ALK+ Anaplastic Large Cell Lymphoma

ALK+ Anaplastic Large Cell Lymphoma

Francisco Vega, MD, PhD

ALK(+) ALCL, classical variant, involving lymph node. The neoplastic cells grow cohesively and preferentially involve sinuses. (Courtesy M. Lim, MD, PhD.)

Necrosis is frequently seen, particularly in those ALK(+) ALCL cases with extensive involvement.



  • Anaplastic lymphoma kinase (ALK) positive, anaplastic large cell lymphoma (ALCL)


  • CD30-positive systemic lymphoma of T- or null cell lineage with chromosomal abnormalities involving 2p23 and ALK

  • Current WHO classification distinguishes 2 types of systemic ALCL

    • ALK(+) and ALK(−)



  • Children and young adults

  • Male predominance

  • B symptoms, especially fever

  • Most patients present with clinical stage III/IV disease

  • Extranodal involvement common (60%)

    • Particularly skin, soft tissue, and lungs

    • Bone marrow (5-30%)

    • Involvement of central nervous system is rare


  • Intensive chemotherapy, doxorubicin-based regimens


  • 5-year survival 90%


Histologic Features

  • Neoplastic cells: Large, irregular, and bizarre

    • Often with polylobated nuclei

  • Cytological spectrum of neoplastic cells from small to large

    • Cell size variability helpful in distinguishing ALCL from classical Hodgkin lymphoma

  • “Hallmark” cells characteristic

    • Large cells with eccentric horseshoe- or kidney-shaped nuclei

    • Prominent paranuclear eosinophilic Golgi region

  • Histologic variants

    • Common or classical (80%)

    • Lymphohistiocytic (5-10%)

    • Small cell (5-10%)

    • Sarcomatoid (1%)



  • Strongly and uniformly positive for CD30 and ALK

  • ALCL can be of T- or null cell lineage

    • In cases of T-cell lineage, aberrant T-cell immunophenotype is common

      • Most tumors do not express CD3, CD5, or T-cell receptors (suggests defective T-cell signaling)

  • Cytotoxic molecules(+)

  • Clusterin(+)

  • EMA(+/−), CD45/LCA(+/−)

  • Bcl-2(−), EBV(−)

  • B-cell antigens(−)

  • Type of ALK staining correlates with type of underlying genetic abnormality

    • Cytoplasmic and nuclear: t(2;5)

    • Cytoplasmic, not coarsely granular: Variant translocations

      • Except t(2;X) and t(2;17)

    • Cytoplasmic, coarsely granular: t(2;17)

    • Membranous: t(2;X)


  • ALK(+) ALCL characterized by chromosomal translocations involving ALK gene at 2p23

  • Methods used for demonstrating ALK abnormalities

    • Conventional cytogenetics

    • Fluorescence in situ hybridization (FISH)

    • Reverse-transcriptase (RT) PCR

    • Long-range PCR

    • Immunohistochemistry

  • Chromosomal translocations

    • 75-80% of cases t(2;5)(p23;q35)

      • t(2;5) juxtaposes nucleophosmin (NPM) gene at 5q35 with ALK gene at 2p23

      • t(2;5) drives expression of novel fusion protein NPM-ALK

    • Variant chromosomal abnormalities (25% of cases)

      • ALK gene rearranged with other genes

      • Tropomyosin 3 (TPM3), t(1;2)(p25;p23)

      • TRK-fused gene (TFG), t(2;3)(p23;q21)

      • ATIC, inv(2)(p23;q35)

      • Moesin (MSN), t(2;X)(p23; q11-12)

      • Clathrin heavy chain (CLTCL), t(2;17)(p23;q23)

      • Tropomyosin 4 (TPM4), t(2;19)(p23;q13.1)

      • ALO17, t(2;17)(p23;q25)

      • MYH9, t(2;22)(p23;q11.2)

    • Additional translocations involving ALK will be recognized in future


Classical Hodgkin Lymphoma (CHL)

  • Immunophenotype very helpful to confirm diagnosis of CHL

  • HRS cells are positive for

    • pax-5 (nuclear and characteristically weak)

    • CD20 or CD79a in 20% of cases; variable

  • Negative for

    • EMA

    • CD45/LCA

    • ALK

  • In contrast, ALK(+) ALCL tumor cells are ALK(+) and pax-5(−)

Jul 8, 2016 | Posted by in PATHOLOGY & LABORATORY MEDICINE | Comments Off on ALK+ Anaplastic Large Cell Lymphoma

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