 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 pi tuitary hormonal deficiencies developed in 8 of 12 patients; these occurred over the course of 20 yr. They were frequently accompanied by structural c hanges of the HPA, although these were often subtle in nature. In addition, symptoms of NEH dysfunction developed in up to 90%; of such patients and c omplicated management. Radiotherapy may be useful in achieving local contro l of tumor, but established anterior, posterior pituitary, and other NEH dy sfunctions do not improve in response to current treatment protocols. Patie nts with LCH and DI, particularly those with multisystem disease and a stru ctural lesion on radiology, should undergo regular and prolonged endocrine assessment to establish anterior pituitary deficiency and provide appropria te hormonal replacement.