Summary
Epstein–Barr virus (EBV) is a ubiquitous herpesvirus with rare but severe potential for lymphoproliferative complications. EBV is associated with a variety of presentations of haemophagocytic ...lymphohistiocytosis (HLH). HLH is a life‐threatening hyperinflammatory syndrome that can occur in patients with genetic defects associated with dysregulation of the immune response (familial HLH) or arise in patients with underlying infection or malignancy (non‐familial or secondary HLH). EBV can both serve as the incidental trigger of familial HLH or as the driving factor in patients with selective inherited vulnerability (e.g. X‐linked lymphoproliferative disease). Alternatively, acute infection can idiosyncratically cause non‐neoplastic HLH in patients without inherited predisposition (i.e. secondary HLH), while EBV‐associated T/natural killer (NK)‐cell lymphoproliferative disorders and lymphomas can cause neoplasia‐associated HLH. The present review will discern between EBV‐associated familial and non‐familial HLH and highlight diagnostic and therapeutic considerations. Non‐familial EBV‐associated HLH is a major diagnostic dilemma, as it represents a diverse spectrum of disease ranging from highly curable (non‐neoplastic EBV‐HLH) to indolent but incurable (chronic active EBV) to acutely fatal (systemic EBV‐positive T‐cell lymphoma of childhood). Increased clinical awareness and understanding of this rare and potentially devastating subset of EBV‐related complications is desperately needed to improve survival for patients with neoplasia‐associated HLH.
Pediatric non‐Hodgkin lymphoma (NHL) includes over 30 histologies (many with subtypes), with approximately 800 cases per year in the United States. Improvements in survival in NHL over the past 5 ...decades align with the overall success of the cooperative trial model with dramatic improvements in outcomes. As an example, survival for advanced Burkitt lymphoma is now >95%. Major remaining challenges include survival for relapsed and refractory disease and long‐term morbidity in NHL survivors. Langerhans cell histiocytosis (LCH) was added to the NHL Committee portfolio in recognition of LCH as a neoplastic disorder and the tremendous unmet need for improved outcomes. The goal of the Children’ Oncology Group NHL Committee is to identify optimal cures for every child and young adult with NHL (and LCH). Further advances will require creative solutions, including engineering study groups to combine rare populations, biology‐based eligibility, alternative endpoints, facilitating international collaborations, and coordinated correlative biology.
Introduction
Internationally validated tools to measure patient‐reported health‐related quality of life (HRQoL) are available, but efforts to translate and culturally validate such tools in ...sub‐Saharan Africa (SSA) are scarce, particularly among children.
Methods
The Patient‐Reported Outcomes Measurement Information System 25‐item pediatric short form (PROMIS‐25) assesses six HRQoL domains—mobility, anxiety, depression, fatigue, peer relationships, and pain interference—by asking four questions per domain. There is a single‐item pain intensity item. The PROMIS‐25 was translated into Chichewa and validated for use in Malawi using mixed qualitative and quantitative methods. The validity and reliability of the PROMIS‐25 was assessed.
Results
Fifty‐four pediatric patients with lymphoma completed the PROMIS‐25. Structural validity was supported by interitem correlations and principal component analysis. Reliability of each scale was satisfactory (range alpha = 0.71‐0.93). Known group validity testing showed that anemic children had worse fatigue (P = 0.016) and children with poor performance status had worse mobility (P < 0.001) and pain interference (P = 0.005). Compared to children with cancer in the United States, children from Malawi reported lower levels of mobility, higher anxiety, higher depressive symptoms, higher fatigue, better satisfaction with peer relationships, and higher pain interference.
Conclusion
Translation and cultural validation of the PROMIS‐25 into Chichewa for Malawi was successful. Baseline HRQoL for patients with pediatric lymphoma in Malawi is poor for all domains except peer relationships. This emphasizes an urgent need to address HRQoL among children undergoing cancer treatment in SSA using self‐reported instruments validated within the local context.
Summary
Non‐Hodgkin lymphoma (NHL) is a heterogeneous group of lymphoid malignancies accounting for a significant portion of cancers occurring in children, adolescents and young adults with an ...increasing incidence with age. The adolescent and young adult (AYA) population presents a specific set of characteristics and challenges. The most common diseases occurring in adolescents and young adults include Burkitt lymphoma, lymphoblastic lymphoma, diffuse large B‐cell lymphoma, anaplastic large cell lymphoma and primary mediastinal B‐cell lymphoma. There is also a higher incidence of primary central nervous system lymphoma in AYA patients. Cure rates largely depend on risk‐stratification, and are generally superior to outcomes in comparison to older adult data but less than in younger children. Here, we review the unique clinical and biological characteristics of NHL occurring in the AYA population with a focus on how to achieve similar curative outcomes in AYA that have been established in younger cohorts.
High‐dose methotrexate (HD‐MTX) with rigorous supportive care is essential to the treatment of pediatric non‐Hodgkin lymphomas (NHL). We describe the safety and tolerability of HD‐MTX in patients ...with NHL treated at our center. In our cohort of 46 patients, the majority had at least one course of delayed clearance and/or creatinine elevation. Additionally, more than one‐third of patients experienced an episode of grade ≥3 mucositis. Creatinine elevations and delayed clearance were independently associated with subsequent grade ≥3 mucositis. We advocate for greater availability of methotrexate monitoring to allow dose escalation of this essential modality around the world.
Pediatric non-Hodgkin lymphoma includes over 30 histologies (many with subtypes), with approximately 800 cases per year in the US, compared to >60,000 cases of adult NHL annually. Improvements in ...survival in pediatric and adolescent mature B cell NHL over the past 5 decades align with the overall success of the cooperative trial model with dramatic improvements in outcomes through dose escalation of chemotherapy and, more recently, targeted therapy with rituximab. Pediatric dose-intense strategies carry risks of long-term consequences, but treatment failure is nearly universally fatal. By comparison, adult mature B cell lymphoma is typically less aggressive and treated with less intense chemotherapy. Optimizing therapy for adolescents and young adults remains a major challenge that requires creative solutions, including engineering study groups to combine biologically comparable adult and pediatric populations and developing effective salvage strategies that will ultimately be required for investigations of front-line dose reduction. In this review, we discuss challenges and opportunities for improving outcomes for adolescents and young adults with high-grade mature B cell lymphomas, diffuse large B cell lymphoma, and primary mediastinal B cell lymphoma.
Kaposi sarcoma (KS) is among the most common childhood malignancies in central, eastern, and southern Africa. Although its unique clinical features have been established, biological mechanisms ...related to the causative agent, KS‐associated herpes‐virus (KSHV), have yet to be explored in children. We performed a prospective observational pilot study to explore associations between KSHV viral load (VL), human interleukin‐6 (IL‐6) and IL‐10 levels, and clinical characteristics of 25 children with KS in Lilongwe, Malawi from June 2013–August 2015. The median age was 6.4 years. Lymphadenopathy was the most common site of KS involvement (64%), followed by skin and oral mucosa (44% each), woody edema (12%), and pulmonary (8%). Baseline samples for plasma KSHV VL, IL‐6 and IL‐10 analyses were available for 18/25 patients (72%) at time of KS diagnosis. KSHV VL was detectable at baseline in 12/18 (67%) patients, the median baseline IL‐6 level was 8.53 pg/mL (range 4.31–28.33), and the median baseline IL‐10 level was 19.53 pg/mL (range 6.91–419.69). Seven (39%) patients presented with an IL‐6 level > 10 pg/mL (exceeding twice the upper limit of normal). Detectable KSHV VL was significantly associated with lymphadenopathic KS (p = 0.004), while having undetectable KSHV VL was associated with a higher likelihood of presenting with hyperpigmented skin lesions (p = 0.01). Detectable KSHV VL and elevated IL‐6 levels are present in a subset of children with KS. Lytic activation of KSHV and associated elevation in KSHV VL may contribute to the unique clinical manifestations of pediatric KS in KSHV‐endemic regions of Africa.
What's new?
Kaposi sarcoma is among the most common childhood malignancies in regions endemic for Kaposi sarcoma‐associated herpesvirus (KSHV), but virological characteristics of the disease remain undefined. Here the authors studied 25 children with Kaposi sarcoma in southeastern Africa and established links between distinct clinical patterns and elevated KSHV viral load and interleukin‐6 levels. The results points to a role of KSHV lytic activation and a potential KSHV inflammatory cytokine syndrome in the lymphadenopathic form of childhood Kaposi sarcoma.
Background
Systemic forms of EBV‐associated T‐cell lymphoproliferative disorders of childhood (S‐EBV‐T‐LPD) comprise three major forms: EBV‐positive hemophagocytic lymphohistiocytosis (EBV‐HLH), ...systemic EBV‐positive T‐cell lymphoma (S‐EBV‐TCL), and systemic chronic active EBV infection (S‐CAEBV). These disorders occur rarely in children in Western countries. Here, we described eight children of such entities.
Design
Eight cases (six clinical and two autopsy) with S‐EBV‐T‐LPD of childhood were retrospectively identified from 1990 to 2015. Clinicopathologic parameters including histomorphology, immunophenotype, EBV studies, and T‐cell receptor gene rearrangement studies were recorded.
Results
Patients include five females and three males of Hispanic, Asian, and Caucasian origins with an age range of 14 months to 9 years. Fever, hepatosplenomegaly, cytopenias, abnormal EBV serologies, and very high EBV viral loads were common findings. Histologic findings showed EBV+ T‐cell infiltrates with variable degrees of architectural distortion and cytologic atypia ranging from no to mild cytologic atypia to overt lymphoma and tissue hemophagocytosis. All showed aberrant CD4+ or CD8+ T cells with dim to absent CD5, CD7, and CD3, and bright CD2 and CD45 by flow cytometry or loss of CD5 by immunohistochemistry. TCR gene rearrangement studies showed monoclonal rearrangements in all clinical cases (6/6). Outcomes were poor with treatment consisting of chemotherapy per the HLH‐94 or HLH‐2004 protocols with or without bone marrow transplant.
Conclusion
In this large pediatric clinicopathologic study of S‐EBV‐T‐LPD of childhood in the United States, EBV‐HLH, S‐EBV‐TCL, and S‐CAEBV show many overlapping features. Diagnosis is challenging, and overall outcome is poor using current HLH‐directed therapies.
Objectives
Kaposi sarcoma (KS) is one of the most common childhood cancers in eastern and central Africa. It has become a treatable disease with increasing availability of antiretroviral therapy ...(ART) and chemotherapy. We aimed to fill the data gap in establishing whether long‐term survival is achievable for children in low‐income countries.
Methods
We retrospectively analysed data for children and adolescents aged ≤ 18.9 years diagnosed with HIV‐related or endemic KS from 2006 to 2015 who received standardized institutional treatment regimens utilizing chemotherapy plus ART (if HIV‐positive) at a tertiary care public hospital in Lilongwe, Malawi. Long‐term survival was analysed and mortality was associated with KS for those with refractory/progressive disease at the time of death.
Results
There were 207 children/adolescents with KS (90.8% HIV‐related); 36.7% were alive, 54.6% had died, and 8.7% had been lost to follow‐up. The median follow‐up time for survivors was 6.9 years (range 4.2–13.9 years). Death occurred at a median of 5.3 months after KS diagnosis (range 0.1–123 months). KS progression was associated with mortality for most (61%) early deaths (survival time of < 6 months); conversely, KS was associated with a minority (31%) of late‐onset deaths (after 24 months). The 7‐year overall survival was 37% 95% confidence interval (CI) 30–44% and was higher for those diagnosed between 2011 and 2015 compared to 2006–2010: 42% (95% CI 33–51%) versus 29% (95% CI 20–39%), respectively (P = 0.01). Among the 66 HIV‐positive survivors, 58% were still on first‐line ART.
Conclusions
Long‐term survival is possible for pediatric KS in low‐resource settings. Despite better survival in more recent years, there remains room for improvement.
Background
Contemporary descriptions of classical Hodgkin lymphoma (cHL) are lacking from sub‐Saharan Africa where human immunodeficiency virus (HIV) and Epstein–Barr virus (EBV) are prevalent.
...Methods
We describe a prospective cHL cohort in Malawi enrolled from 2013 to 2015. Patients received standardized treatment and evaluation, including HIV status and EBV testing of tumors and plasma.
Results
Among 31 patients with confirmed cHL, the median age was 19 years (range, 2–51 years) and 22 (71%) were male. Sixteen patients (52%) had stage III/IV, 25 (81%) B symptoms, and 16 (52%) performance status impairment. Twenty‐three patients (74%) had symptoms >6 months, and 11 of 29 (38%) had received empiric antituberculosis treatment. Anemia was common with median hemoglobin 8.2 g/dL (range, 3.1‐17.1 g/dL), which improved during treatment. No children and 5 of 15 adults (33%) were HIV+. All HIV+ patients were on antiretroviral therapy for a median 15 months (range, 2–137 months), with median CD4 count 138 cells/μL (range, 23–329 cells/μL) and four (80%) having undetectable HIV. EBV was present in 18 of 24 (75%) tumor specimens, including 14 of 20 (70%) HIV− and 4 of 4 (100%) HIV+. Baseline plasma EBV DNA was detected in 25 of 28 (89%) patients, with median viral load 4.7 (range, 2.0–6.7) log10copies/mL, and subsequently declined in most patients. At 12 months, overall survival was 75% (95% confidence interval CI, 55%–88%) and progression‐free survival 65% (95% CI, 42%–81%). Baseline plasma EBV DNA and persistent viremia during treatment were associated with poorer outcomes.
Conclusion
cHL in Malawi is characterized by delayed diagnosis and advanced disease. Most cases were EBV associated and one‐third of adults were HIV+. Despite resource limitations, 12‐month outcomes were good.
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