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| <div style="width: 95%">
| | The ETP-ALL/LBL |
| {| class="wikitable" style="border-style: solid; border-width: 5px; color:black"
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| |colspan="1" style = "font-size:90%; color:black; background:#ddeee1"|'''1. The primitive nature of the blast cells should be demonstrated'''
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| | The immunophenotype of ETP-ALL requires careful consideration – this reflects that the condition was identified using gene expression profiling rather than by immunophenotype. Using immunophenotype to establish the diagnosis is therefore challenging and may underestimate the number of true cases.* and may not be easily separated from ALAL T/my |
| | Or T-ALL |
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| | The approach presently advocated by WHO requires: |
| | 1. Required expression: Cytoplasmic CD3 (may be heterogenous but should be expressed by ≥25% of blasts) |
| | 2. Required expression: One or more myeloid antigen (CD11b, CD13, CD33, CD65, CD117) and/or stem cell antigens (CD34, HLA-DR) |
| | 3. Required absence: CD3, CD1a and CD8 (<5% of blasts) |
| | 4. Required absent/dim CD5 expression (<75% positive blasts) |
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| [[Image:AML M1.png|110px]]
| | Note that CD7 is consistently positive in ETP-ALL and does not count as a stem cell antigen in this context |
| <span style="font-size:90%;"></br>''The "primitive" morphology of blast cells is accompanied by signs of primitive immunophenotype''</span>
| | *CD4 may have the same pattern |
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| *In most cases, AML will demonstrate typical features of immature cells with: '''weak expression of CD45''', and expression of '''CD34''' and/or '''CD117'''. In difficult cases other markers of early differentiation may also help</br>[[Markers used to demonstrate primitive nature in AML|Click for more detailed description of identifying primitive immunophenotype in AML]]
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| *Potential '''difficulties may occur where blast cells have significant differentiation''' to more mature forms their primitive nature may be less easy to demonstrate. This is most frequently encountered in monocytic cases of AML, or in acute promyelocytic leukaemia (APL)</br>[[Atypical patterns of primitive marker expression in acute myeloid leukaemia|Click for a more detailed description of problem areas in identifying primitive immunophenotype]]
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| | The ETP-ALL immunophenotype may also be established by immunohistochemistry. |
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| ---- | | *T-ALL cases that have an immunophenotype similar to ETP-ALL but where CD5 is expressed (≥75% of blasts) may be designated as “near-ETP-ALL”, but the clinical implications of such a designation remain unclear. |
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| <div style="width: 95%">
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| {| class="wikitable" style="border-style: solid; border-width: 5px; color:black"
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| |colspan="1" style = "font-size:90%; color:black; background:#ddeee1"|'''2. Myeloid lineage must be assigned'''
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| |}
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| [[Image:AML M2.png|130px]]
| | Distinction from mixed-phenotype acute leukaemia (MPAL) requires that MPO is not expressed - in this context of ETP-ALL the WHO advocate a threshold of <3% to define negative myeloperoxidase expression (by cytochemistry or flow cytometry). This threshold is different from that of T/myeloid MPAL so may not be optimal but is retained at present. |
| <span style="font-size:90%;"></br>''Like Auer rods or granulation in morphology, immunophenotypic features support assignment to myeloid lineage''</span>
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| The criteria to assign myeloid lineage in AML have been established by the WHO, two alternative sets of criteria may be used (although most cases will meet both):
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| <div style="width: 95%"; >
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| {| class="wikitable"
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| !colspan="1" style = "background:palegrey;border:solid"|Either Criteria 1</br>
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| !colspan="1" style = "background:white; font-size:90%; border:solid; "|A myeloid '''lineage-defining''' marker pattern is present '''and''' no lineage-defining markers of T or B cells are present</br>([[Myeloid lineage-defining markers|Click for detailed description]])
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| |-
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| !colspan="1" style = "background:palegrey;border:solid"|Or Criteria 2</br>
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| |-
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| !colspan="1" style = "background:white;border:solid; font-size:90%;"|At least '''two myeloid lineage-associated''' markers are present '''and''' there are no lineage defining markers of T or B cells '''and''' no more than one: T-cell '''or''' B-cell lineage-associated marker is present</br>([[Myeloid lineage-associated markers|Click for detailed description]])</br>('''NOTE''' when assigning lineage based on these criteria, see also BPDCN in the alternative diagnosis list below)
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| |}
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| '''NOTE''' In some cases an extended marker panel may allow the pattern of differentiation to be identified (e.g. erythroid or megakarocytic). In difficult cases these markers may provide additional evidence of myeloid lineage (although their specificity is often less than the general myeloid-associated markers so care is required when using them in this way). </br>
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| [[Additional immunophenotypic markers useful in lineage assignment or subtyping of AML|Click for table of extended marker set for AML immunophenotype]]
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| ----
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| <div style="width: 95%">
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| {| class="wikitable" style="border-style: solid; border-width: 5px; color:black"
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| |colspan="1" style = "font-size:90%; color:black; background:#ddeee1"|'''3. Alternative diagnoses should be considered and excluded'''
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| |}
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| [[Image:AML M1.png|110px]]
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| <span style="font-size:90%;"></br>''In some cases lineage may be unclear - either because myeloid lineage cannot be confidently assigned, or because markers of other lineage are present - in such cases it is important to consider possible alternative diagnoses''</span>
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| *'''NOTE''' Some "non-lineage" markers are frequently expressed in AML and may be associated with specific AML subtypes, these do not necessarily indicate mixed phenotype ([[Table of frequent aberrant markers in AML|Click here for further detail]])
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| *Other features should give concern for mixed phenotype or alternative diagnosis, it is important in such case that diagostic criteria and alternative diagnoses are carefully considered (see the table below more detailed guidance).
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| '''Table''': Possible alternative diagnoses in difficult cases
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| <div style="width: 95%"; font-size:95%>
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| {| class="wikitable"
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| !colspan="2" style = "background:palegrey;border:solid"|'''Mixed Phenotype Acute Leukaemia''' (MPAL)
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| |-
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| !colspan="2" style = "background:white;border:solid; font-size:90%;"| Consider MPAL if: you are able to assign myeloid lineage '''but''' the cells also express markers that meet the criteria for T or B cell lineage.</br>---- [[Flow cytometry:MPAL|Click here for detailed description of MPAL types]]----</br>
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| |-
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| !colspan="2" style = "background:palegrey;border:solid"|'''Acute Undifferentiated Leukaemia''' (AUL)
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| |-
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| !colspan="2" style = "background:white; border:solid; font-size:90%;"| Consider AUL if: There is insufficient evidence to assign myeloid lineage, '''and''' you cannot assign T-cell or B-cell lineage either</br>----[[Flow cytometry:AUL|Click here for detailed description of AUL]]----</br>
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| |-
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| !colspan="2" style = "background:palegrey;border:solid"|'''Acute Leukaemia of ambiguous lineage not otherwise sepcified''' (ALAL-NOS)
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| |-
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| !colspan="2" style = "background:white; border:solid; font-size:90%;"| Consider '''ALAL-NOS''' if: classification to a single lineage is not possible, but classification cannot be made as AUL, or MPAL.</br>----[[Flow cytometry:ALAL-NOS|Click here for detailed description of ALAL-NOS]]----</br>
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| |-
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| !colspan="2" style = "background:lightgrey;border:solid"|''' Early T-cell precursor ALL'''
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| |-
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| !colspan="2" style = "background:white; border:solid; font-size:90%;"| The marker pattern is of a primitive T cell neoplasm (cCD3 is expressed) but there are limited additional T markers, and at least one myeloid or stem cell marker is also expressed</br>----[[Flow cytometry:ETP-ALL|Click here for detailed description of ETP-ALL]]</br>
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| |-
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| !colspan="2" style = "background:lightgrey;border:solid"|'''Blastic plasmacytoid dendritic cell neoplasm''' (BPDCN)
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| |-
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| !colspan="2" style = "background:white; border:solid; font-size:90%;"| The immunophotype of BPDCN may resemble AML or AUL (almost always with an accompanying skin rash). Myeloid-lineage markers (particularly CD33) are frequently expressed (in rare cases two myeloid markers may be co-expressed allowing potential assignment as AML, although MPO and CD34 should be absent). BPDCN should considered and evidence sought if clinical features fit.</br>---- [[Flow cytometry:BPDCN|Click here for detailed description of BPDCN]]----</br>
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| |}
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| ----
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The ETP-ALL/LBL
The immunophenotype of ETP-ALL requires careful consideration – this reflects that the condition was identified using gene expression profiling rather than by immunophenotype. Using immunophenotype to establish the diagnosis is therefore challenging and may underestimate the number of true cases.* and may not be easily separated from ALAL T/my
Or T-ALL
The approach presently advocated by WHO requires:
1. Required expression: Cytoplasmic CD3 (may be heterogenous but should be expressed by ≥25% of blasts)
2. Required expression: One or more myeloid antigen (CD11b, CD13, CD33, CD65, CD117) and/or stem cell antigens (CD34, HLA-DR)
3. Required absence: CD3, CD1a and CD8 (<5% of blasts)
4. Required absent/dim CD5 expression (<75% positive blasts)
Note that CD7 is consistently positive in ETP-ALL and does not count as a stem cell antigen in this context
- CD4 may have the same pattern
The ETP-ALL immunophenotype may also be established by immunohistochemistry.
- T-ALL cases that have an immunophenotype similar to ETP-ALL but where CD5 is expressed (≥75% of blasts) may be designated as “near-ETP-ALL”, but the clinical implications of such a designation remain unclear.
Distinction from mixed-phenotype acute leukaemia (MPAL) requires that MPO is not expressed - in this context of ETP-ALL the WHO advocate a threshold of <3% to define negative myeloperoxidase expression (by cytochemistry or flow cytometry). This threshold is different from that of T/myeloid MPAL so may not be optimal but is retained at present.