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[[Crizotinib]] has successfully treated patients with ALK positive ALCL refractory to CHOP therapy.<ref>{{cite web|url=http://www.ascopost.com/ViewNews.aspx?nid=12946|title=Crizotinib Produces Durable Responses in Small Study of Patients With Advanced, Chemoresistant ALK-Positive Lymphoma}}</ref> [[Crizotinib]] was administered twice daily, each dose of 250mg.
[[Crizotinib]] has successfully treated patients with ALK positive ALCL refractory to CHOP therapy.<ref>{{cite web|url=http://www.ascopost.com/ViewNews.aspx?nid=12946|title=Crizotinib Produces Durable Responses in Small Study of Patients With Advanced, Chemoresistant ALK-Positive Lymphoma}}</ref> [[Crizotinib]] was administered twice daily, each dose of 250mg.
==References==
{{Reflist|2}}
__NOTOC__
{{SI}}
{{DiseaseDisorder infobox |
  Name          = auses
Anaplastic large cell lymphoma, ALK negative
ls|
  ICD10          = {{ICD10|C|84|4|c|81}} |
  OMIM          = |
  MedlinePlus    = |
  eMedicineSubj  = |
  eMedicineTopic = |
}}
{{CMG}}; {{AE}} {{AP}}
{{SK}} ALCL-ALK(-); ALK-negative ALCL; ALK negative ALCL; ALK negative anaplastic large cell lymphoma
==Overview==
ALK negative anaplastic large cell lymphoma (ALCL) is a type of [[peripheral T-cell lymphoma]] ([[non-Hodgkin's lymphoma]]).  ALK negative ALCL [[T-cell]]s express [[CD30]], but not the ALK ('''A'''naplastic '''L'''ymphoma '''K'''inase) chimeric 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> which explains the difference in clinical outcome compared to that of [[ALK(+)-ALCL]].<ref name="pmid25461779">{{cite journal| author=Xing X, Feldman AL| title=Anaplastic large cell lymphomas: ALK positive, ALK negative, and primary cutaneous. | journal=Adv Anat Pathol | year= 2015 | volume= 22 | issue= 1 | pages= 29-49 | pmid=25461779 | doi=10.1097/PAP.0000000000000047 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25461779  }} </ref> [[T-cell]]s in ALK negative ALCL have a chromosomal rearrangement that involves DUSP22 and TP63 gene. ALK negative ALCL patients with DUSP22 mutation have a higher five-year overall survival rate in comparison with ALK positive ALCL.<ref name="pmid24894770">{{cite journal| author=Parrilla Castellar ER, Jaffe ES, Said JW, Swerdlow SH, Ketterling RP, Knudson RA et al.| title=ALK-negative anaplastic large cell lymphoma is a genetically heterogeneous disease with widely disparate clinical outcomes. | journal=Blood | year= 2014 | volume= 124 | issue= 9 | pages= 1473-80 | pmid=24894770 | doi=10.1182/blood-2014-04-571091 | pmc=PMC4148769 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24894770  }} </ref>
==Historical Perspective==
In 2008, the World Health Organization (WHO) added ALK negative ALCL as a provisional entity in the [[peripheral T-cell lymphoma]] classification.<ref name="ALK">{{cite web|url=http://www.sciencedirect.com/science/article/pii/S104084281200131X|title=Anaplastic large cell lymphoma, ALK-negative}}</ref>
==Causes==
ALK negative ALCL is characterized by a translocation T(6;7)(p25.3;q32.3), which inactivates the DUSP22 gene and leads to a higher proliferation rate.<ref name="pmid21030553">{{cite journal| author=Feldman AL, Dogan A, Smith DI, Law ME, Ansell SM, Johnson SH et al.| title=Discovery of recurrent t(6;7)(p25.3;q32.3) translocations in ALK-negative anaplastic large cell lymphomas by massively parallel genomic sequencing. | journal=Blood | year= 2011 | volume= 117 | issue= 3 | pages= 915-9 | pmid=21030553 | doi=10.1182/blood-2010-08-303305 | pmc=PMC3035081 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21030553  }} </ref> In healthy people, the product of the DUSP22 gene, the DUSP22 protein (also known as the <i>JNK pathway-associated phosphatase</i> or <i>JKAP</i>), inactivates the LCK tyrosine kinase protein during T-cell receptor signaling.<ref>{{cite web|url=http://www.nature.com/ncomms/2014/140409/ncomms4618/full/ncomms4618.html|title=The phosphatase JKAP/DUSP22 inhibits T-cell receptor signalling and autoimmunity by inactivating Lck}}</ref>
DUSP22 mutations are also associated with breast cancer (the UDSMP22 protein can also block [[estrogen receptors]])<ref>{{cite web|url=http://www.bloodjournal.org/content/117/3/915?sso-checked=true|title=Discovery of recurrent t(6;7)(p25.3;q32.3) translocations in ALK-negative anaplastic large cell lymphomas by massively parallel genomic sequencing}}</ref> and primary cutaneous ALCL.<ref name="pmid25461779">{{cite journal| author=Xing X, Feldman AL| title=Anaplastic large cell lymphomas: ALK positive, ALK negative, and primary cutaneous. | journal=Adv Anat Pathol | year= 2015 | volume= 22 | issue= 1 | pages= 29-49 | pmid=25461779 | doi=10.1097/PAP.0000000000000047 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25461779}} </ref>
== Differential Diagnosis==
*Peripheral T-cell lymphoma-not otherwise specified (PTCL-NOS)<ref name="pmid22789917">{{cite journal| author=Ferreri AJ, Govi S, Pileri SA, Savage KJ| title=Anaplastic large cell lymphoma, ALK-negative. | journal=Crit Rev Oncol Hematol | year= 2013 | volume= 85 | issue= 2 | pages= 206-15 | pmid=22789917 | doi=10.1016/j.critrevonc.2012.06.004 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22789917  }} </ref><ref name="ALK+/ALK-">{{cite web|url=http://www.bloodjournal.org/content/111/12/5496?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>
*Classical [[Hodgkin's lymphoma]]<ref name="pmid22789917">{{cite journal| author=Ferreri AJ, Govi S, Pileri SA, Savage KJ| title=Anaplastic large cell lymphoma, ALK-negative. | journal=Crit Rev Oncol Hematol | year= 2013 | volume= 85 | issue= 2 | pages= 206-15 | pmid=22789917 | doi=10.1016/j.critrevonc.2012.06.004 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22789917  }} </ref>
*Primary cutaneous anaplastic large cell lymphoma<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>
*[[Anaplastic large cell lymphoma, ALK positive]]<ref name="ALK+/ALK-">{{cite web|url=http://www.bloodjournal.org/content/111/12/5496?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>
== Epidemiology and Demographics==
ALK negative ALCL represents 2%-3% of all [[non-Hodgkin's lymphomas]] ([[NHL]]) and 12% of all [[T-cell NHL]].<ref name="ALK">{{cite web|url=http://www.sciencedirect.com/science/article/pii/S104084281200131X|title=Anaplastic large cell lymphoma, ALK-negative}}</ref>
===Age===
ALK negative ALCL affects primarily adults between 40-60 years old.
===Gender===
There is a modest male predominance in the prevalence of the disease.<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>
==Risk Factors==
*Breast implants<ref name="pmid22789917">{{cite journal| author=Ferreri AJ, Govi S, Pileri SA, Savage KJ| title=Anaplastic large cell lymphoma, ALK-negative. | journal=Crit Rev Oncol Hematol | year= 2013 | volume= 85 | issue= 2 | pages= 206-15 | pmid=22789917 | doi=10.1016/j.critrevonc.2012.06.004 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22789917  }} </ref>
==Natural History, Complications and Prognosis==
===Prognosis===
The '''I'''nternational '''P'''rognostic '''I'''ndex (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)
*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
==Diagnosis==
===History and Symptoms===
Patients typically present [[B symptoms]] ([[fever]], [[weight loss]] and [[lymphadenopathy]]). ALK negative ALCL patients have a higher incidence of cutaneous, hepatic and gastrointestinal involvement than [[ALK positive ALCL]].<ref name="ALK+/ALK-">{{cite web|url=http://www.bloodjournal.org/content/111/12/5496?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>  Other sites of involvement include the [[bronchus]]<ref name="pmid24427373">{{cite journal| author=Xu X| title=ALK-negative anaplastic large cell lymphoma primarily involving the bronchus: a case report and literature review. | journal=Int J Clin Exp Pathol | year= 2014 | volume= 7 | issue= 1 | pages= 460-3 | pmid=24427373 | doi= | pmc=PMC3885507 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24427373  }} </ref>, [[central nervous system]],<ref name="pmid24649224">{{cite journal| author=Nomura M, Narita Y, Miyakita Y, Ohno M, Fukushima S, Maruyama T et al.| title=Clinical presentation of anaplastic large-cell lymphoma in the central nervous system. | journal=Mol Clin Oncol | year= 2013 | volume= 1 | issue= 4 | pages= 655-660 | pmid=24649224 | doi=10.3892/mco.2013.110 | pmc=PMC3915681 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24649224  }} </ref> [[pancreas]],<ref name="pmid16273656">{{cite journal| author=Savopoulos CG, Tsesmeli NE, Kaiafa GD, Zantidis AT, Bobos MT, Hatzitolios AI et al.| title=Primary pancreatic anaplastic large cell lymphoma, ALK negative: a case report. | journal=World J Gastroenterol | year= 2005 | volume= 11 | issue= 39 | pages= 6221-4 | pmid=16273656 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16273656  }} </ref> [[rectum]],<ref>{{citeweb|url=http://dx.doi.org/10.4236/ojpathology.2013.31007|title=
Anaplastic Large Cell Lymphoma, ALK-Negative Presenting in the Rectum: A Case Report and Review of the Literature}}</ref> [[breast]] peri-implant seromas,<ref name="pmid25490535">{{cite journal| author=Brody GS, Deapen D, Taylor CR, Pinter-Brown L, House-Lightner SR, Andersen J et al.| title=Anaplastic Large Cell Lymphoma (ALCL) Occuring in Women with Breast Implants: Analysis of 173 Cases. | journal=Plast Reconstr Surg | year= 2014 | volume=  | issue=  | pages=  | pmid=25490535 | doi=10.1097/PRS.0000000000001033 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25490535  }} </ref> [[skeletal muscle]],<ref name="pmid25292453">{{cite journal| author=Kubo Y, Aoi J, Johno T, Makino T, Sakai K, Masuguchi S et al.| title=A case of anaplastic large cell lymphoma of skeletal muscle. | journal=J Dermatol | year= 2014 | volume= 41 | issue= 11 | pages= 999-1002 | pmid=25292453 | doi=10.1111/1346-8138.12641 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25292453  }} </ref> and [[bone]].<ref name="pmid25346119">{{cite journal| author=Yu G, Huang X, Li M, Ding Y, Wang X, Lai Y et al.| title=[Clinicopathologic features and prognosis of primary bone anaplastic large cell lymphoma]. | journal=Zhonghua Bing Li Xue Za Zhi | year= 2014 | volume= 43 | issue= 8 | pages= 512-5 | pmid=25346119 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25346119  }} </ref>
===Cytology Findings===
According to the World Health Organization (WHO), the most important factor to diagnose a ALK negative ALCL is morphology and immunophenotype:<ref>{{cite web|url=http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2704299/|title=Anaplastic large cell lymphoma: changes in the World Health Organization classification and perspectives for targeted therapy}}</ref>
====Morphologic criteria====
*Absence of small-to-medium sized lymphocytes.
====Immunophenotype criteria====
*[[CD30]] expression
*Nuclear negativity for the [[PAX5]] transcription factor (usually expressed in [[Hodgkin’s lymphoma]] classic variant)
*Negativity for the [[EBV]] markers EBER and LMP1 (which may be expressed in [[Hodgkin’s lymphoma]] classic variant)
*Presence of clonal [[T-cell receptor]] rearrangements (usually absent in [[Hodgkin’s lymphoma]] classic variant).
===Laboratory Findings<ref name="ALK+/ALK-">{{cite web|url=http://www.bloodjournal.org/content/111/12/5496?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>===
*[[Anemia]]
*[[Thrombocytopenia]]
*Increased [[LDH]]
== Treatment ==
Although the [[peripheral T-cell lymphomas]] are a heterogenous group of pathologies, the treatment is the same:<ref name="pmid24615779">{{cite journal| author=Moskowitz AJ, Lunning MA, Horwitz SM| title=How I treat the peripheral T-cell lymphomas. | journal=Blood | year= 2014 | volume= 123 | issue= 17 | pages= 2636-44 | pmid=24615779 | doi=10.1182/blood-2013-12-516245 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24615779  }} </ref>
===CHOP Regimen===
*This regimen includes:
**[[Cyclophosphamide]]
**[[Doxorubicin]]
**[[Vincristine]]
**[[Prednisone]]
Some evidence suggest that although CHOP regimen is effective in treating the ALK(-) ALCL, a short 2-year event-free survival requires extra management<ref name="pmid24428090">{{cite journal| author=Rattarittamrong E, Norasetthada L, Tantiworawit A, Chai-Adisaksopha C, Nawarawong W| title=CHOEP-21 chemotherapy for newly diagnosed nodal peripheral T-cell lymphomas (PTCLs) in Maharaj Nakorn Chiang Mai Hospital. | journal=J Med Assoc Thai | year= 2013 | volume= 96 | issue= 11 | pages= 1416-22 | pmid=24428090 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24428090  }} </ref>, reason why CHOP regimen must then be followed by an autologous stem cell transplant during remission.<ref name="pmid24615779">{{cite journal| author=Moskowitz AJ, Lunning MA, Horwitz SM| title=How I treat the peripheral T-cell lymphomas. | journal=Blood | year= 2014 | volume= 123 | issue= 17 | pages= 2636-44 | pmid=24615779 | doi=10.1182/blood-2013-12-516245 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24615779  }} </ref>
===Alternative Therapy===
A novel drug, [[Brentuximab]], has effectively treated refractory, [[CD30]] positive ALCL in the japanese population.<ref name="pmid24814862">{{cite journal| author=Ogura M, Tobinai K, Hatake K, Ishizawa K, Uike N, Uchida T et al.| title=Phase I / II study of brentuximab vedotin in Japanese patients with relapsed or refractory CD30-positive Hodgkin's lymphoma or systemic anaplastic large-cell lymphoma. | journal=Cancer Sci | year= 2014 | volume= 105 | issue= 7 | pages= 840-6 | pmid=24814862 | doi=10.1111/cas.12435 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24814862  }} </ref> The most common side effects associated with [[brentuximab]] are [[peripheral sensory neuropathy]] and [[neutropenia]].<ref name="pmid23831822">{{cite journal| author=Terriou L, Bonnet S, Debarri H, Demarquette H, Morschhauser F| title=[Brentuximab vedotin: new treatment for CD30+ lymphomas]. | journal=Bull Cancer | year= 2013 | volume= 100 | issue= 7-8 | pages= 775-9 | pmid=23831822 | doi=10.1684/bdc.2013.1778 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23831822  }} </ref>


==References==
==References==
{{Reflist|2}}
{{Reflist|2}}

Revision as of 14:40, 8 October 2015

 
 
 
 
 
 
 
 
 
B-cell neoplasms
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CD5+
 
 
 
 
 
 
 
CD5-
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CCND1+
 
 
 
CCND1-
 
 
 
 
DLBCL
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pleomorphic MCL
 
 
 
DLBCL, NOS CD5+
 
CD10+
 
 
 
 
 
 
 
CD10-
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
DLBCL, NOS GCB type
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
BCL6+ IRF4/MUM1-
 
BCL6+ IRF4/MUM1+
 
BCL6- IRF4/MUM1+
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
DLBCL, NOS GCB type
 
Non-GCB
 
Post-GCB
 
 



Use of Immunophenotyping/Genetic Testing in Differential Diagnosis of Mature B-Cell and NK/T-Cell Neoplasms


 
 
 
 
 
 
 
 
 
B-cell neoplasms
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CD5+
 
 
 
 
 
 
 
CD5-
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CCND1+
 
 
 
CCND1-
 
 
 
 
DLBCL
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pleomorphic MCL
 
 
 
DLBCL, NOS CD5+
 
CD10+
 
 
 
 
 
 
 
CD10-
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
DLBCL, NOS GCB type
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
BCL6+ IRF4/MUM1-
 
BCL6+ IRF4/MUM1+
 
BCL6- IRF4/MUM1+
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
DLBCL, NOS GCB type
 
Non-GCB
 
Post-GCB
 
 


Angioimmunoblastic T-cell lymphoma Microchapters

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [15]; Associate Editor(s)-in-Chief: Raviteja Guddeti, M.B.B.S. [16]

Overview

Angioimmunoblastic T-cell lymphoma (AILT) is a mature T-cell lymphoma characterized by a polymorphous lymph node infiltrate showing a marked increase in follicular dendritic cells (FDCs) and high endothelial venules (HEVs) and systemic involvement.[1] It is also known as immunoblastic lymphadenopathy (Lukes-Collins Classification) and AILD-type (lymphogranulomatosis X) T-cell lymphoma (Kiel Classification)[1].

Pathophysiology

Genetics

Clonal T-cell receptor gene rearrangements are detected in 75% of cases[2], and immunoglobin gene rearrangements are seen in 10% of cases, and these cases are believed to be due to expanded EBV-driven B-cell populations.[3] Similarly, EBV-related sequences can be detected most cases, usually in B-cells but occasionally in T-cells.[4][5]. Trisomy 3, trisomy 5, and +X are the most frequent chromosomal abnormalities found in cases.[6][7]

Gross Pathology

The normal architecture of a lymph node is partially effaced by a polymorphous infiltrate and residual follicles are commonly seen. The polymorphous infiltrate consists of lymphocytes of moderate size with pale/clear cytoplasm and smaller reactive lymphocytes, eosinophils, histiocytes, plasma cells, and follicular dendritic cells. In addition, blast-like B-cells are occasionally seen. A classic morphological finding is the aborization and proliferation of high endothelial venules.[1] Hyperplastic germinal centers and Reed-Sternberg cells can also be seen.[8][9]

Microscopic Pathology

AILT typically has the phenotype of a mixture of CD4+ and CD8+ T-cells, with a CD4:CD8 ratio greater than unity. Polyclonal plasma cells and CD21+ follicular dendritic cells are also seen.[1] Due to the systemic nature of this disease, neoplastic cells can be found in lymph nodes, liver, spleen, skin, and bone marrow.

Causes

AILT was originally thought to be a premalignant condition, termed angioimmunoblastic lymphadenopathy, and this atypical reactive lymphadenopathy carried a risk for transformation into a lymphoma. Currently, it is postulated that the originating cell for this disease is a mature (post-thymic) CD4+ T-cell that arises de novo, although some researchers argue that there is a premalignant subtype of this disease.[10][11] The Epstein Barr virus (EBV) is observed in the majority of cases, and the virus has been found in the reactive B-cells that comprise part of the polymorphous infiltrate of this disease[4] and in the neoplastic T-cells.[5] Immunodeficiency is also seen with this disease, but it is thought to be a sequela to the condition and not a predisposing factor.

Overview

AILT comprises 15-20% of peripheral T-cell lymphomas and 1-2% of all non-Hodgkin lymphomas.[12]

Age

The typical patient with angioimmunoblastic T-cell lymphoma (AILT) is either middle-aged or elderly.

Gender

No gender preference for this disease has been observed.

Symptoms

Patients with this disease usually present at an advanced stage and show systemic involvement. The clinical findings typically include

Laboratory Findings

The classical laboratory finding is polyclonal hypergammaglobulinemia

Other immunoglobulin derrangements are also seen, including

Treatment

References

  1. ↑ 1.0 1.1 1.2 1.3 [1] Jaffe E.S., Harris N.L., Stein H., Vardiman J.W. (eds): World Health Organization Classification of Tumors. Pathology and Genetics of Tumours of Haemopoietic and Lymphoid Tissues. IARC Press: Lyon 2001
  2. ↑ [2] Feller AC, Griesser H, Schilling CV, Wacker HH, Dallenbach F, Bartels H, Kuse R, Mak TW, Lennert K. "Clonal gene rearrangement patterns correlate with immunophenotype and clinical parameters in patients with angioimmunoblastic lymphadenopathy." Am J Pathol. 1988 Dec;133(3):549-56. PMID: 2849301
  3. ↑ [3] Lipford EH, Smith HR, Pittaluga S, Jaffe ES, Steinberg AD, Cossman J. "Clonality of angioimmunoblastic lymphadenopathy and implications for its evolution to malignant lymphoma." J Clin Invest. 1987 Feb;79(2):637-42. PMID: 3805286
  4. ↑ 4.0 4.1 [4] Weiss LM, Jaffe ES, Liu XF, Chen YY, Shibata D, Medeiros LJ. "Detection and localization of Epstein-Barr viral genomes in angioimmunoblastic lymphadenopathy and angioimmunoblastic lymphadenopathy-like lymphoma." Blood. 1992 Apr 1;79(7):1789-95. PMID: 1373088
  5. ↑ 5.0 5.1 [5] Anagnostopoulos I, Hummel M, Finn T, Tiemann M, Korbjuhn P, Dimmler C, Gatter K, Dallenbach F, Parwaresch MR, Stein H. "Heterogeneous Epstein-Barr virus infection patterns in peripheral T-cell lymphoma of angioimmunoblastic lymphadenopathy type."Blood. 1992 Oct 1;80(7):1804-12. PMID: 1327284
  6. ↑ [6] Kaneko Y, Maseki N, Sakurai M, Takayama S, Nanba K, Kikuchi M, Frizzera G. "Characteristic karyotypic pattern in T-cell lymphoproliferative disorders with reactive "angioimmunoblastic lymphadenopathy with dysproteinemia-type" features." Blood. 1988 Aug;72(2):413-21. PMID: 3261178
  7. ↑ [7] Schlegelberger B, Zhang Y, Weber-Matthiesen K, Grote W. "Detection of aberrant clones in nearly all cases of angioimmunoblastic lymphadenopathy with dysproteinemia-type T-cell lymphoma by combined interphase and metaphase cytogenetics." Blood. 1994 Oct 15;84(8):2640-8. PMID: 7919378
  8. ↑ [8] Quintanilla-Martinez L, Fend F, Moguel LR, Spilove L, Beaty MW, Kingma DW, Raffeld M, Jaffe ES. "Peripheral T-cell lymphoma with Reed-Sternberg-like cells of B-cell phenotype and genotype associated with Epstein-Barr virus infection." Am J Surg Pathol. 1999 Oct;23(10):1233-40. PMID: 10524524
  9. ↑ [9] Ree HJ, Kadin ME, Kikuchi M, Ko YH, Go JH, Suzumiya J, Kim DS. "Angioimmunoblastic lymphoma (AILD-type T-cell lymphoma) with hyperplastic germinal centers." Am J Surg Pathol. 1998 Jun;22(6):643-55. PMID: 9630171
  10. ↑ [10] Frizzera G, Kaneko Y, Sakurai M. "Angioimmunoblastic lymphadenopathy and related disorders: a retrospective look in search of definitions." Leukemia. 1989 Jan;3(1):1-5. PMID: 2642571
  11. ↑ [11] Smith JL, Hodges E, Quin CT, McCarthy KP, Wright DH. "Frequent T and B cell oligoclones in histologically and immunophenotypically characterized angioimmunoblastic lymphadenopathy." Am J Pathol. 2000 Feb;156(2):661-9. PMID: 10666395
  12. ↑ [12] Anon. "A clinical evaluation of the International Lymphoma Study Group classification of non-Hodgkin's lymphoma. The Non-Hodgkin's Lymphoma Classification Project." Blood. 1997 Jun 1;89(11):3909-18. PMID: 9166827
  13. ↑ [13] Siegert W, Nerl C, Agthe A, Engelhard M, Brittinger G, Tiemann M, Lennert K, Huhn D. "Angioimmunoblastic lymphadenopathy (AILD)-type T-cell lymphoma: prognostic impact of clinical observations and laboratory findings at presentation. The Kiel Lymphoma Study Group." Ann Oncol. 1995 Sep;6(7):659-64. PMID: 8664186
  14. ↑ [14] Jaffe ES. "Angioimmunoblastic T-cell lymphoma: new insights, but the clinical challenge remains." Ann Oncol. 1995 Sep;6(7):631-2. PMID: 8664181


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Template:DiseaseDisorder infobox Editor-In-Chief: C. Michael Gibson, M.S., M.D. [17]; Associate Editor(s)-in-Chief: Alberto Plate [18]

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

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.[14]

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).[15] 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.[16] 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:[17]

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

However, recently, the International peripheral T-cell lymphoma Project score (IPTCLP) has demonstrated to be the most accurate score to predict overall survival in patients. [18]

This score includes:

  • Age
  • Eastern Cooperative Oncology Group (ECOG) performance status
  • Platelet count

Diagnosis

History and Symptoms

Most adult patients present with painless lymphadenopathy. Although retroperitoneal and peripheral lymphadenopathy is very common,[19] other possible locations for enlarged lymph nodes include the gastrointestinal tract, the breast,[20] the spleen,[21] the liver,[22] the bone,[22] the heart,[23] and the respiratory tract.[24]

Common symptoms include typical B symptoms: fever, weight loss, and night sweats.[25]

Laboratory Findings

Treatment

CHOP-E Regimen

The CHOP-E regimen includes:

Crizotinib has successfully treated patients with ALK positive ALCL refractory to CHOP therapy.[27] Crizotinib was administered twice daily, each dose of 250mg.

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. ↑ "ALK+ Lymphoma: Clinico-Pathological Findings and Outcome".
  15. ↑ "International Peripheral T-Cell and Natural Killer/T-Cell Lymphoma Study: Pathology Findings and Clinical Outcomes" (PDF).
  16. ↑ "International Prognostic Index for non-Hodgkin lymphoma".
  17. ↑ "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".
  18. ↑ "Comparison of four prognostic scores in peripheral T-cell lymphoma".
  19. ↑ 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.
  20. ↑ 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.
  21. ↑ 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.
  22. ↑ 22.0 22.1 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.
  23. ↑ 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.
  24. ↑ 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.
  25. ↑ "T-cell lymphomas (Lymphoma Association)" (PDF).
  26. ↑ "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".
  27. ↑ "Crizotinib Produces Durable Responses in Small Study of Patients With Advanced, Chemoresistant ALK-Positive Lymphoma".


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Template:DiseaseDisorder infobox Editor-In-Chief: C. Michael Gibson, M.S., M.D. [19]; Associate Editor(s)-in-Chief: Alberto Plate [20]

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

Overview

ALK negative anaplastic large cell lymphoma (ALCL) is a type of peripheral T-cell lymphoma (non-Hodgkin's lymphoma). ALK negative ALCL T-cells express CD30, but not the ALK (Anaplastic Lymphoma Kinase) chimeric protein,[1] which explains the difference in clinical outcome compared to that of ALK(+)-ALCL.[2] T-cells in ALK negative ALCL have a chromosomal rearrangement that involves DUSP22 and TP63 gene. ALK negative ALCL patients with DUSP22 mutation have a higher five-year overall survival rate in comparison with ALK positive ALCL.[3]

Historical Perspective

In 2008, the World Health Organization (WHO) added ALK negative ALCL as a provisional entity in the peripheral T-cell lymphoma classification.[4]

Causes

ALK negative ALCL is characterized by a translocation T(6;7)(p25.3;q32.3), which inactivates the DUSP22 gene and leads to a higher proliferation rate.[5] In healthy people, the product of the DUSP22 gene, the DUSP22 protein (also known as the JNK pathway-associated phosphatase or JKAP), inactivates the LCK tyrosine kinase protein during T-cell receptor signaling.[6]

DUSP22 mutations are also associated with breast cancer (the UDSMP22 protein can also block estrogen receptors)[7] and primary cutaneous ALCL.[2]

Differential Diagnosis

Epidemiology and Demographics

ALK negative ALCL represents 2%-3% of all non-Hodgkin's lymphomas (NHL) and 12% of all T-cell NHL.[4]

Age

ALK negative ALCL affects primarily adults between 40-60 years old.

Gender

There is a modest male predominance in the prevalence of the disease.[1]

Risk Factors

  • Breast implants[8]

Natural History, Complications and Prognosis

Prognosis

The International Prognostic Index (IPI) is used to estimate the prognosis of patients.[10] 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

Diagnosis

History and Symptoms

Patients typically present B symptoms (fever, weight loss and lymphadenopathy). ALK negative ALCL patients have a higher incidence of cutaneous, hepatic and gastrointestinal involvement than ALK positive ALCL.[9] Other sites of involvement include the bronchus[11], central nervous system,[12] pancreas,[13] rectum,[14] breast peri-implant seromas,[15] skeletal muscle,[16] and bone.[17]

Cytology Findings

According to the World Health Organization (WHO), the most important factor to diagnose a ALK negative ALCL is morphology and immunophenotype:[18]

Morphologic criteria

  • Absence of small-to-medium sized lymphocytes.

Immunophenotype criteria

Laboratory Findings[9]

Treatment

Although the peripheral T-cell lymphomas are a heterogenous group of pathologies, the treatment is the same:[19]

CHOP Regimen

Some evidence suggest that although CHOP regimen is effective in treating the ALK(-) ALCL, a short 2-year event-free survival requires extra management[20], reason why CHOP regimen must then be followed by an autologous stem cell transplant during remission.[19]

Alternative Therapy

A novel drug, Brentuximab, has effectively treated refractory, CD30 positive ALCL in the japanese population.[21] The most common side effects associated with brentuximab are peripheral sensory neuropathy and neutropenia.[22]

References

  1. ↑ 1.0 1.1 1.2 Swerdlow, Steven (2008). WHO classification of tumours of haematopoietic and lymphoid tissues. Lyon, France: International Agency for Research on Cancer. ISBN 9789283224310.
  2. ↑ 2.0 2.1 Xing X, Feldman AL (2015). "Anaplastic large cell lymphomas: ALK positive, ALK negative, and primary cutaneous". Adv Anat Pathol. 22 (1): 29–49. doi:10.1097/PAP.0000000000000047. PMID 25461779.
  3. ↑ Parrilla Castellar ER, Jaffe ES, Said JW, Swerdlow SH, Ketterling RP, Knudson RA; et al. (2014). "ALK-negative anaplastic large cell lymphoma is a genetically heterogeneous disease with widely disparate clinical outcomes". Blood. 124 (9): 1473–80. doi:10.1182/blood-2014-04-571091. PMC 4148769. PMID 24894770.
  4. ↑ 4.0 4.1 "Anaplastic large cell lymphoma, ALK-negative".
  5. ↑ Feldman AL, Dogan A, Smith DI, Law ME, Ansell SM, Johnson SH; et al. (2011). "Discovery of recurrent t(6;7)(p25.3;q32.3) translocations in ALK-negative anaplastic large cell lymphomas by massively parallel genomic sequencing". Blood. 117 (3): 915–9. doi:10.1182/blood-2010-08-303305. PMC 3035081. PMID 21030553.
  6. ↑ "The phosphatase JKAP/DUSP22 inhibits T-cell receptor signalling and autoimmunity by inactivating Lck".
  7. ↑ "Discovery of recurrent t(6;7)(p25.3;q32.3) translocations in ALK-negative anaplastic large cell lymphomas by massively parallel genomic sequencing".
  8. ↑ 8.0 8.1 8.2 Ferreri AJ, Govi S, Pileri SA, Savage KJ (2013). "Anaplastic large cell lymphoma, ALK-negative". Crit Rev Oncol Hematol. 85 (2): 206–15. doi:10.1016/j.critrevonc.2012.06.004. PMID 22789917.
  9. ↑ 9.0 9.1 9.2 9.3 "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".
  10. ↑ "International Prognostic Index for non-Hodgkin lymphoma".
  11. ↑ Xu X (2014). "ALK-negative anaplastic large cell lymphoma primarily involving the bronchus: a case report and literature review". Int J Clin Exp Pathol. 7 (1): 460–3. PMC 3885507. PMID 24427373.
  12. ↑ Nomura M, Narita Y, Miyakita Y, Ohno M, Fukushima S, Maruyama T; et al. (2013). "Clinical presentation of anaplastic large-cell lymphoma in the central nervous system". Mol Clin Oncol. 1 (4): 655–660. doi:10.3892/mco.2013.110. PMC 3915681. PMID 24649224.
  13. ↑ Savopoulos CG, Tsesmeli NE, Kaiafa GD, Zantidis AT, Bobos MT, Hatzitolios AI; et al. (2005). "Primary pancreatic anaplastic large cell lymphoma, ALK negative: a case report". World J Gastroenterol. 11 (39): 6221–4. PMID 16273656.
  14. ↑ Template:Citeweb
  15. ↑ Brody GS, Deapen D, Taylor CR, Pinter-Brown L, House-Lightner SR, Andersen J; et al. (2014). "Anaplastic Large Cell Lymphoma (ALCL) Occuring in Women with Breast Implants: Analysis of 173 Cases". Plast Reconstr Surg. doi:10.1097/PRS.0000000000001033. PMID 25490535.
  16. ↑ Kubo Y, Aoi J, Johno T, Makino T, Sakai K, Masuguchi S; et al. (2014). "A case of anaplastic large cell lymphoma of skeletal muscle". J Dermatol. 41 (11): 999–1002. doi:10.1111/1346-8138.12641. PMID 25292453.
  17. ↑ Yu G, Huang X, Li M, Ding Y, Wang X, Lai Y; et al. (2014). "[Clinicopathologic features and prognosis of primary bone anaplastic large cell lymphoma]". Zhonghua Bing Li Xue Za Zhi. 43 (8): 512–5. PMID 25346119.
  18. ↑ "Anaplastic large cell lymphoma: changes in the World Health Organization classification and perspectives for targeted therapy".
  19. ↑ 19.0 19.1 Moskowitz AJ, Lunning MA, Horwitz SM (2014). "How I treat the peripheral T-cell lymphomas". Blood. 123 (17): 2636–44. doi:10.1182/blood-2013-12-516245. PMID 24615779.
  20. ↑ Rattarittamrong E, Norasetthada L, Tantiworawit A, Chai-Adisaksopha C, Nawarawong W (2013). "CHOEP-21 chemotherapy for newly diagnosed nodal peripheral T-cell lymphomas (PTCLs) in Maharaj Nakorn Chiang Mai Hospital". J Med Assoc Thai. 96 (11): 1416–22. PMID 24428090.
  21. ↑ Ogura M, Tobinai K, Hatake K, Ishizawa K, Uike N, Uchida T; et al. (2014). "Phase I / II study of brentuximab vedotin in Japanese patients with relapsed or refractory CD30-positive Hodgkin's lymphoma or systemic anaplastic large-cell lymphoma". Cancer Sci. 105 (7): 840–6. doi:10.1111/cas.12435. PMID 24814862.
  22. ↑ Terriou L, Bonnet S, Debarri H, Demarquette H, Morschhauser F (2013). "[Brentuximab vedotin: new treatment for CD30+ lymphomas]". Bull Cancer. 100 (7–8): 775–9. doi:10.1684/bdc.2013.1778. PMID 23831822.
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