Langerhans Cell Histiocytosis of Skull Base: A Rare Cause of Central Diabetes Insipidus in Young Adults

Abstract

Background

Langerhans cell histiocytosis (LCH) is a rare disorder that can affect multiple organs, including the brain. One of the most common manifestations of LCH in the brain is involvement of the pituitary stalk, which can lead to central diabetes insipidus (CDI).

Case Description

We retrospectively reviewed the medical records of a series of patients with LCH who presented with CDI. The patients' clinicopathology features, laboratory findings, imaging studies, and treatment outcomes were investigated. The three patients were all young adults (22–38 years old) and presented with polyuria and polydipsia. MRI scans showed thickening of the pituitary stalk in all three, while common etiologies were ruled out. Biopsies of the pituitary stalk confirmed the diagnosis of LCH. The patients were further treated with chemotherapy and steroids, and their symptoms improved.

Conclusion

This case series highlights the importance of considering LCH in the differential diagnosis of CDI, especially in young adults. Early diagnosis and treatment are essential to improve outcomes for patients with LCH.

Keywords

pituitary - LCH - diabetes insipidus - skull base - transnasal transsphenoidal surgery

Langerhans cell histiocytosis (LCH) is a rare histiocytic disorder characterized by clonal neoplastic proliferation, accumulation, and pathological dissemination of histiocytes. LCH can affect bones, skin, lungs, and any other organs, and it may be localized or invade multiple organ systems.[1]

Hypothalamic or central diabetes insipidus (CDI) can occur secondary to a large variety of genetic, immunologic, inflammatory, infectious, and structural conditions.[2] It can rarely happen secondary to LCH involvement of the skull bases.[3] The hypothalamic-pituitary region (HPR) is infiltrated in 5 to 50% of all patients with LCH, but most commonly in those with the multifocal disease form of diabetes insipidus, the most frequent hormonal abnormality that can be detected in 15 to 50% of patients with HPR LCH. Pituitary dysfunction occurs in only 5 to 20% of patients, but it is almost always accompanied by CDI.[4] MRI findings of LCH are not specific for differentiating it from other infiltrating diseases of the central nervous system (CNS); that is, neurosarcoidosis and IgG4 hypophysitis.[5] Therefore, histological examinations are necessary to diagnose LCH in the CNS.[6]

In this case series, we report three patients with diabetes insipidus and a progressively growing pituitary stalk mass that was initially of unknown etiology. The mass was found to be LCH only after histology examination, and the patients underwent surgical intervention. All records were retrospectively retrieved from the hospital information system between January 1, 2018, and December 1, 2022. Records were collected on July 1, 2023. Every participant provided written informed consent before enrolment. No identifiable information was accessible to authors other than the author who extracted it from the system (EP).

Case Presentations

Case 1

A 27-year-old otherwise healthy female presented to the endocrinology clinic of Loghman Hospital of Tehran with amenorrhea, polyuria, and polydipsia after giving birth. She had no history of trauma, autoimmunity, headache, or blurred vision. She did not smoke tobacco or consume alcohol. Her medical history was unremarkable, and there was no family history of similar disorders. On physical examination, she was obese (BMI: 31 kg/m²), but there were no other signs of hyperandrogenism or Cushing syndrome. Her neurologic examination and visual field test were unremarkable.

Laboratory tests were normal except for prolactinemia (80 ng/mL [normal range: 5.18–26.83]) and a 24-hour urine output of 4,500 cc with a specific gravity of 1,005. A desmopressin acetate nasal spray (DDAVP) test confirmed the diagnosis of CDI, and a pituitary pathology was suspected. Other anterior pituitary hormonal profiles were within normal range. A brain MRI showed an 8.5 mm × 4 mm lesion in the pituitary stalk ([Fig. 1]). There is a wide variety of differential diagnoses for pituitary stalk thickening ([Table 1]).

Fig. 1 Sagittal (A) and coronal (B) postcontrast T1 sequence revealed pituitary stalk thickening with extension of enhancement to the hypothalamus.

Table 1 Differential diagnoses of thickened hypophyseal stalk

Category	Diagnosis
Neoplastic	Germinoma
	Hypothalamic glioma
	Craniopharyngioma
	Lymphoma
Infectious	Tuberculosis
	Bacterial meningitis
Infiltrative	Neurosarcoidosis
	Lymphocytic hypophysitis
	IGg4-related hypophysitis
	Langerhans cell histiocytosis

To rule out these etiologies following paraclinical tests were requested while all came back negative: chest radiograph, serum erythrocyte sedimentation rate, human chorionic gonadotrophin (hCG), alpha-fetoprotein (AFP), acetylcholine esterase (ACE), IgG4, 1.25 (OH) vitamin D3, antinuclear antibody and anti-pituitary antibodies, lumbar cerebrospinal fluid cytology for ACE, AFP and hCG and cytology smear of malignant cells.

Since no definitive diagnosis could be made, the patient was planned for regular follow-up and hormonal replacement therapy for the affected pituitary hormones. The unknown disease, however, was controlled for 2 years with constitutional treatments, but she was lost to follow-up during the COVID-19 pandemic. She was later referred to the hospital with headache, blurred vision, forgetfulness, and depression, which suggested that the disease had progressed. This was confirmed by brain imaging ([Fig. 2]). As a result, surgery was indicated and was performed through transnasal transsphenoidal endoscopy (TSS), and the mass was successfully resected.

Fig. 2 Sagittal (A) and coronal (B) postcontrast T1 sequence MRI 2 years later depicts intense enhancement in the hypothalamus with pituitary atrophy.

Histopathologic examination of the surgical specimen revealed patchy aggregates of Langerhans cells with pale, eccentric, irregular or bilobed nuclei, fine chromatin, and indistinct nucleoli. These cells were admixed with some mature small lymphocytes and a few eosinophils, and they infiltrated mostly the stalk of the hypophysis. There was mild gliosis, but no evidence of anaplasia, necrosis, or granuloma formation. Immunohistochemistry (IHC) study confirmed the presence of Langerhans cells, which stained positive for S100, CD1α, and langerin. The lymphoid cells were a mix of CD20+ and CD3+, indicating their reactive nature. Ki67 was low, and IDH1 was negative ([Fig. 3]). A whole-body fluorodeoxyglucose (FDG) positron emission tomography (PET) scan was requested. It showed FDG-avid uptake zones in the right mammillary body, extending to the infundibulum of the pituitary gland, as well as lytic lesions in the frontal bone, L3 vertebral body, left ilium, proximal femur diaphysis, and right mandible ([Fig. 4]).

Fig. 3 Langerhans cells stain patchy with CD1α (A) and are S100 positive (×400) (B) with fine eccentric nuclei and pale cytoplasm (×1,000, H&E stain) (C).

Fig. 4 Whole-body fluorodeoxyglucose-positron emission tomography scan showing multiple organ system involvement of pituitary stalk (A), skull (B), lumbar spine (C), ilium (D), femur (E), and mandible (F).

The patient was planned for chemotherapy due to the disseminated involvement and CNS lesion. She was initially treated with prednisolone and cytarabine (100 mg/m² per dose for 5 days per month). Bisphosphonate (zoledronic acid) was administered for bone pain relief, and fluoxetine for psychological symptoms.

Case 2

A 22-year-old woman with acute polyuria and polydipsia presented to the endocrinology clinic and was diagnosed with CDI following a water deprivation and DDAVP test. She had no previous medical history, and her family history was unremarkable. She had not been taking any medications.

Brain MRI revealed a space-occupying lesion in the neurohypophysis ([Fig. 5]). While receiving desmopressin nasal spray for controlling CDI for about 4 months, she became amenorrhoeic. She also complained of hirsutism and loss of libido. Laboratory evaluations revealed hypogonadotropic hypogonadism and decreased IGF-1 a few months later.

Fig. 5 Sagittal (A) and coronal (B) brain MRI views of pituitary skull.

Five years later, during regular follow-ups, neuroimaging studies showed a well-defined T1 and T2 weighted iso-signal lesion within the pituitary stalk and inferior to the hypothalamus, which markedly enhanced following gadolinium injection (5 mm × 5 mm). While she was receiving estrogen, progesterone, and somatotropin, laboratory findings revealed hyperprolactinemia resistant to bromocriptine. She was referred to our tertiary neurosurgery center. Follow-up neuroimaging demonstrated enlargement of the lesion (10 mm × 7 mm). Based on the stalk lesion and endocrinological abnormality, she underwent an uneventful total hypophysectomy and gross total resection of the pituitary stalk lesion via TSS. Pathologic evaluation confirmed the diagnosis ([Fig. 6]), and she was referred to the oncology unit for further evaluation.

Fig. 6 Pathology slides stained with H&E (A for ×400 and B for ×1,000), CD1α (C), CyclinD1 (D), and CD68 (E).

Case 3

A 38-year-old woman was referred to the neurosurgery clinic with polyuria and polydipsia over the past year. She was primarily diagnosed with a 7 mm × 3 mm stalk lesion before referral ([Fig. 7]). Based on the variety of differential diagnoses ([Table 1]), hypothalamic glioma was the suspected differential diagnosis. TSS was indicated due to a lesion growing, and it was performed without any complications ([Fig. 8]). Postoperative laboratory results showed an acute onset of hypernatremia (Na: 155-mEq/L) and severe CDI. DDAVP and fluid replacement were promptly started to control polyuria. Pathology and IHC reports revealed LCH ([Fig. 9]).

Fig. 7 Brain MRI after contrast injection in sagittal (A) and coronal (B) views of the sellar area.

Fig. 8 Endoscope view of tumor bulging through the sellar region (A, B), which was grossly totally resected (C).

Fig. 9 Different staining for Langerhans cells. H&E (A), CD1α (B), CyclinD1 (C), and CD68 (D).

The patient was discharged on postoperative day 7 with levothyroxine and DDAVP and was referred to the oncologist, where she was started on prednisolone, cytarabine (100 mg/m² per dose in 5 days per month), and bisphosphonates.

Discussion

LCH is characterized by abnormal clonal proliferation and accumulation of antigen-presenting dendritic cells at multiple tissues and organs with a wide range of clinical manifestations and histologic presentations.[7] Adult-onset LCH typically involves multisystem organs. The most common CNS manifestation in LCH is the infiltration of the hypothalamic-pituitary region by LCH granuloma, frequently leading to diabetes insipidous and occasionally anterior pituitary hormone deficiency (APD), which requires permanent hormone replacement therapy.[8]

LCH is associated with late-onset neurodegenerative lesions.[9] In our sample, in one case, secondary hypogonadism appeared at the onset of disease, while symptoms like memory loss and depression occurred at later stages, raising the possibility of neurodegeneration. The LCH lesion in this case progressed from the pituitary to the hypothalamus. Similarly, in studies that investigated MRI courses of LCH lesions, alternation from pituitary or hypothalamus to suprasellar extension was reported.[10] [11] [12]

Treatment of LCH is dependent upon organ involvement and the extent of the disease.

Symptomatic involvement of the CNS and multifocal bone lesions indicate systemic chemotherapy.

Despite advances in the understanding of LCH pathogenesis, the current standard therapy for multifocal LCH remains empirical chemotherapy with cytarabine and prednisone formulations.

Radiotherapy is also an effective treatment option for LCH; however, it was not utilized here.[1]

Appropriate management of LCH-induced diabetes insipidus involves diagnosis at early stages with prompt intervention for LCH, which could possibly reverse it and prevent later development of anterior pituitary hormonal deficiencies or neurodegenerative disease.[13]

This case series has several limitations. First, the small sample size prevented us from performing complementary analyses. Second, long-term follow-up data were not available for the patients, so little is known about their recurrence or control of the disease. However, due to the rarity of the condition, this series is one of the largest to date on LCH of the skull base, with a focus on the clinical and pathological features of this entity.

In conclusion, although adult-onset LCH is a rare cause of hypothalamus and pituitary involvement, it should be considered an important differential diagnosis in cases of CDI. However, imaging studies may not be able to definitively diagnose LCH, and histological assessment is required. Suprasellar progression of the lesion to higher CNS structures may be a unique MRI finding in LCH, and can present with neurodegeneration and neuropsychiatric symptoms.

Conflict of Interest

None declared.

Availability of Data and Material

Due to the use of identifiable material, data cannot be shared.

Patients' Consent

All patients provided informed consent for participation prior to inclusion.

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Publication History

Received: 21 January 2025

Accepted: 17 November 2025

Article published online:
04 December 2025