HAEM5:B-lymphoblastic leukaemia/lymphoma with hypodiploidy: Difference between revisions

No recurrent gene rearrangements have been described<ref name=":13">WHO Classification of Tumours: Haematolymphoid Tumours [Internet; Beta Version Ahead of Print](5th ed.), International Agency for Research on Cancer (2022)</ref>.

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B-lymphoblastic leukemia/lymphoma (B-ALL/LBL) is the most common cause of cancer in pediatric patients. It is characterized by recurrent genetic abnormalities of chromosome number, deletions, duplications and translocations. Hypodiploidy, a neoplasm of lymphoblasts containing less than 46 chromosomes<ref name=":13" />. Hypodiploid ALL has poor prognosis and near haploid with worst prognosis<ref name=":13" /><ref name=":2" /><ref name=":3">{{Cite journal|last=Nachman|first=James B.|last2=Heerema|first2=Nyla A.|last3=Sather|first3=Harland|last4=Camitta|first4=Bruce|last5=Forestier|first5=Erik|last6=Harrison|first6=Christine J.|last7=Dastugue|first7=Nicole|last8=Schrappe|first8=Martin|last9=Pui|first9=Ching-Hon|date=2007|title=Outcome of treatment in children with hypodiploid acute lymphoblastic leukemia|url=https://www.ncbi.nlm.nih.gov/pubmed/17473063|journal=Blood|volume=110|issue=4|pages=1112–1115|doi=10.1182/blood-2006-07-038299|issn=0006-4971|pmc=1939895|pmid=17473063}}</ref>.

Please refer to section "Characteristic Chromosomal or Other Global Mutational Patterns" below.

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This entity is defined by the presence of neoplastic lymphoblasts containing less than 46 chromosomes<ref name=":0">Borowitz MJ, et al., (2017). B-Lymphoblastic leukaemia/lymphoma with recurrent genetic abnormalities, 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. IARC Press: Lyon, France, p206.</ref>, and can be subdivided into near-haploid B-ALL/LBL with hypodiploidy (24–31 chromosomes); low-hypodiploid B-ALL/LBL with hypodiploidy (32–39 chromosomes); and high-hypodiploid B-ALL/LBL with hypodiploidy (40–43 chromosomes)<ref name=":13" />.

|Near-haploid B-ALL/LBL with hypodiploidy (24–31 chromosomes)

|The chromosomal loss alone may be enough for leukemogenesis and the unconserved random chromosomes may contain specific genes that increase the oncogenic potential of leukemic cells<ref>{{Cite journal|last=Harrison|first=Christine J.|last2=Moorman|first2=Anthony V.|last3=Barber|first3=Kerry E.|last4=Broadfield|first4=Zoë J.|last5=Cheung|first5=Kan L.|last6=Harris|first6=Rachel L.|last7=Jalali|first7=G. Reza|last8=Robinson|first8=Hazel M.|last9=Strefford|first9=Jonathan C.|date=2005-05|title=Interphase molecular cytogenetic screening for chromosomal abnormalities of prognostic significance in childhood acute lymphoblastic leukaemia: a UK Cancer Cytogenetics Group Study|url=https://pubmed.ncbi.nlm.nih.gov/15877734|journal=British Journal of Haematology|volume=129|issue=4|pages=520–530|doi=10.1111/j.1365-2141.2005.05497.x|issn=0007-1048|pmid=15877734}}</ref><ref>{{Cite journal|last=Raimondi|first=Susana C.|last2=Zhou|first2=Yinmei|last3=Mathew|first3=Susan|last4=Shurtleff|first4=Sheila A.|last5=Sandlund|first5=John T.|last6=Rivera|first6=Gaston K.|last7=Behm|first7=Frederick G.|last8=Pui|first8=Ching-Hon|date=2003-12-15|title=Reassessment of the prognostic significance of hypodiploidy in pediatric patients with acute lymphoblastic leukemia|url=https://pubmed.ncbi.nlm.nih.gov/14669294|journal=Cancer|volume=98|issue=12|pages=2715–2722|doi=10.1002/cncr.11841|issn=0008-543X|pmid=14669294}}</ref>.

|Rare (0.5%)<ref name=":8" />

|D: Needs demonstration of hypodiploidy (≤ 43 chromosomes) by karyotyping and/or FISH analysis; flow cytometry DNA index analysis and/or SNP array analysis to identify masked hypodiploidy.

P: Associated with poor prognosis. 5-year EFS 25–40%<ref name=":8">{{Cite journal|last=Panuciak|first=Kinga|last2=Nowicka|first2=Emilia|last3=Mastalerczyk|first3=Angelika|last4=Zawitkowska|first4=Joanna|last5=Niedźwiecki|first5=Maciej|last6=Lejman|first6=Monika|date=2023-05-15|title=Overview on Aneuploidy in Childhood B-Cell Acute Lymphoblastic Leukemia|url=https://pubmed.ncbi.nlm.nih.gov/37240110|journal=International Journal of Molecular Sciences|volume=24|issue=10|pages=8764|doi=10.3390/ijms24108764|issn=1422-0067|pmc=10218510|pmid=37240110}}</ref>.

 

|No (NCCN)

|It has been observed in the pediatric population with virtually no adult cases reported. Nonrandom retention of the X chromosome plus chromosomes 8, 14, 18, and 21 are frequently observed. The most common targets of aneuploidy are chromosomes 1–7, 9, 11–13, 15–17, 19–20 and 22<ref name=":2" /><ref>{{Cite journal|last=Creasey|first=Thomas|last2=Enshaei|first2=Amir|last3=Nebral|first3=Karin|last4=Schwab|first4=Claire|last5=Watts|first5=Kathryn|last6=Cuthbert|first6=Gavin|last7=Vora|first7=Ajay|last8=Moppett|first8=John|last9=Harrison|first9=Christine J.|date=2021-09|title=Single nucleotide polymorphism array-based signature of low hypodiploidy in acute lymphoblastic leukemia|url=https://pubmed.ncbi.nlm.nih.gov/33938069|journal=Genes, Chromosomes & Cancer|volume=60|issue=9|pages=604–615|doi=10.1002/gcc.22956|issn=1098-2264|pmc=8600946|pmid=33938069}}</ref><ref name=":11">{{Cite journal|last=Harrison|first=Christine J.|last2=Moorman|first2=Anthony V.|last3=Broadfield|first3=Zoë J.|last4=Cheung|first4=Kan L.|last5=Harris|first5=Rachel L.|last6=Reza Jalali|first6=G.|last7=Robinson|first7=Hazel M.|last8=Barber|first8=Kerry E.|last9=Richards|first9=Sue M.|date=2004-06|title=Three distinct subgroups of hypodiploidy in acute lymphoblastic leukaemia|url=https://pubmed.ncbi.nlm.nih.gov/15147369|journal=British Journal of Haematology|volume=125|issue=5|pages=552–559|doi=10.1111/j.1365-2141.2004.04948.x|issn=0007-1048|pmid=15147369}}</ref><ref name=":6" /><ref name=":7">{{Cite journal|last=Holmfeldt|first=Linda|last2=Wei|first2=Lei|last3=Diaz-Flores|first3=Ernesto|last4=Walsh|first4=Michael|last5=Zhang|first5=Jinghui|last6=Ding|first6=Li|last7=Payne-Turner|first7=Debbie|last8=Churchman|first8=Michelle|last9=Andersson|first9=Anna|date=2013-03|title=The genomic landscape of hypodiploid acute lymphoblastic leukemia|url=https://pubmed.ncbi.nlm.nih.gov/23334668|journal=Nature Genetics|volume=45|issue=3|pages=242–252|doi=10.1038/ng.2532|issn=1546-1718|pmc=3919793|pmid=23334668}}</ref>.

Near-haploid and low-hypodiploid B-ALL/LBL may undergo doubling, resulting in a pseudohyperdiploid or near-triploid clone containing up to 78 chromosomes. If the original hypodiploid clone is not present, the hypodiploidy is regarded as masked, and the case may be mistaken for high-hyperdiploid B-ALL/LBL, resulting in an inappropriate prognostication<ref>{{Cite journal|last=Carroll|first=Andrew J.|last2=Shago|first2=Mary|last3=Mikhail|first3=Fady M.|last4=Raimondi|first4=Susana C.|last5=Hirsch|first5=Betsy A.|last6=Loh|first6=Mignon L.|last7=Raetz|first7=Elizabeth A.|last8=Borowitz|first8=Michael J.|last9=Wood|first9=Brent L.|date=2019-10|title=Masked hypodiploidy: Hypodiploid acute lymphoblastic leukemia (ALL) mimicking hyperdiploid ALL in children: A report from the Children's Oncology Group|url=https://pubmed.ncbi.nlm.nih.gov/31425927|journal=Cancer Genetics|volume=238|pages=62–68|doi=10.1016/j.cancergen.2019.07.009|issn=2210-7762|pmc=6768693|pmid=31425927}}</ref><ref>{{Cite journal|last=Creasey|first=Thomas|last2=Enshaei|first2=Amir|last3=Nebral|first3=Karin|last4=Schwab|first4=Claire|last5=Watts|first5=Kathryn|last6=Cuthbert|first6=Gavin|last7=Vora|first7=Ajay|last8=Moppett|first8=John|last9=Harrison|first9=Christine J.|date=2021-09|title=Single nucleotide polymorphism array-based signature of low hypodiploidy in acute lymphoblastic leukemia|url=https://pubmed.ncbi.nlm.nih.gov/33938069|journal=Genes, Chromosomes & Cancer|volume=60|issue=9|pages=604–615|doi=10.1002/gcc.22956|issn=1098-2264|pmc=8600946|pmid=33938069}}</ref>. The two subtypes may be differentiated by SNP array analysis, demonstrating copy-neutral loss of heterozygosity for doubled monosomic chromosomes. The DNA index assessed by flow cytometry may also be helpful if distinct peaks representing the hypodiploid and doubled clones are both detectable<ref>{{Cite journal|last=Yu|first=Chih-Hsiang|last2=Lin|first2=Tze-Kang|last3=Jou|first3=Shiann-Tarng|last4=Lin|first4=Chien-Yu|last5=Lin|first5=Kai-Hsin|last6=Lu|first6=Meng-Yao|last7=Chen|first7=Shu-Huey|last8=Cheng|first8=Chao-Neng|last9=Wu|first9=Kang-Hsi|date=2020-07-13|title=MLPA and DNA index improve the molecular diagnosis of childhood B-cell acute lymphoblastic leukemia|url=https://pubmed.ncbi.nlm.nih.gov/32661308|journal=Scientific Reports|volume=10|issue=1|pages=11501|doi=10.1038/s41598-020-68311-9|issn=2045-2322|pmc=7359332|pmid=32661308}}</ref>.

|Low-hypodiploid B-ALL/LBL with hypodiploidy (32–39 chromosomes)

|More than 90% of low-hypodiploid patients have been identified with ''TP53'' mutations, which occur in virtually all low-hypodiploid B-ALL cases due to the very recurrent loss of chromosome 17<ref name=":6" /><ref name=":9" /><ref name=":10">{{Cite journal|last=Stengel|first=Anna|last2=Schnittger|first2=Susanne|last3=Weissmann|first3=Sandra|last4=Kuznia|first4=Sabrina|last5=Kern|first5=Wolfgang|last6=Kohlmann|first6=Alexander|last7=Haferlach|first7=Torsten|last8=Haferlach|first8=Claudia|date=2014-07-10|title=TP53 mutations occur in 15.7% of ALL and are associated with MYC-rearrangement, low hypodiploidy, and a poor prognosis|url=https://pubmed.ncbi.nlm.nih.gov/24829203|journal=Blood|volume=124|issue=2|pages=251–258|doi=10.1182/blood-2014-02-558833|issn=1528-0020|pmid=24829203}}</ref>. p53 is one of the most prominent tumor suppressors. Its activation as a transcription factor stimulates downstream pathways leading to protective cellular processes, including cell-cycle arrest, apoptosis, and senescence, to prevent the propagation of genetically altered cells<ref>{{Cite journal|last=Vogelstein|first=B.|last2=Lane|first2=D.|last3=Levine|first3=A. J.|date=2000-11-16|title=Surfing the p53 network|url=https://pubmed.ncbi.nlm.nih.gov/11099028|journal=Nature|volume=408|issue=6810|pages=307–310|doi=10.1038/35042675|issn=0028-0836|pmid=11099028}}</ref>.

|Rare in children, recurrent in adolescents, young adults, and adults

|P: Associated with poor prognosis. EFS 30–50%<ref name=":8" />.

|No (NCCN)

|Low-hypodiploid B-ALL/LBL is rare in children (< 1%); however, the frequency increases with age, accounting for 5% of B-ALL/LBL cases in adolescents and young adults, and > 10% of cases in adults. Nonrandom retention of two copies of chromosomes from the following: the sex chromosomes plus chromosomes 1,6, 8, 10, 14, 18, and19.  Chromosome 21 is almost always retained in two copies.

The most common targets of aneuploidy are chromosomes 2–4, 7, 9, 12–13, 15–17 and 20<ref name=":7" />.

|High-hypodiploid B-ALL/LBL with hypodiploidy (40–43 chromosomes)

|Genetic alterations involve ''CDKN2A'' and ''TP53''<ref name=":9" />.

|Rare, occurring in approximately 4% of diagnosed cases of hypodiploidy in both children and adults, but with a predominance of the younger group<ref name=":11" /><ref name=":12" />.

|P: Associated with poor prognosis. EFS 75%<ref>{{Cite journal|last=Pui|first=Ching-Hon|last2=Rebora|first2=Paola|last3=Schrappe|first3=Martin|last4=Attarbaschi|first4=Andishe|last5=Baruchel|first5=Andre|last6=Basso|first6=Giuseppe|last7=Cavé|first7=Hélène|last8=Elitzur|first8=Sarah|last9=Koh|first9=Katsuyoshi|date=2019-04-01|title=Outcome of Children With Hypodiploid Acute Lymphoblastic Leukemia: A Retrospective Multinational Study|url=https://pubmed.ncbi.nlm.nih.gov/30657737|journal=Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology|volume=37|issue=10|pages=770–779|doi=10.1200/JCO.18.00822|issn=1527-7755|pmc=7051863|pmid=30657737}}</ref>.

|No (NCCN)

|Chromosome abnormalities include whole chromosome loss, specifically one sex chromosome and often chromosomes 7, 9, and/or 13.  Also detected are structural anomalies especially dicentric chromosomes involving chromosomes 7, 9 or 12.

'''Note: A slight variation in the range of chromosome number has been reported in the literature in the classification of NH, LH, HH and NH'''<ref name=":0" /><ref name=":1">{{Cite journal|last=Terwilliger|first=T.|last2=Abdul-Hay|first2=M.|date=2017|title=Acute lymphoblastic leukemia: a comprehensive review and 2017 update|url=https://www.ncbi.nlm.nih.gov/pubmed/28665419|journal=Blood Cancer Journal|volume=7|issue=6|pages=e577|doi=10.1038/bcj.2017.53|issn=2044-5385|pmc=5520400|pmid=28665419}}</ref><ref name=":2" /><ref name=":5" /><ref name=":3" /><ref>{{Cite journal|last=Safavi|first=Setareh|last2=Paulsson|first2=Kajsa|date=2017|title=Near-haploid and low-hypodiploid acute lymphoblastic leukemia: two distinct subtypes with consistently poor prognosis|url=https://www.ncbi.nlm.nih.gov/pubmed/27903530|journal=Blood|volume=129|issue=4|pages=420–423|doi=10.1182/blood-2016-10-743765|issn=1528-0020|pmid=27903530}}</ref><ref>{{Cite journal|last=Mehta|first=Parinda 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|''TP53''<br />

|The majority are missense mutations located in exon 7, exon 8, exon 6, and exon 5. Less frequent frameshift mutations in exon 4 and 7 have been described<ref name=":6" />. In general are predicted to be loss of function (LOF) mutations.

|Tumor Supressor Gene

|Common (>90%)

|No established significance

|Approximately 50% of children with low-hypodiploid B-ALL/LBL carry germline ''TP53'' variants associated with Li–Fraumeni syndrome, an autosomal dominant disorder caused by ''TP53'' mutations. These alterations correlate with low-hypodiploid ALL (32–39 chromosomes) and poorer clinical outcomes<ref name=":2" />.

|''RB1''

|Tumor Supressor Gene

|Associated with low-hypodiploid B-ALL.

|''IKZF2''

|No

|Associated with near-haploid B-ALL.

|''NF1, NRAS, KRAS, MAPK1, FLT3 or PTPN11''; Activating mutations<ref name=":2" />

|RTK or Ras signaling

|Constitutive activation of mitogenic and anti-apoptotic pathways, driving uncontrolled cell proliferation, survival, and malignant transformation

Karyotype, flow cytometry DNA index, FISH, and SNP arrays are all useful in establishing the diagnosis.

In Low hypodiploid (LH), several studies have not only identified a high percentage of pediatric patients with ''TP53'' mutations, but close to half displayed germline mutations, suggesting that LH ALL is a manifestation of Li-Fraumeni syndrome in children<ref name=":2" /><ref name=":10" /><ref>{{Cite journal|last=Comeaux|first=Evan Q.|last2=Mullighan|first2=Charles G.|date=2017-03-01|title=TP53 Mutations in Hypodiploid Acute Lymphoblastic Leukemia|url=https://pubmed.ncbi.nlm.nih.gov/28003275|journal=Cold Spring Harbor Perspectives in Medicine|volume=7|issue=3|pages=a026286|doi=10.1101/cshperspect.a026286|issn=2157-1422|pmc=5334249|pmid=28003275}}</ref>.  

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