Difference between revisions of "HAEM5:Chronic lymphocytic leukaemia/small lymphocytic lymphoma"

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{{DISPLAYTITLE:Chronic lymphocytic leukaemia/small lymphocytic lymphoma}}
 
{{DISPLAYTITLE:Chronic lymphocytic leukaemia/small lymphocytic lymphoma}}
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[[HAEM5:Table_of_Contents|Haematolymphoid Tumours (5th ed.)]]
 
  
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{{Under Construction}}
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[[HAEM5:Table_of_Contents|Haematolymphoid Tumours (WHO Classification, 5th ed.)]]
  
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<blockquote class='blockedit'>{{Box-round|title=HAEM5 Conversion Notes|This page was converted to the new template on 2023-12-07. The original page can be found at [[HAEM4:Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma]].
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==Primary Author(s)*==
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}}</blockquote>
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Jaime Nagy, PhD, University of Iowa
  
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<span style="color:#0070C0">(General Instructions – The main focus of these pages is the clinically significant genetic alterations in each disease type. Use [https://www.genenames.org/ <u>HUGO-approved gene names and symbols</u>] (italicized when appropriate), [https://varnomen.hgvs.org/ HGVS-based nomenclature for variants], as well as generic names of drugs and testing platforms or assays if applicable. Please complete tables whenever possible and do not delete them (add N/A if not applicable in the table and delete the examples). Please do not delete or alter the section headings. The use of bullet points alongside short blocks of text rather than only large paragraphs is encouraged. Additional instructions below in italicized blue text should not be included in the final page content. Please also see </span><u>[[Author_Instructions]]</u><span style="color:#0070C0"> and [[Frequently Asked Questions (FAQs)|<u>FAQs</u>]] as well as contact your [[Leadership|<u>Associate Editor</u>]] or [mailto:CCGA@cancergenomics.org <u>Technical Support</u>])</span>
+
Renee Eigsti, MD, Pathology Services of Kalamazoo
  
−
==Primary Author(s)*==
+
Honey Reddi, PhD, Belay Diagnostics
−
Jamie Nagy, PhD, University of Iowa
 
  
−
Honey Reddi, PhD
 
 
__TOC__
 
__TOC__
  
−
==Cancer Category / Type==
+
==WHO Classification of Disease==
  
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Mature B-cell neoplasms
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{| class="wikitable"
−
 
+
!Structure
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==Cancer Sub-Classification / Subtype==
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!Disease
−
 
+
|-
−
Put your text here
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|Book
 +
|Haematolymphoid Tumours (5th ed.)
 +
|-
 +
|Category
 +
|B-cell lymphoid proliferations and lymphomas
 +
|-
 +
|Family
 +
|Mature B-cell neoplasms
 +
|-
 +
|Type
 +
|Pre-neoplastic and neoplastic small lymphocytic proliferations
 +
|-
 +
|Subtype(s)
 +
|Chronic lymphocytic leukaemia/small lymphocytic lymphoma
 +
|}
  
 
==Definition / Description of Disease==
 
==Definition / Description of Disease==
  
−
This is a distinct entity in the 2016 World Health Organization (WHO) classification system<ref>Campo E, et al., (2017). Chronic lymphocytic leukemia/small lymphocytic lymphoma, in World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues, Revised 4th edition. Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Arber DA, Hasserjian RP, Le Beau MM, Orazi A, and Siebert R, Editors. Revised 4th Edition. IARC Press: Lyon, France, p216-221.</ref>. Chronic Lymphocytic Leukemia (CLL) is a chronic lymphoproliferative disorder characterized by monoclonal B cell proliferation.  
+
This is a distinct entity in the [https://tumourclassification.iarc.who.int/welcome/ 5th edition World Health Organization (WHO) classification system].  It was also a distinct entity in the 2016 WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues revised 4th edition<ref name=":1">Campo E, et al., (2017). Chronic lymphocytic leukemia/small lymphocytic lymphoma, in World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues, Revised 4th edition. Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Arber DA, Hasserjian RP, Le Beau MM, Orazi A, and Siebert R, Editors. Revised 4th Edition. IARC Press: Lyon, France, p216-221.</ref>. Chronic Lymphocytic Leukemia (CLL) is a chronic lymphoproliferative disorder characterized by monoclonal B cell proliferation. CLL is defined by the presence of >5x10<sup>9</sup>/L monoclonal B-cells in the peripheral blood. Cells are small, mature appearing lymphocytes with light chain restriction by flow cytometry. The term small lymphocytic lymphoma (SLL) is used for cases with <5x10<sup>9</sup>/L circulating monoclonal B-cells and documented nodal, splenic, or other extramedullary involvement<ref name=":2">{{Cite journal|last=Hallek|first=Michael|last2=Cheson|first2=Bruce D.|last3=Catovsky|first3=Daniel|last4=Caligaris-Cappio|first4=Federico|last5=Dighiero|first5=Guillaume|last6=Döhner|first6=Hartmut|last7=Hillmen|first7=Peter|last8=Keating|first8=Michael J.|last9=Montserrat|first9=Emili|date=2008-06-15|title=Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute-Working Group 1996 guidelines|url=https://pubmed.ncbi.nlm.nih.gov/18216293|journal=Blood|volume=111|issue=12|pages=5446–5456|doi=10.1182/blood-2007-06-093906|issn=1528-0020|pmc=2972576|pmid=18216293}}</ref>.    
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'''CLL Tables''' - A list of clinically significant and/or recurrent CNAs and CN-LOH with potential or strong diagnostic, prognostic and treatment implications in CLL. Table derived from Chun et al., 2018 [<ref>{{Cite journal|last=K|first=Chun|last2=Gd|first2=Wenger|last3=A|first3=Chaubey|last4=Dp|first4=Dash|last5=R|first5=Kanagal-Shamanna|last6=S|first6=Kantarci|last7=R|first7=Kolhe|last8=Dl|first8=Van Dyke|last9=L|first9=Wang|date=2018|title=Assessing copy number aberrations and copy-neutral loss-of-heterozygosity across the genome as best practice: An evidence-based review from the Cancer Genomics Consortium (CGC) working group for chronic lymphocytic leukemia|url=https://pubmed.ncbi.nlm.nih.gov/30554732/|language=en|pmid=30554732}}</ref>] with permission from Cancer Genetics. See [[CLL Tables: Regions of Recurrent Copy Number Change and CN-LOH]]. 
 
  
 
==Synonyms / Terminology==
 
==Synonyms / Terminology==
−
Chronic lymphocytic leukaemia, B―cell type; chronic lymphoid leukaemia; chronic lymphatic leukaemia
+
Chronic lymphocytic leukemia, B-cell type; chronic lymphoid leukemia; chronic lymphatic leukemia
  
 
==Epidemiology / Prevalence==
 
==Epidemiology / Prevalence==
  
−
It is the most common adult leukemia in Western populations, comprising 25% to 30% of all leukemias in the United States. The median age at diagnosis is 70 years. CLL occurrence is more prevalent in anglo americans and much lower in asian populations<ref name=":0">Taneja A, Master SR. (2017) Cancer, Leukemia, Lymphocytic, Chronic (CLL)  SourceStatPearls [I. Treasure Island (FL): StatPearls Publishing. <nowiki>https://www.ncbi.nlm.nih.gov/books/NBK470433/</nowiki>.</ref>.  
+
CLL is the most common leukemia in the Western world with an annual incidence of approximately 5/100,000, comprising 25% to 30% of all leukemias in the United States. The incidence increases with age with a median age at diagnosis of 70 years. CLL can also present in younger individuals with approximately 10% of cases diagnosed in individuals less than 55 years of age<ref>{{Cite journal|last=Parikh|first=Sameer A.|last2=Rabe|first2=Kari G.|last3=Kay|first3=Neil E.|last4=Call|first4=Timothy G.|last5=Ding|first5=Wei|last6=Schwager|first6=Susan M.|last7=Bowen|first7=Deborah A.|last8=Conte|first8=Michael|last9=Jelinek|first9=Diane F.|date=2014-01|title=Chronic lymphocytic leukemia in young (≤ 55 years) patients: a comprehensive analysis of prognostic factors and outcomes|url=https://pubmed.ncbi.nlm.nih.gov/23911703|journal=Haematologica|volume=99|issue=1|pages=140–147|doi=10.3324/haematol.2013.086066|issn=1592-8721|pmc=4007929|pmid=23911703}}</ref>. CLL occurrence is more prevalent in anglo americans and much lower in asian populations<ref name=":0">Taneja A, Master SR. (2017) Cancer, Leukemia, Lymphocytic, Chronic (CLL)  SourceStatPearls [I. Treasure Island (FL): StatPearls Publishing. <nowiki>https://www.ncbi.nlm.nih.gov/books/NBK470433/</nowiki>.</ref>.  
  
 
==Clinical Features==
 
==Clinical Features==
  
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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>
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Most (90%) patients with CLL are asymptomatic and are diagnosed based on routine blood tests<ref name=":1" />. Only 5-10% of patients with CLL present with symptoms of fever, weight loss, night sweats, and/or fatigue<ref name=":0" />.
 
{| class="wikitable"
 
{| class="wikitable"
 
|'''Signs and Symptoms'''
 
|'''Signs and Symptoms'''
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|EXAMPLE Asymptomatic (incidental finding on complete blood counts)
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|Asymptomatic (incidental finding on complete blood counts)
  
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EXAMPLE B-symptoms (weight loss, fever, night sweats)
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Weight loss, fever, night sweats
  
−
EXAMPLE Fatigue
+
Fatigue
  
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EXAMPLE Lymphadenopathy (uncommon)
+
Lymphadenopathy, splenomegaly (less common)
 
|-
 
|-
 
|'''Laboratory Findings'''
 
|'''Laboratory Findings'''
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|EXAMPLE Cytopenias
+
|absolute lymphocytosis
 +
anemia
  
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EXAMPLE Lymphocytosis (low level)
+
thrombocytopenia
 +
 
 +
paraprotein, usually IgM type (~10% of patients)
 +
hypogammaglobulinemia (~30% of patients at diagnosis)
 
|}
 
|}
  
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<blockquote class='blockedit'>{{Box-round|title=v4:Clinical Features|The content below was from the old template. Please incorporate above.}}
 
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Most (90%) patients with CLL are asymptomatic and only 5-10% of patients with CLL present with symptoms of fever, weight loss, night sweats, and/or fatigue<ref name=":0" />.
 
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−
</blockquote>
 
 
==Sites of Involvement==
 
==Sites of Involvement==
−
CLL/SLL involves the blood, bone marrow, and secondary lymphoid tissues such as the spleen, lymph nodes, and Waldeyer ring. Extranodal involvement
+
CLL/SLL involves the blood, bone marrow, and secondary lymphoid tissues such as the spleen, lymph nodes, and Waldeyer ring. Extranodal involvement (e.g. of the skin, gastrointestinal tract, or CNS) occurs in a small subset of cases<ref>{{Cite journal|last=M|first=Ratterman|last2=K|first2=Kruczek|last3=S|first3=Sulo|last4=Td|first4=Shanafelt|last5=Ne|first5=Kay|last6=C|first6=Nabhan|date=2014|title=Extramedullary chronic lymphocytic leukemia: systematic analysis of cases reported between 1975 and 2012|url=https://pubmed.ncbi.nlm.nih.gov/24064196/|language=en|pmid=24064196}}</ref>.
−
 
 
−
(e.g. of the skin, gastrointestinal tract, or CNS) occurs in a small subset of cases<ref>{{Cite journal|last=M|first=Ratterman|last2=K|first2=Kruczek|last3=S|first3=Sulo|last4=Td|first4=Shanafelt|last5=Ne|first5=Kay|last6=C|first6=Nabhan|date=2014|title=Extramedullary chronic lymphocytic leukemia: systematic analysis of cases reported between 1975 and 2012|url=https://pubmed.ncbi.nlm.nih.gov/24064196/|language=en|pmid=24064196}}</ref>.  
 
  
 
==Morphologic Features==
 
==Morphologic Features==
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'''Lymph Nodes:''' Enlarged lymph nodes show diffuse architectural effacement by a proliferation of small lymphocytes with variably prominent scattered paler proliferation centers (pseudofollicles)<ref>Lennert K, editor. (1978). Malignant lymphomas other than Hodgkin’s disease. NewYork: Springer Verlag.</ref>. The predominant cell in the diffuse areas is a '''''typical CLL cell''''' (small lymphocyte with scant cytoplasm, and clumped chromatin). Proliferation centers are composed of small lymphocytes, prolymphocytes, and paraimmunoblasts. Mitotic activity is usually very low.
 
'''Lymph Nodes:''' Enlarged lymph nodes show diffuse architectural effacement by a proliferation of small lymphocytes with variably prominent scattered paler proliferation centers (pseudofollicles)<ref>Lennert K, editor. (1978). Malignant lymphomas other than Hodgkin’s disease. NewYork: Springer Verlag.</ref>. The predominant cell in the diffuse areas is a '''''typical CLL cell''''' (small lymphocyte with scant cytoplasm, and clumped chromatin). Proliferation centers are composed of small lymphocytes, prolymphocytes, and paraimmunoblasts. Mitotic activity is usually very low.
  
−
'''Bone Marrow:''' Biopsy may show interstitial, nodular, mixed (nodular and interstitial), or diffuse involvement. Diffuse involvement is usually associated with more advanced disease<ref>{{Cite journal|last=E|first=Montserrat|last2=N|first2=Villamor|last3=Jc|first3=Reverter|last4=Rm|first4=Brugués|last5=D|first5=Tàssies|last6=F|first6=Bosch|last7=Jl|first7=Aguilar|last8=Jl|first8=Vives-Corrons|last9=M|first9=Rozman|date=1996|title=Bone marrow assessment in B-cell chronic lymphocytic leukaemia: aspirate or biopsy? A comparative study in 258 patients|url=https://pubmed.ncbi.nlm.nih.gov/8611442/|language=en|pmid=8611442}}</ref>. Paratrabecular aggregates are not typical. Proliferation centers can be observed, although they are not as prominent as in lymph nodes, and follicular dendritic cells may be present<ref>{{Cite journal|last=M|first=Chilosi|last2=G|first2=Pizzolo|last3=F|first3=Caligaris-Cappio|last4=A|first4=Ambrosetti|last5=F|first5=Vinante|last6=L|first6=Morittu|last7=F|first7=Bonetti|last8=L|first8=Fiore-Donati|last9=G|first9=Janossy|date=1985|title=Immunohistochemical demonstration of follicular dendritic cells in bone marrow involvement of B-cell chronic lymphocytic leukemia|url=https://pubmed.ncbi.nlm.nih.gov/3891066/|language=en|pmid=3891066}}</ref>. Most cases have > 30% CLL cells in the bone marrow aspirate<ref>{{Cite journal|last=M|first=Hallek|last2=Bd|first2=Cheson|last3=D|first3=Catovsky|last4=F|first4=Caligaris-Cappio|last5=G|first5=Dighiero|last6=H|first6=Döhner|last7=P|first7=Hillmen|last8=Mj|first8=Keating|last9=E|first9=Montserrat|date=2008|title=Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute-Working Group 1996 guidelines|url=https://pubmed.ncbi.nlm.nih.gov/18216293/|language=en|doi=10.1182/blood-2007-06-093906|pmc=PMC2972576|pmid=18216293}}</ref>.
+
'''Bone Marrow:''' Biopsy may show interstitial, nodular, mixed (nodular and interstitial), or diffuse involvement. Diffuse involvement is usually associated with more advanced disease<ref>{{Cite journal|last=E|first=Montserrat|last2=N|first2=Villamor|last3=Jc|first3=Reverter|last4=Rm|first4=Brugués|last5=D|first5=Tàssies|last6=F|first6=Bosch|last7=Jl|first7=Aguilar|last8=Jl|first8=Vives-Corrons|last9=M|first9=Rozman|date=1996|title=Bone marrow assessment in B-cell chronic lymphocytic leukaemia: aspirate or biopsy? A comparative study in 258 patients|url=https://pubmed.ncbi.nlm.nih.gov/8611442/|language=en|pmid=8611442}}</ref>. Paratrabecular aggregates are not typical. Proliferation centers can be observed, although they are not as prominent as in lymph nodes, and follicular dendritic cells may be present<ref>{{Cite journal|last=M|first=Chilosi|last2=G|first2=Pizzolo|last3=F|first3=Caligaris-Cappio|last4=A|first4=Ambrosetti|last5=F|first5=Vinante|last6=L|first6=Morittu|last7=F|first7=Bonetti|last8=L|first8=Fiore-Donati|last9=G|first9=Janossy|date=1985|title=Immunohistochemical demonstration of follicular dendritic cells in bone marrow involvement of B-cell chronic lymphocytic leukemia|url=https://pubmed.ncbi.nlm.nih.gov/3891066/|language=en|pmid=3891066}}</ref>. Most cases have > 30% CLL cells in the bone marrow aspirate<ref name=":2" />.
  
 
'''Peripheral Blood''': Smudge or basket cells are typically observed. In most cases, besides typical CLL cells, other lymphoid cells like prolymphocytes are also observed, but they usually constitute < 15% of the lymphoid cells.  
 
'''Peripheral Blood''': Smudge or basket cells are typically observed. In most cases, besides typical CLL cells, other lymphoid cells like prolymphocytes are also observed, but they usually constitute < 15% of the lymphoid cells.  
  
 
==Immunophenotype==
 
==Immunophenotype==
−
Circulating leukemic B cells express CD19, low surface IgM/lgD, CD20, CD22, and CD79b. Additionally the markers below may be strongly expressed or absent.
+
CLL cells express CD19, CD20, CD5, CD23, CD43, CD200, and LEF1<ref>{{Cite journal|last=Dorfman|first=David M.|last2=Shahsafaei|first2=Aliakbar|date=2010-11|title=CD200 (OX-2 membrane glycoprotein) expression in b cell-derived neoplasms|url=https://pubmed.ncbi.nlm.nih.gov/20959655|journal=American Journal of Clinical Pathology|volume=134|issue=5|pages=726–733|doi=10.1309/AJCP38XRRUGSQOVC|issn=1943-7722|pmid=20959655}}</ref><ref>{{Cite journal|last=Matutes|first=E.|last2=Owusu-Ankomah|first2=K.|last3=Morilla|first3=R.|last4=Garcia Marco|first4=J.|last5=Houlihan|first5=A.|last6=Que|first6=T. H.|last7=Catovsky|first7=D.|date=1994-10|title=The immunological profile of B-cell disorders and proposal of a scoring system for the diagnosis of CLL|url=https://pubmed.ncbi.nlm.nih.gov/7523797|journal=Leukemia|volume=8|issue=10|pages=1640–1645|issn=0887-6924|pmid=7523797}}</ref>. The levels of surface CD20, surface immunoglobulin and CD79b is low compared to normal B-cells<ref>{{Cite journal|last=Moreau|first=E. J.|last2=Matutes|first2=E.|last3=A'Hern|first3=R. P.|last4=Morilla|first4=A. M.|last5=Morilla|first5=R. M.|last6=Owusu-Ankomah|first6=K. A.|last7=Seon|first7=B. K.|last8=Catovsky|first8=D.|date=1997-10|title=Improvement of the chronic lymphocytic leukemia scoring system with the monoclonal antibody SN8 (CD79b)|url=https://pubmed.ncbi.nlm.nih.gov/9322589|journal=American Journal of Clinical Pathology|volume=108|issue=4|pages=378–382|doi=10.1093/ajcp/108.4.378|issn=0002-9173|pmid=9322589}}</ref>. Cells have kappa or lambda restricted Ig light chain expression.
 
{| class="wikitable sortable"
 
{| class="wikitable sortable"
 
|-
 
|-
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==Chromosomal Rearrangements (Gene Fusions)==
 
==Chromosomal Rearrangements (Gene Fusions)==
  
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Put your text here and fill in the table
+
Approximately 32-42% of CLL patients are found to have a translocation noted on conventional G-banding cytogenetics<ref name=":3">{{Cite journal|last=Baliakas|first=Panagiotis|last2=Iskas|first2=Michalis|last3=Gardiner|first3=Anne|last4=Davis|first4=Zadie|last5=Plevova|first5=Karla|last6=Nguyen-Khac|first6=Florence|last7=Malcikova|first7=Jitka|last8=Anagnostopoulos|first8=Achilles|last9=Glide|first9=Sharron|date=2014-03|title=Chromosomal translocations and karyotype complexity in chronic lymphocytic leukemia: a systematic reappraisal of classic cytogenetic data|url=https://pubmed.ncbi.nlm.nih.gov/24166834|journal=American Journal of Hematology|volume=89|issue=3|pages=249–255|doi=10.1002/ajh.23618|issn=1096-8652|pmid=24166834}}</ref><ref>{{Cite journal|last=Van Den Neste|first=E.|last2=Robin|first2=V.|last3=Francart|first3=J.|last4=Hagemeijer|first4=A.|last5=Stul|first5=M.|last6=Vandenberghe|first6=P.|last7=Delannoy|first7=A.|last8=Sonet|first8=A.|last9=Deneys|first9=V.|date=2007-08|title=Chromosomal translocations independently predict treatment failure, treatment-free survival and overall survival in B-cell chronic lymphocytic leukemia patients treated with cladribine|url=https://pubmed.ncbi.nlm.nih.gov/17541398|journal=Leukemia|volume=21|issue=8|pages=1715–1722|doi=10.1038/sj.leu.2404764|issn=0887-6924|pmid=17541398}}</ref><ref>{{Cite journal|last=Mayr|first=Christine|last2=Speicher|first2=Michael R.|last3=Kofler|first3=David M.|last4=Buhmann|first4=Raymund|last5=Strehl|first5=John|last6=Busch|first6=Raymonde|last7=Hallek|first7=Michael|last8=Wendtner|first8=Clemens-Martin|date=2006-01-15|title=Chromosomal translocations are associated with poor prognosis in chronic lymphocytic leukemia|url=https://pubmed.ncbi.nlm.nih.gov/16179374|journal=Blood|volume=107|issue=2|pages=742–751|doi=10.1182/blood-2005-05-2093|issn=0006-4971|pmid=16179374}}</ref>. Balanced translocations involving ''IGH'' are uncommon (4-9% of patients)<ref>{{Cite journal|last=Cavazzini|first=Francesco|last2=Hernandez|first2=Jose Angel|last3=Gozzetti|first3=Alessandro|last4=Russo Rossi|first4=Antonella|last5=De Angeli|first5=Cristiano|last6=Tiseo|first6=Ruana|last7=Bardi|first7=Antonella|last8=Tammiso|first8=Elisa|last9=Crupi|first9=Rosaria|date=2008-08|title=Chromosome 14q32 translocations involving the immunoglobulin heavy chain locus in chronic lymphocytic leukaemia identify a disease subset with poor prognosis|url=https://pubmed.ncbi.nlm.nih.gov/18547320|journal=British Journal of Haematology|volume=142|issue=4|pages=529–537|doi=10.1111/j.1365-2141.2008.07227.x|issn=1365-2141|pmid=18547320}}</ref>.
  
 
{| class="wikitable sortable"
 
{| class="wikitable sortable"
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!Notes
 
!Notes
 
|-
 
|-
−
|EXAMPLE t(9;22)(q34;q11.2)||EXAMPLE 3'ABL1 / 5'BCR||EXAMPLE der(22)||EXAMPLE 20% (COSMIC)
+
|t(14;19)
−
EXAMPLE 30% (add reference)
+
|''IGH::BCL3''
 +
| ||
 +
|No
 
|Yes
 
|Yes
 +
|No
 +
|Inferior prognosis
 +
|-
 +
|t(14;18)
 +
|''IGH::BCL2''
 +
|
 +
|
 +
|No
 +
|No
 +
|No
 +
|No negative effect on outcome observed<ref>{{Cite journal|last=Put|first=N.|last2=Meeus|first2=P.|last3=Chatelain|first3=B.|last4=Rack|first4=K.|last5=Boeckx|first5=N.|last6=Nollet|first6=F.|last7=Graux|first7=C.|last8=Van Den Neste|first8=E.|last9=Janssens|first9=A.|date=2009-06|title=Translocation t(14;18) is not associated with inferior outcome in chronic lymphocytic leukemia|url=https://pubmed.ncbi.nlm.nih.gov/19295547|journal=Leukemia|volume=23|issue=6|pages=1201–1204|doi=10.1038/leu.2009.44|issn=1476-5551|pmid=19295547}}</ref>
 +
|-
 +
|t(8;14)
 +
|''IGH::MYC''
 +
|
 +
|<1%
 
|No
 
|No
 
|Yes
 
|Yes
−
|EXAMPLE
+
|No
−
 
+
|Prolymphocytes are detected in most of these cases. MYC translocations are associated with an inferior prognosis<ref>{{Cite journal|last=Put|first=Natalie|last2=Van Roosbroeck|first2=Katrien|last3=Konings|first3=Peter|last4=Meeus|first4=Peter|last5=Brusselmans|first5=Caroline|last6=Rack|first6=Katrina|last7=Gervais|first7=Carine|last8=Nguyen-Khac|first8=Florence|last9=Chapiro|first9=Elise|date=2012-06|title=Chronic lymphocytic leukemia and prolymphocytic leukemia with MYC translocations: a subgroup with an aggressive disease course|url=https://pubmed.ncbi.nlm.nih.gov/22205151|journal=Annals of Hematology|volume=91|issue=6|pages=863–873|doi=10.1007/s00277-011-1393-y|issn=1432-0584|pmid=22205151}}</ref><ref>{{Cite journal|last=Huh|first=Yang O.|last2=Lin|first2=Katherine I.-Chun|last3=Vega|first3=Francisco|last4=Schlette|first4=Ellen|last5=Yin|first5=C. Cameron|last6=Keating|first6=Michael J.|last7=Luthra|first7=R.|last8=Medeiros|first8=L. Jeffrey|last9=Abruzzo|first9=Lynne V.|date=2008-07|title=MYC translocation in chronic lymphocytic leukaemia is associated with increased prolymphocytes and a poor prognosis|url=https://pubmed.ncbi.nlm.nih.gov/18477041|journal=British Journal of Haematology|volume=142|issue=1|pages=36–44|doi=10.1111/j.1365-2141.2008.07152.x|issn=1365-2141|pmid=18477041}}</ref>.
−
The t(9;22) is diagnostic of CML in the appropriate morphology and clinical context (add reference). This fusion is responsive to targeted therapy such as Imatinib (Gleevec) (add reference).
+
|}
−
|}
+
==Individual Region Genomic Gain/Loss/LOH==
−
 
−
==Individual Region Genomic Gain / Loss / LOH==
 
  
−
Put your text here and fill in the table <span style="color:#0070C0">(''Instructions: Includes aberrations not involving gene fusions. Can include references in the table. Can refer to CGC workgroup tables as linked on the homepage if applicable.'') </span>
+
*Approximately 80% of CLL patients have a cytogenetic abnormality detectable by fluorescence ''in situ'' hybridization (FISH)
 +
*Deletion of chromosome 13q14 detected by FISH is the most common cytogenetic abnormality in CLL. The deleted region includes two microRNAs, ''miR15A'' and ''miR16-1''<ref name=":4">{{Cite journal|last=Liew|first=Danny|last2=Krum|first2=Henry|date=2002-10|title=The role of aldosterone receptor blockade in the management of cardiovascular disease|url=https://pubmed.ncbi.nlm.nih.gov/12431020|journal=Current Opinion in Investigational Drugs (London, England: 2000)|volume=3|issue=10|pages=1468–1473|issn=1472-4472|pmid=12431020}}</ref>. These microRNAs inhibit the expression of genes involved in apoptosis and cell cycle regulation. Deletion of miR15A and miR16-1 leads to upregulation of BCL2<ref>{{Cite journal|last=Cimmino|first=Amelia|last2=Calin|first2=George Adrian|last3=Fabbri|first3=Muller|last4=Iorio|first4=Marilena V.|last5=Ferracin|first5=Manuela|last6=Shimizu|first6=Masayoshi|last7=Wojcik|first7=Sylwia E.|last8=Aqeilan|first8=Rami I.|last9=Zupo|first9=Simona|date=2005-09-27|title=miR-15 and miR-16 induce apoptosis by targeting BCL2|url=https://pubmed.ncbi.nlm.nih.gov/16166262|journal=Proceedings of the National Academy of Sciences of the United States of America|volume=102|issue=39|pages=13944–13949|doi=10.1073/pnas.0506654102|issn=0027-8424|pmc=1236577|pmid=16166262}}</ref>. Deletion of 13q14 as the sole cytogenetic abnormality is associated with a favorable prognosis. Deletions may be heterozygous or homozygous with a similar prognosis. Individuals with a high percentage of nuclei with 13q deletion (>65%) may have a less favorable prognosis<ref>{{Cite journal|last=Van Dyke|first=Daniel L.|last2=Shanafelt|first2=Tait D.|last3=Call|first3=Timothy G.|last4=Zent|first4=Clive S.|last5=Smoley|first5=Stephanie A.|last6=Rabe|first6=Kari G.|last7=Schwager|first7=Susan M.|last8=Sonbert|first8=Jessica C.|last9=Slager|first9=Susan L.|date=2010-02|title=A comprehensive evaluation of the prognostic significance of 13q deletions in patients with B-chronic lymphocytic leukaemia|url=https://pubmed.ncbi.nlm.nih.gov/19895615|journal=British Journal of Haematology|volume=148|issue=4|pages=544–550|doi=10.1111/j.1365-2141.2009.07982.x|issn=1365-2141|pmc=2866061|pmid=19895615}}</ref>
 +
*Deletion of 17p, which includes ''TP53'', is associated with poor prognosis and resistance to standard chemotherapy regimens<ref name=":5">{{Cite journal|last=Döhner|first=H.|last2=Stilgenbauer|first2=S.|last3=Benner|first3=A.|last4=Leupolt|first4=E.|last5=Kröber|first5=A.|last6=Bullinger|first6=L.|last7=Döhner|first7=K.|last8=Bentz|first8=M.|last9=Lichter|first9=P.|date=2000-12-28|title=Genomic aberrations and survival in chronic lymphocytic leukemia|url=https://pubmed.ncbi.nlm.nih.gov/11136261|journal=The New England Journal of Medicine|volume=343|issue=26|pages=1910–1916|doi=10.1056/NEJM200012283432602|issn=0028-4793|pmid=11136261}}</ref>.
  
 +
'''CLL Tables''' - A list of clinically significant and/or recurrent CNAs and CN-LOH with potential or strong diagnostic, prognostic and treatment implications in CLL. Table derived from Chun et al., 2018 [<ref>{{Cite journal|last=K|first=Chun|last2=Gd|first2=Wenger|last3=A|first3=Chaubey|last4=Dp|first4=Dash|last5=R|first5=Kanagal-Shamanna|last6=S|first6=Kantarci|last7=R|first7=Kolhe|last8=Dl|first8=Van Dyke|last9=L|first9=Wang|date=2018|title=Assessing copy number aberrations and copy-neutral loss-of-heterozygosity across the genome as best practice: An evidence-based review from the Cancer Genomics Consortium (CGC) working group for chronic lymphocytic leukemia|url=https://pubmed.ncbi.nlm.nih.gov/30554732/|language=en|pmid=30554732}}</ref>] with permission from Cancer Genetics. See [[CLL Tables: Regions of Recurrent Copy Number Change and CN-LOH]].
 
{| class="wikitable sortable"
 
{| class="wikitable sortable"
 
|-
 
|-
Line 130: Line 154:
 
!Notes
 
!Notes
 
|-
 
|-
−
|EXAMPLE
+
|13
−
 
+
|Loss
−
7
+
|
−
|EXAMPLE Loss
+
|13q14
−
|EXAMPLE
+
|No
−
 
 
−
chr7:1- 159,335,973 [hg38]
 
−
|EXAMPLE
 
−
 
 
−
chr7
 
−
|Yes
 
 
|Yes
 
|Yes
 
|No
 
|No
−
|EXAMPLE
+
|Most common cytogenetic abnormality. Isolated 13q deletion is associated with favorable prognosis<ref name=":4" />.
−
 
 
−
Presence of monosomy 7 (or 7q deletion) is sufficient for a diagnosis of AML with MDS-related changes when there is ≥20% blasts and no prior therapy (add reference).  Monosomy 7/7q deletion is associated with a poor prognosis in AML (add reference).
 
 
|-
 
|-
−
|EXAMPLE
+
|11
−
 
+
|Loss
−
8
+
|
−
|EXAMPLE Gain
+
|11q22.3
−
|EXAMPLE
 
−
 
 
−
chr8:1-145,138,636 [hg38]
 
−
|EXAMPLE
 
−
 
 
−
chr8
 
 
|No
 
|No
 +
|Yes
 
|No
 
|No
 +
|Deletion of ''ATM''. Associated with a poor prognosis.
 +
|-
 +
|17
 +
|Loss
 +
|
 +
|17p13.1
 
|No
 
|No
−
|EXAMPLE
+
|Yes
−
 
+
|Yes
−
Common recurrent secondary finding for t(8;21) (add reference).
+
|Deletion of ''TP53''. Patients with 17p deletion show resistance to genotoxic chemotherapies. ''TP53'' deletion is associated with a poor prognosis<ref name=":5" />.
 
|}
 
|}
−
 
−
<blockquote class='blockedit'>{{Box-round|title=v4:Genomic Gain/Loss/LOH|The content below was from the old template. Please incorporate above.}}
 
−
 
−
{| class="wikitable sortable"
 
−
|-
 
−
!Chromosome Number!!Gain/Loss/Amp/LOH!!Region
 
−
|-
 
−
|EXAMPLE 8||EXAMPLE Gain||EXAMPLE chr8:0-1000000
 
−
|-
 
−
|EXAMPLE 7||EXAMPLE Loss||EXAMPLE chr7:0-1000000
 
−
|}
 
−
 
−
Put your text here and/or fill in the table
 
−
 
−
'''CLL Tables''' - A list of clinically significant and/or recurrent CNAs and CN-LOH with potential or strong diagnostic, prognostic and treatment implications in CLL.  Table derived from Chun et al., 2018 [<nowiki>PMID 30554732</nowiki>] with permission from Cancer Genetics.  See [[CLL Tables: Regions of Recurrent Copy Number Change and CN-LOH]].
 
−
 
−
</blockquote>
 
 
==Characteristic Chromosomal Patterns==
 
==Characteristic Chromosomal Patterns==
  
−
Put your text here <span style="color:#0070C0">(''EXAMPLE PATTERNS: hyperdiploid; gain of odd number chromosomes including typically chromosome 1, 3, 5, 7, 11, and 17; co-deletion of 1p and 19q; complex karyotypes without characteristic genetic findings; chromothripsis'')</span>
+
Common cytogenetic abnormalities include deletions of 13q, 11q, 6q, and 17p, and trisomy 12. Complex karyotypes (three or more chromosomal abnormalities) are detected in approximately 16% of patients<ref name=":3" /><ref name=":6">{{Cite journal|last=Haferlach|first=C.|last2=Dicker|first2=F.|last3=Schnittger|first3=S.|last4=Kern|first4=W.|last5=Haferlach|first5=T.|date=2007-12|title=Comprehensive genetic characterization of CLL: a study on 506 cases analysed with chromosome banding analysis, interphase FISH, IgV(H) status and immunophenotyping|url=https://pubmed.ncbi.nlm.nih.gov/17805327|journal=Leukemia|volume=21|issue=12|pages=2442–2451|doi=10.1038/sj.leu.2404935|issn=1476-5551|pmid=17805327}}</ref>.
  
 
{| class="wikitable sortable"
 
{| class="wikitable sortable"
Line 193: Line 193:
 
!Notes
 
!Notes
 
|-
 
|-
−
|EXAMPLE
+
|13q14 deletion
−
 
+
|No
−
Co-deletion of 1p and 18q
+
|Yes
 +
|No
 +
|Can also be detected in the homozygous state. Biallelic deletions are often cryptic and not cytogenetically visible<ref>{{Cite journal|last=Migliazza|first=A.|last2=Bosch|first2=F.|last3=Komatsu|first3=H.|last4=Cayanis|first4=E.|last5=Martinotti|first5=S.|last6=Toniato|first6=E.|last7=Guccione|first7=E.|last8=Qu|first8=X.|last9=Chien|first9=M.|date=2001-04-01|title=Nucleotide sequence, transcription map, and mutation analysis of the 13q14 chromosomal region deleted in B-cell chronic lymphocytic leukemia|url=https://pubmed.ncbi.nlm.nih.gov/11264177|journal=Blood|volume=97|issue=7|pages=2098–2104|doi=10.1182/blood.v97.7.2098|issn=0006-4971|pmid=11264177}}</ref>. 13q deletion as the sole abnormality is typically associated with a good prognosis, however, CLL with a high percentage of nuclei with 13q deletion may have a more aggressive clinical course<ref>{{Cite journal|last=Dal Bo|first=Michele|last2=Rossi|first2=Francesca Maria|last3=Rossi|first3=Davide|last4=Deambrogi|first4=Clara|last5=Bertoni|first5=Francesco|last6=Del Giudice|first6=Ilaria|last7=Palumbo|first7=Giuseppe|last8=Nanni|first8=Mauro|last9=Rinaldi|first9=Andrea|date=2011-08|title=13q14 deletion size and number of deleted cells both influence prognosis in chronic lymphocytic leukemia|url=https://pubmed.ncbi.nlm.nih.gov/21563234|journal=Genes, Chromosomes & Cancer|volume=50|issue=8|pages=633–643|doi=10.1002/gcc.20885|issn=1098-2264|pmid=21563234}}</ref>
 +
|-
 +
|11q22.3 deletion
 +
|No
 +
|Yes
 +
|No
 +
|11q deletions are most often seen in patients with advanced CLL and are associated with more rapid disease progression<ref>{{Cite journal|last=Döhner|first=H.|last2=Stilgenbauer|first2=S.|last3=James|first3=M. R.|last4=Benner|first4=A.|last5=Weilguni|first5=T.|last6=Bentz|first6=M.|last7=Fischer|first7=K.|last8=Hunstein|first8=W.|last9=Lichter|first9=P.|date=1997-04-01|title=11q deletions identify a new subset of B-cell chronic lymphocytic leukemia characterized by extensive nodal involvement and inferior prognosis|url=https://pubmed.ncbi.nlm.nih.gov/9116297|journal=Blood|volume=89|issue=7|pages=2516–2522|issn=0006-4971|pmid=9116297}}</ref><ref name=":5" />
 +
|-
 +
|Trisomy 12
 +
|No
 +
|Unknown
 +
|No
 +
|Conflicting evidence on prognostic significance. As a sole abnormality may be associated with low risk. Associated with intermediate risk if ''NOTCH1'' mutation is present<ref name=":8" />
 +
|-
 +
|6q21 deletion
 +
|No
 +
|Yes
 +
|No
 +
|Intermediate risk<ref>{{Cite journal|last=Cuneo|first=A.|last2=Rigolin|first2=G. M.|last3=Bigoni|first3=R.|last4=De Angeli|first4=C.|last5=Veronese|first5=A.|last6=Cavazzini|first6=F.|last7=Bardi|first7=A.|last8=Roberti|first8=M. G.|last9=Tammiso|first9=E.|date=2004-03|title=Chronic lymphocytic leukemia with 6q- shows distinct hematological features and intermediate prognosis|url=https://pubmed.ncbi.nlm.nih.gov/14712287|journal=Leukemia|volume=18|issue=3|pages=476–483|doi=10.1038/sj.leu.2403242|issn=0887-6924|pmid=14712287}}</ref>
 +
|-
 +
|17p13 deletion
 +
|No
 +
|Yes
 
|Yes
 
|Yes
 +
|poor prognosis<ref name=":5" />
 +
|-
 +
|Complex karyotype
 
|No
 
|No
 +
|Yes
 
|No
 
|No
−
|EXAMPLE:
+
|Patients with a complex karyotype have a shortened overall survival and are associated with 11q and/or 17p deletions<ref name=":6" /><ref>{{Cite journal|last=Jaglowski|first=Samantha M.|last2=Ruppert|first2=Amy S.|last3=Heerema|first3=Nyla A.|last4=Bingman|first4=Anissa|last5=Flynn|first5=Joseph M.|last6=Grever|first6=Michael R.|last7=Jones|first7=Jeffrey A.|last8=Elder|first8=Patrick|last9=Devine|first9=Steven M.|date=2012-10|title=Complex karyotype predicts for inferior outcomes following reduced-intensity conditioning allogeneic transplant for chronic lymphocytic leukaemia|url=https://pubmed.ncbi.nlm.nih.gov/22831395|journal=British Journal of Haematology|volume=159|issue=1|pages=82–87|doi=10.1111/j.1365-2141.2012.09239.x|issn=1365-2141|pmc=3719859|pmid=22831395}}</ref>.
−
 
 
−
See chromosomal rearrangements table as this pattern is due to an unbalanced derivative translocation associated with oligodendroglioma (add reference).
 
 
|}
 
|}
−
==Gene Mutations (SNV / INDEL)==
+
==Gene Mutations (SNV/INDEL)==
  
−
Put your text here and fill in the table <span style="color:#0070C0">(''Instructions: This table is not meant to be an exhaustive list; please include only genes/alterations that are recurrent and common as well either disease defining and/or clinically significant. Can include references in the table. For clinical significance, denote associations with FDA-approved therapy (not an extensive list of applicable drugs) and NCCN or other national guidelines if applicable; Can also refer to CGC workgroup tables as linked on the homepage if applicable as well as any high impact papers or reviews of gene mutations in this entity.'') </span>
+
*IGHV genes are mutated in 50-70% of cases and unmutated in 30-50%.
 +
*Unmutated IGHV genes have been shown to have a poorer prognosis, along with ''TP53'', ''BIRC3'', ''NOTCH1'', and ''SF3B1'' mutations.
  
 
{| class="wikitable sortable"
 
{| class="wikitable sortable"
Line 215: Line 242:
 
!Notes
 
!Notes
 
|-
 
|-
−
|EXAMPLE: TP53; Variable LOF mutations
+
|IGHV mutations
−
 
+
|Other (IGVH unmutated B lymphocytes are naïve cells. IGHV mutated B lymphocytes are previously-triggered, postgerminal center “memory" cells)
−
EXAMPLE:
+
|50-70%
−
 
 
−
EGFR; Exon 20 mutations
 
−
 
 
−
EXAMPLE: BRAF; Activating mutations
 
−
|EXAMPLE: TSG
 
−
|EXAMPLE: 20% (COSMIC)
 
−
 
 
−
EXAMPLE: 30% (add Reference)
 
−
|EXAMPLE: IDH1 R123H
 
−
|EXAMPLE: EGFR amplification
 
 
|
 
|
 
|
 
|
−
|
+
|No
−
|EXAMPLE:  Excludes hairy cell leukemia (HCL) (add reference).
+
|Yes
 +
|Yes
 +
|Unmutated IGHV genes have a poor prognosis and respond poorly to continuous multiregimen chemotherapy<ref>{{Cite journal|last=Damle|first=R. N.|last2=Wasil|first2=T.|last3=Fais|first3=F.|last4=Ghiotto|first4=F.|last5=Valetto|first5=A.|last6=Allen|first6=S. L.|last7=Buchbinder|first7=A.|last8=Budman|first8=D.|last9=Dittmar|first9=K.|date=1999-09-15|title=Ig V gene mutation status and CD38 expression as novel prognostic indicators in chronic lymphocytic leukemia|url=https://pubmed.ncbi.nlm.nih.gov/10477712|journal=Blood|volume=94|issue=6|pages=1840–1847|issn=0006-4971|pmid=10477712}}</ref><ref>{{Cite journal|last=Hamblin|first=T. J.|last2=Davis|first2=Z.|last3=Gardiner|first3=A.|last4=Oscier|first4=D. G.|last5=Stevenson|first5=F. K.|date=1999-09-15|title=Unmutated Ig V(H) genes are associated with a more aggressive form of chronic lymphocytic leukemia|url=https://pubmed.ncbi.nlm.nih.gov/10477713|journal=Blood|volume=94|issue=6|pages=1848–1854|issn=0006-4971|pmid=10477713}}</ref>
 
<br />
 
<br />
−
|}
 
−
Note: A more extensive list of mutations can be found in cBioportal (https://www.cbioportal.org/), COSMIC (https://cancer.sanger.ac.uk/cosmic), ICGC (https://dcc.icgc.org/) and/or other databases. When applicable, gene-specific pages within the CCGA site directly link to pertinent external content.
 
−
 
−
 
−
<blockquote class='blockedit'>{{Box-round|title=v4:Gene Mutations (SNV/INDEL)|The content below was from the old template. Please incorporate above.}}
 
−
 
−
Prevalence (COSMIC, May 2018)
 
−
NOTCH1 12%
 
−
SF3B1 12%
 
−
ATM 12%
 
−
TP53 11%
 
−
NFKBIE 4%
 
−
XPO1 4%
 
−
BTK 4%
 
−
MED12 3%
 
−
BIRC3 3%
 
−
MYD88 3%
 
−
LRP1b 3%
 
−
POT1 3%
 
−
BRAF 2%
 
−
FAT1 2%
 
−
 
−
{| class="wikitable sortable"
 
 
|-
 
|-
−
!Gene!!Mutation!!Oncogene/Tumor Suppressor/Other!!Presumed Mechanism (LOF/GOF/Other; Driver/Passenger)!!Prevalence (COSMIC/TCGA/Other)
+
|''NOTCH1''; frameshift, nonsense, and missense mutations
 +
|Other (may be important for follicular differentiation and possible cell fate selection within the follicle)
 +
|5-12.3%
 +
|''FBXW7'' mutation and trisomy 12
 +
|''SF3B1'' mutation
 +
|No
 +
|Yes
 +
|No
 +
|intermediate risk<ref name=":7">{{Cite journal|last=Jeromin|first=S.|last2=Weissmann|first2=S.|last3=Haferlach|first3=C.|last4=Dicker|first4=F.|last5=Bayer|first5=K.|last6=Grossmann|first6=V.|last7=Alpermann|first7=T.|last8=Roller|first8=A.|last9=Kohlmann|first9=A.|date=2014-01|title=SF3B1 mutations correlated to cytogenetics and mutations in NOTCH1, FBXW7, MYD88, XPO1 and TP53 in 1160 untreated CLL patients|url=https://pubmed.ncbi.nlm.nih.gov/24113472|journal=Leukemia|volume=28|issue=1|pages=108–117|doi=10.1038/leu.2013.263|issn=1476-5551|pmid=24113472}}</ref><ref name=":8">{{Cite journal|last=Rossi|first=Davide|last2=Rasi|first2=Silvia|last3=Spina|first3=Valeria|last4=Bruscaggin|first4=Alessio|last5=Monti|first5=Sara|last6=Ciardullo|first6=Carmela|last7=Deambrogi|first7=Clara|last8=Khiabanian|first8=Hossein|last9=Serra|first9=Roberto|date=2013-02-21|title=Integrated mutational and cytogenetic analysis identifies new prognostic subgroups in chronic lymphocytic leukemia|url=https://pubmed.ncbi.nlm.nih.gov/23243274|journal=Blood|volume=121|issue=8|pages=1403–1412|doi=10.1182/blood-2012-09-458265|issn=1528-0020|pmc=3578955|pmid=23243274}}</ref>
 
|-
 
|-
−
|EXAMPLE TP53||EXAMPLE R273H||EXAMPLE Tumor Suppressor||EXAMPLE LOF||EXAMPLE 20%
+
|''SF3B1''; missense (most)
−
|}
+
|Other (part of the spliceosome machinery)
−
+
|9-10%
−
===Other Mutations===
+
|Del(11q)
−
{| class="wikitable sortable"
+
|''NOTCH1'' and ''FBXW7'' mutations
 +
|No
 +
|Yes
 +
|No
 +
|intermediate risk<ref name=":7" /><ref name=":8" />
 
|-
 
|-
−
!Type!!Gene/Region/Other
+
|''TP53''; missense (most)
 +
|Tumor suppressor gene
 +
|7.1%
 +
|
 +
|
 +
|No
 +
|Yes
 +
|No
 +
|High risk<ref name=":7" /><ref name=":8" />
 
|-
 
|-
−
|Concomitant Mutations||EXAMPLE IDH1 R123H
+
|''BIRC3''; frameshift and nonsense
−
|-
+
|Tumor suppressor gene
−
|Secondary Mutations||EXAMPLE Trisomy 7
+
|7.2%
−
|-
+
|
−
|Mutually Exclusive||EXAMPLE EGFR Amplification
+
|
 +
|No
 +
|Yes
 +
|Yes
 +
|High risk and subject to failure of FCR chemoimmunotherapy<ref name=":8" /><ref name=":9">{{Cite journal|last=Diop|first=Fary|last2=Moia|first2=Riccardo|last3=Favini|first3=Chiara|last4=Spaccarotella|first4=Elisa|last5=De Paoli|first5=Lorenzo|last6=Bruscaggin|first6=Alessio|last7=Spina|first7=Valeria|last8=Terzi-di-Bergamo|first8=Lodovico|last9=Arruga|first9=Francesca|date=2020|title=Biological and clinical implications of BIRC3 mutations in chronic lymphocytic leukemia|url=https://pubmed.ncbi.nlm.nih.gov/31371416|journal=Haematologica|volume=105|issue=2|pages=448–456|doi=10.3324/haematol.2019.219550|issn=1592-8721|pmc=7012473|pmid=31371416}}</ref><ref>{{Cite journal|last=Blakemore|first=Stuart J.|last2=Clifford|first2=Ruth|last3=Parker|first3=Helen|last4=Antoniou|first4=Pavlos|last5=Stec-Dziedzic|first5=Ewa|last6=Larrayoz|first6=Marta|last7=Davis|first7=Zadie|last8=Kadalyayil|first8=Latha|last9=Colins|first9=Andrew|date=2020-07|title=Clinical significance of TP53, BIRC3, ATM and MAPK-ERK genes in chronic lymphocytic leukaemia: data from the randomised UK LRF CLL4 trial|url=https://pubmed.ncbi.nlm.nih.gov/32015491|journal=Leukemia|volume=34|issue=7|pages=1760–1774|doi=10.1038/s41375-020-0723-2|issn=1476-5551|pmc=7326706|pmid=32015491}}</ref>
 
|}
 
|}
−
 
+
Note: A more extensive list of mutations can be found in cBioportal (https://www.cbioportal.org/), COSMIC (https://cancer.sanger.ac.uk/cosmic), ICGC (https://dcc.icgc.org/) and/or other databases. When applicable, gene-specific pages within the CCGA site directly link to pertinent external content.
−
</blockquote>
 
 
==Epigenomic Alterations==
 
==Epigenomic Alterations==
−
 
+
Whole genome methylation studies have identified three epigenetic subgroups of CLL<ref name=":10">{{Cite journal|last=Queirós|first=A. C.|last2=Villamor|first2=N.|last3=Clot|first3=G.|last4=Martinez-Trillos|first4=A.|last5=Kulis|first5=M.|last6=Navarro|first6=A.|last7=Penas|first7=E. M. M.|last8=Jayne|first8=S.|last9=Majid|first9=A.|date=2015-03|title=A B-cell epigenetic signature defines three biologic subgroups of chronic lymphocytic leukemia with clinical impact|url=https://pubmed.ncbi.nlm.nih.gov/25151957|journal=Leukemia|volume=29|issue=3|pages=598–605|doi=10.1038/leu.2014.252|issn=1476-5551|pmid=25151957}}</ref>. These subgroups are related to different stages of B-cell maturation and include naïve B-cell like, intermediate, and memory B-cell like CLL. Naïve B-cell like epigenetic subgroup mainly has unmutated IGHV, whereas the memory B-like subgroup mainly have mutated IGHV genes. The intermediate epigenetic subgroup was also found to have mainly mutated IGHV, however, is associated with a worse prognosis than the memory B-like subgroup. The epigenetic classification was found to be an independent prognostic factor for time to first treatment<ref name=":10" /><ref>{{Cite journal|last=Oakes|first=Christopher C.|last2=Seifert|first2=Marc|last3=Assenov|first3=Yassen|last4=Gu|first4=Lei|last5=Przekopowitz|first5=Martina|last6=Ruppert|first6=Amy S.|last7=Wang|first7=Qi|last8=Imbusch|first8=Charles D.|last9=Serva|first9=Andrius|date=2016-03|title=DNA methylation dynamics during B cell maturation underlie a continuum of disease phenotypes in chronic lymphocytic leukemia|url=https://pubmed.ncbi.nlm.nih.gov/26780610|journal=Nature Genetics|volume=48|issue=3|pages=253–264|doi=10.1038/ng.3488|issn=1546-1718|pmc=4963005|pmid=26780610}}</ref>.
−
Put your text here
 
  
 
==Genes and Main Pathways Involved==
 
==Genes and Main Pathways Involved==
−
 
−
Put your text here and fill in the table <span style="color:#0070C0">(''Instructions: Can include references in the table.'')</span>
 
 
{| class="wikitable sortable"
 
{| class="wikitable sortable"
 
|-
 
|-
 
!Gene; Genetic Alteration!!Pathway!!Pathophysiologic Outcome
 
!Gene; Genetic Alteration!!Pathway!!Pathophysiologic Outcome
 
|-
 
|-
−
|EXAMPLE: BRAF and MAP2K1; Activating mutations
+
|''NOTCH1''; PEST domain truncation
−
|EXAMPLE: MAPK signaling
+
|Notch signaling
−
|EXAMPLE: Increased cell growth and proliferation
+
|Abnormally stabilized Notch signaling<ref>{{Cite journal|last=Mesini|first=Nicolò|last2=Fiorcari|first2=Stefania|last3=Atene|first3=Claudio Giacinto|last4=Maffei|first4=Rossana|last5=Potenza|first5=Leonardo|last6=Luppi|first6=Mario|last7=Marasca|first7=Roberto|date=2022|title=Role of Notch2 pathway in mature B cell malignancies|url=https://pubmed.ncbi.nlm.nih.gov/36686759|journal=Frontiers in Oncology|volume=12|pages=1073672|doi=10.3389/fonc.2022.1073672|issn=2234-943X|pmc=9846264|pmid=36686759}}</ref>
 
|-
 
|-
−
|EXAMPLE: CDKN2A; Inactivating mutations
+
|''TP53''; deletion and mutations
−
|EXAMPLE: Cell cycle regulation
+
|DNA damage response
−
|EXAMPLE: Unregulated cell division
+
|Cell proliferation and reduced response to cytotoxic chemotherapy<ref>{{Cite journal|last=Aitken|first=Marisa J. L.|last2=Lee|first2=Hun J.|last3=Post|first3=Sean M.|date=2019|title=Emerging treatment options for patients with p53-pathway-deficient CLL|url=https://pubmed.ncbi.nlm.nih.gov/31839919|journal=Therapeutic Advances in Hematology|volume=10|pages=2040620719891356|doi=10.1177/2040620719891356|issn=2040-6207|pmc=6896129|pmid=31839919}}</ref>
 
|-
 
|-
−
|EXAMPLE:  KMT2C and ARID1A; Inactivating mutations
+
|''BIRC3''; mutations
−
|EXAMPLE:  Histone modification, chromatin remodeling
+
|NF-kB signaling
−
|EXAMPLE:  Abnormal gene expression program
+
|Activation of non-canonical NF-kB signaling<ref name=":9" />
 
|}
 
|}
 
==Genetic Diagnostic Testing Methods==
 
==Genetic Diagnostic Testing Methods==
 +
Cytogenetics (FISH, CpG-stimulated Karyotype, SNP microarray)
  
−
Put your text here
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Immunoglobulin Heavy Chain Variable Region Gene (IGHV) mutation status
  
 
==Familial Forms==
 
==Familial Forms==
−
 
+
Familial predisposition is found in 5-10% of patients with CLL<ref>{{Cite journal|last=Goldin|first=Lynn R.|last2=Pfeiffer|first2=Ruth M.|last3=Li|first3=Xinjun|last4=Hemminki|first4=Kari|date=2004-09-15|title=Familial risk of lymphoproliferative tumors in families of patients with chronic lymphocytic leukemia: results from the Swedish Family-Cancer Database|url=https://pubmed.ncbi.nlm.nih.gov/15161669|journal=Blood|volume=104|issue=6|pages=1850–1854|doi=10.1182/blood-2004-01-0341|issn=0006-4971|pmid=15161669}}</ref>. The overall risk of developing CLL is 2-7 times higher in first-degree relatives of individuals with CLL.
−
Put your text here <span style="color:#0070C0">(''Instructions: Include associated hereditary conditions/syndromes that cause this entity or are caused by this entity.'') </span>
 
  
 
==Additional Information==
 
==Additional Information==
  
−
Put your text here
+
Not Applicable
  
 
==Links==
 
==Links==
  
−
[[HAEM5:Monoclonal B-cell lymphocytosis]]
+
Not Applicable
  
 
==References==
 
==References==
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(use the "Cite" icon at the top of the page) <span style="color:#0070C0">(''Instructions: Add each reference into the text above by clicking on where you want to insert the reference, selecting the “Cite” icon at the top of the page, and using the “Automatic” tab option to search such as by PMID to select the reference to insert. The reference list in this section will be automatically generated and sorted.''</span> <span style="color:#0070C0">''If a PMID is not available, such as for a book, please use the “Cite” icon, select “Manual” and then “Basic Form”, and include the entire reference''</span><span style="color:#0070C0">''.''</span><span style="color:#0070C0">) </span> <references />
+
<references />
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'''
 
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==Notes==
 
==Notes==
 
<nowiki>*</nowiki>Primary authors will typically be those that initially create and complete the content of a page.  If a subsequent user modifies the content and feels the effort put forth is of high enough significance to warrant listing in the authorship section, please contact the CCGA coordinators (contact information provided on the homepage).  Additional global feedback or concerns are also welcome.
 
<nowiki>*</nowiki>Primary authors will typically be those that initially create and complete the content of a page.  If a subsequent user modifies the content and feels the effort put forth is of high enough significance to warrant listing in the authorship section, please contact the CCGA coordinators (contact information provided on the homepage).  Additional global feedback or concerns are also welcome.
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<nowiki>*</nowiki>''Citation of this Page'': “Chronic lymphocytic leukaemia/small lymphocytic lymphoma”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated {{REVISIONMONTH}}/{{REVISIONDAY}}/{{REVISIONYEAR}}, <nowiki>https://ccga.io/index.php/HAEM5:Chronic_lymphocytic_leukaemia/small_lymphocytic_lymphoma</nowiki>.
 
<nowiki>*</nowiki>''Citation of this Page'': “Chronic lymphocytic leukaemia/small lymphocytic lymphoma”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated {{REVISIONMONTH}}/{{REVISIONDAY}}/{{REVISIONYEAR}}, <nowiki>https://ccga.io/index.php/HAEM5:Chronic_lymphocytic_leukaemia/small_lymphocytic_lymphoma</nowiki>.
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[[Category:HAEM5]][[Category:DISEASE]][[Category:Diseases C]]
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[[Category:HAEM5]]
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[[Category:DISEASE]]
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[[Category:Diseases C]]

Latest revision as of 17:27, 6 September 2024


Haematolymphoid Tumours (WHO Classification, 5th ed.)

Primary Author(s)*

Jaime Nagy, PhD, University of Iowa

Renee Eigsti, MD, Pathology Services of Kalamazoo

Honey Reddi, PhD, Belay Diagnostics

WHO Classification of Disease

Structure Disease
Book Haematolymphoid Tumours (5th ed.)
Category B-cell lymphoid proliferations and lymphomas
Family Mature B-cell neoplasms
Type Pre-neoplastic and neoplastic small lymphocytic proliferations
Subtype(s) Chronic lymphocytic leukaemia/small lymphocytic lymphoma

Definition / Description of Disease

This is a distinct entity in the 5th edition World Health Organization (WHO) classification system. It was also a distinct entity in the 2016 WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues revised 4th edition[1]. Chronic Lymphocytic Leukemia (CLL) is a chronic lymphoproliferative disorder characterized by monoclonal B cell proliferation. CLL is defined by the presence of >5x109/L monoclonal B-cells in the peripheral blood. Cells are small, mature appearing lymphocytes with light chain restriction by flow cytometry. The term small lymphocytic lymphoma (SLL) is used for cases with <5x109/L circulating monoclonal B-cells and documented nodal, splenic, or other extramedullary involvement[2].

Synonyms / Terminology

Chronic lymphocytic leukemia, B-cell type; chronic lymphoid leukemia; chronic lymphatic leukemia

Epidemiology / Prevalence

CLL is the most common leukemia in the Western world with an annual incidence of approximately 5/100,000, comprising 25% to 30% of all leukemias in the United States. The incidence increases with age with a median age at diagnosis of 70 years. CLL can also present in younger individuals with approximately 10% of cases diagnosed in individuals less than 55 years of age[3]. CLL occurrence is more prevalent in anglo americans and much lower in asian populations[4].

Clinical Features

Most (90%) patients with CLL are asymptomatic and are diagnosed based on routine blood tests[1]. Only 5-10% of patients with CLL present with symptoms of fever, weight loss, night sweats, and/or fatigue[4].

Signs and Symptoms Asymptomatic (incidental finding on complete blood counts)

Weight loss, fever, night sweats

Fatigue

Lymphadenopathy, splenomegaly (less common)

Laboratory Findings absolute lymphocytosis

anemia

thrombocytopenia

paraprotein, usually IgM type (~10% of patients) hypogammaglobulinemia (~30% of patients at diagnosis)

Sites of Involvement

CLL/SLL involves the blood, bone marrow, and secondary lymphoid tissues such as the spleen, lymph nodes, and Waldeyer ring. Extranodal involvement (e.g. of the skin, gastrointestinal tract, or CNS) occurs in a small subset of cases[5].

Morphologic Features

Lymph Nodes: Enlarged lymph nodes show diffuse architectural effacement by a proliferation of small lymphocytes with variably prominent scattered paler proliferation centers (pseudofollicles)[6]. The predominant cell in the diffuse areas is a typical CLL cell (small lymphocyte with scant cytoplasm, and clumped chromatin). Proliferation centers are composed of small lymphocytes, prolymphocytes, and paraimmunoblasts. Mitotic activity is usually very low.

Bone Marrow: Biopsy may show interstitial, nodular, mixed (nodular and interstitial), or diffuse involvement. Diffuse involvement is usually associated with more advanced disease[7]. Paratrabecular aggregates are not typical. Proliferation centers can be observed, although they are not as prominent as in lymph nodes, and follicular dendritic cells may be present[8]. Most cases have > 30% CLL cells in the bone marrow aspirate[2].

Peripheral Blood: Smudge or basket cells are typically observed. In most cases, besides typical CLL cells, other lymphoid cells like prolymphocytes are also observed, but they usually constitute < 15% of the lymphoid cells.

Immunophenotype

CLL cells express CD19, CD20, CD5, CD23, CD43, CD200, and LEF1[9][10]. The levels of surface CD20, surface immunoglobulin and CD79b is low compared to normal B-cells[11]. Cells have kappa or lambda restricted Ig light chain expression.

Finding Marker
Positive (universal) CD5, CD43 and strongly positive

for CD23 and CD200

Negative (universal) CD10 is negative

FMC7 is usually negative or

only weakly expressed.

Subset CD5― or CD23―, FMC7+,

strong surface immunoglobulin, or

CD79b+[12]

Chromosomal Rearrangements (Gene Fusions)

Approximately 32-42% of CLL patients are found to have a translocation noted on conventional G-banding cytogenetics[13][14][15]. Balanced translocations involving IGH are uncommon (4-9% of patients)[16].

Chromosomal Rearrangement Genes in Fusion (5’ or 3’ Segments) Pathogenic Derivative Prevalence Diagnostic Significance (Yes, No or Unknown) Prognostic Significance (Yes, No or Unknown) Therapeutic Significance (Yes, No or Unknown) Notes
t(14;19) IGH::BCL3 No Yes No Inferior prognosis
t(14;18) IGH::BCL2 No No No No negative effect on outcome observed[17]
t(8;14) IGH::MYC <1% No Yes No Prolymphocytes are detected in most of these cases. MYC translocations are associated with an inferior prognosis[18][19].

Individual Region Genomic Gain/Loss/LOH

  • Approximately 80% of CLL patients have a cytogenetic abnormality detectable by fluorescence in situ hybridization (FISH)
  • Deletion of chromosome 13q14 detected by FISH is the most common cytogenetic abnormality in CLL. The deleted region includes two microRNAs, miR15A and miR16-1[20]. These microRNAs inhibit the expression of genes involved in apoptosis and cell cycle regulation. Deletion of miR15A and miR16-1 leads to upregulation of BCL2[21]. Deletion of 13q14 as the sole cytogenetic abnormality is associated with a favorable prognosis. Deletions may be heterozygous or homozygous with a similar prognosis. Individuals with a high percentage of nuclei with 13q deletion (>65%) may have a less favorable prognosis[22]
  • Deletion of 17p, which includes TP53, is associated with poor prognosis and resistance to standard chemotherapy regimens[23].

CLL Tables - A list of clinically significant and/or recurrent CNAs and CN-LOH with potential or strong diagnostic, prognostic and treatment implications in CLL. Table derived from Chun et al., 2018 [[24]] with permission from Cancer Genetics. See CLL Tables: Regions of Recurrent Copy Number Change and CN-LOH.

Chr # Gain / Loss / Amp / LOH Minimal Region Genomic Coordinates [Genome Build] Minimal Region Cytoband Diagnostic Significance (Yes, No or Unknown) Prognostic Significance (Yes, No or Unknown) Therapeutic Significance (Yes, No or Unknown) Notes
13 Loss 13q14 No Yes No Most common cytogenetic abnormality. Isolated 13q deletion is associated with favorable prognosis[20].
11 Loss 11q22.3 No Yes No Deletion of ATM. Associated with a poor prognosis.
17 Loss 17p13.1 No Yes Yes Deletion of TP53. Patients with 17p deletion show resistance to genotoxic chemotherapies. TP53 deletion is associated with a poor prognosis[23].

Characteristic Chromosomal Patterns

Common cytogenetic abnormalities include deletions of 13q, 11q, 6q, and 17p, and trisomy 12. Complex karyotypes (three or more chromosomal abnormalities) are detected in approximately 16% of patients[13][25].

Chromosomal Pattern Diagnostic Significance (Yes, No or Unknown) Prognostic Significance (Yes, No or Unknown) Therapeutic Significance (Yes, No or Unknown) Notes
13q14 deletion No Yes No Can also be detected in the homozygous state. Biallelic deletions are often cryptic and not cytogenetically visible[26]. 13q deletion as the sole abnormality is typically associated with a good prognosis, however, CLL with a high percentage of nuclei with 13q deletion may have a more aggressive clinical course[27]
11q22.3 deletion No Yes No 11q deletions are most often seen in patients with advanced CLL and are associated with more rapid disease progression[28][23]
Trisomy 12 No Unknown No Conflicting evidence on prognostic significance. As a sole abnormality may be associated with low risk. Associated with intermediate risk if NOTCH1 mutation is present[29]
6q21 deletion No Yes No Intermediate risk[30]
17p13 deletion No Yes Yes poor prognosis[23]
Complex karyotype No Yes No Patients with a complex karyotype have a shortened overall survival and are associated with 11q and/or 17p deletions[25][31].

Gene Mutations (SNV/INDEL)

  • IGHV genes are mutated in 50-70% of cases and unmutated in 30-50%.
  • Unmutated IGHV genes have been shown to have a poorer prognosis, along with TP53, BIRC3, NOTCH1, and SF3B1 mutations.
Gene; Genetic Alteration Presumed Mechanism (Tumor Suppressor Gene [TSG] / Oncogene / Other) Prevalence (COSMIC / TCGA / Other) Concomitant Mutations Mutually Exclusive Mutations Diagnostic Significance (Yes, No or Unknown) Prognostic Significance (Yes, No or Unknown) Therapeutic Significance (Yes, No or Unknown) Notes
IGHV mutations Other (IGVH unmutated B lymphocytes are naïve cells. IGHV mutated B lymphocytes are previously-triggered, postgerminal center “memory" cells) 50-70% No Yes Yes Unmutated IGHV genes have a poor prognosis and respond poorly to continuous multiregimen chemotherapy[32][33]


NOTCH1; frameshift, nonsense, and missense mutations Other (may be important for follicular differentiation and possible cell fate selection within the follicle) 5-12.3% FBXW7 mutation and trisomy 12 SF3B1 mutation No Yes No intermediate risk[34][29]
SF3B1; missense (most) Other (part of the spliceosome machinery) 9-10% Del(11q) NOTCH1 and FBXW7 mutations No Yes No intermediate risk[34][29]
TP53; missense (most) Tumor suppressor gene 7.1% No Yes No High risk[34][29]
BIRC3; frameshift and nonsense Tumor suppressor gene 7.2% No Yes Yes High risk and subject to failure of FCR chemoimmunotherapy[29][35][36]

Note: A more extensive list of mutations can be found in cBioportal (https://www.cbioportal.org/), COSMIC (https://cancer.sanger.ac.uk/cosmic), ICGC (https://dcc.icgc.org/) and/or other databases. When applicable, gene-specific pages within the CCGA site directly link to pertinent external content.

Epigenomic Alterations

Whole genome methylation studies have identified three epigenetic subgroups of CLL[37]. These subgroups are related to different stages of B-cell maturation and include naïve B-cell like, intermediate, and memory B-cell like CLL. Naïve B-cell like epigenetic subgroup mainly has unmutated IGHV, whereas the memory B-like subgroup mainly have mutated IGHV genes. The intermediate epigenetic subgroup was also found to have mainly mutated IGHV, however, is associated with a worse prognosis than the memory B-like subgroup. The epigenetic classification was found to be an independent prognostic factor for time to first treatment[37][38].

Genes and Main Pathways Involved

Gene; Genetic Alteration Pathway Pathophysiologic Outcome
NOTCH1; PEST domain truncation Notch signaling Abnormally stabilized Notch signaling[39]
TP53; deletion and mutations DNA damage response Cell proliferation and reduced response to cytotoxic chemotherapy[40]
BIRC3; mutations NF-kB signaling Activation of non-canonical NF-kB signaling[35]

Genetic Diagnostic Testing Methods

Cytogenetics (FISH, CpG-stimulated Karyotype, SNP microarray)

Immunoglobulin Heavy Chain Variable Region Gene (IGHV) mutation status

Familial Forms

Familial predisposition is found in 5-10% of patients with CLL[41]. The overall risk of developing CLL is 2-7 times higher in first-degree relatives of individuals with CLL.

Additional Information

Not Applicable

Links

Not Applicable

References

  1. ↑ 1.0 1.1 Campo E, et al., (2017). Chronic lymphocytic leukemia/small lymphocytic lymphoma, in World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues, Revised 4th edition. Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Arber DA, Hasserjian RP, Le Beau MM, Orazi A, and Siebert R, Editors. Revised 4th Edition. IARC Press: Lyon, France, p216-221.
  2. ↑ 2.0 2.1 Hallek, Michael; et al. (2008-06-15). "Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute-Working Group 1996 guidelines". Blood. 111 (12): 5446–5456. doi:10.1182/blood-2007-06-093906. ISSN 1528-0020. PMC 2972576. PMID 18216293.
  3. ↑ Parikh, Sameer A.; et al. (2014-01). "Chronic lymphocytic leukemia in young (≤ 55 years) patients: a comprehensive analysis of prognostic factors and outcomes". Haematologica. 99 (1): 140–147. doi:10.3324/haematol.2013.086066. ISSN 1592-8721. PMC 4007929. PMID 23911703. Check date values in: |date= (help)
  4. ↑ 4.0 4.1 Taneja A, Master SR. (2017) Cancer, Leukemia, Lymphocytic, Chronic (CLL) SourceStatPearls [I. Treasure Island (FL): StatPearls Publishing. https://www.ncbi.nlm.nih.gov/books/NBK470433/.
  5. ↑ M, Ratterman; et al. (2014). "Extramedullary chronic lymphocytic leukemia: systematic analysis of cases reported between 1975 and 2012". PMID 24064196.
  6. ↑ Lennert K, editor. (1978). Malignant lymphomas other than Hodgkin’s disease. NewYork: Springer Verlag.
  7. ↑ E, Montserrat; et al. (1996). "Bone marrow assessment in B-cell chronic lymphocytic leukaemia: aspirate or biopsy? A comparative study in 258 patients". PMID 8611442.
  8. ↑ M, Chilosi; et al. (1985). "Immunohistochemical demonstration of follicular dendritic cells in bone marrow involvement of B-cell chronic lymphocytic leukemia". PMID 3891066.
  9. ↑ Dorfman, David M.; et al. (2010-11). "CD200 (OX-2 membrane glycoprotein) expression in b cell-derived neoplasms". American Journal of Clinical Pathology. 134 (5): 726–733. doi:10.1309/AJCP38XRRUGSQOVC. ISSN 1943-7722. PMID 20959655. Check date values in: |date= (help)
  10. ↑ Matutes, E.; et al. (1994-10). "The immunological profile of B-cell disorders and proposal of a scoring system for the diagnosis of CLL". Leukemia. 8 (10): 1640–1645. ISSN 0887-6924. PMID 7523797. Check date values in: |date= (help)
  11. ↑ Moreau, E. J.; et al. (1997-10). "Improvement of the chronic lymphocytic leukemia scoring system with the monoclonal antibody SN8 (CD79b)". American Journal of Clinical Pathology. 108 (4): 378–382. doi:10.1093/ajcp/108.4.378. ISSN 0002-9173. PMID 9322589. Check date values in: |date= (help)
  12. ↑ A, Criel; et al. (1999). "The concept of typical and atypical chronic lymphocytic leukaemia". PMID 10194119.
  13. ↑ 13.0 13.1 Baliakas, Panagiotis; et al. (2014-03). "Chromosomal translocations and karyotype complexity in chronic lymphocytic leukemia: a systematic reappraisal of classic cytogenetic data". American Journal of Hematology. 89 (3): 249–255. doi:10.1002/ajh.23618. ISSN 1096-8652. PMID 24166834. Check date values in: |date= (help)
  14. ↑ Van Den Neste, E.; et al. (2007-08). "Chromosomal translocations independently predict treatment failure, treatment-free survival and overall survival in B-cell chronic lymphocytic leukemia patients treated with cladribine". Leukemia. 21 (8): 1715–1722. doi:10.1038/sj.leu.2404764. ISSN 0887-6924. PMID 17541398. Check date values in: |date= (help)
  15. ↑ Mayr, Christine; et al. (2006-01-15). "Chromosomal translocations are associated with poor prognosis in chronic lymphocytic leukemia". Blood. 107 (2): 742–751. doi:10.1182/blood-2005-05-2093. ISSN 0006-4971. PMID 16179374.
  16. ↑ Cavazzini, Francesco; et al. (2008-08). "Chromosome 14q32 translocations involving the immunoglobulin heavy chain locus in chronic lymphocytic leukaemia identify a disease subset with poor prognosis". British Journal of Haematology. 142 (4): 529–537. doi:10.1111/j.1365-2141.2008.07227.x. ISSN 1365-2141. PMID 18547320. Check date values in: |date= (help)
  17. ↑ Put, N.; et al. (2009-06). "Translocation t(14;18) is not associated with inferior outcome in chronic lymphocytic leukemia". Leukemia. 23 (6): 1201–1204. doi:10.1038/leu.2009.44. ISSN 1476-5551. PMID 19295547. Check date values in: |date= (help)
  18. ↑ Put, Natalie; et al. (2012-06). "Chronic lymphocytic leukemia and prolymphocytic leukemia with MYC translocations: a subgroup with an aggressive disease course". Annals of Hematology. 91 (6): 863–873. doi:10.1007/s00277-011-1393-y. ISSN 1432-0584. PMID 22205151. Check date values in: |date= (help)
  19. ↑ Huh, Yang O.; et al. (2008-07). "MYC translocation in chronic lymphocytic leukaemia is associated with increased prolymphocytes and a poor prognosis". British Journal of Haematology. 142 (1): 36–44. doi:10.1111/j.1365-2141.2008.07152.x. ISSN 1365-2141. PMID 18477041. Check date values in: |date= (help)
  20. ↑ 20.0 20.1 Liew, Danny; et al. (2002-10). "The role of aldosterone receptor blockade in the management of cardiovascular disease". Current Opinion in Investigational Drugs (London, England: 2000). 3 (10): 1468–1473. ISSN 1472-4472. PMID 12431020. Check date values in: |date= (help)
  21. ↑ Cimmino, Amelia; et al. (2005-09-27). "miR-15 and miR-16 induce apoptosis by targeting BCL2". Proceedings of the National Academy of Sciences of the United States of America. 102 (39): 13944–13949. doi:10.1073/pnas.0506654102. ISSN 0027-8424. PMC 1236577. PMID 16166262.
  22. ↑ Van Dyke, Daniel L.; et al. (2010-02). "A comprehensive evaluation of the prognostic significance of 13q deletions in patients with B-chronic lymphocytic leukaemia". British Journal of Haematology. 148 (4): 544–550. doi:10.1111/j.1365-2141.2009.07982.x. ISSN 1365-2141. PMC 2866061. PMID 19895615. Check date values in: |date= (help)
  23. ↑ 23.0 23.1 23.2 23.3 Döhner, H.; et al. (2000-12-28). "Genomic aberrations and survival in chronic lymphocytic leukemia". The New England Journal of Medicine. 343 (26): 1910–1916. doi:10.1056/NEJM200012283432602. ISSN 0028-4793. PMID 11136261.
  24. ↑ K, Chun; et al. (2018). "Assessing copy number aberrations and copy-neutral loss-of-heterozygosity across the genome as best practice: An evidence-based review from the Cancer Genomics Consortium (CGC) working group for chronic lymphocytic leukemia". PMID 30554732.
  25. ↑ 25.0 25.1 Haferlach, C.; et al. (2007-12). "Comprehensive genetic characterization of CLL: a study on 506 cases analysed with chromosome banding analysis, interphase FISH, IgV(H) status and immunophenotyping". Leukemia. 21 (12): 2442–2451. doi:10.1038/sj.leu.2404935. ISSN 1476-5551. PMID 17805327. Check date values in: |date= (help)
  26. ↑ Migliazza, A.; et al. (2001-04-01). "Nucleotide sequence, transcription map, and mutation analysis of the 13q14 chromosomal region deleted in B-cell chronic lymphocytic leukemia". Blood. 97 (7): 2098–2104. doi:10.1182/blood.v97.7.2098. ISSN 0006-4971. PMID 11264177.
  27. ↑ Dal Bo, Michele; et al. (2011-08). "13q14 deletion size and number of deleted cells both influence prognosis in chronic lymphocytic leukemia". Genes, Chromosomes & Cancer. 50 (8): 633–643. doi:10.1002/gcc.20885. ISSN 1098-2264. PMID 21563234. Check date values in: |date= (help)
  28. ↑ Döhner, H.; et al. (1997-04-01). "11q deletions identify a new subset of B-cell chronic lymphocytic leukemia characterized by extensive nodal involvement and inferior prognosis". Blood. 89 (7): 2516–2522. ISSN 0006-4971. PMID 9116297.
  29. ↑ 29.0 29.1 29.2 29.3 29.4 Rossi, Davide; et al. (2013-02-21). "Integrated mutational and cytogenetic analysis identifies new prognostic subgroups in chronic lymphocytic leukemia". Blood. 121 (8): 1403–1412. doi:10.1182/blood-2012-09-458265. ISSN 1528-0020. PMC 3578955. PMID 23243274.
  30. ↑ Cuneo, A.; et al. (2004-03). "Chronic lymphocytic leukemia with 6q- shows distinct hematological features and intermediate prognosis". Leukemia. 18 (3): 476–483. doi:10.1038/sj.leu.2403242. ISSN 0887-6924. PMID 14712287. Check date values in: |date= (help)
  31. ↑ Jaglowski, Samantha M.; et al. (2012-10). "Complex karyotype predicts for inferior outcomes following reduced-intensity conditioning allogeneic transplant for chronic lymphocytic leukaemia". British Journal of Haematology. 159 (1): 82–87. doi:10.1111/j.1365-2141.2012.09239.x. ISSN 1365-2141. PMC 3719859. PMID 22831395. Check date values in: |date= (help)
  32. ↑ Damle, R. N.; et al. (1999-09-15). "Ig V gene mutation status and CD38 expression as novel prognostic indicators in chronic lymphocytic leukemia". Blood. 94 (6): 1840–1847. ISSN 0006-4971. PMID 10477712.
  33. ↑ Hamblin, T. J.; et al. (1999-09-15). "Unmutated Ig V(H) genes are associated with a more aggressive form of chronic lymphocytic leukemia". Blood. 94 (6): 1848–1854. ISSN 0006-4971. PMID 10477713.
  34. ↑ 34.0 34.1 34.2 Jeromin, S.; et al. (2014-01). "SF3B1 mutations correlated to cytogenetics and mutations in NOTCH1, FBXW7, MYD88, XPO1 and TP53 in 1160 untreated CLL patients". Leukemia. 28 (1): 108–117. doi:10.1038/leu.2013.263. ISSN 1476-5551. PMID 24113472. Check date values in: |date= (help)
  35. ↑ 35.0 35.1 Diop, Fary; et al. (2020). "Biological and clinical implications of BIRC3 mutations in chronic lymphocytic leukemia". Haematologica. 105 (2): 448–456. doi:10.3324/haematol.2019.219550. ISSN 1592-8721. PMC 7012473 Check |pmc= value (help). PMID 31371416.
  36. ↑ Blakemore, Stuart J.; et al. (2020-07). "Clinical significance of TP53, BIRC3, ATM and MAPK-ERK genes in chronic lymphocytic leukaemia: data from the randomised UK LRF CLL4 trial". Leukemia. 34 (7): 1760–1774. doi:10.1038/s41375-020-0723-2. ISSN 1476-5551. PMC 7326706 Check |pmc= value (help). PMID 32015491 Check |pmid= value (help). Check date values in: |date= (help)
  37. ↑ 37.0 37.1 Queirós, A. C.; et al. (2015-03). "A B-cell epigenetic signature defines three biologic subgroups of chronic lymphocytic leukemia with clinical impact". Leukemia. 29 (3): 598–605. doi:10.1038/leu.2014.252. ISSN 1476-5551. PMID 25151957. Check date values in: |date= (help)
  38. ↑ Oakes, Christopher C.; et al. (2016-03). "DNA methylation dynamics during B cell maturation underlie a continuum of disease phenotypes in chronic lymphocytic leukemia". Nature Genetics. 48 (3): 253–264. doi:10.1038/ng.3488. ISSN 1546-1718. PMC 4963005. PMID 26780610. Check date values in: |date= (help)
  39. ↑ Mesini, Nicolò; et al. (2022). "Role of Notch2 pathway in mature B cell malignancies". Frontiers in Oncology. 12: 1073672. doi:10.3389/fonc.2022.1073672. ISSN 2234-943X. PMC 9846264 Check |pmc= value (help). PMID 36686759 Check |pmid= value (help).
  40. ↑ Aitken, Marisa J. L.; et al. (2019). "Emerging treatment options for patients with p53-pathway-deficient CLL". Therapeutic Advances in Hematology. 10: 2040620719891356. doi:10.1177/2040620719891356. ISSN 2040-6207. PMC 6896129. PMID 31839919.
  41. ↑ Goldin, Lynn R.; et al. (2004-09-15). "Familial risk of lymphoproliferative tumors in families of patients with chronic lymphocytic leukemia: results from the Swedish Family-Cancer Database". Blood. 104 (6): 1850–1854. doi:10.1182/blood-2004-01-0341. ISSN 0006-4971. PMID 15161669.

Notes

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