Abstract

Background: Erdheim-Chester disease (ECD) is a rare non-Langerhans cell histiocytosis classified as a neoplastic hematopoietic disorder. It typically affects adults aged 40–56 years, with a male predominance (2.3–3:1). ECD presents with a wide clinical spectrum, ranging from asymptomatic bone lesions (90% of cases) to severe multisystem involvement, including cardiovascular, pulmonary, and central nervous systems (CNSs). CNS involvement occurs in approximately 50% of cases and is associated with increased morbidity and mortality. The BRAF V600E mutation is found in a significant subset of patients and plays a critical role in diagnosis and targeted therapy.

Case Description: We present the case of a 39-year-old male with central hypothyroidism, progressive visual impairment, and headaches. Magnetic resonance imaging revealed two extra-axial supratentorial lesions. Surgical resection was performed using a “one-and-a-half ” frontotemporal craniotomy, providing optimal multi-angled access. Histopathological examination confirmed ECD with a BRAF V600E mutation. The patient had an uneventful postoperative recovery.

Conclusion: This case highlights the strategic utility of the “one-and-a-half ” frontotemporal craniotomy in the resection of complex supratentorial lesions. It also underscores the critical importance of molecular diagnostics, particularly the identification of the BRAF V600E mutation, in guiding treatment decisions in ECD.

Keywords: BRAF V600E, Central nervous system involvement, Cytokines, Erdheim-Chester disease, Histiocytosis

INTRODUCTION

Erdheim-Chester Disease (ECD), first described in 1930 by Jakob Erdheim and William Chester[ 3 ], is a rare form of histiocytosis characterized by the absence of Langerhans cells.[ 9 ] To date, approximately 600 cases have been reported, predominantly males in their 50s and 60s.[ 8 ] According to the 2021 World Health Organization (WHO) classification, ECD is categorized among hematolymphoid tumors with potential central nervous system (CNS) involvement. Histologically, these tumors are characterized by foamy histiocytes, occasional Touton giant cells, chronic inflammation, and variable degrees of fibrosis.[ 13 ]

The clinical manifestations of ECD are heterogeneous and may include bone pain, diabetes insipidus, neurological and constitutional symptoms, as well as involvement in retroperitoneal, cutaneous, cardiovascular, and respiratory systems. CNS lesions are particularly associated with increased morbidity and mortality, contributing to a poorer overall prognosis.[ 4 ]

CASE PRESENTATION

A 39-year-old male with a history of central hypothyroidism initially presented in October 2022 with a foreign body sensation in the left eye (LE). An ophthalmologic evaluation revealed no ocular pathology. By July 2023, he developed a visual field defect that evolved into left-sided amaurosis and right temporal hemianopia. He also reported daily frontal headaches, rated 4/10 on the analog numerical scale, without associated photophobia, phonophobia, nausea, or vomiting.

The patient was referred to our hospital by his family medicine clinic and was initially evaluated in the emergency department. Laboratory tests [ Table 1 ] confirmed panhypopituitarism, while other serum parameters were within normal limits. The endocrinology department initiated hormone replacement therapy with prednisone and levothyroxine.

Table 1:

Pre-surgery lab tests

Neurological examination showed visual acuity (VA) 20/60 in the right eye, while VA in the LE could not be assessed. Confrontation campimetry revealed temporal hemianopsia in the right eye and complete vision loss in the left eye.

Brain magnetic resonance imaging (MRI) revealed two extra-axial, supratentorial lesions [ Figure 1 ].

Figure 1:

Preoperative magnetic resonance imaging. (a-c) Non-contrast T1-weighted images in (a) sagittal, (b) axial, and (c) coronal planes demonstrate a well-defined extra-axial mass located in the right middle cranial fossa, with extension into the posterior fossa and evident compression of adjacent structures, including the temporal lobe and brainstem. (d and e) Axial T2-weighted sequences reveal a heterogeneously hyperintense lesion associated with mass effect and mild surrounding edema. (f and g) Post-contrast T1-weighted images in (f) axial and (g) coronal planes show vivid, heterogeneous enhancement with a dural tail and invasion of the cavernous sinus.

Surgical resection was performed using an approach that we defined as a “one-and-a-half ” frontotemporal craniotomy. Although the initial goal was to remove the right temporal lesion, presumed to be a meningioma, the approach was preemptively selected to provide access to both lesions through a single craniotomy. This technique allowed Transylvian, pretemporal, and interhemispheric access, enabling resection of the sellar lesion in a subsequent procedure without requiring an additional bone opening.

During the first surgery, the right temporal lesion was removed. It had a whitish appearance, soft eraser-like consistency, and a well-defined arachnoid dissection plane with a dural attachment that was coagulated. Postoperatively, the patient developed polyuria, low urinary osmolarity, and hypernatremia, consistent with diabetes insipidus [ Table 2 ]. This was unexpected following temporal lobe surgery and may suggest early involvement of the hypothalamic-pituitary axis due to mass effect or indirect manipulation during the initial procedure, given the proximity of both lesions. Alternatively, it could have resulted from a cytokine-mediated inflammatory response affecting the hypothalamic-pituitary axis, leading to transient dysfunction. Oral desmopressin was initiated with a favorable response. A second procedure was performed one week later to remove the sellar lesion, which exhibited similar intraoperative features. Although it appeared to be completely resected macroscopically, a follow-up MRI revealed early recurrence. This may be attributed to its infiltrative nature or the presence of microscopic residual tissue beyond the apparent resection margins, which could not be clearly distinguished intraoperatively [ Figure 2 ].

Table 2:

Post-Surgery lab tests

Figure 2:

Intraoperative findings. (a) Microscopic view of the right temporal lesion with a yellowish-white appearance. (b and c) Microscope-assisted resection of the right temporal lesion with dural attachment. (d and e) Microscopic view of the surgical bed in the right temporal fossa, showing coagulated dural implant area. (f and g) Sellae lesion with yellowish appearance, illustrating significant anatomical distortion. RON: Right optic nerve, ICA: Internal carotid artery. (h and i) Interhemispheric microscopic view of sellae lesion resection. TS: Tuberculum sellae, LON: Left optic nerve, OC: Optic chiasm, RON: Right optic nerve. (j) Interhemispheric microscopic view of the surgical bed in the sellae region. TS: Tuberculum sellae, LON: Left optic nerve, OC: Optic chiasm, RON: Right optic nerve.

Histopathology

Intraoperative histopathological evaluation revealed a cytological smear with abundant, largely discohesive, exhibiting variable morphology. The majority of cells were ovoid to irregular in shape, medium to large, with eosinophilic cytoplasm, distinct cellular processes, round nuclei with open chromatin, discrete nucleoli, and mild pleomorphism. Most cells were mononuclear; however, binucleated, epithelioid, multinucleated giant cells resembling ganglion cells are also observed [ Figure 3 ].

Grossly, the specimen consisted of multiple irregular, smooth tissue fragments with a solid, yellow, homogeneous cut surface. Hematoxylin-Eosin staining demonstrated a solid lesion with a discretely trabecular pattern, infiltrated by lymphocytes forming small nests in certain areas. Neoplastic cells exhibited histiocytic features, including the presence of Touton-type giant cells and areas with xanthomatous changes.

Figure 3:

Cytopathological features, Hematoxylin-Eosin ×400: (a) Mononuclear and binuclear neoplastic cells with lymphocytes. (b) Epithelioid neoplastic cells. (c) Multinucleated neoplastic cells. (d) Ganglion-like neoplastic cells with basophilic cytoplasmic inclusions.

Immunohistochemical analysis showed that neoplastic cells were positive for CD68 and Vimentin while negative for Langerin and CD1a. The proliferative index, measured by Ki67, was low (<3%) [ Figure 4 ]. Reverse transcription polymerase chain reaction confirmed the presence of the BRAF V600E mutation, supporting the diagnosis of ECD.

Figure 4:

(a) Fragment of the lesion showing a solid, yellow, and homogeneous cut surface. (b) Solid pattern with nests of lymphocytes, Hematoxylin-Eosin (HE) ×40. (c) Neoplastic cells, some discohesive with a discrete trabecular pattern, HE ×100. (d) Discohesive neoplastic cells with a Touton-type multinucleated giant cell, HE ×400. (e) Xanthomatous neoplastic cells, HE ×400. (f) CD68 positive neoplastic cells, IHQ ×400.

Follow-up and therapeutic plan

The patient remains under regular outpatient follow-up. A brain MRI obtained 5 months postoperatively [ Figure 5 ] showed stable recurrent suprasellar enhancement with no signs of progression. Systemic staging with contrast-enhanced thoracoabdominopelvic computed tomography demonstrated perirenal and mesenteric fat infiltration, a lytic lesion of the fifth right rib, and a granulomatous lesion in the left lung, consistent with multisystem involvement of ECD.

Figure 5:

Postoperative magnetic resonance imaging. (a-c) Non-contrast T1-weighted (a) sagittal, (b) coronal, and (c) T2-weighted coronal images show expected postoperative changes in the sellar, suprasellar, and right middle cranial fossa regions. A small residual component is evident in the suprasellar cistern, appearing iso- to hypointense on T1 and heterogeneously hyperintense on T2. The optic chiasm is decompressed and elevated, with no signs of compression (d-f). (d) Axial T2-weighted, (e) coronal post-contrast T1-weighted, and (f) axial postcontrast T1-weighted images demonstrate residual enhancement in the suprasellar region, consistent with subtotal resection. Notably, there is no evidence of residual tumor in the right temporal fossa, indicating gross total resection of the temporal component.

Given the multifocal nature of the disease and the recurrence of the intracranial lesion, the patient was referred to medical oncology. A combined treatment strategy was initiated, including stereotactic radiosurgery to the suprasellar lesion (25 Gy in five fractions) to achieve local control, followed by systemic chemotherapy using a high-dose methotrexate and cytarabine regimen aimed at modulating the systemic inflammatory component of ECD.

The patient is currently receiving hormone replacement therapy with levothyroxine and prednisone for panhypopituitarism, as well as oral desmopressin for the management of central diabetes insipidus. He continues to be closely monitored by the endocrinology team, in addition to ongoing follow-up by medical oncology and neurosurgery. Periodic MRI scans are scheduled every 6 months, along with regular clinical evaluations to assess therapeutic response and detect any signs of recurrence or progression.

DISCUSSION

ECD is a rare form of non-Langerhans cell histiocytosis. Approximately half of the cases harbor the BRAF V600E mutation, making them candidates for targeted therapy with BRAF inhibitors such as vemurafenib.[ 5 ] ECD typically presents between the ages of 50 and 70, with a male predominance.[ 8 ] According to the 2021 WHO classification, ECD is considered a hematolymphoid neoplasm with potential CNS involvement, believed to arise from clonal proliferation of histiocytes secondary to mitogen-activated protein kinase pathway mutations.[ 13 ]

Neurological symptoms occur in half of patients, either at the onset or during the disease progression. Common initial manifestations include peripheral neuropathy (56%), cognitive impairment (52%), cerebellar ataxia (46%), pyramidal signs (30%), and seizures (8%). Involvement of the neurohypophysis, resulting in diabetes insipidus, is also a recognized feature.[ 2 , 7 ]

In our patient, ganglioglioma was initially considered as a diagnostic possibility due to the presence of ganglion cell-like elements with fine basophilic intracytoplasmic inclusions resembling Nissl substance. Meningioma was also a differential diagnosis based on imaging characteristics; however, the cytological findings were inconsistent with this entity. Some meningioma subtypes, such as clear cell and microcystic variants, may exhibit epithelioid features, and nuclear pseudoinclusions may be helpful in distinguishing them. Notably, psammoma bodies (commonly seen in meningiomas) were absent in this case. While the cellular morphology suggested gemistocytes, the extra-axial location of the lesions made gemistocytic astrocytoma unlikely. The identification of Touton-type giant cells and xanthomatous changes was key in supporting the diagnosis of ECD, although these features may not be readily apparent in intraoperative smears.[ 13 ] Histological sections with HE typically reveal xanthomatous histiocyte infiltration surrounded by fibrosis. Immunohistochemical analysis characteristically shows CD68 (+) and CD1a (−), helping to distinguish ECD from Langerhans cell histiocytosis.[ 11 , 12 ]

An intratumoral inflammatory component, consisting of randomly arranged lymphocytic aggregates, is often observed and correlates with elevated cytokine expression,[ 6 , 7 ] particularly interferon-α, interleukin (IL)-12, and monocyte chemotactic protein-1, along with reduced levels of IL-4 and IL-7.[ 1 ] This cytokine imbalance may contribute to the endocrine dysfunction observed in our patient, particularly the onset of diabetes insipidus after the initial surgery.

At present, there is no standardized treatment for ECD. Immunomodulatory agents such as interferon alpha remain commonly used. Targeted therapies have emerged as effective options, particularly vemurafenib for patients harboring the BRAF V600E mutation. MEK inhibitors such as cobimetinib have shown durable responses in histiocytoses, including ECD, even in BRAF-negative patients. Additional therapeutic options include cytotoxic chemotherapy (e.g., cladribine and cyclophosphamide), molecular targeted therapy (e.g., imatinib and sorafenib), corticosteroids, radiotherapy, and surgical resection. The latter two are mainly palliative, used for symptom relief rather than cure, due to the systemic nature of the disease. Radiotherapy is particularly effective for alleviating pain in patients with skeletal involvement.[ 10 ]

CONCLUSION

The diagnosis of ECD requires a thorough clinical and radiological evaluation, with intracranial lesions often mimicking skull base tumors due to homogeneous gadolinium enhancement and dural tails. Histopathological analysis typically reveals lipid-laden histiocytes, Touton-type giant cells, and fibrosis. Immunohistochemistry is essential, with CD68 positivity and CD1a/CD20 negativity supporting the diagnosis. The differential diagnosis includes neurosarcoidosis, granulomatous infections, leptomeningeal metastasis, lymphoma, and other histiocytic disorders.

Although complete resection is rarely curative due to the systemic nature of ECD, surgery may aid in diagnosis and alleviate mass effects. In this case, the “one-and-a-half ” frontotemporal craniotomy allowed for safe access to both lesions through a single approach.

Molecular testing is key to treatment planning. The presence of a BRAF V600E mutation permits the use of targeted therapies such as vemurafenib, while corticosteroids and chemotherapy remain options in refractory or BRAF-negative cases.

This case underscores the importance of including ECD in the differential diagnosis of atypical extra-axial CNS lesions, the utility of tailored neurosurgical strategies, and the critical role of multidisciplinary care involving pathology, endocrinology, oncology, and neurosurgery.

Ethical approval:

The Institutional Review Board approval is not required.

Declaration of patient consent:

The authors certify that they have obtained all appropriate patient consent.

Financial support and sponsorship:

Nil.

Conflicts of interest:

There are no conflicts of interest.

Use of artificial intelligence (AI)-assisted technology for manuscript preparation:

The authors confirm that there was no use of artificial intelligence (AI)-assisted technology for assisting in the writing or editing of the manuscript and no images were manipulated using AI.

Disclaimer

The views and opinions expressed in this article are those of the authors and do not necessarily reflect the official policy or position of the Journal or its management. The information contained in this article should not be considered to be medical advice; patients should consult their own physicians for advice as to their specific medical needs.

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