Anaplastic large cell lymphoma, ALK positive: Difference between revisions

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{{CMG}}; {{AE}} {{AP}}
{{CMG}}; {{AE}} {{AP}}


{{SK}} ALCL-ALK(+)
{{SK}} ALCL-ALK(+); ALK-positive ALCL; ALK positive ALCL; ALK positive anaplastic large cell lymphoma


==Overview==
==Overview==
The Anaplastic large cell lymphoma ALK-positive ('''A'''naplastic '''L'''lymphoma '''K'''inase) is a [[peripheral T-cell lymphoma]] ([[NHL]]) that consist of [[CD30]]-positive T-cells with abundant cytoplasm, a pleomorphic nucleus (horseshoe-shaped nucleus) and a eosinophilic paranuclear region<ref name="pmid9490693">{{cite journal| author=Benharroch D, Meguerian-Bedoyan Z, Lamant L, Amin C, Brugières L, Terrier-Lacombe MJ et al.| title=ALK-positive lymphoma: a single disease with a broad spectrum of morphology. | journal=Blood | year= 1998 | volume= 91 | issue= 6 | pages= 2076-84 | pmid=9490693 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9490693  }} </ref>. This ALK-positive lymphoma has a translocation in the ALK gene [T(2;5)(p23;q35)], which will in turn, express the ALK protein<ref name=Swerdlow>{{cite book | last = Swerdlow | first = Steven | title = WHO classification of tumours of haematopoietic and lymphoid tissues | publisher = International Agency for Research on Cancer | location = Lyon, France | year = 2008 | isbn = 9789283224310 }}</ref>.
The anaplastic large cell lymphoma (ALCL) ALK-positive ('''A'''naplastic '''L'''lymphoma '''K'''inase) is a [[peripheral T-cell lymphoma]] ([[non-Hodgkin lymphoma]]) characterized by the proliferation of [[CD30]]-positive T-cells which have an abundant cytoplasm, a pleomorphic nucleus (horseshoe-shaped nucleus), and an eosinophilic paranuclear region.<ref name="pmid9490693">{{cite journal| author=Benharroch D, Meguerian-Bedoyan Z, Lamant L, Amin C, Brugières L, Terrier-Lacombe MJ et al.| title=ALK-positive lymphoma: a single disease with a broad spectrum of morphology. | journal=Blood | year= 1998 | volume= 91 | issue= 6 | pages= 2076-84 | pmid=9490693 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9490693  }} </ref> This type of ALK-positive lymphoma is associated with a translocation in the ALK gene [T(2;5)(p23;q35)] which expresses the ALK protein.<ref name=Swerdlow>{{cite book | last = Swerdlow | first = Steven | title = WHO classification of tumours of haematopoietic and lymphoid tissues | publisher = International Agency for Research on Cancer | location = Lyon, France | year = 2008 | isbn = 9789283224310 }}</ref>


==Classification==
==Classification==
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==Pathophysiology ==
==Pathophysiology ==
ALCL morphologic features are variable, which allowed to classify this entity into five morphologic patterns<ref name=Swerdlow>{{cite book | last = Swerdlow | first = Steven | title = WHO classification of tumours of haematopoietic and lymphoid tissues | publisher = International Agency for Research on Cancer | location = Lyon, France | year = 2008 | isbn = 9789283224310 }}</ref>:
The morphologic features of ALCL are variable.  There are five morphological patterns:<ref name=Swerdlow>{{cite book | last = Swerdlow | first = Steven | title = WHO classification of tumours of haematopoietic and lymphoid tissues | publisher = International Agency for Research on Cancer | location = Lyon, France | year = 2008 | isbn = 9789283224310 }}</ref>
*'''"Common" pattern''': Its the most common morphologic variant (75%)<ref name="pmid9736036">{{cite journal| author=Falini B, Bigerna B, Fizzotti M, Pulford K, Pileri SA, Delsol G et al.| title=ALK expression defines a distinct group of T/null lymphomas ("ALK lymphomas") with a wide morphological spectrum. | journal=Am J Pathol | year= 1998 | volume= 153 | issue= 3 | pages= 875-86 | pmid=9736036 | doi=10.1016/S0002-9440(10)65629-5 | pmc=PMC1853018 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9736036  }}</ref>. Cytoplasm may be basophilic or eosinophilic and the cell might have many nuclei with dispersed or clumped chromatin. In large cells, nucleoli tends to be more prominent. Given that the lymphomatous cells grow in the lymph node's sinuses, it may resemble a metastatic tumor.  
 
*'''Lymphohistiocytic pattern (10%)''': histiocytes with acidophilic cytoplasm and a perinuclear clear area, which represents the [[Golgi apparatus]]. This cells have eccentric nuclei with condensed chromatin<ref>{{cite web|url=http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1858171/pdf/amjpathol00028-0072.pdf|title=
*'''"Common" pattern''': This is the most common morphological variant (75%).<ref name="pmid9736036">{{cite journal| author=Falini B, Bigerna B, Fizzotti M, Pulford K, Pileri SA, Delsol G et al.| title=ALK expression defines a distinct group of T/null lymphomas ("ALK lymphomas") with a wide morphological spectrum. | journal=Am J Pathol | year= 1998 | volume= 153 | issue= 3 | pages= 875-86 | pmid=9736036 | doi=10.1016/S0002-9440(10)65629-5 | pmc=PMC1853018 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9736036  }}</ref> The cytoplasm may be either basophilic or eosinophilic and the cell might have many nuclei with dispersed or clumped chromatin. In large cells, nucleoli tend to be more prominent. Given that the lymphomatous cells grow in the lymph node's sinuses, this variant may resemble a metastatic tumor.  
Frequent Expression ofthe NPM-ALK Chimeric Fusion Protein inAnaplastic Large-Cell Lymphoma, Lympho-Histiocytic Type}}</ref>. Lymphomatous cells tend tu cluster around the perivascular area, evidenced by immunostaining with CD30 and ALK antibodies<ref name=Swerdlow>{{cite book | last = Swerdlow | first = Steven | title = WHO classification of tumours of haematopoietic and lymphoid tissues | publisher = International Agency for Research on Cancer | location = Lyon, France | year = 2008 | isbn = 9789283224310 }}</ref>.
 
*'''Hodgkin's like pattern (3.3%)''': Morphological characteristics reassemble [[Hodgkin's lymphoma]], variant nodular sclerosis<ref name="pmid16434897">{{cite journal| author=Vassallo J, Lamant L, Brugieres L, Gaillard F, Campo E, Brousset P et al.| title=ALK-positive anaplastic large cell lymphoma mimicking nodular sclerosis Hodgkin's lymphoma: report of 10 cases. | journal=Am J Surg Pathol | year= 2006 | volume= 30 | issue= 2 | pages= 223-9 | pmid=16434897 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16434897  }} </ref>. Predominates in female patients over male patients.  
*'''Lymphohistiocytic pattern (10%)''': Histiocytes have an acidophilic cytoplasm and a perinuclear clear area, with an eccentric nuclei and condensed chromatin.<ref>{{cite web|url=http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1858171/pdf/amjpathol00028-0072.pdf|title=
**Immunophenotype<ref name="pmid16434897">{{cite journal| author=Vassallo J, Lamant L, Brugieres L, Gaillard F, Campo E, Brousset P et al.| title=ALK-positive anaplastic large cell lymphoma mimicking nodular sclerosis Hodgkin's lymphoma: report of 10 cases. | journal=Am J Surg Pathol | year= 2006 | volume= 30 | issue= 2 | pages= 223-9 | pmid=16434897 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16434897  }} </ref>
Frequent Expression ofthe NPM-ALK Chimeric Fusion Protein inAnaplastic Large-Cell Lymphoma, Lympho-Histiocytic Type}}</ref>  Lymphomatous cells cluster around the perivascular area as demonstrated by immunostaining with CD30 and ALK antibodies.<ref name=Swerdlow>{{cite book | last = Swerdlow | first = Steven | title = WHO classification of tumours of haematopoietic and lymphoid tissues | publisher = International Agency for Research on Cancer | location = Lyon, France | year = 2008 | isbn = 9789283224310 }}</ref>
***Positive: [[CD30]], [[ALK]], [[epithelial membrane antigen]] ([[EMA]]), [[CD43]] (only 66% of the times) and [[perforin]].
 
***Negative: [[CD15]], [[CD20]], Pax5/BSAP and [[EBV]].
*'''Hodgkin's like pattern (3.3%)''': The morphological characteristics of this pattern are similar to the nodular sclerosis variant of [[Hodgkin's lymphoma]].<ref name="pmid16434897">{{cite journal| author=Vassallo J, Lamant L, Brugieres L, Gaillard F, Campo E, Brousset P et al.| title=ALK-positive anaplastic large cell lymphoma mimicking nodular sclerosis Hodgkin's lymphoma: report of 10 cases. | journal=Am J Surg Pathol | year= 2006 | volume= 30 | issue= 2 | pages= 223-9 | pmid=16434897 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16434897  }} </ref> This pattern is predominately more common among female. There are two immunophenotype:<ref name="pmid16434897">{{cite journal| author=Vassallo J, Lamant L, Brugieres L, Gaillard F, Campo E, Brousset P et al.| title=ALK-positive anaplastic large cell lymphoma mimicking nodular sclerosis Hodgkin's lymphoma: report of 10 cases. | journal=Am J Surg Pathol | year= 2006 | volume= 30 | issue= 2 | pages= 223-9 | pmid=16434897 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16434897  }} </ref>
*'''Small cell pattern (8.3%)''': Present nuclear irregularity and perivascular/intravascular distribution<ref name="pmid8394652">{{cite journal| author=Kinney MC, Collins RD, Greer JP, Whitlock JA, Sioutos N, Kadin ME| title=A small-cell-predominant variant of primary Ki-1 (CD30)+ T-cell lymphoma. | journal=Am J Surg Pathol | year= 1993 | volume= 17 | issue= 9 | pages= 859-68 | pmid=8394652 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8394652  }} </ref>. Occasionally, this lymphomatous cells have pale cytoplasm with a central nucleus ("fried egg cell")<ref name=Swerdlow>{{cite book | last = Swerdlow | first = Steven | title = WHO classification of tumours of haematopoietic and lymphoid tissues | publisher = International Agency for Research on Cancer | location = Lyon, France | year = 2008 | isbn = 9789283224310 }}</ref>.
**Positive: [[CD30]], [[ALK]], [[epithelial membrane antigen]] ([[EMA]]), [[CD43]] (only 66% of the times) and [[perforin]]
**Negative: [[CD15]], [[CD20]], Pax5/BSAP and [[EBV]]
 
*'''Small cell pattern (8.3%)''': Cells have nuclear irregularity and perivascular/intravascular distribution.<ref name="pmid8394652">{{cite journal| author=Kinney MC, Collins RD, Greer JP, Whitlock JA, Sioutos N, Kadin ME| title=A small-cell-predominant variant of primary Ki-1 (CD30)+ T-cell lymphoma. | journal=Am J Surg Pathol | year= 1993 | volume= 17 | issue= 9 | pages= 859-68 | pmid=8394652 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8394652  }} </ref> Occasionally, lymphomatous cells have a pale cytoplasm with a central nucleus, described as "fried egg cell".<ref name=Swerdlow>{{cite book | last = Swerdlow | first = Steven | title = WHO classification of tumours of haematopoietic and lymphoid tissues | publisher = International Agency for Research on Cancer | location = Lyon, France | year = 2008 | isbn = 9789283224310 }}</ref>
*'''Giant cell pattern (3.3%)'''
*'''Giant cell pattern (3.3%)'''


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==Causes==
==Causes==


The ALK positive Anaplastic large cell lymphoma has a rearrangement in the Anaplastic Lymphoma Kinase (ALK) gene. The most frequent gene translocation is T(2;5)(p23;q35)<ref name="pmid8122112">{{cite journal| author=Morris SW, Kirstein MN, Valentine MB, Dittmer KG, Shapiro DN, Saltman DL et al.| title=Fusion of a kinase gene, ALK, to a nucleolar protein gene, NPM, in non-Hodgkin's lymphoma. | journal=Science | year= 1994 | volume= 263 | issue= 5151 | pages= 1281-4 | pmid=8122112 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8122112  }} </ref>. This translocation produces a chimeric protein between the nucleolar phosphoprotein (NPM) gene (5q35) a ALK gene (2p23), which has structural similarity to the [[insulin growth factor receptor]].<ref>{{cite web|url=http://go.galegroup.com/ps/retrieve.do?sgHitCountType=None&sort=RELEVANCE&inPS=true&prodId=HRCA&userGroupName=mlin_b_bethidmc&tabID=T002&searchId=R2&resultListType=RESULT_LIST&contentSegment=&searchType=AdvancedSearchForm&currentPosition=1&contentSet=GALE%7CA15341631&&docId=GALE|A15341631&docType=GALE&role=|title=Fusion of kinase gene, ALK, to a nucleolar protein gene, NPM, in non-Hodgkin's lymphoma}}</ref> Normal [[T-cell]]s require [[IL-2]] as a growth factor, while [[T-cell]]s of patients with ALK positive Anaplastic large cell lymphoma, have a constitutive activating [[IL-2 receptor]], caused by the new NMP-ALK chimeric protein.<ref>{{cite web|url=http://go.galegroup.com/ps/retrieve.do?sgHitCountType=None&sort=RELEVANCE&inPS=true&prodId=HRCA&userGroupName=mlin_b_bethidmc&tabID=T002&searchId=R3&resultListType=RESULT_LIST&contentSegment=&searchType=AdvancedSearchForm&currentPosition=1&contentSet=GALE%7CA15341631&&docId=GALE|A15341631&docType=GALE&role=|title=Fusion of kinase gene, ALK, to a nucleolar protein gene, NPM, in non-Hodgkin's lymphoma}}</ref>
ALK positive anaplastic large cell lymphoma is associated with a rearrangement in the anaplastic lymphoma kinase (ALK) gene. The most frequent gene translocation is T(2;5)(p23;q35).<ref name="pmid8122112">{{cite journal| author=Morris SW, Kirstein MN, Valentine MB, Dittmer KG, Shapiro DN, Saltman DL et al.| title=Fusion of a kinase gene, ALK, to a nucleolar protein gene, NPM, in non-Hodgkin's lymphoma. | journal=Science | year= 1994 | volume= 263 | issue= 5151 | pages= 1281-4 | pmid=8122112 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8122112  }} </ref> This translocation leads to a chimeric protein between the nucleolar phosphoprotein (NPM) gene (5q35) and ALK gene (2p23), which has structural similarity to the insulin growth factor receptor.<ref>{{cite web|url=http://go.galegroup.com/ps/retrieve.do?sgHitCountType=None&sort=RELEVANCE&inPS=true&prodId=HRCA&userGroupName=mlin_b_bethidmc&tabID=T002&searchId=R2&resultListType=RESULT_LIST&contentSegment=&searchType=AdvancedSearchForm&currentPosition=1&contentSet=GALE%7CA15341631&&docId=GALE|A15341631&docType=GALE&role=|title=Fusion of kinase gene, ALK, to a nucleolar protein gene, NPM, in non-Hodgkin's lymphoma}}</ref> Normal [[T-cell]]s require [[IL-2]] as a growth factor; [[T-cell]]s of patients with ALK positive anaplastic large cell lymphoma have a constitutive activation of [[IL-2 receptor]] caused by the new NMP-ALK chimeric protein.<ref>{{cite web|url=http://go.galegroup.com/ps/retrieve.do?sgHitCountType=None&sort=RELEVANCE&inPS=true&prodId=HRCA&userGroupName=mlin_b_bethidmc&tabID=T002&searchId=R3&resultListType=RESULT_LIST&contentSegment=&searchType=AdvancedSearchForm&currentPosition=1&contentSet=GALE%7CA15341631&&docId=GALE|A15341631&docType=GALE&role=|title=Fusion of kinase gene, ALK, to a nucleolar protein gene, NPM, in non-Hodgkin's lymphoma}}</ref>


Other genetic gene mutations include<ref>{{cite web|url=http://www.nature.com/nrc/journal/v8/n1/abs/nrc2291.html|title=The anaplastic lymphoma kinase in the pathogenesis of cancer}}</ref>:
Other gene mutations include:<ref>{{cite web|url=http://www.nature.com/nrc/journal/v8/n1/abs/nrc2291.html|title=The anaplastic lymphoma kinase in the pathogenesis of cancer}}</ref>
*T(1;2), encoding a tropomyosin3 (TPM3)/ALK fusion protein (10 to 20 percent of cases)
*T(1;2), encoding a tropomyosin3 (TPM3)/ALK fusion protein (10 to 20%)
*T(2;3), encoding a TRK fusion gene (TFP)/ALK fusion protein (2 to 5 percent of cases)
*T(2;3), encoding a TRK fusion gene (TFP)/ALK fusion protein (2 to 5%
*Inv(2), encoding a ATIC (Pur H gene)/ALK fusion protein (2 to 5 percent of cases)
*Inv(2), encoding a ATIC (Pur H gene)/ALK fusion protein (2 to 5%)
*T(2;17), encoding a clathrin heavy (CLTC)/ALK fusion protein (2 to 5 percent of cases)
*T(2;17), encoding a clathrin heavy (CLTC)/ALK fusion protein (2 to 5%)
*T(2;17), encoding a ALO17/ALK fusion protein (2 to 5 percent of cases)
*T(2;17), encoding a ALO17/ALK fusion protein (2 to 5 percent of cases)
*T(2;19), encoding a tropomyosin 4 (TPM4)/ALK fusion protein (<1 percent of cases)
*T(2;19), encoding a tropomyosin 4 (TPM4)/ALK fusion protein (<1%)
*T(2;22), encoding a non-muscle myosin (MYH9)/ALK fusion protein (<1 percent of cases)
*T(2;22), encoding a non-muscle myosin (MYH9)/ALK fusion protein (<1%)


== Differential Diagnosis ==
== Differential Diagnosis ==
*[[ALCL ALK negative]]
*ALCL ALK negative
*[[Primary cutaneous ALCL]]
*Primary cutaneous ALCL
*DLBCL, anaplastic type
*Diffuse large B-cell lymphoma, anaplastic type
*DLBCL, plasmablastic type
*Diffuse large B-cell lymphoma, plasmablastic type
*[[Hodgkin lymphoma]]
*[[Hodgkin lymphoma]]


== Epidemiology and Demographics==
== Epidemiology and Demographics==
This entity affects primarily young, male patients<ref name="pmid11090048">{{cite journal| author=Stein H, Foss HD, Dürkop H, Marafioti T, Delsol G, Pulford K et al.| title=CD30(+) anaplastic large cell lymphoma: a review of its histopathologic, genetic, and clinical features. | journal=Blood | year= 2000 | volume= 96 | issue= 12 | pages= 3681-95 | pmid=11090048 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11090048  }} </ref> and accounts for 3% of all [[NHL]], 40% of all large cell lymphomas<ref>{{cite web|url=http://www.bloodjournal.org/content/93/8/2697?sso-checked=true|title=ALK+ Lymphoma: Clinico-Pathological Findings and Outcome}}</ref> and 10%-20% of childhood lymphomas, although it is particularly incident in patients between 10 and 29 years<ref>{{cite web|url=http://www.bloodjournal.org/content/93/8/2697?sso-checked=true|title=ALK+ Lymphoma: Clinico-Pathological Findings and Outcome}}</ref>.
ALK positive anaplastic large cell lymphoma affects primarily young (between 10 and 29 years), male patients<ref name="pmid11090048">{{cite journal| author=Stein H, Foss HD, Dürkop H, Marafioti T, Delsol G, Pulford K et al.| title=CD30(+) anaplastic large cell lymphoma: a review of its histopathologic, genetic, and clinical features. | journal=Blood | year= 2000 | volume= 96 | issue= 12 | pages= 3681-95 | pmid=11090048 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11090048  }} </ref> and accounts for 3% of all [[NHL]], 40% of all large cell lymphomas<ref>{{cite web|url=http://www.bloodjournal.org/content/93/8/2697?sso-checked=true|title=ALK+ Lymphoma: Clinico-Pathological Findings and Outcome}}</ref> and 10%-20% of childhood lymphomas.ref>{{cite web|url=http://www.bloodjournal.org/content/93/8/2697?sso-checked=true|title=ALK+ Lymphoma: Clinico-Pathological Findings and Outcome}}</ref>


A more recent study evaluated 1,320 cases of [[peripheral T-cell lymphomas]] and [[NK cell lymphomas]] between 1990 and 2002 in 22 different centers, concluding that the ALK-Positive ALCL is the fifth most incident (6.6% of total patients)<ref>{{cite web|url=http://jco.ascopubs.org/content/26/25/4124.full.pdf|title=International Peripheral T-Cell and Natural Killer/T-Cell Lymphoma Study: Pathology Findings and Clinical Outcomes}}</ref>, although in the United states, it's the most frequent type of [[peripheral T-cell lymphoma]].
According to a study on 1,320 cases of [[peripheral T-cell lymphomas]] and NK cell lymphomas between 1990 and 2002 in 22 different centers, ALK-Positive ALCL is the fifth most common type of peripheral T cell lymphoma (6.6% of total patients).<ref>{{cite web|url=http://jco.ascopubs.org/content/26/25/4124.full.pdf|title=International Peripheral T-Cell and Natural Killer/T-Cell Lymphoma Study: Pathology Findings and Clinical Outcomes}}</ref> In the United states, ALK-Positive ALCL is the most frequent type of [[peripheral T-cell lymphoma]].


==Natural History, Complications and Prognosis==
==Natural History, Complications and Prognosis==


===Prognosis===
===Prognosis===
To establish the prognosis, we use the '''I'''nternational '''P'''rognostic '''I'''index (IPI)<ref>{{cite web|url=http://www.uptodate.com/contents/image?imageKey=HEME%2F70850&topicKey=HEME%2F4705&rank=1%7E150&source=see_link&search=Anaplastic+large+cell+lymphoma%2C+ALK+positive&utdPopup=true|title=International Prognostic Index for non-Hodgkin lymphoma}}</ref>. The IPI accounts 5 variables:  
The '''I'''nternational '''P'''rognostic '''I'''index (IPI) is used to estimate the prognosis of patients.<ref>{{cite web|url=http://www.uptodate.com/contents/image?imageKey=HEME%2F70850&topicKey=HEME%2F4705&rank=1%7E150&source=see_link&search=Anaplastic+large+cell+lymphoma%2C+ALK+positive&utdPopup=true|title=International Prognostic Index for non-Hodgkin lymphoma}}</ref> The IPI takes into account 5 variables:  
*Patient's age (>60 years)
*Patient's age (>60 years)
*Serum [[lactate dehydrogenase]] ([[LDH]]) above normal
*Elevated serum [[lactate dehydrogenase]] ([[LDH]])
*Eastern Cooperative Oncology Group (ECOG) performance status  
*Eastern Cooperative Oncology Group (ECOG) performance status  
*[[Ann Arbor]] clinical stage III or IV
*Ann Arbor clinical stage III or IV
*Number of involved extra nodal sites > 1
*Number of involved extra nodal sites > 1


If any of this criteria is met, one point is awarded for the IPI, which allows to classify patients prognosis into the following categories:  
If any of this criteria is met, one point is awarded for the IPI. The interpretation of the total score is as follows:
*0 to 1: Low risk
*0 to 1: Low risk
*2: Low-intermediate risk
*2: Low-intermediate risk
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*4 to 5: High risk
*4 to 5: High risk


The International Peripheral T cell Lymphoma Project estimated the probability of a 5-years survival for each of the IPI stages<ref>{{cite web|url=http://www.bloodjournal.org/content/111/12/5496.abstract?sso-checked=true|title:ALK− anaplastic large-cell lymphoma is clinically and immunophenotypically different from both ALK+ ALCL and peripheral T-cell lymphoma, not otherwise specified: report from the International Peripheral T-Cell Lymphoma Project}}</ref>:
According to the International Peripheral T cell Lymphoma Project, the estimated 5-years survival for each of the IPI stages are as follows:<ref>{{cite web|url=http://www.bloodjournal.org/content/111/12/5496.abstract?sso-checked=true|title:ALK− anaplastic large-cell lymphoma is clinically and immunophenotypically different from both ALK+ ALCL and peripheral T-cell lymphoma, not otherwise specified: report from the International Peripheral T-Cell Lymphoma Project}}</ref>


*Low risk (IPI 0-1): 90%
*Low risk (IPI 0-1): 90%
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===History and Symptoms===
===History and Symptoms===
Most adult patients present with painless [[lymphadenopathy]]. Although retroperitoneal and peripheral<ref name="pmid25674293">{{cite journal| author=Yu G, Gao Z, Huang X| title=ALK-positive anaplastic large cell lymphoma with an unusual alveolar growth pattern. | journal=Int J Clin Exp Pathol | year= 2014 | volume= 7 | issue= 12 | pages= 9086-9 | pmid=25674293 | doi= | pmc=PMC4314028 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25674293  }} </ref> [[lymphadenopathy]] is very common, other possible locations include the gastrointestinal tract, breast<ref name="pmid25490539">{{cite journal| author=Gidengil CA, Predmore Z, Mattke S, van Busum K, Kim B| title=Breast implant-associated anaplastic large cell lymphoma: a systematic review. | journal=Plast Reconstr Surg | year= 2014 | volume=  | issue=  | pages=  | pmid=25490539 | doi=10.1097/PRS.0000000000001037 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25490539  }} </ref>, spleen<ref name="pmid11097375">{{cite journal| author=Hebeda KM, MacKenzie MA, van Krieken JH| title=A case of anaplastic lymphoma kinase-positive anaplastic large cell lymphoma presenting with spontaneous splenic rupture: an extremely unusual presentation. | journal=Virchows Arch | year= 2000 | volume= 437 | issue= 4 | pages= 459-64 | pmid=11097375 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11097375  }} </ref>, liver<ref name="pmid17396261">{{cite journal| author=Grewal JS, Smith LB, Winegarden JD, Krauss JC, Tworek JA, Schnitzer B| title=Highly aggressive ALK-positive anaplastic large cell lymphoma with a leukemic phase and multi-organ involvement: a report of three cases and a review of the literature. | journal=Ann Hematol | year= 2007 | volume= 86 | issue= 7 | pages= 499-508 | pmid=17396261 | doi=10.1007/s00277-007-0289-3 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17396261  }} </ref>, bone<ref name="pmid17396261">{{cite journal| author=Grewal JS, Smith LB, Winegarden JD, Krauss JC, Tworek JA, Schnitzer B| title=Highly aggressive ALK-positive anaplastic large cell lymphoma with a leukemic phase and multi-organ involvement: a report of three cases and a review of the literature. | journal=Ann Hematol | year= 2007 | volume= 86 | issue= 7 | pages= 499-508 | pmid=17396261 | doi=10.1007/s00277-007-0289-3 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17396261  }} </ref>, heart<ref name="pmid16313264">{{cite journal| author=Lim ZY, Grace R, Salisbury JR, Creamer D, Jayaprakasam A, Ho AY et al.| title=Cardiac presentation of ALK positive anaplastic large cell lymphoma. | journal=Eur J Haematol | year= 2005 | volume= 75 | issue= 6 | pages= 511-4 | pmid=16313264 | doi=10.1111/j.1600-0609.2005.00542.x | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16313264  }} </ref> and respiratory tract<ref name="pmid18670314">{{cite journal| author=Tan DS, Eng PC, Lim ST, Thye LS, Tao M| title=Primary tracheal lymphoma causing respiratory failure. | journal=J Thorac Oncol | year= 2008 | volume= 3 | issue= 8 | pages= 929-30 | pmid=18670314 | doi=10.1097/JTO.0b013e318180271d | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18670314  }} </ref>.
Most adult patients present with painless [[lymphadenopathy]]. Although retroperitoneal and peripheral [[lymphadenopathy]] is very common,<ref name="pmid25674293">{{cite journal| author=Yu G, Gao Z, Huang X| title=ALK-positive anaplastic large cell lymphoma with an unusual alveolar growth pattern. | journal=Int J Clin Exp Pathol | year= 2014 | volume= 7 | issue= 12 | pages= 9086-9 | pmid=25674293 | doi= | pmc=PMC4314028 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25674293  }} </ref> other possible locations for enlarged lymph nodes include the gastrointestinal tract, the breast,<ref name="pmid25490539">{{cite journal| author=Gidengil CA, Predmore Z, Mattke S, van Busum K, Kim B| title=Breast implant-associated anaplastic large cell lymphoma: a systematic review. | journal=Plast Reconstr Surg | year= 2014 | volume=  | issue=  | pages=  | pmid=25490539 | doi=10.1097/PRS.0000000000001037 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25490539  }} </ref> the spleen,<ref name="pmid11097375">{{cite journal| author=Hebeda KM, MacKenzie MA, van Krieken JH| title=A case of anaplastic lymphoma kinase-positive anaplastic large cell lymphoma presenting with spontaneous splenic rupture: an extremely unusual presentation. | journal=Virchows Arch | year= 2000 | volume= 437 | issue= 4 | pages= 459-64 | pmid=11097375 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11097375  }} </ref> the liver,<ref name="pmid17396261">{{cite journal| author=Grewal JS, Smith LB, Winegarden JD, Krauss JC, Tworek JA, Schnitzer B| title=Highly aggressive ALK-positive anaplastic large cell lymphoma with a leukemic phase and multi-organ involvement: a report of three cases and a review of the literature. | journal=Ann Hematol | year= 2007 | volume= 86 | issue= 7 | pages= 499-508 | pmid=17396261 | doi=10.1007/s00277-007-0289-3 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17396261  }} </ref> the bone,<ref name="pmid17396261">{{cite journal| author=Grewal JS, Smith LB, Winegarden JD, Krauss JC, Tworek JA, Schnitzer B| title=Highly aggressive ALK-positive anaplastic large cell lymphoma with a leukemic phase and multi-organ involvement: a report of three cases and a review of the literature. | journal=Ann Hematol | year= 2007 | volume= 86 | issue= 7 | pages= 499-508 | pmid=17396261 | doi=10.1007/s00277-007-0289-3 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17396261  }} </ref> the heart,<ref name="pmid16313264">{{cite journal| author=Lim ZY, Grace R, Salisbury JR, Creamer D, Jayaprakasam A, Ho AY et al.| title=Cardiac presentation of ALK positive anaplastic large cell lymphoma. | journal=Eur J Haematol | year= 2005 | volume= 75 | issue= 6 | pages= 511-4 | pmid=16313264 | doi=10.1111/j.1600-0609.2005.00542.x | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16313264  }} </ref> and the respiratory tract.<ref name="pmid18670314">{{cite journal| author=Tan DS, Eng PC, Lim ST, Thye LS, Tao M| title=Primary tracheal lymphoma causing respiratory failure. | journal=J Thorac Oncol | year= 2008 | volume= 3 | issue= 8 | pages= 929-30 | pmid=18670314 | doi=10.1097/JTO.0b013e318180271d | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18670314  }} </ref>


Common symptoms include typical [[B symptoms]]<ref>{{cite web|url=http://www.lymphomas.org.uk/sites/default/files/pdfs/T-cell-lymphomas.pdf|title=T-cell lymphomas (Lymphoma Association)}}</ref>([[Fever]], [[weight loss]] and [[night sweats]]).
Common symptoms include typical [[B symptoms]]: [[fever]], [[weight loss]], and [[night sweats]].<ref>{{cite web|url=http://www.lymphomas.org.uk/sites/default/files/pdfs/T-cell-lymphomas.pdf|title=T-cell lymphomas (Lymphoma Association)}}</ref>


===Laboratory Findings<ref>{{cite web|url=http://www.bloodjournal.org/content/111/12/5496|title=ALK− anaplastic large-cell lymphoma is clinically and immunophenotypically different from both ALK+ ALCL and peripheral T-cell lymphoma, not otherwise specified: report from the International Peripheral T-Cell Lymphoma Project}}</ref>===
===Laboratory Findings===
*[[Anemia]]
*[[Anemia]]
*[[Thrombocytopenia]]
*[[Thrombocytopenia]]
*Elevated [[lactate dehydrogenase]] ([[LDH]]) levels
*Elevated [[lactate dehydrogenase]] ([[LDH]])<ref>{{cite web|url=http://www.bloodjournal.org/content/111/12/5496|title=ALK− anaplastic large-cell lymphoma is clinically and immunophenotypically different from both ALK+ ALCL and peripheral T-cell lymphoma, not otherwise specified: report from the International Peripheral T-Cell Lymphoma Project}}</ref>


== Treatment ==
== Treatment ==
====CHOP-E Regimen====
====CHOP-E Regimen====
It includes:
The CHOP-E regimen includes:
*[[Cyclophosphamide]]  
*[[Cyclophosphamide]]  
*[[Doxorubicin]]  
*[[Doxorubicin]]  

Revision as of 15:37, 20 February 2015

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Template:DiseaseDisorder infobox Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Alberto Plate [2]

Synonyms and keywords: ALCL-ALK(+); ALK-positive ALCL; ALK positive ALCL; ALK positive anaplastic large cell lymphoma

Overview

The anaplastic large cell lymphoma (ALCL) ALK-positive (Anaplastic Llymphoma Kinase) is a peripheral T-cell lymphoma (non-Hodgkin lymphoma) characterized by the proliferation of CD30-positive T-cells which have an abundant cytoplasm, a pleomorphic nucleus (horseshoe-shaped nucleus), and an eosinophilic paranuclear region.[1] This type of ALK-positive lymphoma is associated with a translocation in the ALK gene [T(2;5)(p23;q35)] which expresses the ALK protein.[2]

Classification

Morphologic Classification[3]

Classical Variants

  • Common pattern ALK positive anaplastic large cell lymphoma

Atypical Variants

  • Small cell ALK positive anaplastic large cell lymphoma
  • Lymphohistiocytic ALK positive anaplastic large cell lymphoma
  • Giant cell ALK positive anaplastic large cell lymphoma
  • Hodgkin's like ALK positive anaplastic large cell lymphoma

Rare Variants

  • Sarcomatoid ALK positive anaplastic large cell lymphoma

Pathophysiology

The morphologic features of ALCL are variable. There are five morphological patterns:[2]

  • "Common" pattern: This is the most common morphological variant (75%).[4] The cytoplasm may be either basophilic or eosinophilic and the cell might have many nuclei with dispersed or clumped chromatin. In large cells, nucleoli tend to be more prominent. Given that the lymphomatous cells grow in the lymph node's sinuses, this variant may resemble a metastatic tumor.
  • Lymphohistiocytic pattern (10%): Histiocytes have an acidophilic cytoplasm and a perinuclear clear area, with an eccentric nuclei and condensed chromatin.[5] Lymphomatous cells cluster around the perivascular area as demonstrated by immunostaining with CD30 and ALK antibodies.[2]
  • Small cell pattern (8.3%): Cells have nuclear irregularity and perivascular/intravascular distribution.[7] Occasionally, lymphomatous cells have a pale cytoplasm with a central nucleus, described as "fried egg cell".[2]
  • Giant cell pattern (3.3%)

One single patient may present more than one morphologic pattern in the same or progressive biopsies[1].

Causes

ALK positive anaplastic large cell lymphoma is associated with a rearrangement in the anaplastic lymphoma kinase (ALK) gene. The most frequent gene translocation is T(2;5)(p23;q35).[8] This translocation leads to a chimeric protein between the nucleolar phosphoprotein (NPM) gene (5q35) and ALK gene (2p23), which has structural similarity to the insulin growth factor receptor.[9] Normal T-cells require IL-2 as a growth factor; T-cells of patients with ALK positive anaplastic large cell lymphoma have a constitutive activation of IL-2 receptor caused by the new NMP-ALK chimeric protein.[10]

Other gene mutations include:[11]

  • T(1;2), encoding a tropomyosin3 (TPM3)/ALK fusion protein (10 to 20%)
  • T(2;3), encoding a TRK fusion gene (TFP)/ALK fusion protein (2 to 5%
  • Inv(2), encoding a ATIC (Pur H gene)/ALK fusion protein (2 to 5%)
  • T(2;17), encoding a clathrin heavy (CLTC)/ALK fusion protein (2 to 5%)
  • T(2;17), encoding a ALO17/ALK fusion protein (2 to 5 percent of cases)
  • T(2;19), encoding a tropomyosin 4 (TPM4)/ALK fusion protein (<1%)
  • T(2;22), encoding a non-muscle myosin (MYH9)/ALK fusion protein (<1%)

Differential Diagnosis

  • ALCL ALK negative
  • Primary cutaneous ALCL
  • Diffuse large B-cell lymphoma, anaplastic type
  • Diffuse large B-cell lymphoma, plasmablastic type
  • Hodgkin lymphoma

Epidemiology and Demographics

ALK positive anaplastic large cell lymphoma affects primarily young (between 10 and 29 years), male patients[12] and accounts for 3% of all NHL, 40% of all large cell lymphomas[13] and 10%-20% of childhood lymphomas.ref>"ALK+ Lymphoma: Clinico-Pathological Findings and Outcome".</ref>

According to a study on 1,320 cases of peripheral T-cell lymphomas and NK cell lymphomas between 1990 and 2002 in 22 different centers, ALK-Positive ALCL is the fifth most common type of peripheral T cell lymphoma (6.6% of total patients).[14] In the United states, ALK-Positive ALCL is the most frequent type of peripheral T-cell lymphoma.

Natural History, Complications and Prognosis

Prognosis

The International Prognostic Iindex (IPI) is used to estimate the prognosis of patients.[15] The IPI takes into account 5 variables:

  • Patient's age (>60 years)
  • Elevated serum lactate dehydrogenase (LDH)
  • Eastern Cooperative Oncology Group (ECOG) performance status
  • Ann Arbor clinical stage III or IV
  • Number of involved extra nodal sites > 1

If any of this criteria is met, one point is awarded for the IPI. The interpretation of the total score is as follows:

  • 0 to 1: Low risk
  • 2: Low-intermediate risk
  • 3: High-intermediate risk
  • 4 to 5: High risk

According to the International Peripheral T cell Lymphoma Project, the estimated 5-years survival for each of the IPI stages are as follows:[16]

  • Low risk (IPI 0-1): 90%
  • Low-intermediate risk (IPI 2): 68%
  • High-intermediate risk (IPI 3): 23%
  • High risk (IPI 4-5): 33%

Diagnosis

History and Symptoms

Most adult patients present with painless lymphadenopathy. Although retroperitoneal and peripheral lymphadenopathy is very common,[17] other possible locations for enlarged lymph nodes include the gastrointestinal tract, the breast,[18] the spleen,[19] the liver,[20] the bone,[20] the heart,[21] and the respiratory tract.[22]

Common symptoms include typical B symptoms: fever, weight loss, and night sweats.[23]

Laboratory Findings

Treatment

CHOP-E Regimen

The CHOP-E regimen includes:

References

  1. ↑ 1.0 1.1 Benharroch D, Meguerian-Bedoyan Z, Lamant L, Amin C, Brugières L, Terrier-Lacombe MJ; et al. (1998). "ALK-positive lymphoma: a single disease with a broad spectrum of morphology". Blood. 91 (6): 2076–84. PMID 9490693.
  2. ↑ 2.0 2.1 2.2 2.3 Swerdlow, Steven (2008). WHO classification of tumours of haematopoietic and lymphoid tissues. Lyon, France: International Agency for Research on Cancer. ISBN 9789283224310.
  3. ↑ "The anaplastic lymphoma kinase in the pathogenesis of cancer". Unknown parameter |A188154738&docType= ignored (help)
  4. ↑ Falini B, Bigerna B, Fizzotti M, Pulford K, Pileri SA, Delsol G; et al. (1998). "ALK expression defines a distinct group of T/null lymphomas ("ALK lymphomas") with a wide morphological spectrum". Am J Pathol. 153 (3): 875–86. doi:10.1016/S0002-9440(10)65629-5. PMC 1853018. PMID 9736036.
  5. ↑ "Frequent Expression ofthe NPM-ALK Chimeric Fusion Protein inAnaplastic Large-Cell Lymphoma, Lympho-Histiocytic Type" (PDF).
  6. ↑ 6.0 6.1 Vassallo J, Lamant L, Brugieres L, Gaillard F, Campo E, Brousset P; et al. (2006). "ALK-positive anaplastic large cell lymphoma mimicking nodular sclerosis Hodgkin's lymphoma: report of 10 cases". Am J Surg Pathol. 30 (2): 223–9. PMID 16434897.
  7. ↑ Kinney MC, Collins RD, Greer JP, Whitlock JA, Sioutos N, Kadin ME (1993). "A small-cell-predominant variant of primary Ki-1 (CD30)+ T-cell lymphoma". Am J Surg Pathol. 17 (9): 859–68. PMID 8394652.
  8. ↑ Morris SW, Kirstein MN, Valentine MB, Dittmer KG, Shapiro DN, Saltman DL; et al. (1994). "Fusion of a kinase gene, ALK, to a nucleolar protein gene, NPM, in non-Hodgkin's lymphoma". Science. 263 (5151): 1281–4. PMID 8122112.
  9. ↑ "Fusion of kinase gene, ALK, to a nucleolar protein gene, NPM, in non-Hodgkin's lymphoma". Unknown parameter |A15341631&docType= ignored (help)
  10. ↑ "Fusion of kinase gene, ALK, to a nucleolar protein gene, NPM, in non-Hodgkin's lymphoma". Unknown parameter |A15341631&docType= ignored (help)
  11. ↑ "The anaplastic lymphoma kinase in the pathogenesis of cancer".
  12. ↑ Stein H, Foss HD, Dürkop H, Marafioti T, Delsol G, Pulford K; et al. (2000). "CD30(+) anaplastic large cell lymphoma: a review of its histopathologic, genetic, and clinical features". Blood. 96 (12): 3681–95. PMID 11090048.
  13. ↑ "ALK+ Lymphoma: Clinico-Pathological Findings and Outcome".
  14. ↑ "International Peripheral T-Cell and Natural Killer/T-Cell Lymphoma Study: Pathology Findings and Clinical Outcomes" (PDF).
  15. ↑ "International Prognostic Index for non-Hodgkin lymphoma".
  16. ↑ http://www.bloodjournal.org/content/111/12/5496.abstract?sso-checked=true. Text "title:ALK− anaplastic large-cell lymphoma is clinically and immunophenotypically different from both ALK+ ALCL and peripheral T-cell lymphoma, not otherwise specified: report from the International Peripheral T-Cell Lymphoma Project" ignored (help); Missing or empty |title= (help)
  17. ↑ Yu G, Gao Z, Huang X (2014). "ALK-positive anaplastic large cell lymphoma with an unusual alveolar growth pattern". Int J Clin Exp Pathol. 7 (12): 9086–9. PMC 4314028. PMID 25674293.
  18. ↑ Gidengil CA, Predmore Z, Mattke S, van Busum K, Kim B (2014). "Breast implant-associated anaplastic large cell lymphoma: a systematic review". Plast Reconstr Surg. doi:10.1097/PRS.0000000000001037. PMID 25490539.
  19. ↑ Hebeda KM, MacKenzie MA, van Krieken JH (2000). "A case of anaplastic lymphoma kinase-positive anaplastic large cell lymphoma presenting with spontaneous splenic rupture: an extremely unusual presentation". Virchows Arch. 437 (4): 459–64. PMID 11097375.
  20. ↑ 20.0 20.1 Grewal JS, Smith LB, Winegarden JD, Krauss JC, Tworek JA, Schnitzer B (2007). "Highly aggressive ALK-positive anaplastic large cell lymphoma with a leukemic phase and multi-organ involvement: a report of three cases and a review of the literature". Ann Hematol. 86 (7): 499–508. doi:10.1007/s00277-007-0289-3. PMID 17396261.
  21. ↑ Lim ZY, Grace R, Salisbury JR, Creamer D, Jayaprakasam A, Ho AY; et al. (2005). "Cardiac presentation of ALK positive anaplastic large cell lymphoma". Eur J Haematol. 75 (6): 511–4. doi:10.1111/j.1600-0609.2005.00542.x. PMID 16313264.
  22. ↑ Tan DS, Eng PC, Lim ST, Thye LS, Tao M (2008). "Primary tracheal lymphoma causing respiratory failure". J Thorac Oncol. 3 (8): 929–30. doi:10.1097/JTO.0b013e318180271d. PMID 18670314.
  23. ↑ "T-cell lymphomas (Lymphoma Association)" (PDF).
  24. ↑ "ALK− anaplastic large-cell lymphoma is clinically and immunophenotypically different from both ALK+ ALCL and peripheral T-cell lymphoma, not otherwise specified: report from the International Peripheral T-Cell Lymphoma Project".
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