Dr Varsha v s/ Dr Rema(Paed Haemato)/ DrPraveena/Dr jayakumar
Five year old boy with h/o on and off abdominal pain and constipation since last 6 months which get relieved only laxatives. Presented withc/o severe pain abdomen and constipation since 3 days.
On examination vitals stable, pallor present. Systemic examination revealed soft but palpable stools and Hepatosplenomegaly. Labs showed anemia with elevated LDH.
USG abdomen was done which showed abdominal lymphadenopathy with multiple enlarged discrete & conglomerate appearing mesenteric & retroperitoneal Lymphnodes.
Differentials considered were:
B cell ALL
TB
Burkitt lymphoma
Diffuse large B cell lymphoma
Labs Tc: 18.8K/uL, N: 77.8%, L: 13.9%, M: 4.8%, Hb: 11.5g/dl, plt: 5lac
Ps: microcytic hypochromic RBC, polychromatophils, no blast or atypical cells, neutrophilic leucocytosis with left shift.
He was further planned for CECT abdomen which showed features suggestive of Lymphoma & aneurysmal dilatation of small bowel loops. CT thorax showed diffuse dilatation of Thymus, suggestive of involvement lymphoma. TB work up done was negative.
Whole Body PET CT Imaging:
Focal abnormal increased FDG uptake in nasopharynx lymphoid tissue. Abnormal focal FDG uptake in following lymph nodal stations: Cervical: i). Multiple left level IV / supraclavicular (SUV Max 7.4) Mediastinal: ii) Left highest mediastinal / upper paratracheal (SUV Max 6.6) iii) Paraoesophageal (SUV Max 6.2) iv) Soft tissue along right inferior pulmonary ligament (SUV Max 7.6). Abdominal: iv) Bilateral common iliac (SUV Max 9.2 left). Abnormal increased FDG uptake noted in conglomerate nodal mass involving mesenteric, para-aortic and aortocaval stations (SUV Max 10.9). No abnormal increased FDG uptake in enlarged bilateral axillary lymph nodes. Abnormal increased FDG uptake in visualised bone marrow in axial skeleton and bilateral femoral shafts (SUV Max 3.4). Abnormal increased FDG uptake in soft tissue lesion involving distal ileum, ileocaecal junction (SUV Max 10.6).
IHC -cells are positive for CD20,PAX-5,CD10,BCL6,c-myc and negative for CD3,BCL2,Tdt Ki 67 95% Findings are of Burkitts lymphoma. Bone Marrow Aspiration: Suggestive of involvement High Grade Hematopoietic Neoplasm likely Burkitt leukemia/lymphoma morphologically. Leukemia/Lymphoma/Myeloma Immunophenotyping Evaluation Flow Cytometry- positive for CD10, CD19, CD20, CD22, cy.CD79a, CD38, CD58 (Subset) and HLA-DR, suggestive of Burkitts Lymphoma. Bone Marrow Biopsy – The medullary spaces show sheets of atypical lymphoid cells with high NC ratio, scant to moderate cytoplasm, round to ovoid nucleus, clumped chromatin and inconspicuous nucleoli, suggestive of involvement Burkitts leukemia / lymphoma. Karyotype: 45,XY,t(8;14;13)(q22;q32;q33),-15,add(17)(p11)[20]. Parents were conselled about the diagnosis of Burkitt’s lymphoma stage IV. He was then shifted to PICU and under strict monitoring treatment was started according to protocol ie, BFM NHL R4 protocol.
Discussion:
Burkitt lymphoma (BL) is an aggressive non-Hodgkin B-cell lymphoma
Incidence: Burkitt lymphoma accounts for approximately 1% to 5% of all non-Hodgkin lymphomas. BL is more common in Caucasians than persons of African or Asian descent. In children younger than 18 years of age, the incidence is approximately 3 to 6 cases per 100,000 children annually.
Etiology: Burkitt lymphoma is associated with Epstein Barr virus. The exact mechanism underlying EBV and B-cell malignancy remains unclear. EBNA1 protein is an EBV latent protein expressed in endemic BL. EBNA2 gene deletion leads to the expression of EBNA3 genes (i.e., EBNA3A-C). Tumor cells derived from these cell lines are resistant to apoptosis. Burkitt lymphoma is endemic to areas where malaria is holoendemic, such as Brazil, Papua New Guinea, and equatorial Africa. Immunodeficiency-associated BL is linked to human immunodeficiency virus (HIV).
Histology: Burkitt lymphoma is an aggressive B-cell lymphoma comprising a monomorphic population of intermediate-sized mature lymphocytes. The cells contain round nuclei with lacy chromatin and may have one or more small nucleoli. The neoplastic cells are highly proliferative, which is reflected in the increased number of mitotic figures. Increased cell turnover is countered increased apoptosis. This results in a “starry sky” appearance due to tingible-body macrophages containing cellular debris. Immunohistochemistry and cytogenetics play a significant role in the diagnosis and management of Burkitt lymphoma. The malignant B-cells express surface IgM. The cells are positive for B-cell markers including CD19, CD20, CD79a, and PAX5. They are positive for germinal center markers CD10 and bcl-6 but are negative for bcl-2. Rapid cell turnover is reflected high Ki67 positivity nearing 100%, which is a very helpful diagnostic clue.
Investigation: In developed countries, BL is suspected microscopy or flow cytometry and confirmed immunohistochemistry and cytogenetics. Others tissue diagnosis is the main stay.
After a tissue diagnosis is made, bone marrow aspiration and biopsy, as well as cerebrospinal fluid (CSF) evaluation is done to assess the extent of involvement. Computerized tomography (CT) scans of the chest, abdomen, and pelvis are performed initially. Whole body PET/CT scans should be done but should not delay therapy. Required lab tests include complete blood count (CBC) with differential, ESR, complete metabolic panel (CMP), PT, PTT, serum lactate dehydrogenase, uric acid, hepatitis B serology, pregnancy testing in women, and HIV testing.
Treatment: In pediatric patients with stage I and II disease, overall survival is greater than 98%. For children with residual or stage III disease it is advised that the patient receives a minimum of four cycles of dose-intensive chemotherapy (i.e. two cycles of cyclophosphamide, vincristine, prednisolone, doxorubicin, and high-dose methotrexate). After which the patient receives two cycles of cytarabine and high-dose methotrexate. Intrathecal therapy is administered concurrently with chemotherapy. Lastly, in pediatric patients with CNS or bone marrow involvement, it is recommended that patients receive up to eight cycles of dose-intensive chemotherapy (i.e. two cycles of cyclophosphamide, vincristine, prednisolone, doxorubicin, and high-dose methotrexate) plus two courses of cytarabine and etoposide, in addition to four courses of maintenance chemotherapy (i.e. vincristine, prednisolone, high-dose methotrexate, cyclophosphamide, doxorubicin, cytarabine, and etoposide). Like residual or stage III disease, intrathecal therapy is administered concomitantly with chemotherapy.
Immunotherapy has a role in treatment. Rituximab (anti-CD20) should be a component of all treatment regimens as it is correlated with a positive prognosis. Newer anti-CD20 agents, ofatumumab and obinutuzumab, are under investigation.
Prognosis: Prognosis is dependent on clinical and histopathologic staging, particularly the extent of disease. It is possible that pediatric patients are better able to tolerate intense chemotherapy. Poor response to cyclophosphamide, prednisolone, and vincristine are poor prognostic indicators, as well as detection of CNS disease at presentation. Elevated lactose dehydrogenase concentrations (twice the upper limit of normal values) is associated with poor outcomes.