Anaplastic large cell lymphoma (ALK+/ALK−)

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Lymphomas

General

• Anaplastic large cell lymphoma (ALCL) is a distinctive CD30-positive peripheral T-cell lymphoma that is rare in the Central Nervous System (CNS).

• It is separated into two distinct types: ALK-positive (ALK+ ALCL) and ALK-negative (ALK- ALCL).

WHO Grade

• The tumour is classified among malignant non-Hodgkin lymphomas.
• So does not have specific numerical CNS WHO grade (1–4) to this entity.

Definition

• Essential
• Biopsy showing an aggressive lymphoma confined to the CNS at presentation.
• Histologically composed of CD30+, large neoplastic lymphoid cells that are negative for B-cell markers and can be ALK+ or ALK-.

• Desirable
• Expression of T cell-specific antigens.
• Gene rearrangement studies showing clonal TR genes.
• FISH showing ALK rearrangement (for ALK+ anaplastic large cell lymphoma).

Numbers

• ALK+ ALCL:
• Occurs from early childhood to young adulthood (median age: ~17 years), with a male preponderance.

• ALK- ALCL:
• Affects adults (median age: 65 years), also with a male preponderance.

Clinical Features

• Patients often present with headache, seizures, nausea, fever, or a combination of these.

• They are frequently initially thought to have an infection.

Localisation

• ALK+ ALCL: Typically occurs as single or multiple supratentorial parenchymal lesions. Involvement of the meninges and (rarely) the skull can occur.

• ALK- ALCL: Usually found as single or multiple lesions, typically supratentorial.

Pathogenesis

• ALK+ ALCL:
• Is driven by oncogenic ALK gene fusions, most commonly with NPM1 (in > 80% of cases).
• These fusions lead to aberrant activation of signalling pathways, including JAK/STAT3.

• ALK- ALCL:
• Carries mutations or gene fusions of other receptor tyrosine kinase genes that activate signalling pathways similar to those activated in ALK+ ALCL, such as JAK/STAT3.

• T-cell Receptor:
• Clonal rearrangements of T-cell receptor (TR) genes are present in the vast majority of cases.

Histopathology

Microscopic Features

• The tumour consists of a diffuse proliferation of large atypical cells.

• It is characterised by hallmark cells with bean-shaped nuclei and an eosinophilic paranuclear area.

• Small cell or lymphohistiocytic patterns have also been observed.

Immunophenotype

• Common: Tumour cells strongly express the CD30 antigen.

• ALK+ ALCL: Cells are ALK+ and EMA+, and may express one or more T-cell antigens.

• ALK- ALCL: ALK is not expressed.

• Lineage: Cells are negative for B-cell markers.

Prognosis

• ALK+ ALCL: Prognosis is similar to or worse than that of systemic ALK+ ALCL, though sustained remission is possible. Treatment failures tend to occur in the CNS.

• ALK- ALCL: Prognosis is poor.

Management

• Staging is required to exclude a systemic primary lymphoma.

• Treatment failures primarily occur in the CNS.