Acute Erythroid Leukemia

Primary Author(s)*

Ashwini Yenamandra PhD FACMG

Cancer Category/Type

Acute Myeloid Leukemia

Cancer Sub-Classification / Subtype

Pure Erythroid Leukemia (PEL) is the only subtype in Acute Erythroid Leukemia (AEL).

Definition / Description of Disease

In the 2008 WHO classification Acute Erythroid leukemia (AEL) was classified into two subtypes, one subtype was Erythroleukemia and second subtype was pure erythroid leukemia (PEL). However, in the 2016 WHO update, erythroleukemia was merged into myelodysplastic syndrome, and PEL was described as the only subtype of AEL [1-12] 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) [1-12].

Synonyms / Terminology

Also known as Di Guglielmo syndrome due to the recognition of the work of Di Guglielmo. [1, 2].

Epidemiology / Prevalence

PEL is extremely rare with a small number of reported cases, accounting for 3-5% of AML cases [1, 2, 10]. Median survival is usually three months [12].

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 [1, 10]. PEL is characterized by neoplastic proliferation composed of >80% immature erythroid precursors of which proerythroblast constitute ≥30%. [12]. 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, thrombocytopenia [1, 10]. Erythroleukemia (erythroid/myeloid) may be de novo or evolved from myeloid or sometimes from myeloproliferative neoplasms (MPN). [1,10].

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[1]. Cells are usually negative for Myeloperoxidase (MPO) and Sudan Black (SBB). Bone marrow biopsy may have undifferentiated cells [1].

Immunophenotype

Differentiated PEL may express Glycophorin and hemoglobin A, absence of myeloperoxidase (MPO) and other myeloid markers [1], Blasts are negative for HLA-Dr, CD34, positive for CD117[1] 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 [1, 12].

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 [1 and AY].]. 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 [10]. 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 [11]

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

JAK2, FLT3, RAS, NPM1, and CEBPA, TP53 mutations have been reported to be rare in PEL [10-12].

Genomic Gain/Loss/LOH

Not Applicable

Chromosome Number	Gain/Loss/Amp/LOH	Region
EXAMPLE 8	EXAMPLE Gain	EXAMPLE chr8:0-1000000
EXAMPLE 7	EXAMPLE Loss	EXAMPLE chr7:0-1000000

Gene Mutations (SNV/INDEL)

Not Applicable

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

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 [3].

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 [1].

Links

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References

1. Arber DA, et al., (2008). Acute myeloid leukaemia with recurrent genetic abnormalities, in World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues, 4thedition.Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Vardiman JW, Editors. IARC Press: Lyon, France, p135-136.

2. Shaowei Qiu, et al., (2017). An analysis of 97 previously diagnosed de novo adult acute erythroid leukemia patients following the 2016 revision to World Health Organization classification. BMC Cancer 17: 544, PMID 28793875.

3. Zhuang Zuo, et al., (2010). Acute Erythroid Leukemia (Review Article). Arch Pathol Lab Med 134:1261-1270, PMID 20807044.

4. Arber DA, et al., (2016). The updated WHO classification of Hematological malignancies. The 2016 revision to the World Health organization classification of myeloid neoplasms and acute leukemia (Review Series). Blood 127(20):2391-2405, PMID 27069254.

5. Zuo Z, et al., (2012). Acute myeloid leukemia (AML) with erythroid predominance exhibits clinical and molecular characteristics that differ from other types of AML. PLoS One 7(7):e41485, PMID 22844482.

6. Grossmann V, et al., (2013). Acute erythroid leukemia (AEL) can be separated into distinct prognostic subsets based on cytogenetic and molecular genetic characteristics. Leukemia 27(9): 1940-1943, PMID 23648669.

7. Porwit A, et al., (2011). Acute myeloid leukemia with expanded erythropoiesis. Haematologica 96(9):1241-1243, PMID 21880638.

8. Hasserjian RP, et al., (2010). Acute erythroid leukemia: a reassessment using criteria refined in the 2008 WHO classification. Blood 115(10):1985-1992, PMID 20040759.

9. Wang SA, et al., (2015). Acute erythroleukemias, acute megakaryoblastic leukemias, and reactive mimics: a guide to a number of perplexing entities. Am J Clin Pathol 144(1):44-60, PMID 26071461.

10. Wang W, et al., (2016). Acute Erythroid Leukemia. Am J Hematol. 2017; 92:292–296, PMID 2800685.

11. Yenamandra A, et al., (2016). Acute Erythroblastic Leukemia (AEL): A Rare Subset of De Novo AML with A Complex Rearrangement Involving ETV6 Locus and Loss of RB1 Locus. Int Clin Pathol J 2(2): 00032, DOI: 10.15406/icpjl.2016.02.00032

12. Fauzia SF, et al., (2017). Pure erythroid leukemia: The sole acute erythroid leukemia. Int J Bone Marrow Res. 2017; 1: 001-05.

Notes

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