A 2-year-old Asian girl presented to our facility on May 2, 2017, for the evaluation of thrombocytopenia. At presentation, the blood routine revealed 11.1 g/dL hemoglobin, 10,000 platelets/μL, and 13,300 white blood cell (WBCs)/μL [59.3% neutrophils, 30.2% lymphocytes, and 9.3% monocytes]. She was intravenously treated with immunoglobulin under the impression of immune thrombocytopenia, and the platelet count increased to 39,000/μL on May 8, 2017. However, the WBC differential count revealed that neutrophils declined to 5.5%, with an absolute neutrophil count (ANC) of 259/μL. Moreover, her body temperature spiked on May 7, 2017, with elevated levels of ferritin (661 ng/mL), C-reactive protein (CRP, 1.24 mg/dL), and liver enzymes, specifically an alanine transaminase (ALT) level of 151 U/L and aspartate transaminase (AST) level of 209 U/L. Viral serologic studies confirmed positivity for Epstein-Barr virus (EBV)-VCA IgM, an EB-VCA IgG titer of 1:320, and a serum EBV viral load of 209,958 copies/mL. Subsequently, progressive pancytopenia, hepatosplenomegaly, abnormal liver function, coagulopathy, and pulmonary infiltration developed within 1 week.
On May 15, 2017, the blood routine revealed a WBC count of 8000/mL, hemoglobin level of 6.6 g/dL, and a platelet count of 62,000/μL; moreover, the ANC decreased to 0%, with remarkable atypical lymphocytosis noted on the peripheral blood smear. Further laboratory investigation revealed 279 U/L ALT, 816 U/L AST, 1.07 mg/dL total bilirubin, 2.5 g/dL albumin, 348 mg/dL triglyceride, 143 mg/dL cholesterol, 695 U/L alkaline phosphatase, 3307 U/L lactate dehydrogenase, and 8.1 mg/dL CRP level. Substantially elevated ferritin level (19,744 ng/mL), urine β2-microglobulin levels (14,264 ng/mL), and serum EBV viral load (359,579,823 copies/mL) were noted. The bone marrow aspirate showed presence of atypical lymphoid cells (white arrows, Fig. 1A); CD3+, CD8+, TIA-1+, and CD56− EBV-encoded RNA-positive (EBER+) T-cell phenotypes with hemophagocytosis (black arrows, Fig. 1A); and an abnormal clone, −6 or del(6)(q12) (Fig. 2). The cytology of pleural effusion also demonstrated prominent hemophagocytosis and medium-to-large atypical lymphocytes (Fig. 1B). The final diagnosis was systemic EBV-positive T-cell lymphoma of childhood with hemophagocytic syndrome. Exome-wide sequencing analysis of PRF1, SH2D1A, and XIAP genes was conducted, and results revealed no pathologic sequence variants.
The patient improved following treatment with immunochemotherapy with HLH-2004 protocol plus rituximab, which began on May 15, 2017. After 4 weeks, significant decreases were observed in the serum EBV viral load (1786 copies/mL), ferritin level (2664 ng/mL), and β2-microglobulin level (783 ng/mL); however, a follow-up bone marrow cytogenetic study revealed the same abnormal clone, indicating residual disease. Beginning on June 14, 2017, the patient was treated for T-cell lymphoma using chemotherapy with vincristine, epirubicin, L-asparaginase, cyclophosphamide, cytarabine, and 6-mercaptopurine. She presented with bone marrow remission 2 months later, with disappearance of the abnormal clone. Allogeneic peripheral blood stem cell transplantation from a matching nonrelative donor was performed in August 2017, with successful engraftment. Currently, the patient is in a disease-free follow-up period 19 months after the initial diagnosis.
Systemic EBV-positive T-cell lymphoma of childhood is extremely rare but occurs more commonly in Asians. This type of cancer has a fulminant clinical course typically associated with hemophagocytic syndrome.1,2 Its prognosis is generally poor, and a treatment strategy is yet to be established. Some reports have indicated that patients who receive allogeneic hematopoietic stem cell transplantation have a more favorable prognosis.1,3 The typical phenotypes are CD2+, CD3+, CD8+, and TIA-1+, whereas CD56 is usually not expressed. Double staining for EBER and CD3 or CD8 is crucial for diagnosis.3–4 The diagnosis of this disease is particularly challenging to pathologists when clinical information and EBER studies are lacking. This type of lymphoma must be diagnosed differentially from acute EBV-associated hemophagocytic lymphohistiocytosis, which is considered nonmalignant. This case report highlights the importance of awareness of this type of rare cancer, a comprehensive diagnostic approach, and close communication between primary care physicians and pathologists.
1. Sato E, Ohga S, Kuroda H, et al. Allogeneic hematopoietic stem cell transplantation for Epstein-Barr virus
-associated T/natural killer-cell lymphoproliferative disease in Japan. Am J Hematol. 2008;83:721–727.
2. Cai Q, Chen K, Young KH. Epstein-Barr virus
-positive T/NK-cell lymphoproliferative disorders. Exp Mol Med. 2015;47:e133.
3. Kimura H, Ito Y, Kawabe S, et al. EBV-associated T/NK-cell lymphoproliferative diseases in nonimmunocompromised hosts: prospective analysis of 108 cases. Blood. 2012;119:673–686.
4. Kasahara Y, Yachie A, Takei K, et al. Differential cellular targets of Epstein-Barr virus
(EBV) infection between acute EBV-associated hemophagocytic lymphohistiocytosis and chronic active EBV infection. Blood. 2001;98:1882–1888.
Keywords:Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.
Epstein-Barr virus; T-cell lymphoma; hemophagocytosis