Systemic Epstein–Barr Virus–Positive T-Cell Lymphoma of Childhood: A Case Series

To the Editor:

Systemic Epstein–Barr virus (EBV)–positive T-cell lymphoma of childhood (SEBVTCL) is a rare, aggressive non-Hodgkin lymphoma primarily described in Asian populations, for which no standard therapy exists [1, 2]. It often occurs following primary EBV infection, or more rarely in the setting of chronic active EBV (CAEBV). SEBVCTL is characterized by a rapidly progressive monoclonal cytotoxic T-cell proliferation, often with concomitant hemophagocytic lymphohistiocytosis (HLH) and multiorgan failure. Clonal T-cell receptor (TCR) gene rearrangements are detected, with the poorest outcomes seen in cases with karyotypic abnormalities [1, 3]. We report four cases of SEBVTCL from multiple institutions, illustrating the importance of high clinical suspicion for prompt diagnosis and therapy initiation (Table 1).

TABLE 1 |.

Clinical and pathologic summary of four pediatric patients with systemic Epstein–Barr virus–positive T-cell lymphoma of childhood.

Case	Age (years) / Sex	Presenting features	Laboratory findings at diagnosis	Hematopathology findings	Treatment regimen	Outcome
1	14 / M	Weight loss, fevers, emesis, HSM, LAD, HLH	EBV viral load 164,000 IU/mL	IHC: CD3+, CD5−, CD8+, EBER+, TCR BetaF1+	Dexamethasone; CHOEP + nivolumab + emapalumab	Death
2	4 / F	Fevers, cytopenias, transaminitis, LAD, HSM	EBV viral load 744,992 IU/mL	IHC: CD3+, CD5−/weak, CD8+, EBER+ TCR gene rearrangement: clonal (beta, gamma)	IVIG + rituximab; Bortezomib + ganciclovir + prednisone; Modified SMILE	Death
3	17 / M	Cough, fevers, weight loss, fatigue, pancytopenia, liver failure, HLH	EBV viral load >5 million IU/mL; CXCL9 >79,000 pg/mL; sIL2R >40,000 U/mL	IHC: CD3+, CD4+, CD8+, EBER+ TCR gene rearrangement: clonal (beta, gamma)	IVIG + rituximab; Dexamethasone + ruxolitinib + etoposide; emapalumab + nivolumab	Death
4	15 / F	Fevers, night sweats, abdominal pain, LAD, septic shock	EBV viral load >5 million IU/mL; CXCL9 >608,000 pg/mL; sIL2R >4000 U/mL	IHC: CD3+, CD7− /weak, CD8+, EBER+ TCR gene rearrangement: clonal (gamma)	D-SMILE; Busulfan, fludarabine, alemtuzumab conditioning for allogenic HSCT	Remission +420 days post-HSCT

Abbreviations: CHOEP, cyclophosphamide, doxorubicin, vincristine, etoposide, prednisone; D-SMILE, daratumumab, methotrexate, ifosfamide, dexamethasone, etoposide, L-asparaginase; EBV, Epstein–Barr virus; F, female; HLH, hemophagocytic lymphohistiocytosis; HSCT, hematopoietic stem cell transplant; HSM, hepatosplenomegaly; IHC, immunohistochemistry; IVIG, intravenous immunoglobulin; LAD, lymphadenopathy; M, male; modified SMILE, dexamethasone, methotrexate, ifosfamide, L-asparaginase, etoposide; TCR, T-cell receptor.

A 14-year-old African American male (Case 1) presented with 2 weeks of emesis, weight loss, and fevers. Positron emission tomography/computed tomography (PET/CT) demonstrated diffuse hypermetabolic lymphadenopathy (LAD) and hepatosplenomegaly (HSM), and he had clinical evidence of HLH. Initial EBV load by quantitative PCR (qPCR) was 164,000 IU/mL. Bone marrow biopsy showed hypercellularity with CD3⁺ CD8⁺ EBV⁺ T cells with aberrant loss of CD5 (Figure 1A–E), and the inguinal lymph node biopsy demonstrated EBV⁺ CD8⁺ T cells (Figure 1F–J) and TCR BetaF1⁺, confirming a diagnosis of SEBVTCL. He began CHOEP (cyclophosphamide, doxorubicin, vincristine, etoposide, prednisone) chemotherapy in addition to emapalumab and nivolumab for secondary HLH. Following Cycle 2, EBV viral load was undetectable. Following the fourth cycle, he again had increasing EBV viral load, CXCL9, and soluble IL2R levels. While awaiting count recovery to receive further therapy, he experienced acute clinical deterioration of unclear etiology that ultimately proved fatal.

FIGURE 1 |.

Histopathologic findings from a 14-year-old male presenting with weight loss, fever, emesis, hepatosplenomegaly, lymphadenopathy, and hemophagocytic lymphohistiocytosis (Case 1). (A–E) Bone marrow core biopsy, 40 × magnification. (A) Hematoxylin and eosin (H&E) stain showing hypercellularity for age with maturing trilineage hematopoiesis. Immunostains highlight a subtle interstitial infiltrate of abnormal T cells expressing CD3 (B), decreased to absent CD5 (C), CD8 (D), and EBER (EBV-encoded RNA by in situ hybridization) (E). (F–J) Inguinal lymph node excisional biopsy 40 × magnification. (F) H&E showing sheets of abnormal lymphoid cells. The abnormal lymphoid cells express EBER (G), CD3 (CD3/EBER double stain) (H), and CD8 (I), and show a high proliferation index by Ki67 (J).

A 4-year-old Hispanic female (Case 2) presented with 1 month of fevers, cytopenias, transaminitis, LAD, and HSM. Infectious workup revealed a high EBV viral load by qPCR (744,992 IU/mL). Initial treatment for EBV viremia with rituximab and intravenous immunoglobulin (IVIG) was ineffective. Liver biopsy revealed numerous small lymphocytes positive for EBER in situ hybridization (EBER-ISH). Thus, she was treated for CAEBV with bortezomib, ganciclovir, and prednisone, which transiently reduced EBV load. Her disease progressed with disseminated LAD, worsening HSM, and bone marrow and central nervous system (CNS) involvement. Further molecular testing demonstrated clonal T-cell receptor beta and gamma gene rearrangements, leading to a diagnosis of SEBVTCL. She was initiated on T-lymphoblastic leukemia-type therapy, followed by a modified SMILE (dexamethasone, methotrexate, ifosfamide, L-asparaginase, etoposide) regimen at an advanced stage, but unfortunately succumbed to her disease.

A 17-year-old Hispanic male (Case 3) presented with 3 weeks of cough, fevers, weight loss, and fatigue. He was found to have pancytopenia, coagulopathy, and acute liver failure. CT scan demonstrated hepatosplenomegaly and minimal lymphadenopathy. Infectious workup revealed a high EBV viral load (qPCR > 5 million IU/mL), with EBV positivity predominantly in T/NK cells on cell-sorting analysis. He had clinical and laboratory evidence of HLH, prompting a diagnosis of EBV-driven HLH. He was initially treated with IVIG and rituximab, then received dexamethasone, ruxolitinib, and etoposide. HLH markers and EBV viral load increased, so emapalumab and nivolumab were added with transient improvement; however, he developed multiorgan failure and died. Repeat bilateral bone marrow biopsy, the results of which became available postmortem, revealed hemophagocytosis, CD8⁺ EBV⁺ cytotoxic T-cell expansion, and clonal T-cell receptor beta and gamma gene rearrangements, indicating a diagnosis of SEBVTCL.

A 15-year-old Hispanic female (Case 4) presented with septic shock after 1 month of neck swelling, fevers, night sweats, and abdominal pain. She was found to have pancytopenia, coagulopathy, and acute liver, renal, and respiratory failure. CT scan demonstrated axillary LAD, HSM, and splenic lesions. Infectious workup revealed a high EBV viral load (qPCR > 5 million IU/mL). HLH labs revealed ferritin greater than 10,000 ng/mL, CXCL9 greater than 608,000 pg/mL, and soluble IL2R greater than 4000 U/mL. Treatment for HLH was initiated with dexamethasone, IVIG, rituximab, and emapalumab. Subsequent axillary lymph node and bilateral bone marrow biopsies revealed EBV⁺ CD8⁺ cytotoxic T cells with hemophagocytosis and clonal TCR gamma gene rearrangements, establishing SEBVTCL as the underlying driver of her secondary HLH. She received two cycles of D-SMILE (daratumumab, methotrexate, ifosfamide, dexamethasone, etoposide, L-asparaginase) on a clinical trial (NYMC-575, NCT03719105), achieving bone marrow measurable residual disease (MRD) negativity and radiographic remission. She received an allogeneic matched stem cell transplant (SCT) following conditioning with busulfan, fludarabine, and alemtuzumab, and remains in remission as of post-transplant Day + 420.

SEBVTCL is a fulminant and rapidly progressive lymphoma with a high mortality rate. It has been reported most commonly in Asian populations, but, as exhibited by our report, it can affect any child. Early clinical suspicion and prompt diagnosis by a skilled pathologist and multidisciplinary team are necessary, as organ dysfunction may limit therapeutic options. Confirmation of EBV infection, tissue immunophenotyping, and confirmation of T-cell clonality aid in the diagnosis. T-cell clonality can be confirmed by molecular testing for clonal TCR gene rearrangements or, alternatively, by dual assessment of TCR beta chain constant region (TRBC)-1/TRBC2 expression on flow cytometry [4]. Case series indicate that asparaginase-or anthracycline-based regimens followed by hematopoietic SCT can lead to a cure [5, 6]. Further research is required to improve the classification and treatment strategies for rare lymphomas like SEBVTCL.