Abstract
[Background] Although the development of genome wide screening for risk stratification in childhood leukemia, immunophenotyping is still essential to decide initial treatment because of quick duration to make diagnosis. Immunophenotyping is also very useful to detect rare subtypes in leukemia. From 2011, Japanese pediatric leukemia/lymphoma study group (JPLSG) started nation-wide immunophenotyping with comprehensive panel including more than 50 antigens for childhood hematological malignancy. This panel led easier diagnosis not only for typical leukemia subtypes such as acute lymphoblastic leukemia (ALL) or acute myelogenous leukemia (AML), but for rare subtypes including mixed phenotype acute leukemia (MPAL), acute undifferentiated leukemia (AUL), and blastic plasmacytoid dendritic cell neoplasms (BPDCN). We report here the significance of comprehensive immunophenotyping panel, then clinical manifestations and immunophenotypic peculiarity of rare subtypes in childhood leukemia.
[Methods] Immunophenotyping was done with comprehensive panel (Table 1) and diagnosis was done according to WHO 2008 classification. Briefly, determination of lineage was usually decided by major lineage specific markers such as myeloperoxidase (MPO), CD19, and cytoplasmic CD3. Then, more detailed categorization was done by analysis with other lineage, differentiation, or activation markers.
[Result] In 4,033 case from January 2012 to December 2016, major immunophenotypes were as follows; B-precursor/pre-B (BCP-) ALL was 2,141, T cell (T-) ALL 348, AML 842, B-ALL 74, Lymphomas 171, transient myeloproliferative disorder (TAM) 244, chornic myelogenous leukemia (CML) 72. Out of other 141 cases, we also found 32 MPAL, 16 AUL, and 7 BPDCN. According to detailed immunophenotyping, MPAL cases could be divided into 3 distinct clusters, T-ALL/ AML-M1 biphenotypic subtype (8 cases), BCP-ALL/AML-M5 bilineal subtype (11), and BCP-ALL with MPO expression subtype (13). Furthermore, distinct cluster, 'early T cell progenitor ALL (ETP)-like subtype' was also distinguished from AUL.
[Discussion] Acute leukemia of ambiguous lineage and BPDCN are both rare subtypes of acute leukemia. According to WHO 2008 classification, acute leukemia of ambiguous lineage is further classified as MPAL, AUL and natural killer lymphoblastic leukemia. In this study, we evaluate 32 MPAL, 16 AUL and 7 BPDCN. It is of note that we could not identify no natural killer lymphoblastic leukemia in this childhood leukemia cohort. We also evaluate 32 MPAL cases, which showed 3 distinct subgroups. T-ALL oriented cases indicate only one subtype 'T-ALL/AML-M1 biphenotypic', which indicated relatively older age, usually diagnosed as AML-M1 with morphologic FAB classification, and received mostly myeloid oriented therapy. BCP-ALL related cases were also divided into two groups, BCP-ALL/AML-M5 bilineal, and BCP-ALL with MPO expression. Bilineal leukemia often found in infantile ALL with MLL gene rearrangement (4 out of 11 cases), but still found 7 older cases without MLL gene rearrangemnt. Bilineal leukemia occasionally cause lineage-switch relapse, so diagnosis of bilineal leukemia seems to be very significant. Recent studies showed leukemia with ZNF384 fusion indicate CD10 negative or low BCP-ALL, and tended to express MPO. Our cases also tended to indicate negative or low CD10 expression. In addition, ETP-ALL like cases were positive for T cell antigens such as CD2 and/or CD7 and also some myeloid antigens but lacked cytoplasmic CD3 expression.
In conclusion, we identified a spectrum of rare subtypes in childhood leukemia, including MPAL, AUL, and BPDCN by adoption of comprehensive immunophnotyping panel. In most of childhood MPAL cases were divided into 3 distinct clusters. It must be useful information for detection of genetic abnormality.
No relevant conflicts of interest to declare.
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