Denovo B- Lymphoblastic Leukaemia/Lymphoma with double hit gene rearrangements (MYC/BCL-2), del9p and precursor immunophenotype presented with spinal cord compression & associated with good prognosis Dina Sameh
1,3 Soliman ,
1 Al-Sabbagh ,
1 Ibrahim ,
Ahmad Feryal Shehab Halima El-Omri 2 and Mohamed Yassin 2
2 Fareed ,
Mohamed
4 Talaat
1Department
of Laboratory Medicine and Pathology, National Center for Cancer Care and Research, Hamad Medical Corporation, Doha- Qatar. 2Department of Hematology and Medical Oncology, National Center for Cancer Care and Research, Hamad Medical Corporation, Doha, Qatar. 3Department of Clinical Pathology, National Cancer Institute, Cairo University, Cairo, Egypt. 4 Department of Radiology, Hamad Medical Corporation, Doha- Qatar.
Introduction: Double hit lymphomas are aggressive mature B-cell neoplasms associated with rearrangements involving MYC and BCL2. Such double-hit events are extremely rare in Bcell precursor acute lymphoblastic leukemia, especially in young adults. According to WHO Classification 2008 WHO, most cases with MYCyBCL2 double-hit rearrangements have histologic features of diffuse large B-cell lymphoma (DLBCL) or B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and Burkitt lymphoma (BCLU).
Case Report
Discussion A
Our Patient is 29 year-old male with no significant past medical history, presented with cheek swelling of two months-duration associated with intermittent fever and night sweats with no significant weight loss. Biochemical work-up showed very high LDH 2,026.0 U/L. Peripheral blood showed pancytopenia: (ANC) at 0.1x10^3/ul, hemoglobin of 7.9 gm/dl and Platelets of 59 x10^3/uL with many circulating blasts (77%). Bone marrow (BM) aspirate smear showed extensive infiltration with 97% blasts, small in size with very high nucleocytoplasmic ratio and multiple prominent nucleoli. Few blasts show fine cytoplasmic blebs/ pseudopods (fig1) BM biopsy reflected marked hypercellularity (~100%), diffusely infiltrated with lymphoid blasts with finely dispersed nuclear chromatin and prominent nucleoli. (fig.2). By immunohistochemistry, the blasts were positive for TDT, PAX-5 (fig.3 A & B), CD10 and CD20. There is megakaryocytic proliferation with some clustering (fig. B). Flow cytometric revealed ~96%, blasts with immunophenotype classic of precursor B-lymphoblastic leukaemia: CD45 (dim), CD19, CD79a, CD10, HLADR, Tdt and CD20 and negative for cytoplasmic IgM. Karyotype: 46,XY,del(6)(q21q23),t(8;22)(q24.1;q11.2),t(14;18)(q32;q21)[20] FISH analysis for CDKN2A probe revealed deletion of the short arm of chromosome 9 (9p) in 94% of the cells analyzed. After release of cytogenetics result, cMYC, BCL-2 immunostains were performed on BMB and showed strong diffuse positivity (fig3 C& D) with negative expression of BCL-6. A diagnosis of B-Lymphoblastic Leukaemia/Lymphoma with combined t(8;22)(q24.1;q11.2)and t(14;18)(q32;q21) was made.
Very few cases (ten cases so far) of double-hit denovo ALL (DH – denovo ALL) with a well-documented true immature immunophenotype (positive for TdT and negative for surface light chains ) are reprted in literature [2-7].
Figure1: Wright stain, 1,000× magnification): Aspirate smear shows extensive infiltration with blasts; small in size with very high nucleocytoplasmic ratio and multiple prominent nucleoli. Few blasts show fine cytoplasmic blebs/ pseudopods.
A = A
B
A
B
TDT
Pax-5
C
D
BCL-2
c-MYC
Figure3: Immunohistochemistry on bone marrow biopsy showing diffuse infiltration by lymphoid blasts, positive for TdT(20X), PAX-5(10X), BCL-2(10X), and c-MYC (10X).
Conclusion It is of clinical and diagnostic importance to recognize and characterize this rare entity by using integrated pathologic, immunohistochemical, immunophenotypic and cytogenetics. It is also importance to identify the pathogenesis and molecular mechanisms implemented in this extraggressive lymphoid neoplasm which probably necessitate a customized and perhaps more intensive treatment protocols.
The possibility of lymphoblastic transformation on top of follicular lymphoma in this case was confounded, given the patient young age with acute sudden onset, the classic precursor B-ALL morphologic and immunophenotypic profile with diffuse marrow involvement and absent paratrabecular localization.
Figure 2: Bone marrow biopsy (H&E): showing marked hypercellularity (~100%) and diffuse infiltration with monomorphic population of small to medium sized lymphoid blasts. The blasts in the center of the biopsy appear larger with more prominent nucleoli compared to periphery (figure A)(10x). Marked megakaryocytic hyperplasia(20x)
Few days later, the patient developed fever and massive pleural effusion on which flow cytometry was performed and showed malignant effusion with 96% of blasts. The patient had evident bleeding tendency with significant massive bleeding from BM aspiration site and massive hemothorax, Coagulopathy work-up revealed acquired factor XIII deficiency at 38% with normal PT and APTT and . The patient then developed an acute onset paraplegia (power 0 out of 5) and sensory level up to T10. An urgent MRI spine showed acute cord compression secondary to huge paravertebral and intraspinal mass. Fig 4 (A,B). An emergency radiotherapy to the spinal cord (ten fractions) were given. Two weeks post radiotherapy, the patient was started on hyperCVAD protocol. After completion of radiotherapy and chemotherapy, the patient improved dramatically with power reached 4/5 in his lower limb and achieved complete remission confirmed by MRI spine Fig.4 (C), PET SCAN, CT & BM. The patient was in complete remission CR for 13 months after the initial presentation at last follow-up.
In contrast to DHL, which is a disease of elderly, upon literature review we found out that DH denovo ALL is more frequent among pediatrics and young adults with age ranging between 15 and 24 years.
Figure 4: (A&B): sagittal &axial post contrast fat saturated images of thoracolumbar spine before treatment show posterior intraspinal extradural mass lesion extending from T2 to T8 levels in sagital image, they are seen mildly compression the posterior aspect of cord, more from left side at T3 in axial image (arrow in B) with extension into both neural foramina more in left side as well as small paraspinal soft tissue component. (C&D) sagittal and axial post contrast fat saturated images at the same level after treatment show significant improvement with only small residual component seen posterior to cord at T3 level and extending into left neural foramina (arrow in D).
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Another morphologically interesting feature, is the presence of marked megakaryocytic hyperplasia (fig2 B) which raised the suspicion of the presence of an underlying myeloproliferative neoplasm; soon excluded by negative Jak2 and CALR mutations analysis and disappearance of this features in subsequent Bone marrows. Since the patient had transient acquired factor XIII deficiency, we assumed that this unexpected megakaryocytic proliferation might be a compensatory reactive mechanism to patient’s active bleeding. In the same way our case shared many of the previously reported clinical characteristics, However, In contrast to most other reported cases, this case achieved a very good response to hyper-CVAD with complete remission 13 months after initial diagnosis at last follow-up.
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