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.

    Article Bibliography

    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