| Abstract|| |
Cytogenetics has a pivotal role in risk stratification of acute myeloid leukemia (AML). We report a case of AML with a t(4;12)(q12;p13). To the best of our knowledge, there are about 24 cases of t(4;12) reported in AML which are usually misdiagnosed as lymphoproliferative disorders on morphological assessment. This case showed specific clinical, morphological, and immunophenotypic features such as (1) pseudo lymphoid morphology, (2) dysplasia in granulocytic series, (3) an immature immunophenotype with positivity for CD34 and CD117, and (4) poor treatment response.
Keywords: Acute myeloid leukemia, dysplasia, pseudo lymphoid morphology, t(4;12)
|How to cite this article:|
Patel UV, Arun S R, Mishra DK, Parihar M. Acute myeloid leukemia with t(4;12)(q12;p13): A morphological dilemma. Indian J Pathol Microbiol 2016;59:545-7
|How to cite this URL:|
Patel UV, Arun S R, Mishra DK, Parihar M. Acute myeloid leukemia with t(4;12)(q12;p13): A morphological dilemma. Indian J Pathol Microbiol [serial online] 2016 [cited 2019 Jul 19];59:545-7. Available from: http://www.ijpmonline.org/text.asp?2016/59/4/545/191814
| Introduction|| |
Cytogenetic analysis is the established frontline investigation in evaluating genetic aberrations in acute myeloid leukemias (AMLs) at diagnosis. The pretreatment karyotype predicts response to induction therapy, relapse risk, and overall survival (OS). Chromosomal abnormalities are detected in approximately 55% of AML. Recurring chromosomal translocations that were included in the WHO classification of acute leukemias in 2001 provided clues to the better understanding of the process of leukemogenesis and the recognition of various genes located at the breakpoints of these translocations. Many of these chromosomal changes are consistently associated with specific subtypes of AML and correlate with specific morphologic or immunophenotypic subtypes.  The morphological and immunophenotypic features of certain cytogenetically defined entities have been well established, for example, core-binding factor leukemias, AML with t(6;9), or AML with abnormalities of the long arm of chromosome 3. 
In the present paper, we report the characteristic morphological features of AML associated with a rare translocation between the long arm of chromosome 4 and the short arm of chromosome 12, i.e. t(4;12)(q12;p13) along with a review of the literature. Leukemia associated with t(4;12) is known to have blast morphology akin to mature lymphoid cells, commonly resulting in a diagnosis of lymphoproliferative disorder as a differential on morphological analysis. Awareness of this entity is essential as it is seen in AML and associated with high-risk disease and poor outcome.
| Case Report|| |
A 42-year-old male presented with a 3-month history of fever and anorexia. On physical examination, he was pale, cachectic, and had splenomegaly. Blood counts showed anemia (Hb-6.8 g/dl), leukocytosis (total leukocyte count - 323,900/mm 3 ), and thrombocytopenia (platelet count - 14,000/mm 3 ). The peripheral blood film showed more than 90% of the atypical cells with mature lymphoid morphology. A diagnosis of lymphoproliferative disorder was given on peripheral blood, and a bone marrow examination and immunophenotyping were suggested. Bone marrow aspirate (BMA) showed 95% cells with atypical lymphoid cell-like morphology [Figure 1]a. Granulocytic series showed dysplastic features [Figure 1]a. Megakaryocytes were not seen.
Based on the morphology, immunophenotypic analysis using chronic lymphoproliferative disorder (CLPD) panel was done. The atypical cells showed dim CD45 (100%), dim-to-moderate CD7 (94%), and dim CD4 (31%). All the other B-cell (CD19, CD20, CD10, and CD23) and T-cell (CD2, CD3, CD5, and CD8) markers were negative. As the CLPD panel did not show any significant findings, acute leukemia panel was processed. The analysis showed dim-to-moderate CD13 (95%), dim-to-moderate CD33 (96%), dim-to-moderate CD117 (93%), dim-to-moderate CD34 (93%), dim-to-moderate human leukocyte antigen-DR (HLA-DR) (61%), dim-to-moderate CD56 (78%), and dim cytoplasmic myeloperoxidase (26%).
Blasts were negative for myeloperoxidase on cytochemistry. Bone marrow biopsy showed a hypercellular marrow with an increase in atypical lymphoid-appearing cells and Grade 3 fibrosis.
The conventional karyotyping analysis was performed on BMA using standard protocols, which included two types of cultures one with colcemid and other without colcemid and harvested after 17 h and reported according to the International System for Human Cytogenetic Nomenclature, 2013. Cytogenetic analysis of BMA cultures showed 46, XY, t(4;12)(q12;p13) [Figure 1]b in all the twenty metaphases analyzed. Thus, the diagnosis of AML with t(4;12) was made. Fluorescence in situ hybridization analysis using LSI ETV6 break-apart probe (Vysis, Abbott) confirmed the rearrangement of ETV6 gene present on the short arm of chromosome 12 in 95% of the cells [Figure 1]c.
|Figure 1: (a) Bone marrow aspirate showing blasts with pseudo-lymphoid morphology and a dysplastic myeloid cell, (b) karyotype showing t(4;12)(p12;p13), (c) fluorescence in situ hybridization using break-apart probe for ETV6 gene (Vysis, Abbott) showing one intact yellow fusion signal (normal chromosome 12) indicating normal ETV6 gene and distinct broken apart red (derivative chromosome 4) and green (derivative chromosome 12) signals indicating ETV6 gene involvement|
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The patient was treated with induction therapy using idarubicin and cytarabine on a 7 + 3 protocol. Postinduction, BMA showed persistent disease with 35% blast. The second induction was not given due to the poor general condition of the patient. The patient was put on palliative care and sent home.
| Discussion|| |
According to Harada et al., , acute leukemia with t(4;12) is a rare event with an estimated incidence of 0.6% among adults (mean age: 66 years), with a male to female preponderance of 1.2:1 showing distinct and peculiar clinical and morphological features. There has been occasional mention of such cases in literature with obvious resemblances such as the presence of dysplasia in all the three erythroid, myeloid, and megakaryocytic lineages, low or absent myeloperoxidase activity, basophilia, and an atypical myeloblast morphology resembling lymphocytes described as pseudo-lymphoid morphology. ,,, Intensive induction therapy achieves remission in one-third of the patients of AML with t(4;12), along with the presence of persistent dysplasia. According to MA Sk et al.  , all the patients with persistent disease died within 6 months of diagnosis. The characteristic features of AML with t(4;12) are pseudo-lymphoid morphology of the blasts, dysplasia of erythroid, myeloid, and megakaryocytic lineages, and distinct phenotype expressing CD7, CD34, and HLA-DR, suggesting stem cell origin of blasts.
Sainty et al.  reported a case of t(4;12) in a CD7-negative AML, contrary to the literature that suggested the t(4;12) was restricted to a special phenotype of CD7-positive AML. According to literature, majority of the cases with t(4;12) correspond to AML-M0, complete morphological remission is achieved in about one-third of the patients, and OS ranged from few months to 51 months. 
The t(4;12) is reported in 24 myeloid [Table 1] and four lymphoid leukemias, though the B-ALL cases seem to have a more distal breakpoint in 4q13 or 21. The t(4;12) leads to the fusion of CHIC2 gene present on 4q11-12 to ETV6 gene on 12p13.  The ETV6 gene has thirty partner genes and it is involved in precursor B-ALL with t(12;21)(p13;q22), chronic myelomonocytic leukemia with t(5;12)(q33;p13), and AML with t(4;12)(q11-12;p13). 
A rare entity called AML with t(4;12)(q12;p13) is the sign of early hematopoietic genetic disruption, which also evinces with lymphocytes looking like circulating myeloblasts. Stem cell origin is suggested by immunophenotyping. Further research is vindicated as the prognosis with these translocation-associated patients is poor. Upgraded comprehension of the pathophysiology of the translocation is imperative so that the battle against these highly resistant cases can be won.
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Conflicts of interest
There are no conflicts of interest.
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Department of Cytogenetics, Tata Medical Center, Rajarhat, New Town, Kolkata - 700 156, West Bengal
Source of Support: None, Conflict of Interest: None