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Abstract
“Lineage switch” is term described when leukemic cells on relapse exhibit a new phenotype, where losses of one lineage defining markers with simultaneous gain of another lineage defining markers occur. Relapse of acute leukemia is although a very common event, lineage switch occurs and reported very rarely in such cases. The pathogenesis involved in this phenomenon remains unclear; however plasticity of hematopoietic progenitor affected by intrinsic and extrinsic environmental cues can be a possible explanation. In most of the cases at the time of relapse conversion of B-acute lymphoblastic leukemia (ALL) to acute myeloid leukemia (AML) occurs. Here, we presented an unusual case of 10 year old boy with AML switched to T-ALL upon relapse, which is very rare and not well documented till date in literature. The diagnosis was further supported by morphologic, cytochemistry and flowcytometric immunophenotyping (FCM-IPT). Prognosis and survival of such cases remains poor even by the use of standard chemotherapy.
Keywords: AML, cytochemistry, flowcytometric immunophenotyping, lineage switch, T-ALL
How to cite this article: Introduction 
Leukemic lineage conversion from one lineage to another in the disease course has been reported in literature, but not very well described so far. This is known to be associated with poor prognosis, despite administration of chemotherapy based on immunophenotype findings.[1],[2]
Of note, switch from acute lymphoblastic leukemia (ALL) to acute myeloid leukemia (AML) is encounter more frequently because of clonal heterogeneity is more commonly seen in AML. Only a few cases has been reported, that is of AML to B-ALL.[3],[4]
An exceptional case narrated here is a patient of AML who switched to T-ALL in his course of medical care. This phenomenon is rarest of rare and not reported in literature so far in best of our knowledge.
Case Report A 14 year old child presented with relapse of acute leukemia, in August 2018. He was diagnosed primarily as non-APML-AML outside in 2014.
At time of initial diagnosis he presented to the medical care with complain of fever and constitutional symptoms. On examination pallor was present, however there was no significant lymphadenopathy/organomegaly. The initial laboratory findings revealed hemoglobin (Hb) 8.4 gm/L, total leucocyte count (TLC) 57.8 × 109/L and platelet count 68 × 109/L. Differential count revealed 79% leucoblasts along with 12% lymphocytes and 9% polymorphs. Serum lactate dehydrogenase (LDH) was high (1223 U/L) (Normal Value: 120-246 U/L). There was no significant past medical/surgical/family history.
The bone marrow (BM) performed initially, was hypercellular with 75% of leucoblasts. The Flowcytometric immunophenotyping (FCM-IPT) was performed outside and revealed dim CD45+ leucoblast with expression of CD33+, CD117+, MPO+ with dim positivity for CD34 and CD38. B-Lymphoid markers (CD 10, CD19, CD20, CD79a), T-Lymphoid Markers (CD3, CD4, CD5, CD7 including cytCD3) and others (HLA-DR, TdT) were negative [Table 1] and [Figure 1].
Table 1: Summary of Immunomarkers Profile at time of initial diagnosis and at relapse
Figure 1: At the time of initial diagnosis Antigen expression pattern. Statics dot plots reveal (a) P1-Blast- Red, P2- Monocytes- green, P3- Lymphocyte- blue, P4- Polymorphs- Purple. (b and c) 33% CD34 positive blast with negative expression of B-lymphoid marker. (d and e) T tube reveals negative expression for CD3, CD5 and CD7. (f-k) Blast express CD33, CD117, MPO with negative cytoCD3, CD13, cytoCD79a and HLA-DRWith all above features diagnosis of AML was made. Baseline diagnostic cytogenetic study was not performed. Standard AML Chemotherapy was planned but because of financial constraints he was put on Metronomic chemotherapy (which is not the standard of care), including 6-Mercaptopurine (6-MP), etoposide and prednisolone. He received this Metronomic chemotherapy from December 2014 to January 2017 outside our hospital. He was tolerating this chemotherapy well without transfusion dependency.
Patient again became symptomatic in august 2018 and then presented to us with complain of fever lasting for fifteen days. General examination showed pallor with no organomegaly or lymphadenopathy. The laboratory findings revealed Hb 9.5 gm/L, TLC 0.6 × 109/L and platelet count 89 × 109/L. On peripheral blood examination revealed pancytopenia with few leucoblasts. Serum LDH was raised (331.59 IU/L).
BM revealed 92% leucoblast. Morphologically these blasts were of lymphoid appearance with coarse chromatin and showed MPO negativity on cytochemistry. Due to morphological features are confusing FCM-IPT performed; surprisingly there is emergence of T-lineage defining marker. CytCD3 was homogenous bright positive along with bright homogenous expression of surface CD7 and heterogeneous dim CD5 (21% population). Leucoblast also reveal expression of CD13 (dim), CD33, CD34 and CD38. Lineage defining markers of B-cell (CD19, CD20, CD22 and CD79a), myeloid (MPO) and monocytic markers (CD11c, CD14, CD64) were negative in addition to other negative markers including CD4, CD8, CD10, CD117, HLA-DR and surfaceCD3. FCM-IPT was diagnostic of Early T- Precursor Acute Lymphoblastic Leukemia (T-ALL). CD1a marker was negative at time of relapse [Table 1] and [Figure 2]. Cerebrospinal fluid (CSF) cytology was negative for blast.
Figure 2: At the time of Relapse: Antigen expression pattern. Statics dot plots reveal (a) Blast (red), Mature Lymphocytes (green) and polymorphs (light blue). (b and c) 76.8% CD34 and CD38 positive Blast show negative expression for B-Lymphoid Marker. (d and e) T tube reveals surface CD3 and CD56 negative blast with expression of CD5 and CD7. (f and g) Blast reveal Dim heterogeneous expression of CD13, CD33 and Negative for CD117 and HLA-DR. (h-k) T Tube reveals CD34 positive Blast expressing bright cytCD3 and CD7 (Origi)Since it was a follow up case of AML, now the immunoprofile of relapse leukemia is of T-ALL. Immunohistochemistry (IHC) on bone marrow biopsy was also performed for reconfirmation which revealed immunoexpression of CD2, CD3, CD34 and TdT whereas CD4, CD15, CD117 and MPO were negative. Thus, MPO negativity was confirmed by triple methods including cytochemistry, FCM and IHC (as recommended by WHO). Expression of CD3 was also duly confirmed (FCM + IHC). There was no expression of a lymphoid lineage defining or supporting markers at the time of initial diagnosis. So, change in morphology as well as immunophenotype at relapse indicated switch in lineage to T-ALL.
Notably, karyotyping analysis for our patient was performed at relapse and did found complex alteration in cytogenetics - 47XY, t (1;22;16) (p13;q13;q12), t21. Further molecular studies (FLT3, NRAS/KRAS, DNMT3A and IDH1/2) were also advised but due to financial constraints it was not done [Figure 3].
He was started with induction chemotherapy with pediatric chemotherapeutic regimen (BFM-95) protocol from 01/10/2018. He received Triple intrathecal and steroids with day eight injection daunomycin, vincristine and one dose of injection L-asparginase. However, due to financial constraints parents again were not willing for further definitive chemotherapy and within a year patient succumbed of this disease.
Discussion Leukemia usually during the disease course shows fidelity towards its committed lineage. However, occasionally, there is complete morphologic and immunophenotypic alteration of leukemic cells and they undergo a conversion from one cell lineage to another, due to the effect of chemotherapy during treatment or at the time of relapse.[5] Several hypothetical mechanisms exist in literature but central mechanism still remains unclear.
Among them first is stem cell plasticity in the original clone which goes through a conversion in phenotype with or without a change in genotype. Another possible mechanism was clonal selection as there may be multiple neoplastic populations (subclone) with different phenotype. The major apparent leukemic clone was removed by use of chemotherapy, however expansion of these minor subclones occurred in face of lineage switch. Bi- and Oligopotential progenitors (common progenitor model) retain by tumor cell and play a potential role in leukemic transformation, which influenced by intracellular and extracellular signals.[2],[6]
Rossi et al.[5] during their study reported a large cohort of 1482 patients with pediatric leukemia's, found incidence of phenotypic lineage switch in 0.6% cases (9/1482). Among them ALL to AML (7/9) switch is more common than AML to B-ALL (2/9). Dorantes-Acosta E et al.,[3] Krawczuk-Rybak M et al.[4] also reported a lineage switch from AML to B- ALL. Gerr et al.,[7] and Ittel et al.[8] reported case studies which show switched to AML after initial diagnosis. In a case study by Park et al.[9] there is a lineage switch documented from B ALL - T ALL - AML.
Zardo et al.[10] proposed that chromatin pattern plays a pivotal role in gene expression; decide the fate and differentiation of cell state. Complex cytogenetic alteration in presented case might be a cause of chromosomal instability and fragility induced by chemotherapy, comprised one possible explanation for this rare conversion. However, lacuna in this case was non-availability of baseline cytogenetic study. So, definite evidence of clonal evolution cannot be demonstrated.
Rossi et al.[5] found conversion time range, from day 8th to 6 months from initial diagnosis, whereas in presenting case it was approximately four year (2014 to 2018). There was no evidence of B/T lymphoid lineage specific markers at the time of initial diagnosis until the patient relapsed, which proposed the unique switch of lineage from myeloid to T-ALL.
There are not much data on lineage conversion available, probably because of FCM-IPT is generally performed initially but not at the time of relapse or along the treatment, and thus the actual incidence of these events might be underestimated. During the treatment, if there is change in blast morphology, the FCM-IPT should be performed to confirm the presence of any subclone or emergence of new clone, which are usually resistant to treatment as reported by Rossi et al.[5] However in this case also on extended gaze into initial flowcytometry images, possibility of very minor subclone cannot be ruled out. Hence, we recommended FCM-IPT at the time of relapse to confirm these rare events before re-initiation of relapse treatment protocol or whenever there is suspicious change in morphology.
The pathogenesis of acute leukemia is well studied and understood, however the exact and well-defined mechanism for lineage switch has to be explored. Further, sequential phenotyping and cytogenetic studies at initial and on relapse may capitulate for early detection of lineage switch and standard treatment initiation.
Here, we present a rare case of lineage switch, from AML to T-ALL which consider of great value due to different treatment approach. So, with better understanding of the genetic basis of lineage conversion, new therapies can be designed to address this rare lineage switch phenomenon with improved insight.
Acknowledgement
I would like to extend my sincere thanks to CORE DIAGNOSTICS for providing initial Flow cytometry images. [Figure 1] and karyotyping image [Figure 3] (www. corediagnostics.in).
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The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
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Conflicts of interest
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References 
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CheckDOI: 10.4103/ijpm.ijpm_441_21
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