View source for HAEM4Backup:Pure Erythroid Leukemia

==Primary Author(s)*==

Ashwini Yenamandra PhD FACMG

__TOC__

==Cancer Category/Type==

[[AML|Acute Myeloid Leukemia]]

==Cancer Sub-Classification / Subtype==

Pure Erythroid Leukemia (PEL) is now the only type of Acute Erythroid Leukemia (AEL).

==Definition / Description of Disease==

In the 2008 WHO classification, Acute Erythroid leukemia (AEL) was classified into two subtypes: Erythroleukemia (erythroid/myeloid) and Pure Erythroid Leukemia (PEL). However, in the 2016 WHO update, Erythroleukemia was merged into myelodysplastic syndrome, while PEL is now the only type of AEL<ref name=":0">Arber DA, et al., (2008). World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues, 4th edition. Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Vardiman JW, Editors. IARC Press: Lyon, France, p135-136.</ref><ref name=":1">{{Cite journal|last=Qiu|first=Shaowei|last2=Jiang|first2=Erlie|last3=Wei|first3=Hui|last4=Lin|first4=Dong|last5=Zhang|first5=Guangji|last6=Wei|first6=Shuning|last7=Zhou|first7=Chunlin|last8=Liu|first8=Kaiqi|last9=Wang|first9=Ying|date=2017|title=An analysis of 97 previously diagnosed de novo adult acute erythroid leukemia patients following the 2016 revision to World Health Organization classification|url=https://www.ncbi.nlm.nih.gov/pubmed/28793875|journal=BMC cancer|volume=17|issue=1|pages=534|doi=10.1186/s12885-017-3528-6|issn=1471-2407|pmc=5550989|pmid=28793875}}</ref><ref name=":2">{{Cite journal|last=Zuo|first=Zhuang|last2=Polski|first2=Jacek M.|last3=Kasyan|first3=Armen|last4=Medeiros|first4=L. Jeffrey|date=2010|title=Acute erythroid leukemia|url=https://www.ncbi.nlm.nih.gov/pubmed/20807044|journal=Archives of Pathology & Laboratory Medicine|volume=134|issue=9|pages=1261–1270|doi=10.1043/2009-0350-RA.1|issn=1543-2165|pmid=20807044}}</ref><ref name=":3">{{Cite journal|last=Arber|first=Daniel A.|last2=Orazi|first2=Attilio|last3=Hasserjian|first3=Robert|last4=Thiele|first4=Jürgen|last5=Borowitz|first5=Michael J.|last6=Le Beau|first6=Michelle M.|last7=Bloomfield|first7=Clara D.|last8=Cazzola|first8=Mario|last9=Vardiman|first9=James W.|date=2016|title=The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia|url=https://www.ncbi.nlm.nih.gov/pubmed/27069254|journal=Blood|volume=127|issue=20|pages=2391–2405|doi=10.1182/blood-2016-03-643544|issn=1528-0020|pmid=27069254}}</ref><ref name=":4">{{Cite journal|last=Zuo|first=Zhuang|last2=Medeiros|first2=L. Jeffrey|last3=Chen|first3=Zhao|last4=Liu|first4=Dingsheng|last5=Bueso-Ramos|first5=Carlos E.|last6=Luthra|first6=Rajyalakshmi|last7=Wang|first7=Sa A.|date=2012|title=Acute myeloid leukemia (AML) with erythroid predominance exhibits clinical and molecular characteristics that differ from other types of AML|url=https://www.ncbi.nlm.nih.gov/pubmed/22844482|journal=PloS One|volume=7|issue=7|pages=e41485|doi=10.1371/journal.pone.0041485|issn=1932-6203|pmc=3402404|pmid=22844482}}</ref><ref name=":5">{{Cite journal|last=Grossmann|first=V.|last2=Bacher|first2=U.|last3=Haferlach|first3=C.|last4=Schnittger|first4=S.|last5=Pötzinger|first5=F.|last6=Weissmann|first6=S.|last7=Roller|first7=A.|last8=Eder|first8=C.|last9=Fasan|first9=A.|date=2013|title=Acute erythroid leukemia (AEL) can be separated into distinct prognostic subsets based on cytogenetic and molecular genetic characteristics|url=https://www.ncbi.nlm.nih.gov/pubmed/23648669|journal=Leukemia|volume=27|issue=9|pages=1940–1943|doi=10.1038/leu.2013.144|issn=1476-5551|pmid=23648669}}</ref><ref name=":6">{{Cite journal|last=Porwit|first=Anna|last2=Vardiman|first2=James W.|date=2011|title=Acute myeloid leukemia with expanded erythropoiesis|url=https://www.ncbi.nlm.nih.gov/pubmed/21880638|journal=Haematologica|volume=96|issue=9|pages=1241–1243|doi=10.3324/haematol.2011.050526|issn=1592-8721|pmc=3166090|pmid=21880638}}</ref><ref name=":7">{{Cite journal|last=Hasserjian|first=Robert P.|last2=Zuo|first2=Zhuang|last3=Garcia|first3=Christine|last4=Tang|first4=Guilin|last5=Kasyan|first5=Armen|last6=Luthra|first6=Rajyalakshmi|last7=Abruzzo|first7=Lynne V.|last8=Kantarjian|first8=Hagop M.|last9=Medeiros|first9=L. Jeffrey|date=2010|title=Acute erythroid leukemia: a reassessment using criteria refined in the 2008 WHO classification|url=https://www.ncbi.nlm.nih.gov/pubmed/20040759|journal=Blood|volume=115|issue=10|pages=1985–1992|doi=10.1182/blood-2009-09-243964|issn=1528-0020|pmc=2942006|pmid=20040759}}</ref><ref name=":8">{{Cite journal|last=Wang|first=Sa A.|last2=Hasserjian|first2=Robert P.|date=2015|title=Acute Erythroleukemias, Acute Megakaryoblastic Leukemias, and Reactive Mimics: A Guide to a Number of Perplexing Entities|url=https://www.ncbi.nlm.nih.gov/pubmed/26071461|journal=American Journal of Clinical Pathology|volume=144|issue=1|pages=44–60|doi=10.1309/AJCPRKYAT6EZQHC7|issn=1943-7722|pmid=26071461}}</ref><ref name=":9">{{Cite journal|last=Wang|first=Wei|last2=Wang|first2=Sa A.|last3=Medeiros|first3=L. Jeffrey|last4=Khoury|first4=Joseph D.|date=2017|title=Pure erythroid leukemia|url=https://www.ncbi.nlm.nih.gov/pubmed/28006859|journal=American Journal of Hematology|volume=92|issue=3|pages=292–296|doi=10.1002/ajh.24626|issn=1096-8652|pmid=28006859}}</ref><ref name=":10">{{Cite journal|last=A|first=Yenamandra|date=2016|title=Acute Erythroblastic Leukemia (AEL): A Rare Subset of De Novo AML with A Complex Rearrangement Involving ETV6 Locus and Loss of RB1 Locus|url=https://medcraveonline.com/ICPJL/acute-erythroblastic-leukemia-ael-a-rare-subset-of-de-novo-aml-with-a-complex-rearrangement-involving-etv6-locus-and-loss-of-rb1-locus.html|journal=International Clinical Pathology Journal|volume=2|issue=2|doi=10.15406/icpjl.2016.02.00032}}</ref><ref name=":11">{{Cite journal|last=Fs|first=Khan|date=2017|title=Pure Erythroid Leukemia: The Sole Acute Erythroid Leukemia|url=https://www.heighpubs.org/hbmr/ijbmr-aid1001.php|journal=International Journal of Bone Marrow Research|volume=1|issue=1|pages=001–005|doi=10.29328/journal.ijbmr.1001001}}</ref>. PEL is a distinct entity in the World Health Organization (WHO) classification system within the section of [[Acute Myeloid Leukemia (AML), Not Otherwise Specified]].  PEL is a rare form of acute leukemia with an aggressive clinical course and is characterized by an uncontrolled proliferation of immature erythroid precursors (proerythroblastic or undifferentiated)<ref name=":0" /><ref name=":1" /><ref name=":2" /><ref name=":3" /><ref name=":4" /><ref name=":5" /><ref name=":6" /><ref name=":7" /><ref name=":8" /><ref name=":9" /><ref name=":10" /><ref name=":11" />.

==Synonyms / Terminology==

Also known as AML-M6b and Di Guglielmo syndrome due to the recognition of the work of Di Guglielmo<ref name=":0" /><ref name=":1" />.

==Epidemiology / Prevalence==

PEL is extremely rare with a small number of reported cases, accounting for 3-5% of AML cases<ref name=":0" /><ref name=":1" /><ref name=":9" />. Median survival is usually three months<ref name=":11" />.

==Clinical Features==

PEL has an aggressive clinical course with neoplastic proliferation of immature erythroid precursor (proerythroblastic or undifferentiated) cells. Average survival rate is three months<ref name=":0" /><ref name=":9" />. PEL is characterized by neoplastic proliferation composed of >80% immature erythroid precursors of which proerythroblasts constitute ≥30%<ref name=":11" />. Clinical features include profound anemia, circulating erythroblasts, pancytopenia, extensive bone marrow involvement, fatigue, infections, weight loss, fever, night sweats, hemoglobin level under 10.0 g/dL, and thrombocytopenia<ref name=":0" /><ref name=":9" />.
==Sites of Involvement==

Bone marrow, Blood

==Morphologic Features==

PEL is characterized by medium to large erythroblasts with round nuclei, fine chromatin and one or more nucleoli (proerythroblast). Cytoplasm is deeply basophilic, often granular with demarcated vacuoles and are often Periodic-Acid-Schiff stain (PAS) positive. Blasts can be small and may resemble lymphoblasts<ref name=":0" />. Cells are usually negative for Myeloperoxidase (MPO) and Sudan Black (SBB).  Bone marrow biopsy may have undifferentiated cells<ref name=":0" />.

==Immunophenotype==

Differentiated PEL may express Glycophorin and hemoglobin A, absence of myeloperoxidase (MPO) and other myeloid markers<ref name=":0" />.  Blasts are negative for HLA-Dr and CD34 but positive for CD117<ref name=":0" />. Immature forms can be negative for Glycophorin or weekly expressed. Positive for Carbonic anhydrase 1, Gero antobody against the Gerbich blood group or CD36 especially at earlier stages of differentiation. CD41 and CD61 are negative<ref name=":0" /><ref name=":11" />. 

{| class="wikitable sortable"
|-
!Finding!!Marker
|-
|Positive (universal)||Hemoglobin A, Glycophorin A, Spectrin, ABH blood group antigens, and HLA-DR
|-
|Positive (subset)||CD13, CD33, CD34, CD117 (KIT), and MPO, Gerbich blood group (Gero) antibody, carbonic anhydrase 1, and CD36, CD41 and CD61
|-
|Negative (universal)||Myeloid-associated markers such as MPO,CD13,CD33,CD61, B and T Cell markers -CD10, CD19, CD79a, CD2, CD3, CD5,  monocytic markers CD11c CD14
Megakaryoblastic markers: CD61, Others: CD34, anti-kappa, anti-lambda, CD45

|-
|Negative (subset)||HLA-DR, CD34, Glycophorin A
|}

==Chromosomal Rearrangements (Gene Fusions)==

The genetic abnormalities that have been identified in PEL are similar to that of AML and MDS and consists of complex chromosomal abnormalities including -5/del(5q), -7/del(7q), +8 and/or RUNX1 and TP53 mutations<ref name=":0" />. Rearrangement of NFIA-CBFA2T3 with t(1;16)(p31;q24) and MYND8-RELA with t(11;20)(p11;q11) have been reported in rare cases<ref name=":9" />. A complex karyotype with 46,XY,der(5)del(5)(p15.1p15.1)t(5;12;7)(p15.1;p13;q32),der(7)t(5;12;7),der(12)del(12)p13p13)t(5;12;7),del(13)(q12q14) was reported in a two year old boy with PEL<ref name=":10" />. 

[[File:pic-1.png|frame|center| Karyotype of two year old boy with PEL<ref name=":10" />.]]

[[File:FISH for ETV6 and RUNX1.jpg|frame|left| FISH for ETV6 and RUNX1 in two year old boy with PEL<ref name=":10" />.]]

[[File:FISH for EGR1 and D5S23,D5S721 (5p-).jpg|frame|center| FISH for EGR1 and D5S23,D5S721 (5p-) in two year old boy with PEL<ref name=":10" />.]]


[[File:FISH for RB1 and 13q34 (13q deletion).jpg|frame|center| FISH for RB1 and 13q34 (13q deletion) in two year old boy with PEL<ref name=":10" />.]]


{| class="wikitable sortable"
|-
!Chromosomal Rearrangement!!Genes in Fusion (5’ or 3’ Segments)!!Pathogenic Derivative!!Prevalence
|-
|t(1;16)(p31;q24)||5’NFIA/ 3’CBFA2T3||der(16)||Rare
|-
|t(11;20)(p11;q11)||5’MYND8/ 3’RELA||der(11)||Rare
|}

==Characteristic Chromosomal Aberrations / Patterns==


==Genomic Gain/Loss/LOH==

Not Applicable

{| class="wikitable sortable"
|-
!Chromosome Number!!Gain/Loss/Amp/LOH!!Region
|-
|5||Loss||Whole chromosome or q-arm
|-
|7||Loss||Whole chromosome or q-arm
|-
|8||Gain||Whole chromosome
|-
|17||Loss||P-arm
|-
|}

==Gene Mutations (SNV/INDEL)==

JAK2, FLT3, RAS, NPM1, and CEBPA mutations have been reported to be rare in PEL<ref name=":9" /><ref name=":10" /><ref name=":11" />.  Intraclonal heterogeneity and founder mutations of TP53 were reported in 92% (11 out of 12 cases) while  co-occurrence of TP53 mutation and deletion due to chromosome 17p abnormalities were detected in 73% of PEL cases<ref>{{Cite journal|last=Montalban-Bravo|first=Guillermo|last2=Benton|first2=Christopher B.|last3=Wang|first3=Sa A.|last4=Ravandi|first4=Farhad|last5=Kadia|first5=Tapan|last6=Cortes|first6=Jorge|last7=Daver|first7=Naval|last8=Takahashi|first8=Koichi|last9=DiNardo|first9=Courtney|date=2017|title=More than 1 TP53 abnormality is a dominant characteristic of pure erythroid leukemia|url=https://www.ncbi.nlm.nih.gov/pubmed/28246192|journal=Blood|volume=129|issue=18|pages=2584–2587|doi=10.1182/blood-2016-11-749903|issn=1528-0020|pmc=5418636|pmid=28246192}}</ref>.

{| class="wikitable sortable"
|-
!Gene!!Mutation!!Oncogene/Tumor Suppressor/Other!!Presumed Mechanism (LOF/GOF/Other; Driver/Passenger)!!Prevalence (COSMIC/TCGA/Other)
|-
|EXAMPLE TP53||EXAMPLE R273H||EXAMPLE Tumor Suppressor||EXAMPLE LOF||EXAMPLE 20%
|}	
		
===Other Mutations===
{| class="wikitable sortable"
|-
!Type!!Gene/Region/Other
|-
|Concomitant Mutations||EXAMPLE IDH1 R123H
|-
|Secondary Mutations||EXAMPLE Trisomy 7
|-
|Mutually Exclusive||EXAMPLE EGFR Amplification
|}

==Epigenomics (Methylation)==

Not Applicable

==Genes and Main Pathways Involved==

The molecular mechanism is not completely understood.

==Diagnostic Testing Methods==

Morphology and IHC.

==Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications)==

PEL has rapid and aggressive clinical course. Patients with PEL are treated similar to other types of AML. Stem cell transplantation (SCT) may have an improvement in the outcome of the disease. No therapeutic agents for specific target pathways are currently available<ref name=":2" />.

==Familial Forms==

Not Applicable

==Other Information==

Differential Diagnosis: PEL without morphological differentiation of erythroid maturation can be difficult to distinguish from megakaryoblastic leukemia (AML), ALL or lymphoma. The erythroid precursor immunophenotype helps in the diagnosis. Some cases can be complex with concurrent erythroid megakaryocytic involvement<ref name=":0" />.

==Links==

*[[Acute Erythroid Leukemia]]

==References==
<references />

==Notes==
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[[Category:Translocation Chromosome 1]]
[[Category:Translocation Chromosome 16]]
[[Category:Translocation Chromosome 11]]
[[Category:Translocation Chromosome 20]]
[[Category:Structural Chromosome Abnormalities]]
[[Category:Structural Chromosome Abnormalities in AML]]
[[Category:Structural Abnormalities Chromosome 1]]
[[Category:Structural Abnormalities Chromosome 16]]
[[Category:Structural Abnormalities Chromosome 11]]
[[Category:Structural Abnormalities Chromosome 20]]
[[Category:Loss Chromosome 5]]
[[Category:Loss Chromosome 7]]
[[Category:Loss Chromosome 17]]
[[Category:Gain Chromosome 8]]
[[Category:Fusion Genes in AML]]
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[[Category:Fusion Genes C]]
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