Langerhans cell histiocytosis

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Histiocytic tumour

General

• Langerhans cell histiocytosis LCH is a clonal proliferation of Langerhans type cells manifesting in the CNS or the meninges.

• It pathologically corresponds to its counterparts occurring elsewhere in the body.

• AKA
• Histiocytosis X

• Langerhans cells
• Are a type of dendritic cell that reside in the skin and mucosal epithelia
• They are antigen-presenting cells that have roles in the immune system12.
• Monocyte lineage

Definition

• Essential:
• A population of cells showing cytological features of Langerhans cells AND expressing CD1a and/or CD207 (langerin).

• Desirable:
• S100 positivity.
• BRAF and MAP2K1 mutation status.

Numbers

• Most cases occur in childhood.
• Peak incidence between one and three years of age

• The estimated annual incidence rate is 0.5 cases per 100,000 individuals aged $< 15$ years.
• 70% pt < 20yrs old

• The male-to-female ratio is 1.2:1.

WHO Grade

• A specific numerical CNS WHO grade (1–4) is not provided in the classification..

Pathogenesis

• Molecular Alterations:
• The most frequent alteration is the BRAF p.V600E mutation, occurring in about 50% of cases.
• Single cases of BRAF p.V600D or ARAF mutations, or BRAF fusions, have been reported.
• In BRAF-wildtype cases, MAP2K1 mutations are found in about 25%.
• NRAS, KRAS, and PIK3CA mutations have been reported in single cases

• Signalling Pathway: Activation of the MAPK pathway can be inferred from immunohistochemistry for phosphorylated ERK.

Localisation

• The CNS can be affected via
• Direct invasion from
• Craniofacial bone and skull base
• Most common presentation of CNS involvement
• 56%
• With or without soft-tissue extension
• Meninges
• Extra-axial masses
• Hypothalamic-pituitary region (50%)
• Meninges (29%)
• Choroid plexus (6%)
• Leukoencephalopathy-like pattern
• With or without dentate nucleus or basal ganglia neurodegeneration, is seen in 36%
• Cerebral atrophy occurs in 8%
• Primary intraparenchymal CNS masses
• Rare

Subtypes

• Unifocal: eosinophilic granuloma and/or histiocytosis X.
• Rare (1/1200 new cases/yr in US).
• More common in children.
• Slowly progressing disease → good prognosis
• May occur in bone, skin, lungs, or stomach.

• Multifocal unisystem:
• Seen mostly in children.
• Fever, bone & skin lesions

• Multifocal multisystem:
• Letterer-Siwe disease:
• A fulminant, malignant lymphoma of infancy
• Hand-Schüller-Christian triad:
• DI (from invasion of pituitary stalk) + exophthalmos (from intraorbital tumour) + lytic bone lesions (particularly of cranium).
• Poor prognosis disease

Clinical features

• Neurogenic (central) diabetes insipidus
• Occurring in
• 25% of cases overall
• 50% of cases of multisystem disease
• In about 60% of patients also showing signs of hypothalamic dysfunction
• Obesity
• Hypopituitarism
• Growth retardation

• Neurodegeneration characterised by psychomotor deterioration and ataxia
• Neurodegenerative lesions range from asymptomatic imaging abnormalities to tremors, gait disturbances, dysarthria, dysphagia, motor spasticity, ataxia, behavioural disturbances, learning difficulties, global cognitive deficits, and/or psychiatric disease

• Obstructive hydrocephalus

Pathophysiology

• Unknown

• Abnormal immune response is thought to play a potentially important etiological role
• Defective interactions between T cells and macrophages.

Genetic profile

• BRAF V600E mutations in 38-58% of cases

• If BRAF-wildtype
• 33-50% harbour MAP2K1 mutations

• Interferon gamma and IL4 polymorphisms affect susceptibility to Langerhans cell histiocytosis and might be responsible for some of the clinical variation

Histopathology

Macroscopic

• Intracranial Langerhans cell histiocytosis lesions are
• Often yellow or white
• Range from discrete dural-based nodules to granular parenchymal infiltrates

Microscopy

• Langerhans cell histiocytosis infiltrates are composed of
• Langerhans cells
• Macrophages
• Lymphocytes
• Plasma cells
• Variable eosinophils

• There is abundant pale to eosinophilic cytoplasm

• Touton giant cells may be seen
• Touton giant cells are a type of multinucleated giant cell seen in lesions with high lipid content

• In the neurodegenerative lesions of the cerebellum and brain stem,
• No Langerhans cells,
• Marked inflammation accompanies severe neuronal and axonal loss

• Eosinophils may aggregate and undergo necrosis, producing granulomas or abscesses.

• Ki-67 proliferation index: highly variable (can reach 50%)

 

Immunophenotype

• Neoplastic Langerhans cells
• + consistently
• CD1a
• S100 protein
• Vimentin
• Langerin (CD207)
• + low
• CD68 (generally paranuclear)
• HLA-DR (generally paranuclear)
• PTPRC
• Lysozyme
• About 50-60% of cells express the BRAF p.V600E protein.

Radiology

• MRI
• Intra-axial:
• General
• Tumour-like lesions:
• Appear hypointense on T1-weighted images and hyperintense on T2-weighted images, and show contrast enhancement after gadolinium infusion.
• Supratentorial Areas:
• Symmetrical T1 hyperintensity of the basal ganglia and nonspecific white matter T2 hyperintensity are observed.
• Atrophy:
• Diffuse CNS atrophy may appear over time.
• Diabetes insipidus
• Most common CNS manifestation
• Lack of T1-weighted high intensity of the posterior pituitary with associated enhancement and thickening (>3 mm) of the infundibulum
• This loss of the normal posterior pituitary bright spot is thought to be a result of the loss of vasopressin stores
• This is characteristic of CNS involvement in LCH, but is also non-specific
• Neurodegenerative changes
• Second most common CNS
• Initially T1 high intensity + variable T2 intensity, → then marked T2-weighted high intensity
• Neurodegenerative lesions are not contrast enhancing and do not exert mass effect.
• Contrast enhancement is variable throughout the temporal progression of the disease
• Posterior Fossa:
• Bilateral symmetric parenchymal lesions of the cerebellum (especially the dentate nuclei) and basal ganglia, however uncommonly other regions of the brain and brainstem (especially the pons) may be affected and cerebral atrophy may also be noted
• Neurodegenerative lesions show symmetrical T2 hyperintensity of the corpus medullare and symmetrical T1 hyperintensity of the dentate nuclei.
• Mass lesions are the least common CNS manifestation
• Variable MR appearance
• Can arise from the
• Meninges (especially the dura mater),
• Pineal gland,
• Choroid plexus,
• Hypothalamus,
• Ependyma,
• Intraparenchymal (rare)
• Depending on size and location, may cause obstructive hydrocephalus
• Extraaxial
• Skull
• Solitary or multiple punched out lytic lesions without sclerotic rim
• Double contour or bevelled edge appearance may be seen due to asymmetrical involvement of the inner and outer tables (hole within a hole) sign
• Button sequestrum representing residual bone
• Geographic skull
• Skull: X-rays may show bone lucency at the site of disease.
• Spine
• Vertebra plana:
• Most common cause of vertebra plana in children;
• More often in thoracic spine
• Aka pancake or silver dollar or coin-on-edge vertebra,
• Term given when a vertebral body has lost almost its entire height anteriorly and posteriorly, representing a very advanced compression fracture.
• MRI
• T1: Typically hypointense to isointense
• T2: hyperintense
• STIR: hyperintense
• T1 C+ (Gd): often shows diffuse contrast enhancement

Management

• Tumour-like lesions
• Tendency toward spontaneous regression
• Multiple lesions are usually associated with extracalvarial bony involvement and are often treated with chemotherapy and/or low dose radiation therapy.
• Indomethacin
• Sensitive to conventional treatments like vinblastine or cladribine.
• Single lesions are treated by curettage.
• Targeted Therapy
• Molecular targeted therapies, specifically MAPK signalling pathway inhibitors, yield a high tumour response rate when an actionable target is present.
• Very radiosensitive.

• Neurodegenerative lesions
• Relatively resistant or poorly sensitive to multiple therapeutic strategies, including radiotherapy, immunosuppressive drugs, and molecular targeted drugs.

Prognosis

• Tumour-like lesions:
• Associated with a favourable prognosis and high tumour response rate to appropriate therapy.
• Unifocal disease may spontaneously recover or requires only minimal treatment (e.g. surgical resection),

• Neurodegenerative lesions:
• Neurodegenerative Langerhans cell histiocytosis seems to be progressive, with neurocognitive symptoms present in about 25% of patients after 6 years

• Overall survival rates

Yrs	%
5	88
15	88
20	77

• Event-free survival rate of only 30% at 15 years

• Multisystemic disease with organ dysfunction may require systemic chemotherapy.
• Mortality rate: 20%

• Late sequelae are seen in 64% present with
• Skeletal defects (42%)
• Diabetes insipidus (25%)
• Growth failure (20%)
• Hearing loss (16%)
• Other CNS dysfunction (14%)

• No prognostic significance of histopathological features (cytological atypia and mitotic activity)

• Malignant Langerhans cell histiocytosis does exist
• Characterised by
• Morphologically: malignant-appearing Langerhans cells
• Clinically: atypical organ involvement and an aggressive clinical course
• Very rare
• Frequency of CNS involvement is unknown