Diabetes insipidus associated with a thickened pituitary stalk in a case of Langerhans Cell Histiocytosis.

Diabetes insipidus (DI) associated with a thickened pituitary stalk is a diagnostic challenge in the pediatric population. Langerhans Cell Histiocytosis (LCH) is a rare cause of this entity. A 4-year-old male child presented with central DI of 1-year duration, associated with a thickened pituitary stalk. The etiology for the same remained elusive as the patient had no other manifestation to suggest LCH. A year later, the patient developed a left frontal scalp swelling. Neuroradiology demonstrated multiple punched out osteolytic lesions in both the frontal bones. The infundibulum was thickened and showed post-contrast enhancement. Histology and immunohistochemistry (IHC) of the biopsy specimen confirmed LCH. The child was administered chemotherapy according to LCH protocol, which resulted in 33% reduction in the size of the skull lesions. The DI was controlled with medical management. The present case highlights the need for serial follow-up and magnetic resonance (MR) imaging that led to a diagnosis of LCH. The clinical presentation and management of central DI and a thickened pituitary stalk is presented and the relevant literature is discussed.

Introduction

The common etiologies presenting with central diabetes insipidus (DI) associated with a thickened pituitary stalk in the pediatric population are: Langerhans Cell Histiocytosis (LCH), central nervous system tumors such as germinoma and craniopharyngioma, granulomatous lesions like tuberculosis and sarcoidosis and autoimmune disorders like lymphocytic infundibuloneurohypophysitis.

LCH is a rare disease caused by abnormal proliferation of antigen presenting cell of dendritic lineage, known as Langerhans cell. It has a reported incidence of 0.2–2.0 cases per 100,000 children under the age of 15 years.[1] The commonest skeletal site for LCH involvement is the diploe of the skull. DI is the earliest and principal manifestation of central nervous system involvement, and neuroradiology demonstrates a thickened infundibular stalk.[1]

Case Report

A 4-year-old male child presented with excessive urine output and increased frequency of micturition. He had complaints of increased thirst and fluid intake for 6 months. There was no history of trauma, autoimmunity and tuberculosis, joint pain and deformity. DI was confirmed with water deprivation test and decreased random urine osmolality value of 77.00 mosm/kg (normal serum osmolality: 295.00 mosm/kg). Urine specific gravity was 1.005. Magnetic resonance imaging (MRI) showed a uniformly thickened pituitary stalk that enhanced on contrast administration. There was no other cranial pathology detected. All investigations performed to rule out the common causes for DI with a thickened pituitary stalk in pediatric population were within normal limits. These tests included chest radiograph, complete hemogram, erythrocyte sedimentation rate, serum electrolytes, blood sugar, and glycosylated hemoglobin and were within the normal range. The anti-diuretic hormone (ADH) level was 0.30 pg/mL and was in the subnormal range. The serum human chorionic gonadotrophin (hCG), acetylcholine esterase (ACE) and 1,25(OH)2 vitamin D3 were within normal limits. Antinuclear antibody and antipituitary antibodies were negative. The anterior pituitary hormonal profile included cortisol 18.0 μg/dL, adrenocorticotrophic hormone (ACTH) 45.6 pg/mL, tri-iodothyronine (T3) 142.0 μg/dL, tetra-iodothyronine (T4) 8.2 μg/dL, thyroid stimulating hormone (TSH) 3.15 μIU/mL, growth hormone (GH) 0.7 ng/mL and prolactin 27.0 ng/mL. Lumbar cerebrospinal fluid (CSF) cytology was normal and CSF ACE and HCG were negative. In spite of extensive investigations, no definitive etiology for the central DI and thickened infundibulum could be established, and hence the patient was kept under regular follow-up. Repeated neurological and ophthalmological examinations were performed to detect progression of the disease. The DI was treated medically with nasal desmopressin spray and the clinical response was immediate with decrease in urine output and resolution of nocturnal enuresis.

After 6 months, the child developed a left scalp swelling. At this stage, he had no history of fever, lethargy, skin eruptions or weight loss and examination did not reveal any lymphadenopathy and hepatosplenomegaly. The computed tomography (CT) scan of the brain showed two punched out lytic lesions in the skull with soft tissue swelling [Figure 1]. MRI brain showed a persistent thickened pituitary stalk in addition to confirming CT findings [Figure 2]. Histological examination of biopsy of the skull lesion revealed the tumor to consist of malignant tumor cells arranged as plump spindles and giant multinucleate cells [Figure 3]. Inflammatory cells including eosinophils were seen between the tumor cells. Immunohistochemistry (IHC) demonstrated the tumor cell positivity for CD1a and S-100. The histology was diagnostic of LCH. A bone scan using Tc99m MDP injection showed osteolytic lesion in left parietal bone and osteoblastic lesions in both the frontal bones suggesting skull involvement, but no evidence of osteoblastic lesion was seen in rest of the skeletal system. Bone marrow aspiration showed normocellular areas with trilineage hematopoiesis, no increase in blasts and no granulomas. Liver biopsy showed no infiltration of liver by LCH. His chest X-ray was clear and skeletal survey did not show any other lesion. After confirming the diagnosis and extent of disease, the child was planned for chemotherapy according to LCH protocol. The patient was given six cycles of initial treatment of injection vinblastin at a dosage of 6 mg/m2 at an interval of 1 week for each cycle. The continuation treatment consisted of injection vinblastin at the same dosage every third week and tablet omnacortil at a dosage of 40 mg/m2 from day 1 to day 5 every third week and tablet 6-mercaptopurine (MP) at a dosage of 50 mg/m2 on all days except Sundays for a total duration of 12 months including the initial treatment.

Figure 1

(a) Post-contrast axial computed tomography (CT) scan shows left frontal skull lesion that involves the entire thickness of the skull. (b) Axial bone window demonstrates osteolytic punched out frontal lesions

Figure 2

Post-contrast magnetic resonance (MR) (a) coronal and (b) sagittal images show a contrast-enhancing thickened pituitary stalk. An associated left frontal intradiploic skull lesion is noted

Figure 3

(a) Photomicrograph of the left frontal biopsy demonstrates a tumor with malignant cells arranged as plump spindles. Giant multinucleate cells with scattered inflammatory cells including eosinophils are seen (×10). (b) High power photomicrograph (×40). (c) Immunohistochemistry (IHC) staining positive for CD1a (×10). (d) IHC staining positive for S-100 (×10)

Discussion

Central DI with thickening of the pituitary stalk on MRI may result from various infiltrative diseases. Although 50% of the cases are idiopathic, other most common causes include LCH, central nervous system tumors such as germinoma and craniopharyngioma, granulomatous lesions like tuberculosis and sarcoidosis and autoimmune disorders like lymphocytic infundibuloneurohypophysitis.[2] To determine the precise etiology on the basis of MRI findings is a difficult task and barely 35% of the cases are diagnosed on serial imaging studies, which is a significant increase from 15% diagnosed on first imaging. Germinomas are rapidly evolving tumors associated with deficiency of anterior pituitary hormones; thus, serial scans elicit their diagnosis. Lymphocytic infundibuloneurohypophysitis has been seen to be associated with vasopressin-cell autoantibodies and other organ specific autoimmunity and some of these cases may also show spontaneous resolution of pituitary stalk thickening.

Since the etiological diagnosis of central DI with thickening of the pituitary stalk may not be apparent at the time of detection of DI, serial imaging and close follow-up of these patients to reach a conclusive diagnosis is necessary and mandatory to avoid the attendant risks of pituitary stalk biopsy.[2] DI may occur before, simultaneously and after the other multisystem manifestations, making the diagnosis difficult in the initial stages, as seen in our case.

LCH is a rare disease caused by activation of monocyte–macrophage system. CNS involvement has been reported in 16% of the cases of LCH.[3] Hypothalamic pituitary axis is the most common site of involvement in the brain. It is most commonly seen in children of age group between 2 and 5 years. The disease has got varying spectrum ranging from single osteolytic bone lesion (eosinophilic granuloma) seen in children between 5 and 15 years of age, multisystem disease (Hand-Schuller Christian disease) with skeletal and extraskeletal reticuloendothelial and pituitary gland involvement seen in children 1–5 years of age to rapid fulminant course (Letterer - Siwe Disease) seen most commonly in children less than 2 years of age.[4]

The clinical presentation depends on the site involved in central nervous system. DI is the most common presentation and is seen in 25% of the cases.[5] The next most common endocrinopathy is GH deficiency seen in 10% of the cases.[6] LCH associated neurodegenerative lesions may be clinically silent or may lead to tremors, gait disturbance, other cognitive disturbance and even frank psychosis.[7] These lesions have sharp borders with unequal involvement of inner and outer tables, giving beveled edge appearance on radiology.[8]

Radiological manifestations of the disease include thickening of pituitary stalk more than 3 mm, with loss of physiological hyperintense signal in posterior pituitary on T1W images signifying loss of ADH storage granules.[9] This may progress to a mass lesion involving pituitary and hypothalamus. Besides tumorous lesion, the second most common radiological manifestation is pathological changes in the cerebellum, basal ganglia and pons with hyperintense signals on T2WI and hyper- or hypointense signals on T1WI images.

Histological examination is the definitive diagnostic test for LCH. They stain positive for histochemical stains, S-100 and CD1a. Neuropathological examination shows three types of pattern as follows. The first is a circumscribed granuloma consisting of CD1a+ cells with CD8+ T lymphocytic infiltration. These lesions have predilection for circumventricular organs like pituitary stalk and pineal gland. The second pattern is a neurodegenerative lesion affecting the cerebellum and brain stem lacking CD1a+ cells but predominant CD8+ with axonal degeneration and secondary myelin loss. Over time, this results in atrophy. In the third pattern, infundibular granulomas infiltrate CNS parenchyma by CD1a+ histiocytes.[10]

The treatment of LCH is challenging and a single modality of treatment has not been established. DI is usually permanent and requires lifelong nasal vasopressin. An active lesion is treated by chemotherapy. Although radiation is not the treatment of choice, it may be used as an alternative. A complete clinical resolution is unusual. For tumorous lesions, surgery, radiation or standard LCH chemotherapy may be employed. The optimal management for neurodegenerative lesions is not established.