Anaplastic large cell lymphoma (ALCL)

2003-08-01   Jean-Loup Huret 

1.Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers France

Clinics and Pathology

Epidemiology

ALCL represent about 5% of non Hodgkin lymphomas (NHL) in adults, and 15% of pediatric NHL (i.e. 20-30% of large cell lymphomas in children). ALK+ ALCL represent 50 to 60% of ALCL cases. ALK+ ALCL predominantly affect young male patients (most cases occur before the age of 40 yrs), while ALK- ALCL is found in older patients (median age around 50 yrs) of both sex.

Clinics

ALK+ ALCL presents as an aggressive disease with systemic signs, and extranodal sites (bone marrow, skin, bone, soft tissues, and organs); less agressive presentation in ALK- ALCL cases (but a worse prognosis, see below).
Note: ALK+ ALCL without the t(2;5) (so called cytoplasmic only ALK cases) show clinical features similar to those of classical ALK+ ALCL. Were found in a recent series: mean age: 19 yrs, range 4 to 45 yrs; male/female ratio: 1.5, presentation with advanced disease (stage III-IV in 9 of 15 cases), systemic symptoms (11/15), and frequent involvement of extranodal sites.

Pathology

3 main histopathological types are found;
  • the common type, characterized by large lymphoid cells with horseshoe shaped nuclei with many nucleoli, and large cytoplasm; may be ALK + or - ALCL,
  • the small cell type, together with the above described cells, show small and medium sized cells; almost exclusively ALK+ cases,
  • the lymphohistiocytic type also contains a number of reactive histiocytes, which, earlier, lead to the misdiagnosis of malignant histiocytosis; almost always ALK+ cases.
    All the 3 forms contain large cells, positive for CD30 (on the cell membrane and the golgi ); they are mostly epithelial membrane antigen (EMA) positive.
    most cases are T-cell cases (often cytotoxic T-cells), or may be null cases, the null cases often involving the T-cell; B-cell cases may belong to a different category; ALK+/IgA+ immunoblastic large B-cell lymphomas could exist.
    Aside are primary cutaneous anaplastic large cell lymphomas, a disease with indolent clinical course, negative for ALK, lacking the t(2;5) or variant translocations, close to the benign lymphomatoid papulosis.
    Note: there are cases where the differential diagnosis between Hodgkin disease (HD) -where CD30 is also strongly expressed- and ALCL is difficult (cases previously called ALCL-HD like).
  • Prognosis

    ALK+ ALCL have a favourable prognosis, whichever the ALK partner is: 70% to 80% 5 yrs survival, while ALK- ALCL cases have a much poorer prognosis (5 yrs survival in only 30%-40%). ALK+ cases without NPM1 involvement.

    Note

  • The genetic background in ALK- cases remains unknown.
  • ALK+ cases are the result of the formation of a hybrid gene between ALK and either NPM1 (in 70-80% of the cases), or TPM3 (in 20% of the cases) or, rarely: MSN, ATIC, TFG, CLTC, ALO17, or MYH9 (these latter being "cytoplasm only" or cytoplasmic (TPM3, ATIC, TFG, CLTC, ALO17, MYH9) or membrane restricted (MSN) ALK+ ALCL).
  • Genes Involved and Proteins

    Gene name
    ALK (anaplastic lymphoma receptor tyrosine kinase)
    Location
    2p23.2
    Protein description
    1620 amino acids; 177 kDa; glycoprotein (200 kDa mature protein); membrane associated tyrosine kinase receptor.
    Gene name
    NPM1 (nucleophosmin)
    Location
    5q35.1
    Protein description
    Nuclear localisation; RNA binding nucleolar phosphoprotein involved in preribosomal assembly.
    Gene name
    CLTC (clathrin heavy polypeptide)
    Location
    17q23.1
    Protein description
    1675 amino acids, 191 kDa; Component of the vesicles matrix originated from the plasma membrane or the golgi.
    Gene name
    RNF213 (lymphoma oligomerization partner on chromosome 17)
    Location
    17q25.3
    Protein description
    1599 amino acids.
    Gene name
    MYH9 (myosin, heavy polypeptide 9, non-muscle)
    Location
    22q12.3
    Protein description
    1960 amino acids; 227 kDa; binds actin; protein of the cytoskeleton.
    Somatic mutations
    Apart from the TFG-ALK herein described, TFG is also known to de fused to NTRK1 in a subset of thyroid papillary carcinomas.

    Result of the Chromosomal Anomaly

    Description

    5 partner - 3 ALKN-term amino acids from the partner gene fused to the 562 C-term amino acids from ALK (i.e. the entire cytoplasmic portion of ALK with the tyrosine kinase domain); homodimerization of the fusion protein.

    Bibliography

    Pubmed IDLast YearTitleAuthors
    91214811997Role of the nucleophosmin (NPM) portion of the non-Hodgkin's lymphoma-associated NPM-anaplastic lymphoma kinase fusion protein in oncogenesis.Bischof D et al
    107023932000ATIC-ALK: A novel variant ALK gene fusion in anaplastic large cell lymphoma resulting from the recurrent cryptic chromosomal inversion, inv(2)(p23q35).Colleoni GW et al
    121125242002Identification of novel fusion partners of ALK, the anaplastic lymphoma kinase, in anaplastic large-cell lymphoma and inflammatory myofibroblastic tumor.Cools J et al
    90782871997Cytogenetics of lymphomas: a brief review of its theoretical and practical significance.Donner LR et al
    109949992000Pathobiology of NPM-ALK and variant fusion genes in anaplastic large cell lymphoma and other lymphomas.Drexler HG et al
    105529611999Lymphomas expressing ALK fusion protein(s) other than NPM-ALK.Falini B et al
    105562171999TRK-fused gene (TFG) is a new partner of ALK in anaplastic large cell lymphoma producing two structurally different TFG-ALK translocations.Hernández L et al
    90538411997Molecular characterization of ALK, a receptor tyrosine kinase expressed specifically in the nervous system.Iwahara T et al
    102161061999A new fusion gene TPM3-ALK in anaplastic large cell lymphoma created by a (1;2)(q25;p23) translocation.Lamant L et al
    128001562003Non-muscle myosin heavy chain (MYH9): a new partner fused to ALK in anaplastic large cell lymphoma.Lamant L et al
    107068872000Inv(2)(p23q35) in anaplastic large-cell lymphoma induces constitutive anaplastic lymphoma kinase (ALK) tyrosine kinase activation by fusion to ATIC, an enzyme involved in purine nucleotide biosynthesis.Ma Z et al
    126610112003Fusion of ALK to the Ran-binding protein 2 (RANBP2) gene in inflammatory myofibroblastic tumor.Ma Z et al
    21565481990CD30-positive large cell lymphomas ('Ki-1 lymphoma') are associated with a chromosomal translocation involving 5q35.Mason DY et al
    81221121994Fusion of a kinase gene, ALK, to a nucleolar protein gene, NPM, in non-Hodgkin's lymphoma.Morris SW et al
    113803912001Alk+ CD30+ lymphomas: a distinct molecular genetic subtype of non-Hodgkin's lymphoma.Morris SW et al
    103815341999t(1;2)(q21;p23) and t(2;3)(p23;q21): two novel variant translocations of the t(2;5)(p23;q35) in anaplastic large cell lymphoma.Rosenwald A et al
    106101191999Complex variant translocation t(1;2) with TPM3-ALK fusion due to cryptic ALK gene rearrangement in anaplastic large-cell lymphoma.Siebert R et al
    110900482000CD30(+) anaplastic large cell lymphoma: a review of its histopathologic, genetic, and clinical features.Stein H et al
    113108342001Molecular characterization of a new ALK translocation involving moesin (MSN-ALK) in anaplastic large cell lymphoma.Tort F et al
    108077892000Further demonstration of the diversity of chromosomal changes involving 2p23 in ALK-positive lymphoma: 2 cases expressing ALK kinase fused to CLTCL (clathrin chain polypeptide-like).Touriol C et al
    107060822000A new variant anaplastic lymphoma kinase (ALK)-fusion protein (ATIC-ALK) in a case of ALK-positive anaplastic large cell lymphoma.Trinei M et al
    76629791995Analysis of the t(2;5)(p23;q35) translocation by reverse transcription-polymerase chain reaction in CD30+ anaplastic large-cell lymphomas, in other non-Hodgkin's lymphomas of T-cell phenotype, and in Hodgkin's disease.Wellmann A et al
    97635511998The cryptic inv(2)(p23q35) defines a new molecular genetic subtype of ALK-positive anaplastic large-cell lymphoma.Wlodarska I et al

    Summary

    Note

    Anaplastic large cell lymphoma can be classified into:
  • 1- primary systemic ALK+ ALCL,
  • 2- primary systemic ALK- ALCL,
  • 3- primary cutaneous ALCL (see in paragraph Pathology).
    The 2 first categories are defined according to the involvement (or not) of ALK in fusion proteins with various partners (see below); ALK+ ALCL cases are sometimes called ALK lymphomas, or ALKomas.
    ALK+ ALCL can be further divided into t(2;5) cases, with NPM1-ALK fusion protein which localises both in the cytoplasm and in the nucleus, and t(2;Var), involving various partners and ALK, and a cytoplasmic localization of the fusion protein; the latter are called "cytoplasm only" ALK+ ALCL.
    ALCL may also arise from transformation of another lymphoma mycosis fungoides, peripheral T-cell lymphoma, ...); these ALCL are called secondary ALCL, and they bear a poor prognosis.
  • Citation

    Jean-Loup Huret

    Anaplastic large cell lymphoma (ALCL)

    Atlas Genet Cytogenet Oncol Haematol. 2003-08-01

    Online version: http://atlasgeneticsoncology.org/haematological/2103/anaplastic-large-cell-lymphoma-(alcl)

    Historical Card

    2001-08-01 Anaplastic large cell lymphoma (ALCL) by  Jean-Loup Huret 

    Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers France

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