Adult-Onset Langerhans Cell Histiocytosis with Central Nervous System Neurodegeneration and Neuropsychiatric Symptoms: A Case Report with Novel Imaging and Genetic Insights

INTRODUCTION

Langerhans cell histiocytosis (LCH) is the neoplastic clonal expansion of early myeloid precursor cells, resulting in the aggregation of Langerin-positive pathologic dendritic cells into granulomatous lesions, which may be organ-specific or multisystemic. This is an extremely rare disease, especially in adult patients, with an estimated incidence of 0.07 per million cases per year. Central nervous system (CNS) involvement is known to occur. If it does so as an aspect of multisystem disease, the clinical picture is classified as risk-organ involving or not, depending on whether the liver, spleen, or bone marrow are also affected.¹ CNS involvement is further divided into focal mass lesions and lesions associated with neurodegeneration.² Neurodegenerative LCH accounts for only 1.8–8.6% of LCH patients and is a devastating, progressive, and permanent entity that may affect the cerebrum, cerebellum, basal ganglia, hypothalamus, pons, pituitary, or choroid plexus. It may present with ataxia, dysarthria, dysmetria, learning difficulties, or behaviour abnormalities.^3,4

Discussed here is such a case of a 55-year-old woman with generalised itching who was diagnosed with LCH after developing behavioural disturbances. Due to its rarity and varied, non-specific presentation, LCH is usually not suspected in adult patients. However, as this case demonstrates, LCH should be investigated in patients with suggestive features, considering the grievous consequences of the disease and the prognostic benefit from timely treatment.

CASE REPORT

A 55-year-old postmenopausal woman presented with complaints of intense generalised itching for the past 18 months. She had been undergoing treatment for diabetes, hypertension, and hypothyroidism for 2.5 years. The sensation was equal on both flexor and extensor surfaces, more pronounced in the lower limbs, and not associated with any redness. It was disabling and intense enough to disturb her sleep. In the last year, she had also developed itchy, discharging papular lesions over her scalp. The lesions were progressive, hyperkeratotic, yellow, and greasy and were associated with hair loss. These had initially been diagnosed as seborrheic dermatitis and were treated with selenium shampoo, resulting in relief after 2 months of application. At the same time frame, she developed multiple perianal and bilateral axillary noduloulcerative lesions. The lesions were aspirated, revealing nonspecific findings. However, the patient then began exhibiting irrelevant speech, aggressive behaviour, and crying episodes, prompting further assessment at our institution. On examination, the patient had normal vitals (pulse 88 beats/min, blood pressure 100/70 mm Hg, and oxygen saturation 98%). She was conscious and cooperative but exhibited decreased communication. Her Mini-Mental State Examination score was 22 out of 30. She was edentulous, having lost all her teeth, and showed marked temporal hollowing. The pruritic scalp lesions and noduloulcerative lesions in the perianal and axillary regions were clear and are as shown in Figure 1. No abnormalities were found on motor or sensory examination, and other systems were normal. Laboratory investigations revealed anemia (haemoglobin 8.2 mg/dL) and elevated alkaline phosphatase (1607 IU/L). Futher neuroimaging work-up (as shown in [Figure 2]) with a positron emission tomography-computed tomography (PET-CT) scan showed increased metabolism in the left scalp, perianal region, right axillary skin, pancreatic body, and a focal hypermetabolic soft-tissue lesion in the suprasellar region. In the brain, hypometabolism was noted in the frontal, anterior, temporal, and posterior cingulate cortices, whereas hypermetabolism was noted in the midbrain, pons, and cerebellum. A magnetic resonance imaging (MRI) scan of the brain revealed thickening and enhancement of the pituitary stalk with abnormal signals and enhancement in both hypothalami, consistent with histiocytic hypophysitis. This was supported by low titres of follicle-stimulating hormone (FSH) (8.57 mIU/mL), luteinising hormone (LH) (2.02 mIU/mL), and insulin-like growth factor-1 (IGF-1) (23.59 ng/mL) and elevated serum prolactin (136.6 ng/mL). Thyroid and adrenal function tests were normal. The perianal and axillary lesions were sampled by fine needle aspiration cytology, which revealed inflammatory cells, few histiocytes, and occasional multinucleated giant cells. The lesions were biopsied, and histopathological analysis showed fragments lined by squamous epithelium with underlying sheets of atypical cells with plasmacytoid morphology, bizarre nuclei and multinucleation, and a few scattered eosinophils. Immunohistochemistry showed strong positivity for S100p and CD1a markers, as well as Score 2 + for BRAF VE1, and weak focal staining for CD43, as seen in Figure 3. Ultimately, the patient was diagnosed with adult-onset multisystemic neurodegenerative LCH without risk organ involvement and with a BRAF V600E mutation. The patient was started on a prednisolone and vinblastine regimen for a year; however, she did not follow the advised treatment and ultimately succumbed to the illness, further details of which are not known.

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Figure 1:

Postmenopausal woman in her mid-fifties showing (A) Axillary noduloulcerative lesions consistent with cutaneous Langerhans cell histiocytosis. (B) Perianal noduloulcerative lesions.

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Figure 2:

Results of imaging studies. (A) X-ray scans of the skull showing edentulous upper and lower jaws (white arrows). (B) Positron emission tomography-computed tomography scans showing hypermetabolic (red arrow) and hypometabolic lesions in the brain. (C) Magnetic resonance imaging scan of the brain showing hypophysitis (blue arrow).

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Figure 3:

Histopathological findings after biopsy of lesions, with immunohistochemical markers. (A) shows infiltrate of large histiocytes with irregular grooved nuclei admixed with eosinophils and occasional multinucleate cells (scale = 10µm). (B) shows diffuse strong positivity for S100p (red arrow) (scale = 25µm). (C) shows diffuse strong positivity for CD1a (scale = 50µm). (D) shows positivity for BRAF VE1 (score 2+) (scale = 50µm)

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DISCUSSION

LCH is a rare clonal disorder of myeloid-derived dendritic cells, most commonly seen in children. When it does occur in adults, typically after the fourth decade, it often presents with multisystem involvement, observed in up to two-thirds of cases.¹ Cutaneous lesions are among the most common initial findings, particularly in the scalp, intertriginous regions, and genital areas, the latter being more frequent in women.¹ In this patient, the scalp and axillary lesions mimicked seborrheic dermatitis, which initially delayed diagnosis. Notably, similar dermatologic presentations are seen in Parkinson’s disease (PD), a much more common neurodegenerative condition, further complicating the diagnostic pathway.⁵ However, the absence of extrapyramidal features and the neuroimaging findings helped to distinguish this case from PD.

Neuroimaging was critical in supporting the diagnosis. PET-CT scan revealed both hypermetabolic and hypometabolic regions within the brain, including the midbrain, pons, and cerebellum, as well as frontal and temporal cortices – findings increasingly recognised as characteristic of neurodegenerative CNS LCH.^2,3 MRI showed pituitary stalk thickening and bilateral hypothalamic enhancement, consistent with histiocytic hypophysitis.² Interestingly, the patient exhibited anterior pituitary hormone deficiencies, low FSH, LH, and IGF-1 with hyperprolactinemia, yet did not present with diabetes insipidus, which is typically associated with posterior pituitary involvement. This highlights a broader clinical spectrum of endocrine dysfunction in LCH, especially in adults. Although her hypothyroidism could potentially reflect central aetiology due to pituitary infiltration, this could not be definitively confirmed.

Importantly, this case illustrates the underrecognised psychiatric and behavioural manifestations of neurodegenerative LCH. The patient’s aggressive behaviour, emotional instability, and irrelevant speech are increasingly acknowledged as part of the disease’s CNS involvement, yet are frequently misdiagnosed as primary psychiatric conditions.⁴ In patients presenting with such symptoms alongside systemic or dermatologic findings, a high index of suspicion for rare infiltrative diseases like LCH is warranted. Early behavioural and psychiatric changes may be subtle yet diagnostically significant, and may serve as early markers of CNS involvement and prompt advanced imaging before irreversible progression.

It was the histopathological analysis combined with immunohistochemistry that confirmed the diagnosis of LCH. The biopsy revealed atypical histiocytes with plasmacytoid morphology and positivity for CD1a and S100p features pathognomonic of LCH.¹ Immunostaining for BRAF VE1 confirmed the presence of the BRAF V600E mutation, which is associated with more severe, multisystemic disease, poorer prognosis, and higher relapse rates.⁶ This mutation offers a therapeutic window for the use of targeted agents such as BRAF inhibitors (e.g. vemurafenib), which have shown encouraging results in refractory or relapsing cases and are currently under further investigation.⁷ The presence of this mutation underscores the importance of molecular testing in cases of adult LCH, where it may guide individualised and precision-based management strategies.

Despite the initiation of a 12-month regimen of vinblastine and prednisolone, shown to reduce reactivation rates in multi-system LCH without risk-organ involvement in the LCH-III trial, the patient did not adhere to the prescribed treatment.⁸ Unfortunately, her condition deteriorated, and she succumbed to the illness. Further clinical details regarding her decline are unavailable. This highlights the critical need for consistent patient education, multidisciplinary follow-up and long-term adherence to therapy in managing complex adult LCH.

This case highlights the rare and diagnostically elusive nature of adult-onset LCH with neurodegenerative CNS involvement and the need for a high clinical suspicion to diagnose it. It should be noted that behavioural and psychiatric symptoms may precede or parallel CNS findings and should not be overlooked, while anterior pituitary dysfunction without diabetes insipidus can expand the known endocrine spectrum of CNS LCH. These insights underscore the evolving understanding of adult LCH and the importance of an integrated, multidisciplinary approach in its diagnosis and management.

CONCLUSION

This case highlights the rare and diagnostically elusive nature of adult-onset LCH with neurodegenerative CNS involvement and the need for a high clinical suspicion to diagnose it. It should be noted that behavioural and psychiatric symptoms may precede or parallel CNS findings and should not be overlooked, while anterior pituitary dysfunction without diabetes insipidus can expand the known endocrine spectrum of CNS LCH. These insights underscore the evolving understanding of adult LCH and the importance of an integrated, multidisciplinary approach in its diagnosis and management.