Anaplastic large cell lymphoma (ALCL)

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Anaplastic large cell lymphoma (ALCL)

Written	2003-08	Jean-Loup Huret
		Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers France

This article is an update of :

	2001-08	Jean-Loup Huret
		Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers France

(Note : for Links provided by Atlas : click)

Identity

ICD-Topo C420,C421,C424 BLOOD, BONE MARROW, & HEMATOPOIETIC SYS

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.

Genetics

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 Name ALK (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 Name MSN (moesin)

Location Xq12

Protein 576 amino acids, 68 kDa; cytoskeleton protein; binds to the plasma membrane and interacts with actin.

Gene Name TPM3 (tropomyosin 3)

Location 1q21.3

Protein 284 amino acids, 33 kDa; coilde coil structure; role in Calcium dependant actin-myosin interaction.

Gene Name ATIC (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 Name TFG (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 Name NPM1 (nucleophosmin)

Location 5q35.1

Protein Nuclear localisation; RNA binding nucleolar phosphoprotein involved in preribosomal assembly.

Gene Name CLTC (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 Name RNF213 (lymphoma oligomerization partner on chromosome 17)

Location 17q25.3

Protein 1599 amino acids.

Gene Name MYH9 (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.

Bibliography

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

Molecular characterization of ALK, a receptor tyrosine kinase expressed specifically in the nervous system.

Iwahara T, Fujimoto J, Wen D, Cupples R, Bucay N, Arakawa T, Mori S, Ratzkin B, Yamamoto T

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.

Siebert R, Gesk S, Harder L, Steinemann D, Grote W, Schlegelberger B, Tiemann M, Wlodarska I, Schemmel V

Blood. 1999 ; 94 (10) : 3614-3617.

PMID 10610119

CD30(+) anaplastic large cell lymphoma: a review of its histopathologic, genetic, and clinical features.

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).

Touriol C, Greenland C, Lamant L, Pulford K, Bernard F, Rousset T, Mason DY, Delsol G

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.

Trinei M, Lanfrancone L, Campo E, Pulford K, Mason DY, Pelicci PG, Falini B

Cancer research. 2000 ; 60 (4) : 793-798.

PMID 10706082

Analysis 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, Otsuki T, Vogelbruch M, Clark HM, Jaffe ES, Raffeld M

Blood. 1995 ; 86 (6) : 2321-2328.

PMID 7662979

The cryptic inv(2)(p23q35) defines a new molecular genetic subtype of ALK-positive anaplastic large-cell lymphoma.

Wlodarska I, De Wolf-Peeters C, Falini B, Verhoef G, Morris SW, Hagemeijer A, Van den Berghe H

Blood. 1998 ; 92 (8) : 2688-2695.

PMID 9763551

Citation

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 : http://AtlasGeneticsOncology.org/Anomalies/AnaplLargeCelLymphID2103.html

History of this paper:

Huret, JL. Anaplasic large cell lymphoma (ALCL). Atlas Genet Cytogenet Oncol Haematol. 2001;5(4):274-276.

http://documents.irevues.inist.fr/bitstream/handle/2042/37786/08-2001-AnaplLargeCelLymphID2103.pdf

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

Genes AKT1 ALK RNF213 ATIC BCAR1 BIRC7 CCNB1 CDC25A CDC42 CLTC
CLTCL1 DPP4 EEF1G EML4 ENPP2 FAS FGFR1 HNRNPD IDH2 IL21R
IL22 IL22 IL22RA1 ITK MSN MYH9 NOTCH1 NPM1 PTPN6 PTPN6
RARA RNASET2 S100A10 TFG TPM3 TRAP1 ZAP70 ZBTB7A

External links

COSMIC Histo = - Site = haematopoietic_and_lymphoid_tissue (COSMIC)

arrayMap (UZH-SIB Zurich) Topo ( C42) Morph ( 9714/3) - [auto + random 100 samples .. if exist ] [tabulated segments]

REVIEW articles automatic search in PubMed

Last year articles automatic search in PubMed

All articles automatic search in PubMed

Home Genes Leukemias Solid Tumors Cancer-Prone Deep Insight Case Reports Journals Portal Teaching

For comments and suggestions or contributions, please contact us

jlhuret@AtlasGeneticsOncology.org.

ICD-Topo	C420,C421,C424 BLOOD, BONE MARROW, & HEMATOPOIETIC SYS
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.

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.

Gene Name	ALK (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 Name	MSN (moesin)
Location	Xq12
Protein	576 amino acids, 68 kDa; cytoskeleton protein; binds to the plasma membrane and interacts with actin.

Gene Name	TPM3 (tropomyosin 3)
Location	1q21.3
Protein	284 amino acids, 33 kDa; coilde coil structure; role in Calcium dependant actin-myosin interaction.

Gene Name	ATIC (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 Name	TFG (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 Name	NPM1 (nucleophosmin)
Location	5q35.1
Protein	Nuclear localisation; RNA binding nucleolar phosphoprotein involved in preribosomal assembly.

Gene Name	CLTC (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 Name	RNF213 (lymphoma oligomerization partner on chromosome 17)
Location	17q25.3
Protein	1599 amino acids.

Gene Name	MYH9 (myosin, heavy polypeptide 9, non-muscle)
Location	22q12.3
Protein	1960 amino acids; 227 kDa; binds actin; protein of the cytoskeleton.

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.

Genes	AKT1	ALK	RNF213	ATIC	BCAR1	BIRC7	CCNB1	CDC25A	CDC42	CLTC
	CLTCL1	DPP4	EEF1G	EML4	ENPP2	FAS	FGFR1	HNRNPD	IDH2	IL21R
	IL22	IL22	IL22RA1	ITK	MSN	MYH9	NOTCH1	NPM1	PTPN6	PTPN6
	RARA	RNASET2	S100A10	TFG	TPM3	TRAP1	ZAP70	ZBTB7A

COSMIC	Histo = - Site = haematopoietic_and_lymphoid_tissue (COSMIC)
arrayMap (UZH-SIB Zurich)	Topo ( C42) Morph ( 9714/3) - [auto + random 100 samples .. if exist ] [tabulated segments]

REVIEW articles	automatic search in PubMed
Last year articles	automatic search in PubMed
All articles	automatic search in PubMed