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| __NOTOC__
| | #REDIRECT[[Anaplastic large cell lymphoma]] |
| {{SI}}
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| {{DiseaseDisorder infobox |
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| Name = auses
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| Anaplastic large cell lymphoma, ALK negative
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| ls|
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| ICD10 = {{ICD10|C|84|4|c|81}} |
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| OMIM = |
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| MedlinePlus = |
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| eMedicineSubj = |
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| eMedicineTopic = |
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| {{CMG}}; {{AE}} {{AP}}
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| {{SK}} ALCL-ALK(-); ALK-negative ALCL; ALK negative ALCL; ALK negative anaplastic large cell lymphoma
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| ==Overview==
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| The ALK negative anaplastic large cell lymphoma is a [[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> reason why the clinical outcome is more variable than the [[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> Instead, this [[T-cell]]s have a chromosomal rearrangement, affecting DUSP22 and TP63 gene. ALK(-) patients with DUSP22 mutation have shown to have a higher five-year overall survival rate in comparison to [[ALK(+)-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>
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| ==Historical Perspective==
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| The WHO added the ALK(-) ALCL as a provisional entity since 2008 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>
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| ==Classification==
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| ===Morphologic Classification===
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| ==Pathophysiology ==
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| ==Causes==
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| ALK negative ALCL have a T(6;7)(p25.3;q32.3), which inactivates the DUSP22 gene.<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 the 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>
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| == Differential Diagnosis==
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| *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>
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| *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>
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| *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>
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| *[[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>
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| == Epidemiology and Demographics==
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| The ALK(-) ALCL represents 2%-3% of all [[NHL]] and 12% of all [[T-cell]] [[Non-Hodgkin's lymphomas]].<ref name="ALK">{{cite web|url=http://www.sciencedirect.com/science/article/pii/S104084281200131X|title=Anaplastic large cell lymphoma, ALK-negative}}</ref> Affects primarily adults between 40-60 years old, with a modest male predominance, in comparison to women.<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>
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| ==Risk Factors==
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| *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>
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| ==Natural History, Complications and Prognosis==
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| ===Prognosis===
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| 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:
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| *Patient's age (>60 years)
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| *Elevated serum [[lactate dehydrogenase]] ([[LDH]])
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| *Eastern Cooperative Oncology Group (ECOG) performance status
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| *Ann Arbor clinical stage III or IV
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| *Number of involved extra nodal sites > 1
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| If any of this criteria is met, one point is awarded for the IPI. The interpretation of the total score is as follows:
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| *0 to 1: Low risk
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| *2: Low-intermediate risk
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| *3: High-intermediate risk
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| *4 to 5: High risk
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| ==Diagnosis==
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| ===History and Symptoms===
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| 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=
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| 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>
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| ===Cytology Findings===
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| 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>
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| ====Morphologic criteria====
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| *Absence of small-to-medium sized lymphocytes.
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| ====Immunophenotype criteria====
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| *[[CD30]] expression
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| *Nuclear negativity for the [[PAX5]] transcription factor (usually expressed in [[Hodgkin’s lymphoma]] classic variant)
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| *Negativity for the [[EBV]] markers EBER and LMP1 (which may be expressed in [[Hodgkin’s lymphoma]] classic variant)
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| *Presence of clonal [[T-cell receptor]] rearrangements (usually absent in [[Hodgkin’s lymphoma]] classic variant).
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| ===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>===
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| *[[Anemia]]
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| *[[Thrombocytopenia]]
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| *Increased [[LDH]]
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| == Treatment ==
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| 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>
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| ===CHOP Regimen===
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| *This regimen includes:
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| **[[Cyclophosphamide]]
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| **[[Doxorubicin]]
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| **[[Vincristine]]
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| **[[Prednisone]]
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| 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>
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| ===Alternative Therapy===
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| 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>
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| ==References==
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| {{Reflist|2}}
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