HAEM5:ALK-positive anaplastic large cell lymphoma: Difference between revisions

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 Put your text here and fill in the table <span style="color:#0070C0">(''Instruction: Can include references in the table'') </span>
+CD30 expression on ALCL (ALK+ or ALK-) allows for targeted therapy<ref name=":2" />
+*First-line therapy: [https://www.fda.gov/drugs/fda-approves-brentuximab-vedotin-previously-untreated-salcl-and-cd30-expressing-ptcl Brentuximab] (anti-CD30) vedotin + CHP (cyclophosphamide, doxorubicin, and prednisone)
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 ==Chromosomal Rearrangements (Gene Fusions)==
-Put your text here and fill in the table
+FISH is not required for diagnosis in routine practice <ref name=":27" /><ref name=":28" />.
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 |No
 |Yes
-|ALK inhibition ([https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-crizotinib-children-and-young-adults-relapsed-or-refractory-systemic-anaplastic-large#:~:text=Approvals%20and%20Databases-,FDA%20approves%20crizotinib%20for%20children%20and%20young%20adults%20with%20relapsed,systemic%20anaplastic%20large%20cell%20lymphoma&text=On%20January%2014%2C%202021%2C%20the,(Xalkori%2C%20Pfizer%20Inc.) crizotinib]) can be an effective 2nd-line therapeutic strategy as ALK is essential for the proliferation and survival of ALK+ ALCL cells<ref name=":21" /><ref name=":2" /><ref name=":22" />
+|Approximately 80% of cases show a cytogenetic translocation t(2;5) (NPM1-ALK, t(2;5)(p23;q35)) which fuses the ''ALK'' gene to the nucleophosmine (NPM) gene at 5q35, resulting in the overexpression and constitutive activation of a chimeric ALK fusion protein, which plays an important role in ALK-mediated oncogenesis.
+'''<u>Of note, identifying the ''ALK'' fusion partner is not considered necessary in routine clinical practice.</u>'''
+Detecting minimal residual disease by PCR for ''[[NPM1-ALK]]'' (not readily commercially available) in bone marrow and peripheral blood during treatment could identify patients at risk of relapse<ref name=":29" />
+ALK inhibition ([https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-crizotinib-children-and-young-adults-relapsed-or-refractory-systemic-anaplastic-large#:~:text=Approvals%20and%20Databases-,FDA%20approves%20crizotinib%20for%20children%20and%20young%20adults%20with%20relapsed,systemic%20anaplastic%20large%20cell%20lymphoma&text=On%20January%2014%2C%202021%2C%20the,(Xalkori%2C%20Pfizer%20Inc.) crizotinib]) can be an effective 2nd-line therapeutic strategy as ALK is essential for the proliferation and survival of ALK+ ALCL cells<ref name=":21" /><ref name=":2" /><ref name=":22" />
 *Drug resistance may develop due to:
@@ Line 262: / Line 275: @@
 *Approximately 80% of cases show a cytogenetic translocation t(2;5) (NPM1-ALK, t(2;5)(p23;q35)) which fuses the ''ALK'' gene to the nucleophosmine (NPM) gene at 5q35, resulting in the overexpression and constitutive activation of a chimeric ALK fusion protein, which plays an important role in ALK-mediated oncogenesis.<ref name=":20">{{Cite journal|last=Morris|first=S. W.|last2=Kirstein|first2=M. N.|last3=Valentine|first3=M. B.|last4=Dittmer|first4=K. G.|last5=Shapiro|first5=D. N.|last6=Saltman|first6=D. L.|last7=Look|first7=A. T.|date=1994-03-04|title=Fusion of a kinase gene, ALK, to a nucleolar protein gene, NPM, in non-Hodgkin's lymphoma|url=https://pubmed.ncbi.nlm.nih.gov/8122112/|journal=Science (New York, N.Y.)|volume=263|issue=5151|pages=1281–1284|doi=10.1126/science.8122112|issn=0036-8075|pmid=8122112}}</ref>
 **
-*''ALK'' translocations may be seen in multiple malignancies including epithelial malignancies<ref>{{Cite journal|last=Holla|first=Vijaykumar R.|last2=Elamin|first2=Yasir Y.|last3=Bailey|first3=Ann Marie|last4=Johnson|first4=Amber M.|last5=Litzenburger|first5=Beate C.|last6=Khotskaya|first6=Yekaterina B.|last7=Sanchez|first7=Nora S.|last8=Zeng|first8=Jia|last9=Shufean|first9=Md Abu|date=2017-1|title=ALK: a tyrosine kinase target for cancer therapy|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5171696/|journal=Cold Spring Harbor Molecular Case Studies|volume=3|issue=1|pages=a001115|doi=10.1101/mcs.a001115|issn=2373-2873|pmc=5171696|pmid=28050598}}</ref><ref>{{Cite journal|last=Amatu|first=Alessio|last2=Somaschini|first2=Alessio|last3=Cerea|first3=Giulio|last4=Bosotti|first4=Roberta|last5=Valtorta|first5=Emanuele|last6=Buonandi|first6=Pasquale|last7=Marrapese|first7=Giovanna|last8=Veronese|first8=Silvio|last9=Luo|first9=David|date=2015-12-22|title=Novel CAD-ALK gene rearrangement is drugable by entrectinib in colorectal cancer|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4701996/|journal=British Journal of Cancer|volume=113|issue=12|pages=1730–1734|doi=10.1038/bjc.2015.401|issn=0007-0920|pmc=4701996|pmid=26633560}}</ref><ref>{{Cite journal|last=Camidge|first=D. Ross|last2=Kono|first2=Scott A.|last3=Lu|first3=Xian|last4=Okuyama|first4=Sonia|last5=Barón|first5=Anna E.|last6=Oton|first6=Ana B.|last7=Davies|first7=Angela M.|last8=Varella-Garcia|first8=Marileila|last9=Franklin|first9=Wilbur|date=2011-04|title=Anaplastic lymphoma kinase gene rearrangements in non-small cell lung cancer are associated with prolonged progression-free survival on pemetrexed|url=https://pubmed.ncbi.nlm.nih.gov/21336183/|journal=Journal of Thoracic Oncology: Official Publication of the International Association for the Study of Lung Cancer|volume=6|issue=4|pages=774–780|doi=10.1097/JTO.0b013e31820cf053|issn=1556-1380|pmc=3626562|pmid=21336183}}</ref><ref>{{Cite journal|last=Choi|first=Young Lim|last2=Takeuchi|first2=Kengo|last3=Soda|first3=Manabu|last4=Inamura|first4=Kentaro|last5=Togashi|first5=Yuki|last6=Hatano|first6=Satoko|last7=Enomoto|first7=Munehiro|last8=Hamada|first8=Toru|last9=Haruta|first9=Hidenori|date=2008-07-01|title=Identification of novel isoforms of the EML4-ALK transforming gene in non-small cell lung cancer|url=https://pubmed.ncbi.nlm.nih.gov/18593892/|journal=Cancer Research|volume=68|issue=13|pages=4971–4976|doi=10.1158/0008-5472.CAN-07-6158|issn=1538-7445|pmid=18593892}}</ref><ref>{{Cite journal|last=Kelly|first=Lindsey M.|last2=Barila|first2=Guillermo|last3=Liu|first3=Pengyuan|last4=Evdokimova|first4=Viktoria N.|last5=Trivedi|first5=Sumita|last6=Panebianco|first6=Federica|last7=Gandhi|first7=Manoj|last8=Carty|first8=Sally E.|last9=Hodak|first9=Steven P.|date=2014-03-18|title=Identification of the transforming STRN-ALK fusion as a potential therapeutic target in the aggressive forms of thyroid cancer|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3964116/|journal=Proceedings of the National Academy of Sciences of the United States of America|volume=111|issue=11|pages=4233–4238|doi=10.1073/pnas.1321937111|issn=0027-8424|pmc=3964116|pmid=24613930}}</ref><ref>{{Cite journal|last=Ambrosini|first=Margherita|last2=Del Re|first2=Marzia|last3=Manca|first3=Paolo|last4=Hendifar|first4=Andrew|last5=Drilon|first5=Alexander|last6=Harada|first6=Guilherme|last7=Ree|first7=Anne Hansen|last8=Klempner|first8=Samuel|last9=Mælandsmo|first9=Gunhild Mari|date=2022-04|title=ALK Inhibitors in Patients With ALK Fusion-Positive GI Cancers: An International Data Set and a Molecular Case Series|url=https://pubmed.ncbi.nlm.nih.gov/35476549/|journal=JCO precision oncology|volume=6|pages=e2200015|doi=10.1200/PO.22.00015|issn=2473-4284|pmid=35476549}}</ref>, inflammatory myofibroblastic tumor<ref>{{Cite journal|last=Bridge|first=Julia A.|last2=Kanamori|first2=Masahiko|last3=Ma|first3=Zhigui|last4=Pickering|first4=Diane|last5=Hill|first5=D. Ashley|last6=Lydiatt|first6=William|last7=Lui|first7=Man Yee|last8=Colleoni|first8=Gisele W. B.|last9=Antonescu|first9=Cristina R.|date=2001-8|title=Fusion of the ALK Gene to the Clathrin Heavy Chain Gene, CLTC, in Inflammatory Myofibroblastic Tumor|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1850566/|journal=The American Journal of Pathology|volume=159|issue=2|pages=411–415|issn=0002-9440|pmc=1850566|pmid=11485898}}</ref><ref>{{Cite journal|last=Lawrence|first=B.|last2=Perez-Atayde|first2=A.|last3=Hibbard|first3=M. K.|last4=Rubin|first4=B. P.|last5=Dal Cin|first5=P.|last6=Pinkus|first6=J. L.|last7=Pinkus|first7=G. S.|last8=Xiao|first8=S.|last9=Yi|first9=E. S.|date=2000-08|title=TPM3-ALK and TPM4-ALK oncogenes in inflammatory myofibroblastic tumors|url=https://pubmed.ncbi.nlm.nih.gov/10934142/|journal=The American Journal of Pathology|volume=157|issue=2|pages=377–384|doi=10.1016/S0002-9440(10)64550-6|issn=0002-9440|pmc=1850130|pmid=10934142}}</ref><ref>{{Cite journal|last=Ma|first=Zhigui|last2=Hill|first2=D. Ashley|last3=Collins|first3=Margaret H.|last4=Morris|first4=Stephan W.|last5=Sumegi|first5=Janos|last6=Zhou|first6=Ming|last7=Zuppan|first7=Craig|last8=Bridge|first8=Julia A.|date=2003-05|title=Fusion of ALK to the Ran-binding protein 2 (RANBP2) gene in inflammatory myofibroblastic tumor|url=https://pubmed.ncbi.nlm.nih.gov/12661011/|journal=Genes, Chromosomes & Cancer|volume=37|issue=1|pages=98–105|doi=10.1002/gcc.10177|issn=1045-2257|pmid=12661011}}</ref>, non-Hodgkin's lymphoma<ref>{{Cite journal|last=Pan|first=Zenggang|last2=Hu|first2=Shimin|last3=Li|first3=Min|last4=Zhou|first4=Yi|last5=Kim|first5=Young S.|last6=Reddy|first6=Vishnu|last7=Sanmann|first7=Jennifer N.|last8=Smith|first8=Lynette M.|last9=Chen|first9=Mingyi|date=2017-01|title=ALK-positive Large B-cell Lymphoma: A Clinicopathologic Study of 26 Cases With Review of Additional 108 Cases in the Literature|url=https://pubmed.ncbi.nlm.nih.gov/27740969/|journal=The American Journal of Surgical Pathology|volume=41|issue=1|pages=25–38|doi=10.1097/PAS.0000000000000753|issn=1532-0979|pmid=27740969}}</ref><ref>{{Cite journal|last=Laurent|first=Camille|last2=Do|first2=Catherine|last3=Gascoyne|first3=Randy D.|last4=Lamant|first4=Laurence|last5=Ysebaert|first5=Loïc|last6=Laurent|first6=Guy|last7=Delsol|first7=Georges|last8=Brousset|first8=Pierre|date=2009-09-01|title=Anaplastic lymphoma kinase-positive diffuse large B-cell lymphoma: a rare clinicopathologic entity with poor prognosis|url=https://pubmed.ncbi.nlm.nih.gov/19636007/|journal=Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology|volume=27|issue=25|pages=4211–4216|doi=10.1200/JCO.2008.21.5020|issn=1527-7755|pmid=19636007}}</ref><ref>{{Cite journal|last=Sakamoto|first=Kana|last2=Nakasone|first2=Hideki|last3=Togashi|first3=Yuki|last4=Sakata|first4=Seiji|last5=Tsuyama|first5=Naoko|last6=Baba|first6=Satoko|last7=Dobashi|first7=Akito|last8=Asaka|first8=Reimi|last9=Tsai|first9=Chien-Chen|date=2016-04|title=ALK-positive large B-cell lymphoma: identification of EML4-ALK and a review of the literature focusing on the ALK immunohistochemical staining pattern|url=https://pubmed.ncbi.nlm.nih.gov/26781614/|journal=International Journal of Hematology|volume=103|issue=4|pages=399–408|doi=10.1007/s12185-016-1934-1|issn=1865-3774|pmid=26781614}}</ref>, and ALK+ histiocytosis <ref>{{Cite journal|last=Takeyasu|first=Yuki|last2=Okuma|first2=Hitomi S.|last3=Kojima|first3=Yuki|last4=Nishikawa|first4=Tadaaki|last5=Tanioka|first5=Maki|last6=Sudo|first6=Kazuki|last7=Shimoi|first7=Tatsunori|last8=Noguchi|first8=Emi|last9=Arakawa|first9=Ayumu|date=2021|title=Impact of ALK Inhibitors in Patients With ALK-Rearranged Nonlung Solid Tumors|url=https://pubmed.ncbi.nlm.nih.gov/34036223/|journal=JCO precision oncology|volume=5|pages=PO.20.00383|doi=10.1200/PO.20.00383|issn=2473-4284|pmc=8140781|pmid=34036223}}</ref><ref>{{Cite journal|last=Chang|first=Kenneth Tou En|last2=Tay|first2=Amos Zhi En|last3=Kuick|first3=Chik Hong|last4=Chen|first4=Huiyi|last5=Algar|first5=Elizabeth|last6=Taubenheim|first6=Nadine|last7=Campbell|first7=Janine|last8=Mechinaud|first8=Francoise|last9=Campbell|first9=Martin|date=2019-05|title=ALK-positive histiocytosis: an expanded clinicopathologic spectrum and frequent presence of KIF5B-ALK fusion|url=https://pubmed.ncbi.nlm.nih.gov/30573850/|journal=Modern Pathology: An Official Journal of the United States and Canadian Academy of Pathology, Inc|volume=32|issue=5|pages=598–608|doi=10.1038/s41379-018-0168-6|issn=1530-0285|pmid=30573850}}</ref><ref>{{Cite journal|last=Chan|first=John K. 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+*'''''ALK translocations may be seen in multiple malignancies including epithelial malignancies<ref>{{Cite journal|last=Holla|first=Vijaykumar R.|last2=Elamin|first2=Yasir Y.|last3=Bailey|first3=Ann Marie|last4=Johnson|first4=Amber M.|last5=Litzenburger|first5=Beate C.|last6=Khotskaya|first6=Yekaterina B.|last7=Sanchez|first7=Nora S.|last8=Zeng|first8=Jia|last9=Shufean|first9=Md Abu|date=2017-1|title=ALK: a tyrosine kinase target for cancer therapy|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5171696/|journal=Cold Spring Harbor Molecular Case Studies|volume=3|issue=1|pages=a001115|doi=10.1101/mcs.a001115|issn=2373-2873|pmc=5171696|pmid=28050598}}</ref><ref>{{Cite journal|last=Amatu|first=Alessio|last2=Somaschini|first2=Alessio|last3=Cerea|first3=Giulio|last4=Bosotti|first4=Roberta|last5=Valtorta|first5=Emanuele|last6=Buonandi|first6=Pasquale|last7=Marrapese|first7=Giovanna|last8=Veronese|first8=Silvio|last9=Luo|first9=David|date=2015-12-22|title=Novel CAD-ALK gene rearrangement is drugable by entrectinib in colorectal cancer|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4701996/|journal=British Journal of Cancer|volume=113|issue=12|pages=1730–1734|doi=10.1038/bjc.2015.401|issn=0007-0920|pmc=4701996|pmid=26633560}}</ref><ref>{{Cite journal|last=Camidge|first=D. Ross|last2=Kono|first2=Scott A.|last3=Lu|first3=Xian|last4=Okuyama|first4=Sonia|last5=Barón|first5=Anna E.|last6=Oton|first6=Ana B.|last7=Davies|first7=Angela M.|last8=Varella-Garcia|first8=Marileila|last9=Franklin|first9=Wilbur|date=2011-04|title=Anaplastic lymphoma kinase gene rearrangements in non-small cell lung cancer are associated with prolonged progression-free survival on pemetrexed|url=https://pubmed.ncbi.nlm.nih.gov/21336183/|journal=Journal of Thoracic Oncology: Official Publication of the International Association for the Study of Lung Cancer|volume=6|issue=4|pages=774–780|doi=10.1097/JTO.0b013e31820cf053|issn=1556-1380|pmc=3626562|pmid=21336183}}</ref><ref>{{Cite journal|last=Choi|first=Young Lim|last2=Takeuchi|first2=Kengo|last3=Soda|first3=Manabu|last4=Inamura|first4=Kentaro|last5=Togashi|first5=Yuki|last6=Hatano|first6=Satoko|last7=Enomoto|first7=Munehiro|last8=Hamada|first8=Toru|last9=Haruta|first9=Hidenori|date=2008-07-01|title=Identification of novel isoforms of the EML4-ALK transforming gene in non-small cell lung cancer|url=https://pubmed.ncbi.nlm.nih.gov/18593892/|journal=Cancer Research|volume=68|issue=13|pages=4971–4976|doi=10.1158/0008-5472.CAN-07-6158|issn=1538-7445|pmid=18593892}}</ref><ref>{{Cite journal|last=Kelly|first=Lindsey M.|last2=Barila|first2=Guillermo|last3=Liu|first3=Pengyuan|last4=Evdokimova|first4=Viktoria N.|last5=Trivedi|first5=Sumita|last6=Panebianco|first6=Federica|last7=Gandhi|first7=Manoj|last8=Carty|first8=Sally E.|last9=Hodak|first9=Steven P.|date=2014-03-18|title=Identification of the transforming STRN-ALK fusion as a potential therapeutic target in the aggressive forms of thyroid cancer|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3964116/|journal=Proceedings of the National Academy of Sciences of the United States of America|volume=111|issue=11|pages=4233–4238|doi=10.1073/pnas.1321937111|issn=0027-8424|pmc=3964116|pmid=24613930}}</ref><ref>{{Cite journal|last=Ambrosini|first=Margherita|last2=Del Re|first2=Marzia|last3=Manca|first3=Paolo|last4=Hendifar|first4=Andrew|last5=Drilon|first5=Alexander|last6=Harada|first6=Guilherme|last7=Ree|first7=Anne Hansen|last8=Klempner|first8=Samuel|last9=Mælandsmo|first9=Gunhild Mari|date=2022-04|title=ALK Inhibitors in Patients With ALK Fusion-Positive GI Cancers: An International Data Set and a Molecular Case Series|url=https://pubmed.ncbi.nlm.nih.gov/35476549/|journal=JCO precision oncology|volume=6|pages=e2200015|doi=10.1200/PO.22.00015|issn=2473-4284|pmid=35476549}}</ref>, inflammatory myofibroblastic tumor<ref>{{Cite journal|last=Bridge|first=Julia A.|last2=Kanamori|first2=Masahiko|last3=Ma|first3=Zhigui|last4=Pickering|first4=Diane|last5=Hill|first5=D. Ashley|last6=Lydiatt|first6=William|last7=Lui|first7=Man Yee|last8=Colleoni|first8=Gisele W. B.|last9=Antonescu|first9=Cristina R.|date=2001-8|title=Fusion of the ALK Gene to the Clathrin Heavy Chain Gene, CLTC, in Inflammatory Myofibroblastic Tumor|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1850566/|journal=The American Journal of Pathology|volume=159|issue=2|pages=411–415|issn=0002-9440|pmc=1850566|pmid=11485898}}</ref><ref>{{Cite journal|last=Lawrence|first=B.|last2=Perez-Atayde|first2=A.|last3=Hibbard|first3=M. K.|last4=Rubin|first4=B. P.|last5=Dal Cin|first5=P.|last6=Pinkus|first6=J. L.|last7=Pinkus|first7=G. S.|last8=Xiao|first8=S.|last9=Yi|first9=E. S.|date=2000-08|title=TPM3-ALK and TPM4-ALK oncogenes in inflammatory myofibroblastic tumors|url=https://pubmed.ncbi.nlm.nih.gov/10934142/|journal=The American Journal of Pathology|volume=157|issue=2|pages=377–384|doi=10.1016/S0002-9440(10)64550-6|issn=0002-9440|pmc=1850130|pmid=10934142}}</ref><ref>{{Cite journal|last=Ma|first=Zhigui|last2=Hill|first2=D. Ashley|last3=Collins|first3=Margaret H.|last4=Morris|first4=Stephan W.|last5=Sumegi|first5=Janos|last6=Zhou|first6=Ming|last7=Zuppan|first7=Craig|last8=Bridge|first8=Julia A.|date=2003-05|title=Fusion of ALK to the Ran-binding protein 2 (RANBP2) gene in inflammatory myofibroblastic tumor|url=https://pubmed.ncbi.nlm.nih.gov/12661011/|journal=Genes, Chromosomes & Cancer|volume=37|issue=1|pages=98–105|doi=10.1002/gcc.10177|issn=1045-2257|pmid=12661011}}</ref>, non-Hodgkin's lymphoma<ref>{{Cite journal|last=Pan|first=Zenggang|last2=Hu|first2=Shimin|last3=Li|first3=Min|last4=Zhou|first4=Yi|last5=Kim|first5=Young S.|last6=Reddy|first6=Vishnu|last7=Sanmann|first7=Jennifer N.|last8=Smith|first8=Lynette M.|last9=Chen|first9=Mingyi|date=2017-01|title=ALK-positive Large B-cell Lymphoma: A Clinicopathologic Study of 26 Cases With Review of Additional 108 Cases in the Literature|url=https://pubmed.ncbi.nlm.nih.gov/27740969/|journal=The American Journal of Surgical Pathology|volume=41|issue=1|pages=25–38|doi=10.1097/PAS.0000000000000753|issn=1532-0979|pmid=27740969}}</ref><ref>{{Cite journal|last=Laurent|first=Camille|last2=Do|first2=Catherine|last3=Gascoyne|first3=Randy D.|last4=Lamant|first4=Laurence|last5=Ysebaert|first5=Loïc|last6=Laurent|first6=Guy|last7=Delsol|first7=Georges|last8=Brousset|first8=Pierre|date=2009-09-01|title=Anaplastic lymphoma kinase-positive diffuse large B-cell lymphoma: a rare clinicopathologic entity with poor prognosis|url=https://pubmed.ncbi.nlm.nih.gov/19636007/|journal=Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology|volume=27|issue=25|pages=4211–4216|doi=10.1200/JCO.2008.21.5020|issn=1527-7755|pmid=19636007}}</ref><ref>{{Cite journal|last=Sakamoto|first=Kana|last2=Nakasone|first2=Hideki|last3=Togashi|first3=Yuki|last4=Sakata|first4=Seiji|last5=Tsuyama|first5=Naoko|last6=Baba|first6=Satoko|last7=Dobashi|first7=Akito|last8=Asaka|first8=Reimi|last9=Tsai|first9=Chien-Chen|date=2016-04|title=ALK-positive large B-cell lymphoma: identification of EML4-ALK and a review of the literature focusing on the ALK immunohistochemical staining pattern|url=https://pubmed.ncbi.nlm.nih.gov/26781614/|journal=International Journal of Hematology|volume=103|issue=4|pages=399–408|doi=10.1007/s12185-016-1934-1|issn=1865-3774|pmid=26781614}}</ref>, and ALK+ histiocytosis''''' ''<ref>{{Cite journal|last=Takeyasu|first=Yuki|last2=Okuma|first2=Hitomi S.|last3=Kojima|first3=Yuki|last4=Nishikawa|first4=Tadaaki|last5=Tanioka|first5=Maki|last6=Sudo|first6=Kazuki|last7=Shimoi|first7=Tatsunori|last8=Noguchi|first8=Emi|last9=Arakawa|first9=Ayumu|date=2021|title=Impact of ALK Inhibitors in Patients With ALK-Rearranged Nonlung Solid Tumors|url=https://pubmed.ncbi.nlm.nih.gov/34036223/|journal=JCO precision oncology|volume=5|pages=PO.20.00383|doi=10.1200/PO.20.00383|issn=2473-4284|pmc=8140781|pmid=34036223}}</ref><ref>{{Cite journal|last=Chang|first=Kenneth Tou En|last2=Tay|first2=Amos Zhi En|last3=Kuick|first3=Chik Hong|last4=Chen|first4=Huiyi|last5=Algar|first5=Elizabeth|last6=Taubenheim|first6=Nadine|last7=Campbell|first7=Janine|last8=Mechinaud|first8=Francoise|last9=Campbell|first9=Martin|date=2019-05|title=ALK-positive histiocytosis: an expanded clinicopathologic spectrum and frequent presence of KIF5B-ALK fusion|url=https://pubmed.ncbi.nlm.nih.gov/30573850/|journal=Modern Pathology: An Official Journal of the United States and Canadian Academy of Pathology, Inc|volume=32|issue=5|pages=598–608|doi=10.1038/s41379-018-0168-6|issn=1530-0285|pmid=30573850}}</ref><ref>{{Cite journal|last=Chan|first=John K. C.|last2=Lamant|first2=Laurence|last3=Algar|first3=Elizabeth|last4=Delsol|first4=Georges|last5=Tsang|first5=William Y. W.|last6=Lee|first6=King C.|last7=Tiedemann|first7=Karin|last8=Chow|first8=Chung W.|date=2008-10-01|title=ALK+ histiocytosis: a novel type of systemic histiocytic proliferative disorder of early infancy|url=https://pubmed.ncbi.nlm.nih.gov/18660380/|journal=Blood|volume=112|issue=7|pages=2965–2968|doi=10.1182/blood-2008-03-147017|issn=1528-0020|pmid=18660380}}</ref>.''
 [[File:FISH break apart probe for ALK gene .jpg|alt=|none|thumb|640x640px|FISH break apart probe for ''ALK'' gene showing a split signal indicating ''ALK'' rearrangement in a case of ALK(+) ALCL.]]
@@ Line 331: / Line 344: @@
 *As stated above, the diagnosis is based on histology and immunohistochemistry
-*FISH is not required for diagnosis in routine practice <ref>{{Cite journal|last=Falini|first=B.|last2=Bigerna|first2=B.|last3=Fizzotti|first3=M.|last4=Pulford|first4=K.|last5=Pileri|first5=S. A.|last6=Delsol|first6=G.|last7=Carbone|first7=A.|last8=Paulli|first8=M.|last9=Magrini|first9=U.|date=1998-09|title=ALK expression defines a distinct group of T/null lymphomas ("ALK lymphomas") with a wide morphological spectrum|url=https://pubmed.ncbi.nlm.nih.gov/9736036/|journal=The American Journal of Pathology|volume=153|issue=3|pages=875–886|doi=10.1016/S0002-9440(10)65629-5|issn=0002-9440|pmc=1853018|pmid=9736036}}</ref><ref>{{Cite journal|last=Pittaluga|first=S.|last2=Wlodarska|first2=I.|last3=Pulford|first3=K.|last4=Campo|first4=E.|last5=Morris|first5=S. W.|last6=Van den Berghe|first6=H.|last7=De Wolf-Peeters|first7=C.|date=1997-08|title=The monoclonal antibody ALK1 identifies a distinct morphological subtype of anaplastic large cell lymphoma associated with 2p23/ALK rearrangements|url=https://pubmed.ncbi.nlm.nih.gov/9250148/|journal=The American Journal of Pathology|volume=151|issue=2|pages=343–351|issn=0002-9440|pmc=1858018|pmid=9250148}}</ref>
+*FISH is not required for diagnosis in routine practice <ref name=":27">{{Cite journal|last=Falini|first=B.|last2=Bigerna|first2=B.|last3=Fizzotti|first3=M.|last4=Pulford|first4=K.|last5=Pileri|first5=S. A.|last6=Delsol|first6=G.|last7=Carbone|first7=A.|last8=Paulli|first8=M.|last9=Magrini|first9=U.|date=1998-09|title=ALK expression defines a distinct group of T/null lymphomas ("ALK lymphomas") with a wide morphological spectrum|url=https://pubmed.ncbi.nlm.nih.gov/9736036/|journal=The American Journal of Pathology|volume=153|issue=3|pages=875–886|doi=10.1016/S0002-9440(10)65629-5|issn=0002-9440|pmc=1853018|pmid=9736036}}</ref><ref name=":28">{{Cite journal|last=Pittaluga|first=S.|last2=Wlodarska|first2=I.|last3=Pulford|first3=K.|last4=Campo|first4=E.|last5=Morris|first5=S. W.|last6=Van den Berghe|first6=H.|last7=De Wolf-Peeters|first7=C.|date=1997-08|title=The monoclonal antibody ALK1 identifies a distinct morphological subtype of anaplastic large cell lymphoma associated with 2p23/ALK rearrangements|url=https://pubmed.ncbi.nlm.nih.gov/9250148/|journal=The American Journal of Pathology|volume=151|issue=2|pages=343–351|issn=0002-9440|pmc=1858018|pmid=9250148}}</ref>
 Prognosis
@@ Line 339: / Line 352: @@
 *Different ''ALK'' translocation partners do not have prognostic significance
 *Survival is predicted by International Prognostic Index (IPI) with overall long term survival rate approaching 80%
-*Detecting minimal residual disease by PCR for ''[[NPM1-ALK]]'' (not readily commercially available) in bone marrow and peripheral blood during treatment could identify patients at risk of relapse<ref>{{Cite journal|last=C|first=Damm-Welk|last2=L|first2=Mussolin|last3=M|first3=Zimmermann|last4=M|first4=Pillon|last5=W|first5=Klapper|last6=I|first6=Oschlies|last7=Es|first7=d'Amore|last8=A|first8=Reiter|last9=W|first9=Woessmann|date=2014|title=Early assessment of minimal residual disease identifies patients at very high relapse risk in NPM-ALK-positive anaplastic large-cell lymphoma|url=https://pubmed.ncbi.nlm.nih.gov/24297868/|language=en|pmid=24297868}}</ref>
+*Detecting minimal residual disease by PCR for ''[[NPM1-ALK]]'' (not readily commercially available) in bone marrow and peripheral blood during treatment could identify patients at risk of relapse<ref name=":29">{{Cite journal|last=C|first=Damm-Welk|last2=L|first2=Mussolin|last3=M|first3=Zimmermann|last4=M|first4=Pillon|last5=W|first5=Klapper|last6=I|first6=Oschlies|last7=Es|first7=d'Amore|last8=A|first8=Reiter|last9=W|first9=Woessmann|date=2014|title=Early assessment of minimal residual disease identifies patients at very high relapse risk in NPM-ALK-positive anaplastic large-cell lymphoma|url=https://pubmed.ncbi.nlm.nih.gov/24297868/|language=en|pmid=24297868}}</ref>
-*Small-cell or lymphohistiocytic patterns tend to present with disseminated disease and have a less favorable prognosis than the common pattern<ref>{{Cite journal|last=L|first=Lamant|last2=K|first2=McCarthy|last3=E|first3=d'Amore|last4=W|first4=Klapper|last5=A|first5=Nakagawa|last6=M|first6=Fraga|last7=J|first7=Maldyk|last8=I|first8=Simonitsch-Klupp|last9=I|first9=Oschlies|date=2011|title=Prognostic impact of morphologic and phenotypic features of childhood ALK-positive anaplastic large-cell lymphoma: results of the ALCL99 study|url=https://pubmed.ncbi.nlm.nih.gov/22084369/|language=en|pmid=22084369}}</ref>
+*'''''Small-cell or lymphohistiocytic patterns tend to present with disseminated disease and have a less favorable prognosis than the common pattern<ref>{{Cite journal|last=L|first=Lamant|last2=K|first2=McCarthy|last3=E|first3=d'Amore|last4=W|first4=Klapper|last5=A|first5=Nakagawa|last6=M|first6=Fraga|last7=J|first7=Maldyk|last8=I|first8=Simonitsch-Klupp|last9=I|first9=Oschlies|date=2011|title=Prognostic impact of morphologic and phenotypic features of childhood ALK-positive anaplastic large-cell lymphoma: results of the ALCL99 study|url=https://pubmed.ncbi.nlm.nih.gov/22084369/|language=en|pmid=22084369}}</ref>'''''
 *NOTCH1 may be a biomarker for risk of relapse<ref name=":5" />
-Therapy
+'''''Therapy'''''
 *CD30 expression on ALCL (ALK+ or ALK-) allows for targeted therapy<ref name=":2">{{Cite journal|displayauthors=1|last=National Comprehensive Cancer Network|first=|date=January 2021|title=NCCN Clinical Practice Guidelines in Oncology: T-cell lymphomas|url=https://www.nccn.org/professionals/physician_gls/pdf/t-cell.pdf|journal=|volume=|pages=|via=}}</ref>
@@ Line 352: / Line 365: @@
 **#See also gene mutations section above
 **#Engagement of other cell signaling pathways
-*Preclinical models suggest role of:
+*'''''Preclinical models suggest role of:'''''
-**Combination therapy with hypomethylating agents (such as azacitidine) and epigenetic modifying drugs (such as romidepsin, a histone deacetylase inhibitor)<ref>{{Cite journal|last=Rozati|first=Sima|last2=Cheng|first2=Phil F.|last3=Widmer|first3=Daniel S.|last4=Fujii|first4=Kazuyasu|last5=Levesque|first5=Mitchell P.|last6=Dummer|first6=Reinhard|date=2016-04-15|title=Romidepsin and Azacitidine Synergize in their Epigenetic Modulatory Effects to Induce Apoptosis in CTCL|url=https://pubmed.ncbi.nlm.nih.gov/26660520|journal=Clinical Cancer Research: An Official Journal of the American Association for Cancer Research|volume=22|issue=8|pages=2020–2031|doi=10.1158/1078-0432.CCR-15-1435|issn=1557-3265|pmid=26660520}}</ref>
+**'''''Combination therapy with hypomethylating agents (such as azacitidine) and epigenetic modifying drugs (such as romidepsin, a histone deacetylase inhibitor)<ref>{{Cite journal|last=Rozati|first=Sima|last2=Cheng|first2=Phil F.|last3=Widmer|first3=Daniel S.|last4=Fujii|first4=Kazuyasu|last5=Levesque|first5=Mitchell P.|last6=Dummer|first6=Reinhard|date=2016-04-15|title=Romidepsin and Azacitidine Synergize in their Epigenetic Modulatory Effects to Induce Apoptosis in CTCL|url=https://pubmed.ncbi.nlm.nih.gov/26660520|journal=Clinical Cancer Research: An Official Journal of the American Association for Cancer Research|volume=22|issue=8|pages=2020–2031|doi=10.1158/1078-0432.CCR-15-1435|issn=1557-3265|pmid=26660520}}</ref>'''''
-**Inhibitors of HSP90 and mTOR inhibition<ref name=":3" />
+**'''''Inhibitors of HSP90 and mTOR inhibition<ref name=":3" />'''''
-**NOTCH1 inhibition by γ-secretase inhibitors (GSI) in combination with crizotinib may provide synergistic anti-tumor activity, or as a single agent in ALK-inhibitor resistant cell lines<ref name=":5" />
+**'''''NOTCH1 inhibition by γ-secretase inhibitors (GSI) in combination with crizotinib may provide synergistic anti-tumor activity, or as a single agent in ALK-inhibitor resistant cell lines<ref name=":5" />'''''
 </blockquote>
@@ Line 510: / Line 523: @@
 |No
 |Yes
-|
+|May be a biomarker for risk of relapse<ref name=":5" />
 |-
 |TP53<ref name=":4" />
@@ Line 530: / Line 543: @@
 |
 |Yes
-|
+|ALK kinase domain secondary mutations, including L1196 M, G1269A, L1152R, C1156Y, I1171T, F1174 L, G1202R, and S1206Y, have been identified as the key mechanism of resistance
-*ALK kinase domain secondary mutations, including L1196 M, G1269A, L1152R, C1156Y, I1171T, F1174 L, G1202R, and S1206Y, have been identified as the key mechanism of resistance
 *
 |}