Changes

{{DISPLAYTITLE:Chronic lymphocytic leukaemia/small lymphocytic lymphoma}}

{{DISPLAYTITLE:Chronic lymphocytic leukaemia/small lymphocytic lymphoma}}

[[HAEM5:Table_of_Contents|Haematolymphoid Tumours (5th ed.)]]

[[HAEM5:Table_of_Contents|Haematolymphoid Tumours (5th ed.)]]

 

Honey Reddi, PhD, Belay Diagnostics

Jamie Nagy, PhD, University of Iowa

__TOC__

__TOC__

==Cancer Category / Type==

==Cancer Category/Type==

Mature B-cell neoplasms

Mature B-cell neoplasms

==Cancer Sub-Classification / Subtype==

==Cancer Sub-Classification / Subtype==

==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 >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<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>.    

 

'''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==

Put your text here and fill in the table <span style="color:#0070C0">(''Instruction: Can include references in the table'') </span>

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'''

|EXAMPLE Asymptomatic (incidental finding on complete blood counts)

|Asymptomatic (incidental finding on complete blood counts)

EXAMPLE B-symptoms (weight loss, fever, night sweats)

Weight loss, fever, night sweats

EXAMPLE Fatigue

Fatigue

EXAMPLE Lymphadenopathy (uncommon)

Lymphadenopathy, splenomegaly (less common)

|-

|-

|'''Laboratory Findings'''

|'''Laboratory Findings'''

|EXAMPLE Cytopenias

|absolute lymphocytosis

EXAMPLE Lymphocytosis (low level)

 

paraprotein, usually IgM type (~10% of patients)

hypogammaglobulinemia (~30% of patients at diagnosis)

|}

|}

==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==

'''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"

|-

|-

==Chromosomal Rearrangements (Gene Fusions)==

==Chromosomal Rearrangements (Gene Fusions)==

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"

!Notes

!Notes

|-

|-

|EXAMPLE t(9;22)(q34;q11.2)||EXAMPLE 3'ABL1 / 5'BCR||EXAMPLE der(22)||EXAMPLE 20% (COSMIC)

|t(14;19)

|''IGH::BCL3''

| ||

|No

|Yes

|Yes

|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>.

{| class="wikitable sortable"

{| class="wikitable sortable"

|-

|-

!Notes

!Notes

|-

|-

|EXAMPLE

|13

 

|Loss

|

|EXAMPLE Loss

|13q14

|EXAMPLE

|No

 

|EXAMPLE

 

|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

|

|EXAMPLE Gain

|11q22.3

|EXAMPLE

 

|EXAMPLE

 

|No

|No

|No

|No

|No

|No

|EXAMPLE

|Yes

 

|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

|}

|}

==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"

!Notes

!Notes

|-

|-

|EXAMPLE

|13q14 deletion

 

Co-deletion of 1p and 18q

|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>

|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" />

|Yes

|Yes

|No

|No

|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"

!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)

|50-70%

 

 

EXAMPLE: BRAF; Activating mutations

|EXAMPLE: TSG

|EXAMPLE: 20% (COSMIC)

 

EXAMPLE: 30% (add Reference)

|

|

|

|

|

|No

|EXAMPLE:  Excludes hairy cell leukemia (HCL) (add reference).

|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 />

|-

|-

!Gene!!Mutation!!Oncogene/Tumor Suppressor/Other!!Presumed Mechanism (LOF/GOF/Other; Driver/Passenger)!!Prevalence (COSMIC/TCGA/Other)

|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

|High risk<ref name=":7" /><ref name=":8" />

|-

|-

|Concomitant Mutations||EXAMPLE IDH1 R123H

|''BIRC3''; frameshift and nonsense

|-

|Secondary Mutations||EXAMPLE Trisomy 7

|-

|

|Mutually Exclusive||EXAMPLE EGFR Amplification

|

|No

|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==

 

==Genes and Main Pathways Involved==

==Genes and Main Pathways Involved==

{| 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==

==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==

==Links==

==Links==

==References==

==References==

(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 />

 

 

==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.

<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>.

[[Category:HAEM5]][[Category:DISEASE]][[Category:Diseases C]]

[[Category:HAEM5]]

[[Category:DISEASE]]

[[Category:Diseases C]]