|Year : 2015 | Volume
| Issue : 2 | Page : 181-186
|Flow cytometric analysis of Mixed phenotype acute leukemia: Experience from a tertiary oncology center
Renu Sukumaran1, Rekha A Nair1, Priya Mary Jacob1, Kunjulekshmi Amma Raveendran Nair Anila1, Shruthy Prem2, Rajeswary Binitha3, Parukuttyamma Kusumakumary3
1 Division of Pathology, Regional Cancer Centre, Trivandrum, Kerala, India
2 Division of Medical Oncology, Regional Cancer Centre, Trivandrum, Kerala, India
3 Division of Pediatric Oncology, Regional Cancer Centre, Trivandrum, Kerala, India
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|Date of Web Publication||17-Apr-2015|
| Abstract|| |
Introduction: Mixed phenotype acute leukemia (MPAL) is a rare subset of acute leukemia where the blasts exhibit lineage specific antigens of more than one lineage. Flow cytometric immunophenotyping is essential for the diagnosis of MPAL and the accurate diagnosis highly depends on the panel of markers used. The precise incidence of MPAL is uncertain as various institutions use different combinations of antibodies to assign the blasts to a particular lineage. Aim: The aim was to study the immunoprofile of acute leukemia including aberrant antigen expressions and to study the incidence, clinical features, laboratory findings, and immunophenotype of MPAL in our institution. Materials and Methods: All cases of acute leukemias in which flow cytometric analysis during 1-year period from July 2012 to July 2013 were included in this study. Results: During the study period, flow cytometric analysis of 506 cases was performed. B lymphoblastic leukemia was the most common subtype of acute leukemia. CD13 was the most common aberrant antigen expression in acute lymphoblastic leukemia and CD7 was the most common aberrant antigen expression in acute myeloid leukemia. A diagnosis of MPAL was made in 15 cases, which accounted for 2.96% of all leukemias. 9 cases were diagnosed as T/myeloid, 5 cases as B/myeloid and 1 case as B/T. Conclusion: Mixed phenotype acute leukemia is a rare subset of acute leukemia. Flow cytometry is critical in establishing a diagnosis of MPAL. The panel of antibodies used is important in the identification of the "mixed" phenotype. Cytoplasmic markers (cytoplasmic MPO, cytoplasmic 79a, cytoplasmic 22 and cytoplasmic CD3) should be included in the primary flow cytometric panel.
Keywords: Aberrant antigen expression, flow cytometry, mixed phenotype acute leukemia
|How to cite this article:|
Sukumaran R, Nair RA, Jacob PM, Nair Anila KR, Prem S, Binitha R, Kusumakumary P. Flow cytometric analysis of Mixed phenotype acute leukemia: Experience from a tertiary oncology center. Indian J Pathol Microbiol 2015;58:181-6
|How to cite this URL:|
Sukumaran R, Nair RA, Jacob PM, Nair Anila KR, Prem S, Binitha R, Kusumakumary P. Flow cytometric analysis of Mixed phenotype acute leukemia: Experience from a tertiary oncology center. Indian J Pathol Microbiol [serial online] 2015 [cited 2019 Dec 10];58:181-6. Available from: http://www.ijpmonline.org/text.asp?2015/58/2/181/155309
| Introduction|| |
In most cases of acute leukemias, blasts are assigned to a single lineage based on morphology, cytochemistry and immunoprofile. Mixed phenotype acute leukemia (MPAL) is a rare subset of acute leukemia where the blasts exhibit antigens of more than one lineage to a significant degree, such that it cannot be assigned to one specific lineage. It comprises of leukemias that contain a single population of blasts that express antigens of more than one lineage (biphenotypic acute leukemia), or separate population of blasts of more than one lineage (bilineal acute leukemia). Cross lineage antigen expression is common in acute leukemias and should not be classified as MPAL. WHO has suggested strict criteria for the diagnosis of MPAL and flowcytometric immunophenotyping is essential in the diagnosis of MPAL. 
| Materials and Methods|| |
All cases of acute leukemias where flow cytometric analysis was done for diagnosis during a period of 1-year from July 2012 to July 2013 were included in this retrospective study.
All specimens were obtained and prepared for morphologic examination using standard techniques. Peripheral blood smears and bone marrow aspirates were air dried and stained with Giemsa stain. Myeloperoxidase was done routinely in all peripheral smears and bone marrow aspirate smears. Other cytochemical stains - periodic acid-Schiff, nonspecific esterase and specific esterase were done according to the morphological details of the cells.
Four color flow cytometry analysis was performed using FACS caliber (Becton Dickinson, San Jose, CA, USA). Standard lyse-wash procedure was used. The cells were stained with various combinations of fluorescein isothiocyanate (FITC), phycoerythrin (PE), Peridinin chlorophyll protein (PerCP)and Allophycocyanin (APC) labeled monoclonal antibodies against the following antigens and the specific clones used were obtained from Becton Dickinson, San Jose, CA-CD13 PE (L138), CD14 APC (MoP9), CD33 FITC (BD P67.6), CD64 FITC (10.1), CD117 APC (104D2), CD11c PE (S-HCL-3), CD10 FITC (HI10a),CD19 APC (SJ25C1),CD20 APC (L27), CD2 PE (S5.2), CD3 APC ( SK7), CD5 PE (L17F12), CD7 FITC (4H9), CD56 PE (MY31), CD34PE (My10) and HLADR APC (L243). Cytoplasmic markers-anti MPO FITC (5B8), cytoplasmic CD79a PE (2ST8.5H7), cytoplasmic CD3 APC (SK7) and cytoplasmic CD22 PE (5-HCL-1) - were included in the primary flow cytometry panel. Glycophorin A PE (GA-R2), CD61 FITC (RUU-PL7F12), CD4 PE (SK3), CD8 FITC (SK1), and terminal deoxynucleotidyl transferase (Tdt) FITC (E17-1519) were done in secondary panel when indicated. CD45 gating was used to identify the blast population.
The distribution of acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL) and MPAL was noted. The aberrant coexpression of antigens in AML and ALL were studied. The cases of MPAL were reviewed, and the clinical findings of each case were noted including the presence of lymphadenopathy and hepatosplenomegaly. The laboratory parameters including total count, differential count, percentage of blasts and cytochemistry in peripheral smear and bone marrow were noted. The flow cytometric analysis of cases of MPAL was reviewed. The assignment of blasts to different lineages was analyzed.
| Results|| |
During the study period, flow cytometric analysis of 506 cases of acute leukemia was performed. Of these, 205 were children and 301 were adults. B Lymphoblastic leukemia (B-ALL) accounted for 217 (42.9%) cases and T-ALL accounted for 58 (11.46%) cases. AML was diagnosed in 216 (42.69%) cases.
Aberrant antigen expressions
CD13 expression was noted in 96 cases (44.2%) of B-ALL and in 16 cases (27.6%) of T-ALL. Coexpression of CD33 was noted in 7 cases (3.2%) of B-ALL and in 2 cases (3.4%) of T-ALL. CD117 was positive in 6 cases (2.76%) of B-ALL and in 3 cases (5.2%) of T-ALL.
B lymphoblastic leukemia showed coexpression of CD5 in 5 cases (2.3%), CD2 in 4 cases (1.8%) and CD7 in 1 case (0.46%). CD10 was positive in 18 cases (31%) of T-ALL.
Aberrant antigens expressed in AML included CD7, CD56, CD19, CD5 and CD2. CD7 expression was noted in 24 (11.11%) cases, and CD56 expression was noted in 23 cases (10.65%). CD19 was expressed in 16 cases (7.4%), CD5 in 8 cases (3.7%) and CD2 in 6 cases (2.8%) of AML.
Mixed phenotype acute leukemia
A diagnosis of MPAL was made based on WHO guidelines [Table 1].  There were 15 cases of MPAL, which accounted for 2.96% of all acute leukemias. Age ranged from 8 months to 60 years. 5 cases were children and ten were adults. Lymphadenopathy was noted in 6 cases, and hepatosplenomegaly was present in 3 cases. Low hemoglobin level (<10 g/dL) was noted in 11 cases. White blood cell count was within normal limits in 7 cases whereas 6 cases showed leukocytosis and 2 cases showed leukopenia. Thrombocytopenia (platelet count <100 10 9 ) was observed in 10 cases. Lactate dehydrogenase was elevated in 12 cases.
|Table 1: Requirements for assigning more than one lineage to a single blast population|
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Giemsa-stained smears showed two separate blast populations in 6 cases. Myeloperoxidase was positive by cytochemistry in 5 cases.
A diagnosis of MPAL-T/myeloid was made in 9 cases [Figure 1] and [Table 2] and B/myeloid in 5 cases [Figure 2] and [Table 3]. A diagnosis of B/T was given in 1 case [Figure 3].
|Figure 1: Gated population of cells are positive for CD34, CD7, CD117, CD13, HLADR, Cy MPO, Cy CD3|
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|Figure 2: Gated population of cells are positive for CD34, CD10, CD7, CD19, CD13, CD33, HLA DR, CD5, CyMPO, Cy CD79a, Cy CD22|
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|Figure 3: Gated population of cells are positive for CD7, CD19, CD5, HLADR, CD11c, Cy CD3, Cy CD79a, Cy CD22|
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The cases which showed two populations of blasts on Giemsa-stained smears, 5 cases were diagnosed as T/myeloid MPAL and 1 case as B/myeloid MPAL on flow cytometry. In flow cytometry all these cases showed single population of blasts [Figure 1].
T-cell lineage was assigned by positivity of surface or cytoplasmic CD3 expression and was demonstrated in 10 cases (9 cases of T/myeloid and 1 case of B/T). Cytoplasmic CD3 was positive in all the 10 cases, whereas surface CD3 was positive in only 2 cases [Table 2]. In the 2 cases were surface CD3 was positive, the surface CD3 expression was dim compared to the cytoplasmic CD3 and the blasts showed CD34 positivity [Figure 4].
|Figure 4: Gated population of cells are positive for CD34, CD2, CD7, CD3, CD13, CD33, CD5, Cy CD3, Cy MPO|
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Diagnosis of B/Myeloid MPAL was made in 5 cases. B cell lineage was assigned by CD19 expression associated with expression of at least two other B cell markers (CD10, cytoplasmic CD79a/cytoplasmic CD22) in 3 cases and by strong expression of CD19 along with strong expression of CD10 in 2 cases [Table 3].
Assignment of myeloid commitment in MPAL was demonstrated in 14 cases by the myeloperoxidase positivity. Flow cytometry demonstrated myeloperoxidase positivity in 12/14 cases whereas cytochemistry showed myeloperoxidase positivity in 5/14 cases. In the 2 cases where flow cytometry failed to detect myeloperoxidase positivity, cytochemistry showed myeloperoxidase positive blasts.
In our series, 10 patients took chemotherapy. Four pediatric patients were treated with ALL regimens based on a Modified BFM 95 protocol and they attained remission after 4 weeks of induction chemotherapy. They were continued on chemotherapy and are still in remission. Hyper CVAD regimen was given to two adult patients, one achieved complete remission at the end of 1-month and the other patient achieved late complete remission. Palliative chemotherapy was given to four adult patients considering poor performance status, age of the patient and financial constraints. Of these four patients, three patients expired during treatment and one achieved remission.
| Discussion|| |
Majority of cases of acute leukemias are classified as ALL or AML depending on the specific lineage origin, either lymphoid or myeloid, exhibited by blasts.  A minority of cases of acute leukemias will show no evidence of differentiation along a single lineage. These leukemias are termed acute leukemias of ambiguous lineage and consist of two separate entities. When the blasts exhibit no lineage-specific antigens, it is termed acute undifferentiated leukemia. When the blasts express antigens of more than one lineage, to such a degree that it is not possible to assign to any particular lineage with certainty, it is called MPAL. 
In 1980, when monoclonal antibodies were first used to categorize leukemic cells, reports of bipenotypic acute leukemia appeared in literature. One of these publications noted the coexpression of myeloperoxidase and Tdt in AML.  Mirro et al. noted the frequency and significance of acute leukemias expressing both lymphoid and myeloid characteristics.  However, the markers identified were not lineage specific. When more antibodies became available, it was found that aberrant expression of antigens of another lineage is not very uncommon in acute leukemias and these should not be categorized as biphenotypic acute leukemia. Catovsky et al. in 1991 proposed a scoring system to diagnose this distinct type of acute leukemia.  Scoring criteria by European Group for Immunological classification of Acute Leukemia (EGIL), aimed at distinguishing cases of MPAL from those with aberrant antigen expressions.  It allowed a better definition of biphenotypic acute leukemia. In EGIL scoring system, the various markers were assigned with a score of 2, 1 or 0.5 and cases with a score of >2 for at least two lineages were classified as biphenotypic acute leukemia. , However, the lack of lineage specificity for most of the markers questioned the significance of this approach. WHO 2008 has established strict criteria for the diagnosis of MPAL and defined the lineage-specific markers for each lineage.
Aberrant coexpression of antigens
Aberrant coexpression of one or two markers of another lineage is common in leukemias.  MPAL should be distinguished from acute leukemias with cross lineage antigen expressions. In this study, CD13 was the most common aberrant antigen expression in ALL. CD13 expression was noted in 96 cases (44.2%) of B-ALL and in 16 cases (27.6%) of T-ALL. Aberrant coexpressions of antigens were seen in 77 cases (35.65%) of AML, in which CD7 was the most frequent. Other cross lineage antigens expressed in AML included CD56, CD19, CD5 and CD2.
Mixed phenotype acute leukemia
Mixed phenotype acute leukemia can be B/Myeloid, T/Myeloid or B/T. Rare cases of trilineage MPAL is also described. ,,,, The mixed phenotype in T/myeloid or B/myeloid MPAL can occur in three ways:
- Two distinct blast populations, one showing immunophenotype of AML and the other showing immunophenotype of lymphoid blast population,
- Single population of blasts meeting criteria of B-ALL/T-ALL with expression of myeloperoxidase,
- Single population of blasts meeting criteria of B-ALL/T-ALL with evidence of monocytic differentiation.
Morphology can suggest the presence of two types of blasts, but immunophenotyping is absolutely essential in the identification of this rare subset of leukemia. According to 2008 WHO classification, the myeloid lineage assignment is defined by the expression of myeloperoxidase positivity or by the presence of at least two monocytic markers. T-cell lineage commitment is established by the presence of cytoplasmic or surface expression of CD3. B cell lineage assignment requires either expression of strong CD19 with strong expression of additional B-cell marker or weak CD19 expression with an expression of two additional B-cell markers. 
Although the EGIL previously recommended a cut-off of 20% for most of the markers and 10% for markers including MPO and CD3, because of their high specificity, this is not adopted by WHO. ,
During the study period of 1-year, a diagnosis of MPAL was made in 15 patients. T/myeloid was the predominant type with 9 cases. This is in contrast to the majority of the published studies where B/myeloid constitutes the predominating type of MPAL. ,,
T/myeloid mixed phenotype acute leukemia
T cell lineage was assigned by positivity of surface or cytoplasmic CD3 expression. Cytoplasmic CD3 was positive in all the 9 cases of T/myeloid MPAL, whereas surface CD3 positivity was noted only in 2 cases. This highlights the importance of doing cytoplasmic markers in the diagnosis. If cytoplasmic markers are not included in the primary flow cytometric panel, majority of cases of T/myeloid MPAL will be diagnosed as AML and the T cell lineage will remain unrecognized. Among the T/myeloid MPAL, CD7 was positive in 9 cases. CD5 positivity noted in 8 cases and CD2 positivity noted in 3 cases.
B/myeloid mixed phenotype acute leukemia
This category was diagnosed in 5 cases. There is no single marker, which is sufficiently specific to indicate B-cell differentiation with certainty. CD19 expression associated with expression of at least two other B cell markers was present in 3 cases, whereas strong expression of CD19 along with strong expression of CD10 was noted in 2 cases.
Myeloid lineage was established in 14 cases (9 cases of T/myeloid and 5 cases of B/myeloid) by the presence of myeloperoxidase positivity. Cytochemistry showed myeloperoxidase positivity in 5/14 cases. Myeloperoxidase positivity was demonstrated by flow cytometric analysis in 12/14 cases. In the 2 cases, where flow cytometry could not detect myeloperoxidase positivity, cytochemistry showed myeloperoxidase positivity. This points to the importance of doing both cytochemistry and flow cytometry for myeloperoxidase as myeloperoxidase is a very important lineage specific marker for myeloid lineage. Studies comparing the sensitivity of flow cytometry and enzyme cytochemistry in detecting myeloperoxidase positivity show the concomitant use of both these methods increase the sensitivity. The EGIL guidelines defined MPO positivity in flow cytometry by the presence of this enzyme in 10% or more of blast cells. In their study, Peffault de Latour et al. compared the 3% threshold positivity for enzyme cytochemistry, and 10% and 3% threshold positivity for flow cytometry and they found that flow cytometry was less sensitive than enzyme cytochemistry when using the currently recommended threshold of 10% but a 3% cut off showed more sensitivity and was superior to enzyme cytochemistry in detecting myeloperoxidase positivity. 
B/T mixed phenotype acute leukemia
A diagnosis of MPAL B/T was made in 1 case where a single population of blasts demonstrated B lineage commitment (positivity for CD19, cytoplasmic 79a and cytoplasmic CD22) and T lineage commitment (positivity for cytoplasmic CD3).
Mixed phenotype acute leukemia is thought to arise from a multipotential hemopoietic stem cell that has the potential to differentiate into any lineage. Most of the reported cases of MPAL express early hematopoietic markers - CD34 and HLADR suggesting an early precursor stem cell origin.  In our series, 14/15 cases of MPAL demonstrated CD34 positivity. HLADR was positive in 13/15 cases. Another explanation for the development of MPAL is that the blasts originate from a lymphoid precursor that has reactivated a myeloid differentiation program.
The optimal therapeutic approach to MPAL has not been defined. Whether these patients to be treated with regimens designed for AML or ALL is still unclear.  In a study by Aribi et al., complete remission was attained in 78% cases treated with ALL regimen and 57% cases treated with AML regimen.  Rubio et al. noticed biphenotypic T/Myeloid appears to respond to induction therapy designed for AML.  Rubnitz et al. reviewed the response to treatment in MPAL patients and found that complete remission in 83% patients received ALL regimen and in 52% in those received AML regimen.  However, the overall outcome was definitely inferior to those of standard ALL. ,,
In a recently published larger analysis of 100 MPAL patients, complete remission was achieved in 85% patients with ALL treatment and 41% patients treated with AML treatment.  The overall median survival in their series was 18 months. The survival at 5 years was 37%. Children had a better survival than adults. Our data also suggest that children, who received ALL directed treatment, had a better response to treatment.
Mixed phenotype acute leukemia are rare leukemias. Strict diagnostic criteria should be followed in the diagnosis. Accurate diagnosis is important because of the worse clinical outcome. It should be distinguished from acute myeloid and lymphoid leukemias with cross-lineage antigen expression. Immunophenotyping is absolutely essential in the diagnosis. Various institutions often use minimal antibodies in their flowcytometric immunophenotypic panel to assess cell lineage because of limitations like cost of reagents and manpower. The lineage specific markers including the cytoplasmic markers should be included in the primary flow cytometry panel for the identification and proper categorization of MPAL.
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Dr. Rekha A Nair
Division of Pathology, Regional Cancer Centre, Trivandrum - 695 011, Kerala
Source of Support: None, Conflict of Interest: None
[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2], [Table 3]
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