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Anaplastic large cell lymphoma (ALCL)

Written2003-08Jean-Loup Huret
Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers France
This article is an update of :
2001-08Jean-Loup Huret
Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers France

(Note : for Links provided by Atlas : click)


ICD-Morpho 9714/3 Anaplastic large cell lymphoma, ALK positive
Atlas_Id 2103
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.
  • 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.


  • 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).
  • Cytogenetics

    Cytogenetics Morphological t(2;5)(p23;q35) in the classical form with NPM1 involvement on chromosome 5, t(X;2)(q11;p23), t(1;2)(q25;p23), inv(2)(p23q35), t(2;3)(p23;q21), t(2;17)(p23;q23), t(2;17)(p23;q25) or t(2;22)(p23;q11.2) can also be found.

    Genes involved and Proteins

    Note These translocations involve ALK in 2p23, and either MSN in Xq11, TPM3 in 1q25, ATIC in 1q35, TFG in 3q21, NPM1 in 5q35, CLTC in 17q23, ALO17 in 17q25, and MYH9 in 22q11.2.
    Gene NameALK (anaplastic lymphoma receptor tyrosine kinase)
    Location 2p23.2
    Protein 1620 amino acids; 177 kDa; glycoprotein (200 kDa mature protein); membrane associated tyrosine kinase receptor.
    Gene NameMSN (moesin)
    Location Xq12
    Protein 576 amino acids, 68 kDa; cytoskeleton protein; binds to the plasma membrane and interacts with actin.
    Gene NameTPM3 (tropomyosin 3)
    Location 1q21.3
    Protein 284 amino acids, 33 kDa; coilde coil structure; role in Calcium dependant actin-myosin interaction.
    Gene NameATIC (5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/IMP cyclohydrolase)
    Location 2q35
    Protein 591 amino acids, 64 kDa; bifunctional purine biosythesis: 9th and 10th step of the de novo purine synthesis.
    Gene NameTFG (TRK-fused gene)
    Location 3q12.2
    Protein 406 amino acids, 44 kDa; widely expressed.
    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.
    Gene NameNPM1 (nucleophosmin)
    Location 5q35.1
    Protein Nuclear localisation; RNA binding nucleolar phosphoprotein involved in preribosomal assembly.
    Gene NameCLTC (clathrin heavy polypeptide)
    Location 17q23.1
    Protein 1675 amino acids, 191 kDa; Component of the vesicles matrix originated from the plasma membrane or the golgi.
    Gene NameRNF213 (lymphoma oligomerization partner on chromosome 17)
    Location 17q25.3
    Protein 1599 amino acids.
    Gene NameMYH9 (myosin, heavy polypeptide 9, non-muscle)
    Location 22q12.3
    Protein 1960 amino acids; 227 kDa; binds actin; protein of the cytoskeleton.

    Result of the chromosomal anomaly

    Hybrid gene
    Description 5' partner - 3' ALK
    Fusion Protein
    Description N-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.

    To be noted

    ALK and some of the above ALK partners, or closely related genes, are found implicated both in anaplastic large cell lymphoma and in inflammatory myofibroblastic tumours; this is a new concept, that 2 different types of tumour may result from the same chromosomal/genes rearrangement.


    Role of the nucleophosmin (NPM) portion of the non-Hodgkin's lymphoma-associated NPM-anaplastic lymphoma kinase fusion protein in oncogenesis.
    Bischof D, Pulford K, Mason DY, Morris SW
    Molecular and cellular biology. 1997 ; 17 (4) : 2312-2325.
    PMID 9121481
    ATIC-ALK: A novel variant ALK gene fusion in anaplastic large cell lymphoma resulting from the recurrent cryptic chromosomal inversion, inv(2)(p23q35).
    Colleoni GW, Bridge JA, Garicochea B, Liu J, Filippa DA, Ladanyi M
    The American journal of pathology. 2000 ; 156 (3) : 781-789.
    PMID 10702393
    Identification of novel fusion partners of ALK, the anaplastic lymphoma kinase, in anaplastic large-cell lymphoma and inflammatory myofibroblastic tumor.
    Cools J, Wlodarska I, Somers R, Mentens N, Pedeutour F, Maes B, De Wolf-Peeters C, Pauwels P, Hagemeijer A, Marynen P
    Genes, chromosomes & cancer. 2002 ; 34 (4) : 354-362.
    PMID 12112524
    Anaplastic large cell lymphomas, Primary systemic (T/Null cell type).
    Delsol G, Ralfkiaer E, Stein H, Wright D, Jaffe E
    World Health Organization (WHO) Classification of Tumors. Pathology and Genetics of tumours of Haematopoietic and Lymphoid Tissues. 2001 pp 230-235.
    Cytogenetics of lymphomas: a brief review of its theoretical and practical significance.
    Donner LR
    Cancer genetics and cytogenetics. 1997 ; 94 (1) : 20-26.
    PMID 9078287
    Pathobiology of NPM-ALK and variant fusion genes in anaplastic large cell lymphoma and other lymphomas.
    Drexler HG, Gignac SM, von Wasielewski R, Werner M, Dirks WG
    Leukemia : official journal of the Leukemia Society of America, Leukemia Research Fund, U.K. 2000 ; 14 (9) : 1533-1559.
    PMID 10994999
    Lymphomas expressing ALK fusion protein(s) other than NPM-ALK.
    Falini B, Pulford K, Pucciarini A, Carbone A, De Wolf-Peeters C, Cordell J, Fizzotti M, Santucci A, Pelicci PG, Pileri S, Campo E, Ott G, Delsol G, Mason DY
    Blood. 1999 ; 94 (10) : 3509-3515.
    PMID 10552961
    TRK-fused gene (TFG) is a new partner of ALK in anaplastic large cell lymphoma producing two structurally different TFG-ALK translocations.
    Hernández L, Pinyol M, Hernández S, Beá S, Pulford K, Rosenwald A, Lamant L, Falini B, Ott G, Mason DY, Delsol G, Campo E
    Blood. 1999 ; 94 (9) : 3265-3268.
    PMID 10556217
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    Oncogene. 1997 ; 14 (4) : 439-449.
    PMID 9053841
    A new fusion gene TPM3-ALK in anaplastic large cell lymphoma created by a (1;2)(q25;p23) translocation.
    Lamant L, Dastugue N, Pulford K, Delsol G, Mariamé B
    Blood. 1999 ; 93 (9) : 3088-3095.
    PMID 10216106
    Non-muscle myosin heavy chain (MYH9): a new partner fused to ALK in anaplastic large cell lymphoma.
    Lamant L, Gascoyne RD, Duplantier MM, Armstrong F, Raghab A, Chhanabhai M, Rajcan-Separovic E, Raghab J, Delsol G, Espinos E
    Genes, chromosomes & cancer. 2003 ; 37 (4) : 427-432.
    PMID 12800156
    Inv(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, Cools J, Marynen P, Cui X, Siebert R, Gesk S, Schlegelberger B, Peeters B, De Wolf-Peeters C, Wlodarska I, Morris SW
    Blood. 2000 ; 95 (6) : 2144-2149.
    PMID 10706887
    Fusion of ALK to the Ran-binding protein 2 (RANBP2) gene in inflammatory myofibroblastic tumor.
    Ma Z, Hill DA, Collins MH, Morris SW, Sumegi J, Zhou M, Zuppan C, Bridge JA
    Genes, chromosomes & cancer. 2003 ; 37 (1) : 98-105.
    PMID 12661011
    CD30-positive large cell lymphomas ('Ki-1 lymphoma') are associated with a chromosomal translocation involving 5q35.
    Mason DY, Bastard C, Rimokh R, Dastugue N, Huret JL, Kristoffersson U, Magaud JP, Nezelof C, Tilly H, Vannier JP
    British journal of haematology. 1990 ; 74 (2) : 161-168.
    PMID 2156548
    Fusion of a kinase gene, ALK, to a nucleolar protein gene, NPM, in non-Hodgkin's lymphoma.
    Morris SW, Kirstein MN, Valentine MB, Dittmer KG, Shapiro DN, Saltman DL, Look AT
    Science (New York, N.Y.). 1994 ; 263 (5151) : 1281-1284.
    PMID 8122112
    Alk+ CD30+ lymphomas: a distinct molecular genetic subtype of non-Hodgkin's lymphoma.
    Morris SW, Xue L, Ma Z, Kinney MC
    British journal of haematology. 2001 ; 113 (2) : 275-295.
    PMID 11380391
    t(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, Ott G, Pulford K, Katzenberger T, Kühl J, Kalla J, Ott MM, Mason DY, Müller-Hermelink HK
    Blood. 1999 ; 94 (1) : 362-364.
    PMID 10381534
    Complex variant translocation t(1;2) with TPM3-ALK fusion due to cryptic ALK gene rearrangement in anaplastic large-cell lymphoma.
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    PMID 10610119
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    Stein H, Foss HD, Dürkop H, Marafioti T, Delsol G, Pulford K, Pileri S, Falini B
    Blood. 2000 ; 96 (12) : 3681-3695.
    PMID 11090048
    Molecular characterization of a new ALK translocation involving moesin (MSN-ALK) in anaplastic large cell lymphoma.
    Tort F, Pinyol M, Pulford K, Roncador G, Hernandez L, Nayach I, Kluin-Nelemans HC, Kluin P, Touriol C, Delsol G, Mason D, Campo E
    Laboratory investigation; a journal of technical methods and pathology. 2001 ; 81 (3) : 419-426.
    PMID 11310834
    Further 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).
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    Blood. 2000 ; 95 (10) : 3204-3207.
    PMID 10807789
    A new variant anaplastic lymphoma kinase (ALK)-fusion protein (ATIC-ALK) in a case of ALK-positive anaplastic large cell lymphoma.
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    PMID 10706082
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    PMID 7662979
    The cryptic inv(2)(p23q35) defines a new molecular genetic subtype of ALK-positive anaplastic large-cell lymphoma.
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    This paper should be referenced as such :
    Huret, JL ; Huret, JL
    Anaplasic large cell lymphoma (ALCL)
    Atlas Genet Cytogenet Oncol Haematol. 2003;7(4):262-265.
    Free journal version : [ pdf ]   [ DOI ]
    On line version :
    History of this paper:
    Huret, JL. Anaplasic large cell lymphoma (ALCL). Atlas Genet Cytogenet Oncol Haematol. 2001;5(4):274-276.

    Other genes implicated (Data extracted from papers in the Atlas) [ 38 ]


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