Anaplastic Large Cell Lymphoma, ALK-Positive

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Primary Authors*

Sumire Kitahara, MD

Miguel Gonzalez Mancera, MD

Cedars-Sinai, Los Angeles, CA

Cancer Category/Type

Cancer Sub-Classification / Subtype

  • Systemic T-cell lymphoma

Definition / Description of Disease

Anaplastic Large Cell Lymphoma, ALK-Positive (ALK+ ALCL) is a T-cell lymphoma characterized by usually large lymphoma cells with abundant cytoplasm and pleomorphic nuclei, often horse-shoe shaped (see Morphologic Features below), with a chromosomal rearrangement involving the ALK gene resulting in expression of ALK protein and CD30

Synonyms / Terminology

  • Ki-1 (CD30) lymphoma - obsolete

Epidemiology / Prevalence

  • ALCL (ALK+, ALK-, and primary cutaneous) account for <5% of all cases of non-Hodgkin lymphoma (NHL)[1]
  • ALK+ ALCL[1]
    • ~3% of adult NHL
    • 10-20% of childhood lymphomas
    • Most frequent in the first three decades of life
    • Male:female = 1.5:1

Clinical Features

  • Most patients (70%) present with advanced (stage III-IV) disease and B-symptoms.[2]

Sites of Involvement[1]

  • Lymph nodes and extranodal sites (most commonly skin, bone, soft tissue, lungs and liver)
  • Bone marrow involvement detected in 30% when using immunohistochemistry (CD30 and EMA). Can miss marrow involvement by H&E evaluation alone, which detects involvement with ~10% incidence.[3]

Morphologic Features

"Hallmark cells"[4][5]

  • Lymphoma cells characterized by eccentric, horseshoe-shaped or kidney-shaped nuclei, often with eosinophilic cytoplasm accentuated near the nucleus
  • Usually large in size, but may also be smaller
  • Present in varying proportions
  • Seen in all morphological variants/patterns of ALK+ ALCL

Morphological variants/patterns

  1. Common (60%): predominant population of large hallmark cells
  2. Lymphohistiocytic (10%): lymphoma cells are admixed with numerous reactive histiocytes that may obscure the lymphoma cells; lymphoma cells often cluster around vessels and are often smaller than in the common pattern
  3. Small cell (5-10%): predominant population of smaller lymphoma cells; hallmark cells are often concentrated around vessels; may also see "fried egg cells" (pale cytoplasm with central nucleus) or signet ring-like cells; can misdiagnose of peripheral T-cell lymphoma, NOS
  4. Hodgkin-like (3%): mimics nodular sclerosis classic Hodgkin lymphoma
  5. Composite (15%): more than one pattern in a single lymph node

When lymph node is only partially involved, lymphoma characteristically grows in the sinuses, which may mimic a metastatic tumor.


ALK+ ALCL show the following staining pattern[6][7]:

  • CD30+: Cell membrane and Golgi; large lymphoma cells show strongest staining; smaller cells may show weak, partial to negative staining
  • ALK+: cellular location of ALK staining varies depending on ALK translocation partner. In the most common t(2;5), most cases show both cytoplasmic and nuclear ALK staining. In the small cell variant, staining is usually restricted to the nucleus
  • EMA+: some cases show positivity in only a proportion of lymphoma cells
  • CD3(-): >75% of cases are CD3-negative
  • CD4>>>CD8
  • CD2 and CD5: Majority positive
  • Cytotoxic marker(s)+: TIA1, granzyme B and/or perforin
  • CD45: variably positive
  • CD25+
  • BCL2-negative

Chromosomal Rearrangements (Gene Fusions)

  • ALK(+) ALCL is characterized by chromosomal translocations involving ALK gene, a receptor tyrosine kinase domain at 2p23.
  • Approximately 80% of cases show a cytogenetic translocation t(2;5) (NPM1-ALK, t(2;5)(p23;q35)) which fuses the ALK gene to the nucleophosmine (NPM) gene at 5q35, resulting in the overexpression and constitutive activation of a chimeric ALK fusion protein, which plays an important role in ALK-mediated oncogenesis.[8]
  • ALK translocations may be seen in multiple malignancies including epithelial malignancies[9][10][11][12][13][14], inflammatory myofibroblastic tumor[15][16][17], non-Hodgkin's lymphoma[18][19][20], and ALK+ histiocytosis [21][22][23].
FISH break apart probe for ALK gene showing a split signal indicating ALK rearrangement in a case of ALK(+) ALCL.

Table below shows described ALK translocations with ALK staining pattern, and frequency of cases. Of note, identifying the ALK fusion partner is not considered necessary in routine clinical practice.



ALK partner ALK staining pattern Percentage

of cases

t(2;5)(p23;q35) NPM1 Nuclear, nucleolar, diffuse cytoplasmic 84%
t(1;2)(q25;p23)[24] TPM3 Diffuse cytoplasmic with peripheral intensification 13%
inv(2)(p23q35)[25] ATIC Diffuse cytoplasmic 1%
t(2;3)(p23;q12.2)[26] TFG Diffuse cytoplasmic <1%
t(2;17)(p23;q23)[27] CLTC Granular cytoplasmic <1%
t(X;2)(q11-22;p23)[28] MSN Membrane <1%
t(2;19)(p23;p13.1)[29] TPM4 Diffuse cytoplasmic <1%
t(2;22)(p23;q11.2)[30] MYH9 Diffuse cytoplasmic <1%
t(2;17)(p23;q25)[29] RNF213 Diffuse cytoplasmic <1%
t(2;9)(p23;q33)[31] TRAF-1 Diffuse cytoplasmic <1%

Characteristic Chromosomal Aberrations / Patterns

See other sections.

Genomic Gain/Loss/LOH

Frequent secondary chromosomal imbalances are seen in ALK+ ALCL (58% of cases), as based on comparative genomic hybridization analysis[32].

Chromosome Number Gain/Loss/Amp/LOH Frequency Comment
2q Gain 12%
4q Loss 28%
11q22 (ATM) Loss, LOH 28%
13q Loss 28% Also see in ALK- cases
7p Gain 12% Also seen in ALK- cases
17p13 (TP53) Gain 28%
17p13 (TP53) Loss[33] 9% More common in ALK- cases (42%)
17q24-qter Gain 28%

Gene Mutations (SNV/INDEL)

  • Limited literature on somatic mutations in ALK+ ALCL
Gene Function or Presumed Mechanism Frequency
LRP1B[34] Tumor suppressor 19%
NOTCH1[35] Activating 9.3% (T349P)

10.2% (T311P)

TP53[34] Tumor suppressor 11%
  • Epigenetic modifier genes: KMT2D, TET2, EP300, KMT2C[34]
  • Other mutations: EPHA5

Negative genes mutations:

  • JAK1, STAT3: Mutations described in ALK(-) ALCL[36], and breast implant-associated anaplastic large cell lymphoma (BIA-ALCL)[37]
  • RHOA, DNMT3A, CD28: Mutations described in peripheral T cell-lymphoma (PTCL), NOS, and in angioimmunoblastic T-cell lymphoma (AITL)[38]
  • IDH2 mutations are relatively specific for AITL[39][40]

A variety of mechanisms for the acquired resistance to ALK inhibitors, such as crizotinib, have been described:

  • ALK kinase domain secondary mutations, including L1196 M, G1269A, L1152R, C1156Y, I1171T, F1174 L, G1202R, and S1206Y, have been identified as the key mechanism of resistance[41][42][43][44][45][46][47]
  • The G1269A mutation, in which the glycine at 1269 is substituted with an alanine, causes steric hindrance, resulting in decreased affinity for crizotinib.[48][49]
  • Gain in ALK copy number and loss of ALK gene rearrangement have also been implicated in the development of acquired resistance to crizotinib.[43][44][45]

Epigenomics (Methylation)

  • NPM-ALK via STAT3-activated DNA methyltransferases[50] uses epigenetic silencing mechanisms to:
    • Downregulate tumor suppressor genes to maintain its own expression (i.e. to inhibit downregulation of NPM-ALK). Silenced tumor suppressors include:
      • STAT5A[51]
      • SHP-1 phosphotyrosine phosphatase[52]
      • IL-2Rγ[53]
      • miR-150[54]
      • DNMT1 mRNA inhibitor miR-21[53]
    • Silence T-cell receptor complex and signaling pathway (CD3e, ZAP70, LAT, SLP76)[55]
  • Histone H3 lysine 27 (H3K27) trimethylation silences promoters of important T-cell transcription factor genes (GATA3, TCF1 and LEF1)[56]
  • Reader is directed to this review for more comprehensive review of epigenetics in peripheral T-cell lymphomas[57]

Genes and Main Pathways Involved

  • Activation of the ALK catalytic domain leads to the oncogenic properties of the ALK protein, leading to activation of multiple signaling cascades including[58]:
    • RAS-ERK
    • JAK/STAT
      • STAT3 is a pivotal transcription factor in most ALCL subtypes:
        • NPM1/ALK and variants lead to expression of ALK fusion proteins with constitutive ALK tyrosine kinase activity, which converges in the activation of the downstream oncogenic transcription factor STAT3[36][38].
        • In the absence of ALK fusions there are activation JAK1 and/or STAT3 mutations in ALK(-) ALCL [36], and some BIA-ALCL. [59].
    • PI3K/AKT/mTOR
  • ALK-NPM-STAT3 induces:
    • See Epigenomics section above
    • TGF beta, IL-10, PD-L1/CD274 to create immunosuppressive microenvironment and evasion of immune system[60][61][62]
    • ICOS expression (CD28 costimulatory receptor superfamily)
    • HIF1α expression induces expression of VEGF (tumor angiogenesis); allows lymphoma cells to adapt to hypoxic conditions[63]
  • Expression of embryonic genes (SOX2, SALL4) promoting stem cell-like program
  • Deregulation of microRNAs (miR-155, miR-101, miR-17-92 cluster, miR-26a, miR-16)[64][65][66][67][68]

Diagnostic Testing Methods

  • Diagnosis is based on histologic evaluation and immunohistochemical positivity for CD30 and ALK on the T-lymphoma cells.
  • FISH using an ALK breakapart probe or karyotype analysis can detect ALK translocations, but is not required for diagnosis as it can be established by morphology and immunohistochemistry.

Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications)


  • As stated above, the diagnosis is based on histology and immunohistochemistry
  • FISH is not required for diagnosis in routine practice [69][70]


  • ALK+ ALCL has a better survival rate compared to ALK-negative ALCL
    • However, differences in patient age (younger in ALK+) may account for this better survival[71]
  • Different ALK translocation partners do not have prognostic significance
  • Survival is predicted by International Prognostic Index (IPI) with overall long term survival rate approaching 80%
  • Detecting minimal residual disease by PCR for NPM1-ALK (not readily commercially available) in bone marrow and peripheral blood during treatment could identify patients at risk of relapse[72]
  • Small-cell or lymphohistiocytic patterns tend to present with disseminated disease and have a less favorable prognosis than the common pattern[73]
  • NOTCH1 may be a biomarker for risk of relapse[35]


  • CD30 expression on ALCL (ALK+ or ALK-) allows for targeted therapy[74]
    • First-line therapy: Brentuximab (anti-CD30) vedotin + CHP (cyclophosphamide, doscorubicin, and prednisone)
  • ALK inhibition (crizotinib) can be an effective 2nd-line therapeutic strategy as ALK is essential for the proliferation and survival of ALK+ ALCL cells[75][74][76]
    • Drug resistance may develop due to:
      1. Mutations of the ALK gene impairing binding of the inhibitor[77]; other ALK inhibitors are not currently FDA-approved for use in ALK+ ALCL
      2. See also gene mutations section above
      3. Engagement of other cell signaling pathways
  • Preclinical models suggest role of:
    • Combination therapy with hypomethylating agents (such as azacitidine) and epigenetic modifying drugs (such as romidepsin, a histone deacetylase inhibitor)[78]
    • Inhibitors of HSP90 and mTOR inhibition[77]
    • NOTCH1 inhibition by γ-secretase inhibitors (GSI) in combination with crizotinib may provide synergistic anti-tumor activity, or as a single agent in ALK-inhibitor resistant cell lines[35]

Familial Forms

  • None

Other Information

  • None


  • See References.


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