Case Summary

A previously healthy, middle-aged patient presented to the emergency department due to multiple falls stemming from acutely worsening ataxia and lower extremity weakness. Before presentation, the patient reportedly had several months of declining cognitive function, including slower processing speed, difficulties with long-term planning, and a suspected new left-hand tremor. There was no reported headache, nausea, or vomiting, and no reported history of smoking, alcohol, or drug use, or known malignancy.

Head CT demonstrated a hyperdense mass in the right frontal lobe with surrounding edema. Subsequent MRI showed multiple supratentorial and infratentorial enhancing lesions, which were initially presumed to be intracranial metastases. CT of the chest, abdomen, and pelvis was unremarkable. Lumbar puncture showed no evidence of malignancy or infectious etiology.

The patient underwent stereotactic biopsy of the dominant right frontal lobe lesion, which demonstrated reactive white matter with areas of vacuolization and foci of florid macrophage infiltrate, highlighted by CD163 (block A1 only) and CD68 immunohistochemical stains. CD1a was negative. These results were ultimately considered nonspecific.

Approximately 3 months after initial presentation, the patient was readmitted to the neurology service due to worsening functional status and progressive neurological deficits. Repeat MRI of the head showed several new lesions in the right frontal lobe and along the left interhemispheric falx. MRI of the entire spine showed scattered enhancing lesions throughout the cervical and thoracic cord. Whole-body PET was unremarkable. An additional extensive infectious and inflammatory workup was unrevealing.

Targeted next-generation sequencing was then performed on the specimen from the right frontal lobe biopsy, which demonstrated a BRAF p.V600E mutation. A combination of clinical, radiologic, and pathologic findings, therefore, led to a presumptive diagnosis of Erdheim-Chester disease (ECD).

Imaging Findings

CT of the head demonstrated a hyperdense mass in the right frontal lobe with mild surrounding vasogenic edema (Figure 1). Subsequent MRI of the head showed numerous enhancing foci throughout the cerebral and cerebellar hemispheres and the brainstem (Figure 1).

(A) Axial noncontrast CT of the head showing a rounded hyperdense mass in the posterior aspect of the right superior frontal gyrus with surrounding vasogenic edema (yellow arrow). (B) Axial T1-weighted postcontrast and (C) axial FLAIR MRI images showing multiple enhancing and FLAIR hyperintense lesions in the right greater than left frontal lobes (yellow arrows), the largest of which corresponds to the hyperdense mass noted on noncontrast CT of the head. (D) Axial T1-weighted postcontrast images showing multiple additional enhancing foci in the left pons, bilateral temporal lobes, and right cerebellar hemisphere (yellow arrows).
Figure 1. (A) Axial noncontrast CT of the head showing a rounded hyperdense mass in the posterior aspect of the right superior frontal gyrus with surrounding vasogenic edema (yellow arrow). (B) Axial T1-weighted postcontrast and (C) axial FLAIR MRI images showing multiple enhancing and FLAIR hyperintense lesions in the right greater than left frontal lobes (yellow arrows), the largest of which corresponds to the hyperdense mass noted on noncontrast CT of the head. (D) Axial T1-weighted postcontrast images showing multiple additional enhancing foci in the left pons, bilateral temporal lobes, and right cerebellar hemisphere (yellow arrows).

Follow-up MRI of the head approximately 3 months after initial presentation showed increasingly conspicuous punctate enhancing lesions in the posterior right frontal lobe with a new small dural-based lesion along the left interhemispheric falx (Figure 2). MRI of the spine showed multiple small and ill-defined T2 hyperintense enhancing intramedullary lesions within the cervical and thoracic cord (Figure 3).

(A) Axial postcontrast MRI image showing slightly enlarged enhancing lesions in the posterior right frontal lobe (yellow arrow). (B) Coronal T1-weighted postcontrast MRI demonstrating a new small dural-based lesion along the left interhemispheric falx (yellow arrow).
Figure 2. (A) Axial postcontrast MRI image showing slightly enlarged enhancing lesions in the posterior right frontal lobe (yellow arrow). (B) Coronal T1-weighted postcontrast MRI demonstrating a new small dural-based lesion along the left interhemispheric falx (yellow arrow).
(A) Sagittal T2-weighted and (B) T1-weighted postcontrast MRI images showing subtle T2 hyperintense and enhancing intramedullary lesions within the thoracic cord (yellow arrows).
Figure 3. (A) Sagittal T2-weighted and (B) T1-weighted postcontrast MRI images showing subtle T2 hyperintense and enhancing intramedullary lesions within the thoracic cord (yellow arrows).

Diagnosis

Erdheim-Chester disease.

Differential considerations would include intracranial metastases, central nervous system (CNS) lymphoma, or possibly neurosarcoidosis. Alternative BRAF p.V600E mutant histiocytic neoplasms would include Rosai-Dorfman disease and Langerhans cell histiocytosis (LCH).

Discussion

ECD is a rare and potentially fatal multiorgan hematopoietic histiocytic neoplasm occurring primarily in middle-aged adults.1 Tumors are characterized by the accumulation of foamy macrophages that are CD68+, CD163+, and CD1a-. S100 is typically negative or only weakly positive, which, when taken in conjunction with the negative CD1a, can help to distinguish it from LCH.2 BRAF V600E point mutation is present in approximately 50% of cases. BRAF V600-mutant ECD can be treated with BRAF inhibitors such as vemurafenib, while BRAF wild-type ECD may be treated with mitogen-activated extracellular signal-regulated kinase pathway inhibitors.3

Clinical manifestations and disease progression are varied and highly dependent on the specific systems involved. While skeletal manifestations are most common (noted in up to 90% of reported cases), ECD can also manifest with retroperitoneal fibrosis, renal failure, diabetes insipidus (DI), and cardiac disease.2 CNS involvement is far less common, with only an estimated 15-25% of cases demonstrating disease within the neuraxis.4 Cerebellar and pyramidal syndromes are the most frequent neurologic manifestations, in addition to cognitive difficulties, neuropsychiatric disturbances, and cranial nerve palsies.4 CNS involvement has also been shown to carry a worse prognosis with higher mortality. Notably, isolated CNS disease without involvement of other organ systems, such as in this case, is exceedingly rare.

Neuroradiologic manifestations of ECD are varied and can include dural-based masses, supratentorial and infratentorial enhancing foci, orbital lesions, invasion of the hypothalamic pituitary axis (HPA), and spinal cord involvement.5 While both meningiomas and ECD-related dural-based masses will show homogeneous enhancement, the lesions associated with ECD will more often demonstrate T2 hypointensity.6 Obstructive hydrocephalus may also develop due to dural involvement.

Parenchymal lesions typically demonstrate T2/FLAIR hyperintensity with relatively homogeneous enhancement. These lesions are often found in the brainstem and cerebellum, followed by the frontal and parietal lobes.7 The pons is the most common site of disease in the brainstem.

Disease involving the HPA typically manifests with loss of the posterior pituitary bright spot and thickening of the infundibulum.7 DI is a common association with ECD, although the diagnosis of DI often precedes the confirmation of ECD by several years.

Despite being started on vemurafenib and repeat courses of steroids, the patient’s functional status continued to decline with worsened global weakness, decreased verbal output, and failure to thrive. Due to the patient’s poor prognosis and global decline, the patient was discharged to a hospice facility.

Conclusion

ECD is an uncommon but increasingly recognized multiorgan histiocytic neoplasm with an estimated 1500 reported cases in the literature. Isolated involvement of the CNS without disease in other organ systems is exceedingly rare. Timely diagnosis of ECD can be challenging, especially given the rarity of the disease and the highly variable clinical presentation. This case highlights the value of utilizing all available clinical, radiologic, and histologic data to improve diagnostic accuracy and facilitate optimal patient outcomes.