Pediatric HIV+ Kaposi sarcoma exhibits clinical, virological, and molecular features different from the adult disease.

BACKGROUNDKaposi sarcoma (KS) is among the most common childhood cancers in Eastern and Central Africa. Pediatric KS has a distinctive clinical presentation compared with adult KS, which includes a tendency for primary lymph node involvement, a considerable proportion of patients lacking cutaneous lesions, and a potential for fulminant disease. The molecular mechanisms or correlates for these disease features are unknown.METHODSThis was a cross-sectional study. All cases were confirmed by IHC for KS-associated herpesvirus (KSHV) LANA protein. Baseline blood samples were profiled for HIV and KSHV genome copy numbers by qPCR and secreted cytokines by ELISA. Biopsies were characterized for viral and human transcription, and KSHV genomes were determined when possible.RESULTSSeventy participants with pediatric KS were enrolled between June 2013 and August 2019 in Malawi and compared with adult patients with KS. They exhibited high KSHV genome copy numbers and IL-6/IL-10 levels. Four biopsies (16%) had a viral transcription pattern consistent with lytic viral replication.CONCLUSIONThe unique features of pediatric KS may contribute to the specific clinical manifestations and may direct future treatment options.FUNDINGUS National Institutes of Health U54-CA-254569, PO1-CA019014, U54-CA254564, RO1-CA23958.

Divergent clinical presentations and outcomes among children and adolescents with Kaposi sarcoma in Malawi and Tanzania.

OBJECTIVES: The Kaposi sarcoma (KS) T0 versus T1 staging classification does not address the unique clinical features of paediatric KS in human gammaherpesvirus 8 (HHV-8) endemic regions of Africa. This study seeks to define patterns of childhood KS using a paediatric-specific approach. METHODS: The Lilongwe paediatric KS staging classification categorizes disease based on clinical phenotype: stage 1 = mild/moderate KS limited to cutaneous/oral involvement, stage 2 = primarily lymphadenopathic disease, stage 3 = woody edema KS, stage 4 = visceral and/or severe/disseminated mucocutaneous disease. Characteristics and outcomes were evaluated from paediatric referral centres in Lilongwe, Malawi, and Mbeya, Tanzania. RESULTS: Among 171 patients, the median age was 9.3 years, 37% (n = 63) were female, and 87% (n = 149) had HIV. Breakdown by stage was as follows: 18% (n = 31) stage 1, 33% (n = 56) stage 2, 19% (n = 33) stage 3, and 30% (n = 51) stage 4. Age (younger stage 2 and older stage 3), severe CD4 count suppression (lower CD4 for stages 1 and 4), and presence of severe anaemia and thrombocytopenia (worse for stages 2 and 4) differed across stages. Estimated 2-year event-free survival/progression-free survival/overall survival by stage was as follows: stage 1, 81%/81%/87%; stage 2, 50%/50%/63%; stage 3, 24%/49%/81%; and stage 4, 29%/34%/54%. Sub-analysis of stage 2 lymphadenopathic KS demonstrated superior long-term 6-year event-free survival of 70% (95% confidence interval [CI] 49-83) for younger children (aged <7 years) versus 27% (95% CI 8-51) for older children. CONCLUSIONS: This paediatric-specific staging classification categorizes patients with distinct characteristics and patterns of treatment response. This platform may guide clinicians to provide risk-stratified treatment with the hope of improving survival among children with KS.

Long-term outcomes for children and adolescents with Kaposi sarcoma.

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.

Association between Antiretroviral Therapy and Cancers among Children Living with HIV in Sub-Saharan Africa.

Approximately 91% of the world's children living with HIV (CLWH) are in sub-Saharan Africa (SSA). Living with HIV confers a risk of developing HIV-associated cancers. To determine the incidence and risk factors for cancer among CLWH, we conducted a nested case-control study of children 0-18 years from 2004-2014 at five centers in four SSA countries. Incident cases of cancer and HIV were frequency-matched to controls with HIV and no cancer. We calculated the incidence density by cancer type, logistic regression, and relative risk to evaluate risk factors of cancer. The adjusted incidence density of all cancers, Kaposi sarcoma, and lymphoma were 47.6, 36.6, and 8.94 per 100,000 person-years, respectively. Delayed ART until after 2 years of age was associated with cancer (OR = 2.71, 95% CI 1.51, 4.89) even after adjusting for World Health Organization clinical stage at the time of enrolment for HIV care (OR = 2.85, 95% CI 1.57, 5.13). The relative risk of cancer associated with severe CD4 suppression was 6.19 (p = 0.0002), 2.33 (p = 0.0042), and 1.77 (p = 0.0305) at 1, 5, and 10 years of ART, respectively. The study demonstrates the high risk of cancers in CLWH and the potential benefit of reducing this risk by the early initiation of ART.

Anemia at Intensive Care Unit Admission and Hospital Mortality Among Patients at a Referral Hospital in Malawi.

BACKGROUND: Anemia is associated with intensive care unit (ICU) outcomes, but data describing this association in sub-Saharan Africa are scarce. Patients in this region are at risk for anemia due to endemic conditions like malaria and because transfusion services are limited. METHODS: This was a prospective cohort study of ICU patients at Kamuzu Central Hospital (KCH) in Malawi. Exclusion criteria included age <5 years, pregnancy, ICU readmission, or admission for head injury. Cumulative incidence functions and Fine-Gray competing risk models were used to evaluate hemoglobin (Hgb) at ICU admission and hospital mortality. RESULTS: Of 499 patients admitted to ICU, 359 were included. The median age was 28 years (interquartile ranges (IQRs) 20-40) and 37.5% were men. Median Hgb at ICU admission was 9.9 g/dL (IQR 7.5-11.4 g/dL; range 1.8-18.1 g/dL). There were 61 (19%) patients with Hgb < 7.0 g/dL, 59 (19%) with Hgb 7.0-8.9 g/dL, and 195 (62%) with Hgb ≥ 9.0 g/dL. Hospital mortality was 51%, 59%, and 54%, respectively. In adjusted analyses, anemia was associated with hospital mortality but was not statistically significant. CONCLUSIONS: This study provides preliminary evidence that anemia at ICU admission may be an independent predictor of hospital mortality in Malawi. Larger studies are needed to confirm this association.

Recommendations for treating life-threatening Kaposi sarcoma during pregnancy in HIV-positive women in low income countries.

In areas of high HIV and human herpes virus 8 prevalence, life-threatening forms of Kaposi sarcoma (KS) can occur in HIV-positive women during pregnancy. Treating KS in pregnancy must balance both the well-being of the mother with the health of the fetus, yet data and recommendations on the best treatment approach for KS during pregnancy are limited. Without effective treatment, which can be difficult to obtain in low income countries (LICs), the mother and infant are at risk for poor outcomes. A successful case report is used as teaching example, followed by a detailed review of the literature that culminates in recommendations for treating KS during pregnancy among HIV-positive women in LICs. A 31-year-old HIV-positive woman presented for care in April 2016 at 28 weeks gestation with extensive KS skin lesions, KS lymphadenopathy, and a large oropharynx KS lesion causing partial airway obstruction. She had initiated antiretroviral therapy (ART) months prior and was virally suppressed, suggesting KS-immune reconstitution inflammatory syndrome. Due to the severity of KS and her third trimester status, combination chemotherapy was initiated using bleomycin, vincristine, and doxorubicin followed by maintenance therapy with paclitaxel. She showed remarkable response to the chemotherapy and had a normal vaginal delivery of a healthy baby at full term. Full clinical remission was achieved, and her baby was HIV-negative with no negative health effects of the KS or the chemotherapy. Review of the sparse existing literature demonstrates the importance, safety, and effectiveness of treating KS during pregnancy. We offer simple adaptable treatment recommendations for use in treating HIV-positive women with KS during pregnancy in LICs. Life-threatening KS can be treated using chemotherapy and ART in resource-limited settings, allowing for good outcomes in mother and infant. While monotherapy with liposomal doxorubicin or paclitaxel is preferred, these are often not available in LICs. As alternatives, bleomycin, vincristine, and doxorubicin can be safely used during the second and/or third trimesters for treating KS. Following a simple treatment approach can be an effective way to treat KS in pregnancy for pregnant women living with HIV in an LIC setting.

Factors influencing diagnostic delays of pediatric cancers in Botswana.

BACKGROUND: A major barrier in improving cancer outcomes in Botswana and other low- and middle-income countries is timely access to care. Understanding time to diagnosis of pediatric cancers in Botswana and evaluating factors contributing to delays was necessary to inform interventions. METHODS: A retrospective cohort study of children diagnosed with cancer at Princess Marina Hospital from 2008 to 2015 was performed utilizing the Botswana Pediatric Oncology Database. The time to diagnosis, pretreatment center delay, and pathology turnaround time were calculated. Time to diagnosis was analyzed using univariate and multivariate analyses to determine association with age, sex, distance to a treatment center, HIV status, cancer type, outcome, and presence of metastasis at diagnosis. RESULTS: The median time to diagnosis was 10.7 weeks, median pretreatment center delay was 9.6 weeks, and median pathology turnaround time was 3 weeks. Longer time to diagnosis was significantly correlated with presence of metastasis at diagnosis. Age, sex, distance to a treatment center, HIV status, cancer type, and outcome were not significantly associated with diagnostic delay. CONCLUSION: Children with cancer in Botswana have more than three months of symptoms prior to diagnosis, which is associated with metastasis at diagnosis. Efforts should be made to empower and promote awareness of pediatric cancer symptoms among caregivers and community healthcare providers in order to shorten time to presentation at a treatment center.

Infantile Pyknocytosis: An Uncommon Cause of Newborn Hemolytic Anemia.

Infantile pyknocytosis is a rare cause of neonatal hemolytic anemia, which presents in the first few weeks of life. We report a classic case of infantile pyknocytosis that presented to our institution with rebound hyperbilirubinemia after receiving phototherapy. The infant was found to have a hemoglobin of 5.8 g/dL, requiring a total of 15 mL/kg of red blood cells (in 2 separate transfusions) before discharge. The diagnosis was ultimately made by a review of the peripheral blood smear. We review the literature and suggest pediatricians consider infantile pyknocytosis on their differential when hemolytic anemia presents in the newborn period.

Kaposi Sarcoma Herpesvirus Inflammatory Cytokine Syndrome-like Clinical Presentation in Human Immunodeficiency Virus-infected Children in Malawi.

We describe 7 human immunodeficiency virus-infected Malawian children with Kaposi sarcoma who met criteria for Kaposi sarcoma herpesvirus (KSHV) inflammatory cytokine syndrome. Each presented with persistent fevers, bulky lymphadenopathy, massive hepatosplenomegaly, and severe cytopenias. Plasma analyses were performed in 2 patients, both demonstrating extreme elevations of KSHV viral load and interleukin 6.

KSHV viral load and Interleukin-6 in HIV-associated pediatric Kaposi sarcoma-Exploring the role of lytic activation in driving the unique clinical features seen in endemic regions.

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.

Endemic Kaposi sarcoma in HIV-negative children and adolescents: an evaluation of overlapping and distinct clinical features in comparison with HIV-related disease.

BACKGROUND: Endemic Kaposi sarcoma (KS) was first described in African children over fifty years ago, but has recently been overshadowed by HIV-related disease. We aimed to evaluate the similarities and differences between endemic HIV-negative and epidemic HIV-positive pediatric KS in a KS-associated herpesvirus-endemic region of Africa. METHODS: We describe clinical characteristics of 20 HIV-negative children with endemic KS over a six-year period and compare findings with a historical control-an HIV-related pediatric KS cohort from Lilongwe, Malawi. RESULTS: The HIV-negative endemic KS cohort was 70% male with a median age of 9.3 years. Lymph node involvement was present in 50%, hyperpigmented skin lesions in 45%, and woody edema in 40%. One patient (5%) presented with oral KS involvement and no patients presented initially with visceral KS. Significant anemia (hemoglobin < 8 g/dL) and thrombocytopenia (platelet count < 100 × 109/L) were found at time of original KS diagnosis in 45 and 40% respectively. In both HIV-negative and HIV-positive cohorts, lymphadenopathy was the most common presentation, prototypical skin lesions were often absent, severe cytopenias were a common clinical feature, and treatment outcomes were similar. Patients with endemic KS demonstrated less frequent oral involvement (5% versus 29%, P = 0.03) and a lower proportion of patients with visceral involvement (0% versus 16%, P = 0.06). CONCLUSIONS: These data suggest clinical overlap between epidemiological variants. Treatment protocols for pediatric KS in sub-Saharan Africa should be devised to include both endemic HIV-negative and epidemic HIV-related disease to better define the clinical and biological comparison.

Establishing a Pediatric Hematology-Oncology Program in Botswana.

PURPOSE: Annually, 300,000 children are diagnosed with cancer, and the majority of these children live in low- and middle-income countries (LMICs). Currently, there is incomplete information on pediatric cancer incidence, diagnosis distribution, and treatment outcomes in Africa. Since 2007, a pediatric hematology-oncology program has been operating in Botswana through a partnership between the Botswana government, Baylor College of Medicine, and Texas Children's Hospital. METHODS: To better understand patient characteristics and outcomes at Botswana's only pediatric cancer program, a hospital-based data base-the Botswana Pediatric Oncology Database-was established in 2014. Children younger than 18 years of age at the time of diagnosis who presented between 2008 and 2015 were included. Data for this study were extracted in February 2016. RESULTS: Of the 240 potential enrollees, 185 (77%) children met eligibility for this study. The median age was 6.4 years, and 50.8% were male. Leukemia was the most common malignancy representing 18.9% of the cohort and 88.1% of the total cohort had a histopathologic diagnosis. HIV seropositivity was confirmed in 13.5%. The 2-year overall survival of all pediatric cancer diagnoses was 52.4%. Abandonment of treatment occurred in 3.8% of patients. CONCLUSION: In the first 9 years of the program, capacity has been developed through a longstanding partnership between Botswana and Baylor College of Medicine/Texas Children's Hospital that has led to children receiving care for cancer and blood disorders. Although continued improvements are necessary, outcomes to date indicate that children with cancer in Botswana can be successfully diagnosed and treated.

Identifying opportunities to bridge disparity gaps in curing childhood cancer in Malawi: Malignancies with excellent curative potential account for the majority of diagnoses.

The majority of African children with cancer die without access to resources. We describe efforts to build a public treatment program with curative intent for childhood cancer in Lilongwe, Malawi despite severe limitations in diagnostic and therapeutic resources. We retrospectively analyzed a cohort of childhood cancer patients at Kamuzu Central Hospital from 12/2011-6/2013. Consistently available chemotherapeutic agents were limited to cyclophosphamide, vincristine, doxorubicin, bleomycin, methotrexate, and prednisone. Of 258 newly diagnosed childhood malignancies, 17 patients with retinoblastoma were excluded from clinical analyses due to insufficient clinical data. Among the remainder of the cohort (n = 241), 42% were female with median age 8.4 years (range 0.6-17.9). Forty-six (19%) were HIV-infected (42 Kaposi sarcoma, 3 Burkitt lymphoma, 1 Hodgkin lymphoma). The most common clinical presentations were palpable abdominal mass (41%), peripheral lymphadenopathy (33%), and jaw mass (17%). Nearly two-thirds of total diagnoses were accounted for by Burkitt lymphoma (n = 74), Kaposi sarcoma (n = 52), Hodgkin lymphoma (n = 21), and Wilms tumor (n = 19). Twelve-month overall survival for these 4 most common diagnoses was 54% (95% confidence interval 46-61) versus 19% (95% confidence interval 11-30) for all other diagnoses (median follow-up 19 months). Treatment-related mortality was highest in patients with non-Wilms solid tumors of the abdomen (48% versus 10% for the overall cohort, p < 0.001), while treatment abandonment was highest in patients with bone and soft-tissue sarcomas (29% versus 14% overall, p = 0.05). Childhood cancers with excellent curative potential accounted for the majority of patients, establishing an opportunity to build treatment programs with curative intent despite severe limitations.

Beyond Endemic Burkitt Lymphoma: Navigating Challenges of Differentiating Childhood Lymphoma Diagnoses Amid Limitations in Pathology Resources in Lilongwe, Malawi.

Background. Although Burkitt lymphoma (BL) is the most common childhood lymphoma in sub-Saharan Africa, Hodgkin lymphoma (HL) and other non-Hodgkin lymphomas occur. Diagnosing non-jaw mass presentations is challenging with limited pathology resources. Procedure. We retrospectively analyzed 114 pediatric lymphomas in Lilongwe, Malawi, from December 2011 to June 2013 and compared clinical versus pathology-based diagnoses over two time periods. Access to pathology resources became more consistent in 2013 compared with 2011-2012; pathology interpretations were based on morphology only. Results. Median age was 8.4 years (2.1-16.3). The most common anatomical sites of presentation were palpable abdominal mass 51%, peripheral lymphadenopathy 35%, and jaw mass 34%. There were 51% jaw masses among clinical diagnoses versus 11% in the pathology-based group (P < .01), whereas 62% of pathology diagnoses involved peripheral lymphadenopathy versus 16% in the clinical group (P < .01). The breakdown of clinical diagnoses included BL 85%, lymphoblastic lymphoma (LBL) 9%, HL 4%, and diffuse large B-cell lymphoma (DLBCL) 1%, whereas pathology-based diagnoses included HL 38%, BL 36%, LBL 15%, and DLBCL 11% (P < .01). Lymphoma diagnosis was pathology confirmed in 19/66 patients (29%) in 2011-2012 and 28/48 (60%) in 2013 (P < .01). The percentage of non-BL diagnoses was consistent across time periods (35%); however, 14/23 (61%) non-BL diagnoses were pathology confirmed in 2011-2012 versus 16/17 (94%) in 2013. Conclusions. Lymphomas other than Burkitt accounted for 35% of childhood lymphoma diagnoses. Over-reliance on clinical diagnosis for BL was a limitation, but confidence in non-BL diagnoses improved with time as pathology confirmation became standard. Increased awareness of non-BL lymphomas in equatorial Africa is warranted.

Pediatric Cancer Recognition Training in Botswana.

Delayed presentation of children with cancer is a significant barrier to improving the survival from children's cancer in low- and middle-income countries (LMICs). Botswana, a country of approximately 2 million people in southern Africa, has only 1 pediatric cancer treatment program, based at Princess Marina Hospital (PMH) in the capital of Gaborone. A pediatric cancer recognition training program was developed that reached 50% of the government hospitals in Botswana teaching 362 health care workers how to recognize and refer children with cancer to PMH. Through evaluation of attendees, limitations in pediatric cancer training and general knowledge of pediatric cancer were identified. Attendees demonstrated improvement in their understanding of pediatric cancer and the referral process to PMH following the workshop.

Profound Vitamin B12 Deficiency in a 1-Year-Old Child in Botswana: A Call to Initiate Early Empiric Therapy.

Vitamin B12 deficiency is a rare diagnosis in young children. We present the case of a 1-year-old Zimbabwean child with profound anemia. Further testing revealed undetectable levels of vitamin B12 and positive intrinsic factor antibodies that were drawn after the initiation of empiric treatment with parenteral vitamin B12. We report the evaluation and management of vitamin B12 deficiency in a resource-limited setting. Vitamin B12 deficiency should be considered in children presenting with unexplained cytopenias with consideration of empiric treatment with parenteral vitamin B12, as developmental and neurological complications of vitamin B12 deficiency can be devastating and permanent.

Mapping the Epidemiology of Kaposi Sarcoma and Non-Hodgkin Lymphoma Among Children in Sub-Saharan Africa: A Review.

Children with human immunodeficiency virus (HIV) have an increased risk of developing Kaposi Sarcoma (KS) and non-Hodgkin lymphoma (NHL) compared to HIV-negative children. We compiled currently published epidemiologic data on KS and NHL among children in sub-Saharan Africa (SSA). Among countries with available data, the median incidence of KS was 2.05/100,000 in the general pediatric population and 67.35/100,000 among HIV-infected children. The median incidence of NHL was 1.98/100,000 among the general pediatric population, while data on NHL incidence among HIV-infected children were lacking. Larger regional studies are needed to better address the dearth of epidemiologic information on pediatric KS and NHL in SSA.

Clinical Factors Associated with Long-Term Complete Remission versus Poor Response to Chemotherapy in HIV-Infected Children and Adolescents with Kaposi Sarcoma Receiving Bleomycin and Vincristine: A Retrospective Observational Study.

Kaposi sarcoma (KS) is the most common HIV-associated malignancy in children and adolescents in Africa. Pediatric KS is distinct from adult disease. We evaluated the clinical characteristics associated with long-term outcomes. We performed a retrospective observational analysis of 70 HIV-infected children and adolescents with KS less than 18 years of age diagnosed between 8/2010 and 6/2013 in Lilongwe, Malawi. Local first-line treatment included bleomycin and vincristine plus nevirapine-based highly active anti-retroviral therapy (HAART). Median age was 8.6 years (range 1.7-17.9); there were 35 females (50%). Most common sites of presentation were: lymph node (74%), skin (59%), subcutaneous nodules (33%), oral (27%), woody edema (24%), and visceral (16%). Eighteen (26%) presented with lymphadenopathy only. Severe CD4 suppression occurred in 28%. At time of KS diagnosis, 49% were already on HAART. Overall, 28% presented with a platelet count < 100 x 109/L and 37% with hemoglobin < 8 g/dL. The 2-year event-free (EFS) and overall survival (OS) were 46% and 58% respectively (median follow-up 29 months, range 15-50). Multivariable analysis of risk of death and failure to achieve EFS demonstrated that visceral disease (odds ratios [OR] 19.08 and 11.61, 95% CI 2.22-163.90 and 1.60-83.95 respectively) and presenting with more than 20 skin/oral lesions (OR 9.57 and 22.90, 95% CI 1.01-90.99 and 1.00-524.13 respectively) were independent risk factors for both. Woody edema was associated with failure to achieve EFS (OR 7.80, 95% CI 1.84-33.08) but not death. Univariable analysis revealed that lymph node involvement was favorable for EFS (OR 0.28, 95% CI 0.08-0.99), while T1 TIS staging criteria, presence of cytopenias, and severe immune suppression were not associated with increased mortality. Long-term complete remission is achievable in pediatric KS, however outcomes vary according to clinical presentation. Based on clinical heterogeneity, treatment according to risk-stratification is necessary to improve overall outcomes.