Authors: Haley Corbin, Vandana Baloda, Nathanael Bailey, Svetlana Yatsenko
Clinical History
A toddler-age boy with no significant past medical history presented to a primary care provider for evaluation of bumps noted on the skin over a period of a few days. Physical examination was remarkable for right-sided inguinal lymphadenopathy consisting of two 3-4 cm nontender, mobile, rubbery lymph nodes, and the patient was sent to the emergency department for further evaluation. Complete blood count and basic metabolic panel were within normal limits with a slightly elevated uric acid of 5.5 mg/dL and mildly elevated lactate dehydrogenase (LDH) with hemolysis. Ultrasound revealed likely reactive lymphadenopathy with recommendation for close follow-up given the size of the lymph nodes.
On re-evaluation of the patient approximately two weeks later, his lymphadenopathy was persistent, and repeat labs showed leukocytosis, as follows:
A peripheral blood smear showed numerous circulating blastoid cells characterized by small to intermediate size, scant cytoplasm, rare nucleoli, and some irregular nuclear contours (Figure 1-A). No significant cytoplasmic vacuolization was present.
Peripheral blood flow cytometry revealed an abnormal circulating B-cell population (around 60% of cells) with the following phenotype:
Subsequent bone marrow biopsy, touch imprint, and aspirate showed a B-lineage neoplasm with blastoid morphology almost entirely involving the bone marrow in diffuse sheets and representing about 90% of the cells in the sample (Figure 1-B,C). The bone marrow differential was as follows:
Results of immunohistochemical studies performed on the bone marrow biopsy for further characterization of the infiltrate were as follows:
Overall, the cells in the bone marrow showed a lymphoblastic morphology similar in appearance to the blasts in the peripheral blood, however flow cytometry and immunohistochemical findings showed a CD19-positive B-lineage phenotype with somewhat intermediate features, making definitive classification difficult. Specifically, the cells lacked clear expression of markers of immaturity (CD34, TdT, CD99), and they showed surface kappa immunoglobulin light chain expression and CD45 positivity slightly dimmer than expression in mature B cells, yet CD20 was positive only in a subset of the abnormal cells, more suggestive of an immature phenotype.
Given the diagnostic challenges associated with this case in the setting of a transitional-appearing phenotype, the bone marrow was sent for cytogenetic studies to test for common chromosomal aberrations associated with B-cell acute lymphoblastic leukemia.
G-banding chromosome analysis showed an apparently normal male karyotype: 46,XY[20]. No clonal, numerical, or structural abnormalities were observed. Fluorescence in situ hybridization (FISH) analysis performed on interphase cells was negative for trisomies 4 and 10, negative for loss of JAK2, negative for the CRLF2, ABL2, PDGFRB, MYC and ABL1 gene rearrangements, and negative for BCR::ABL1 and ETV6::RUNX1 gene fusions (not shown). FISH testing for KMT2A break-apart rearrangement revealed a loss of one signal for 3’ KMT2A in 41.5% of cells (Figure 2).
Further, microarray analysis identified a loss in the 11q23.3 region encompassing the 3’ region of the KMT2A gene and the 5’ region of the CBL gene (Figure 3). The breakpoints for the deletion were located between exons 10 and 11 of KMT2A, and exons 2 and 3 of the CBL gene. Together with the FISH KMT2A break-apart probe showing loss of one 3’ signal, this suggests the presence of a rare KMT2A::CBL fusion. In addition, microarray analysis detected a loss in 9p13 including part of the PAX5 gene (Figure 3).
The patient was started on four drug induction chemotherapy (cytarabine, vincristine, doxorubicin +dexrazoxane, and calaspargase) per protocol AALL1732. The patient tolerated chemotherapy well with an appropriate decrease in white blood cell count and resolution of lymphadenopathy.