Neurosurgery notes/Tumours/Haematolymphoid and histiocytic tumours/Histiocytic tumour/Erdheim Chester disease

Erdheim Chester disease

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Histiocytic tumour

General

  • Similar histologically and immunohistochemically to its counterparts occurring elsewhere.
  • Systemic lesions may be present or absent.
  • Erdheim-Chester disease (ECD) of the CNS or the meninges, with or without systemic lesions, pathologically corresponds to its counterparts occurring elsewhere.
  • It is a clonal histiocytosis.
  • It is characteried by foamy histiocytes, occasional Touton giant cells, chronic inflammation, and variable fibrosis.

Definition

  • Essential:
    • A population of foamy cells expressing histiocytic antigens.
    • Negativity for Langerhans cell markers (CD1a and/or CD207 [langerin]).
  • Desirable:
    • Exclusion of other lines of differentiation (glial, epithelial, melanocytic, lymphocytic, etc.).
    • Exclusion of reactive and demyelinating lesions.
    • BRAF, MAP2K1, and KRAS or NRAS mutation status.
    • Potential systemic manifestations on imaging.

Numbers

  • Neurological complications occur in 30–50% of patients with $\text{Erdheim-Chester disease}$.
  • It predominantly occurs in men.
  • It typically affects patients aged about 50 years.

WHO Grade

  • No grade

Localisation

  • Brain
    • Preferentially the cerebellum and brain stem
  • Spinal cord
  • Cerebellopontine angle
  • Choroid plexus
  • Pituitary
  • Meninges
  • Orbit

Histopathology

Macroscopic

  • It manifests as widespread intraparenchymal lesions (in 44% of cases), dural thickening or a meningioma-like mass (37%), or a combination of both (19%).
  • Nerve root or pituitary stalk lesions also occur.

Microscopic

  • Infiltrates are composed of foamy to epithelioid histiocytes with small nuclei.
  • Touton-type multinucleated giant cells, scant lymphocytes, rare eosinophils, and variable fibrosis or gliosis that is often rich in Rosenthal fibres (piloid gliosis) are present.
  • Histiocytes may resemble astrocytes when embedded in densely fibrillar CNS parenchyma.

Immunophenotype

  • The neoplastic histiocytes are positive for CD68, CD163, CD14, and factor XIIIa.
  • They are variably positive for S100.
  • They are negative for CD1a.
  • About half express BRAF p.V600E.

Genetic features

  • Common alterations include BRAF p.V600E mutations (in as many as 50% of cases).
  • MAP2K1 mutations (in up to 30% of cases), KRAS and/or NRAS mutations (up to 20% of cases), and other genetic alterations pertaining to the MAPK pathway are found.
  • Single cases reporting ARAF mutations or BRAF, NTRK1, ALK, or ETV3 fusions have been noted.
  • PIK3CA mutations can occur alone or in combination with BRAF p.V600E mutations (in about 11% of all cases).
  • Activation of EPHB2 (ERK) and a potentially targetable alteration of a MAPK pathway gene are found in nearly all cases.
  • In patients with both Erdheim-Chester disease and Langerhans cell histiocytosis, the frequency of BRAF p.V600E mutation is higher (82% of lesions).

Clinical Features

  • Tumour-like lesions
    • Symptoms are related to tumour location
    • Causing increased intracranial pressure, focal neurological deficits, and seizures.
  • Neurodegenerative lesions
    • Causing cerebellar symptoms, pyramidal tract signs, pseudobulbar palsy, or cognitive disturbances.
    • Histiocyte infiltration can lead to neurodegenerative lesions in the brain and nervous system. These lesions cause brain tissue damage resembling neurodegeneration, such as atrophy, demyelination, and focal abnormalities
  • Infiltration of large arteries may induce stroke.

Radiological Features

  • Tumour lesions on MRI are isointense or hypointense on T1-weighted images, contrast enhancing, and associated with mass effect and perilesional oedema.
    • May resemble meningioma on imaging
    • Demonstrate delayed gadolinium enhancement
  • Diffuse CNS atrophy may appear over time.
  • More than 10% of patients are asymptomatic despite abnormal CNS MRI findings.
  • Neurodegenerative lesions
    • Do not exert mass effect, are not contrast enhancing, and are not surrounded by perilesional oedema.
    • In the posterior fossa show symmetrical T2 hyperintensity of the corpus medullare and symmetrical T1 hyperintensity of the dentate nuclei.
    • In supratentorial areas show nonspecific white matter T2 hyperintensity and symmetrical T1 hyperintensity of the basal ganglia.
T2
T2
 
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T1+C

Management

  • Therapeutic options include surgery, cladribine, immunomodulators, and molecular targeted therapies including BRAF inhibitors and MEK inhibitors.
    • For tumours with BRAF V600E mutation, therapy with vemurafenib may lead to complete clinical remission of CNS lesions and systemic disease
  • Neurodegenerative lesions are relatively resistant to therapeutic interventions.

Prognosis

  • Tumour-like lesions are associated with a favourable prognosis and high tumour response rate to appropriate therapy.
  • Neurodegenerative lesions show neurological symptoms that tend to worsen slowly over decades.