Lymphomas constitute a significant proportion of childhood malignancies and represent an important cause of cancer-related morbidity and mortality in the pediatric population. Globally, lymphomas are the third most common malignancy among children in developed countries [1] and account for a substantial disease burden in low- and middle-income countries. In India, childhood lymphomas rank as the second most common pediatric malignancy, reflecting both the large population base and distinct epidemiological patterns observed in the region [2,3]. Among lymphomas, non-Hodgkin’s lymphoma (NHL) is particularly noteworthy in children due to its aggressive biological behavior, rapid progression, and potential for early dissemination. Pediatric NHL comprises a heterogeneous group of malignancies arising from lymphoid tissues, with marked variation in histological subtypes, clinical presentation, and age distribution [4,5]. Unlike adult NHL, pediatric NHL is predominantly high-grade, with common subtypes including Burkitt lymphoma, lymphoblastic lymphoma, diffuse large B-cell lymphoma, and anaplastic large cell lymphoma. These subtypes differ in their site of origin, pattern of spread, and response to therapy, contributing to the wide spectrum of clinical manifestations seen at diagnosis. Children often present with extranodal disease, bulky tumors, bone marrow involvement, or central nervous system infiltration, which can complicate early recognition and management. Over the past few decades, the prognosis of pediatric NHL has improved remarkably, particularly in high-income countries. Advances in multi-agent intensive chemotherapy, risk-adapted treatment protocols, improved supportive care, and early recognition of treatment-related complications have resulted in long-term survival rates exceeding 80–90% for several NHL subtypes in developed nations [6,7,8]. The incorporation of precise histopathological classification, immunophenotyping, and cytogenetic analysis has further enabled tailored therapeutic approaches, reducing both disease-related mortality and treatment-associated toxicity. Despite these advances, the outcomes of children with NHL in developing countries such as India remain suboptimalwhen compared to those reported from high-resource settings. Several challenges contribute to this disparity, including late presentation with advanced-stage disease, poor nutritional status, treatment interruptions, limited access to specialized pediatric oncology services, and variations in supportive care infrastructure [9,10]. Socioeconomic constraints and disparities in healthcare accessibility between urban and rural populations further exacerbate these issues, often leading to delayed diagnosis and incomplete treatment. In addition, treatment-related complications such as infections and therapy-related toxicities remain significant contributors to morbidity and mortality in resource-limited settings. Another major limitation in the Indian context is the scarcity of comprehensive published data on pediatric NH. Most available studies are either small case series or derived from tertiary centers with heterogeneous treatment protocols. The lack of uniform, nationally adopted treatment guidelines and limited availability of advanced diagnostic facilities in many centers contribute to variability in outcomes. Furthermore, survival rates reported from Indian studies are generally lower than those observed in developed countries, highlighting the need for region-specific data to understand disease patterns and treatment outcomes more accurately. In this context, single-center experiences from different regions of India play a crucial role in bridging the existing knowledge gap. Such studies provide valuable insights into the clinical profile, histological distribution, treatment approaches, and outcomes of pediatric NHL in real-world settings. They also help identify region-specific challenges, including delays in diagnosis, treatment compliance, and resource limitations, which are essential for improving pediatric cancer care in low- and middle-income countries. The present study aims to analyze the clinical and demographic characteristics of children diagnosed with NHL at our institution. In addition, the study seeks to evaluate treatment outcomes and survival patterns in this cohort. By documenting our institutional experience, we hope to contribute to the limited Indian literature on pediatric NHL and provide data that may assist in refining treatment strategies, optimizing supportive care, and ultimately improving outcomes for children with NHL in similar resource-constrained settings.

Study design and study population This retrospective descriptive study was conducted in the Division of Paediatric Hematology Oncology, Department of Pediatrics, at a tertiary care teaching institute in South India. Medical records of children and adolescents aged less than 18 years who were diagnosed with non-Hodgkin’s lymphoma (NHL) between January 2015 and December 2021 were reviewed, covering a total study period of seven years. All consecutive patients fulfilling the age criteria and having a confirmed diagnosis of NHL during the study period were included. Children with incomplete diagnostic data or inadequate follow-up records were excluded from the analysis. The study was approved by the Institutional Research Ethics Committee of SRMCH. Confidentiality of patient information was strictly maintained throughout the data collection and analysis process. Data collection and clinical evaluation Data were extracted retrospectively from hospital medical records using a structured data collection format. Information regarding demographic characteristics, clinical presentation, duration of symptoms prior to diagnosis, physical examination findings, laboratory parameters, imaging findings, histopathological diagnosis, immunophenotypic classification, staging details, treatment protocols, treatment-related complications, and outcomes were systematically recorded. Clinical presentation at diagnosis was documented in detail, including the presence of lymphadenopathy, extranodal disease, mediastinal mass, abdominal involvement, bone marrow infiltration, and constitutional symptoms. Baseline laboratory investigations, including complete blood counts, renal and liver function tests, serum lactate dehydrogenase, and uric acid levels, were also reviewed wherever available. Diagnostic evaluation and staging The diagnosis of NHL was primarily established based on histopathological examination of image-guided biopsy specimens obtained from the involved mass, supplemented by a comprehensive immunohistochemistry panel to accurately classify the lymphoma subtype. In children presenting with mediastinal masses and features of superior mediastinal syndrome, diagnostic procedures were tailored to minimize procedural risk, and the least invasive diagnostic modality was preferred. In such cases, diagnosis was attempted using pleural fluid cytology with flow cytometry, bone marrow aspiration and biopsy, or peripheral lymph node biopsy, as clinically appropriate. For patients who had undergone diagnostic biopsies at outside institutions, histopathology slides and tissue blocks were reviewed by pathologists at our center as part of a multidisciplinary tumor board process prior to initiation of therapy, ensuring diagnostic concordance and uniform classification. Staging evaluation was performed in all patients at diagnosis. Imaging modalities included contrast-enhanced computed tomography (CT) scans of the neck, chest, abdomen, and pelvis, or whole-body positron emission tomography–computed tomography (PET-CT), depending on availability and clinical indication. Bone marrow aspiration and biopsy were performed in all patients as part of staging, and cerebrospinal fluid (CSF) analysis was undertaken to assess central nervous system involvement. Disease staging was assigned according to the St Jude/Murphy staging system [11], taking into account the extent of nodal and extranodal involvement, bone marrow infiltration, and central nervous system disease. Treatment protocols and supportive care All children diagnosed with NHL received standardized treatment protocols based on histological subtype. Patients with B-cell NHL were treated uniformly according to the UK Children’s Cancer Study Group (UK-CCSG) FAB LMB 96 protocol, with the addition of rituximab for Group C disease as per institutional practice. Children diagnosed with lymphoblastic lymphoma were treated using high-risk acute lymphoblastic leukemia–based protocols, while those with anaplastic large cell lymphoma were managed using the ALCL 99 protocol. Treatment decisions were made in multidisciplinary meetings and adhered to protocol-specified risk stratification and dose modifications where required. Comprehensive supportive care measures were instituted for all patients. Tumor lysis syndrome prophylaxis was provided universally, with hyperhydration and allopurinol initiated at diagnosis. Rasburicase was administered to children with evidence of hyperuricemia or those presenting with bulky disease or high tumor burden. All patients received Pneumocystis carinii prophylaxis with oral cotrimoxazole administered twice daily for two consecutive days each week, except during periods of high-dose methotrexate therapy. Antimicrobial prophylaxis with fluconazole and acyclovir, as well as primary or secondary prophylaxis with granulocyte colony-stimulating factor (G-CSF), was provided as clinically indicated based on treatment phase and hematological parameters. Episodes of febrile neutropenia were managed with broad-spectrum intravenous antibiotics according to institutional protocols, and blood product support was provided when indicated. For children requiring prolonged chemotherapy exceeding three months, long-term venous access was secured using either a chemoport or a peripherally inserted central catheter (PICC line). Response assessment and follow-up Response to therapy was assessed at the completion of treatment using appropriate imaging modalities, including CT or PET-CT, based on the initial disease presentation and subtype. Bone marrow and CSF evaluations were repeated when clinically indicated; none of the patients in the present cohort had documented CSF involvement at diagnosis or during follow-up. Complete remission was defined as the complete disappearance of all measurable or evaluable disease, with absence of blasts in the bone marrow and CSF, in accordance with standard response criteria. Disease progression was defined as the appearance of new lesions or a greater than 25% increase in the size of existing lesions [12]. Following completion of therapy, patients were monitored through a structured follow-up schedule. Clinical evaluations and relevant investigations were performed every three months for the first two years and subsequently every six months for the next three years, completing a total follow-up period of five years. During follow-up visits, attention was paid to disease recurrence, treatment-related late effects, and overall survival. Statistical analysis Data were entered into a computerized database and analyzed using SPSS v26.0. Continuous variables were summarized as mean with standard deviation or median with range, depending on data distribution, while categorical variables were expressed as frequencies and percentages. Overall survival and event-free survival were calculated using the Kaplan–Meier method, and survival curves were compared using the log-rank test where applicable. A p-value of less than 0.05 was considered statistically significant.

There were a total 841 children under 18 years of age who were diagnosed with various malignancies during the study period of five years; of which 76 children were diagnosed with lymphoma - 40 children with Hodgkin’s lymphoma and 36 children with Non-Hodgkin’s lymphoma. Among the 36 children with NHL 75% were male (n = 27) and 25% were female (n = 9). Median age of presentation was 7.5years. The presentations were seen only in 32 children. Table 1 outlines the clinical characteristics and emergency presentations among children diagnosed with non-Hodgkin’s lymphoma. Gastrointestinal symptoms were the most common presenting features, reported in 18 children (56.3%), followed by neck swelling in 12 (37.5%) and fever in 9 (28.1%). Respiratory symptoms such as cough and respiratory distress were observed in 5 children (15.6%), while weight loss was noted in 4 (12.5%). Painful episodes and ocular complaints, including proptosis or reduced vision, were each documented in 3 children (9.4%), and swelling of the legs was seen in 2 (6.3%). Other rare presentations—such as right hemiparesis, voice change, dysphagia, multiple cutaneous swellings, and localized thigh or gluteal swellings—were observed in 1 child each. Importantly, potentially life-threatening emergency presentations were not uncommon, with intestinal obstruction or intussusception occurring in 5 children (15.6%), acute airway obstruction in 2 (6.3%), and superior or inferior vena cava obstruction and central nervous system complications in 1 child each (3.1%), emphasizing the aggressive and acute presentation of pediatric NHL. Table 1: Clinical characteristics of children diagnosed with NHL (n=32) Clinical features N (%) Gastrointestinal symptoms Vomiting, loose stools, constipation, abdomen distension or lump 18(56.3%) Neck swelling 12 (37.5%) Fever 9 (28.1%) Respiratory symptoms Cough, respiratory distress, cold 5 (15.6%) Weight loss 4 (12.5%) Painful episodes 3 (9.4%) Ocular complaints Proptosis, decreased vision 3 (9.4%) Swelling of legs 2 (6.3%) Others Right hemiparesis, voice change, difficulty in swallowing, multiple cutaneous swelling, thigh swelling, gluteal swelling 1 each Potential emergency presentation n (%) Intestinal obstruction / intussusception 5 (15.6%) Acute airway obstruction 2 (6.3%) Superior vena cava / inferior vena cava obstruction 1 (3.1%) CNS complication 1 (3.1%) Table 2: Extra nodal distribution of NHL children, N=23 Extra nodal sites N (%) Gastrointestinal tract ( small bowel, large bowel, stomach, duodenum, mysentery) 8 (20%) Skeletal system (femur, sacrum, mandible) 5 (12.5%) Ovary 2 (6%) Liver, kidney, eyes, 8 (25%) Spleen, paranasal sinuses, sacral nerve roots, bone marrow, pharynx 10 (31.3%) Skin, base of tongue, Waldeyer ring, pancreas, thyroid gland 5 (15.6%) Table 2 summarizes the distribution of extranodal involvement among 23 children with non-Hodgkin’s lymphoma. The most frequently involved extranodal sites were the spleen, paranasal sinuses, sacral nerve roots, bone marrow, and pharynx, affecting 10 children (31.3%). Involvement of solid organs such as the liver, kidney, and eyes was observed in 8 children (25%), while gastrointestinal tract involvement—including the small bowel, large bowel, stomach, duodenum, and mesentery—was noted in 8 children (20%). Skeletal involvement of sites such as the femur, sacrum, and mandible occurred in 5 children (12.5%), and ovarian involvement was identified in 2 children (6%). Less commonly affected sites included the skin, base of tongue, Waldeyer’s ring, pancreas, and thyroid gland, collectively seen in 5 children (15.6%), reflecting the broad and heterogeneous extranodal disease distribution in pediatric non-Hodgkin’s lymphoma. Table 3: Histological Subtypes and Immunophenotypic Distribution of Non-Hodgkin’s Lymphoma (n = 36) NHL subtype N (%) B-cell NHL (total) 21 (58.3) Burkitt’s lymphoma 14 (38.9) Diffuse large B-cell lymphoma (DLBCL) 5 (13.9) Primary mediastinal large B-cell lymphoma 1 (2.8) Primary CNS lymphoma 1 (2.8) T-cell NHL (total) 15 (41.6) Lymphoblastic lymphoma 9 (25.0) Anaplastic large T-cell lymphoma (ALCL) 5 (13.9) Subcutaneous panniculitis-like T-cell lymphoma 2 (5.6) Table 3 depicts the histological and immunophenotypic profile of children diagnosed with NHL. B-cell NHL constituted 21 cases (58.3%), with Burkitt’s lymphoma being the most common subtype (14 children, 38.9%), followed by diffuse large B-cell lymphoma (5 children, 13.9%). T-cell NHL accounted for 15 cases (41.6%), predominantly lymphoblastic lymphoma (9 children, 25%) and anaplastic large cell lymphoma (5 children, 13.9%). Rare subtypes included primary mediastinal large B-cell lymphoma and primary CNS lymphoma (1 case each, 2.8% each), as well as 2 cases (5.6%) of subcutaneous panniculitis-like T-cell lymphoma, highlighting the histological heterogeneity of pediatric NHL. Table 4; Disease Stage at Presentation, Treatment Delivery, Toxicity, and Outcomes among Children with NHL Variable N (%) Stage at diagnosis Advanced stage (Stage III–IV) 24 (66.7) Early stage (Stage I–II) 12 (33.3) Treatment initiation (n = 36) Treated at study centre 32 (88.9) Referred to other centre 3 (8.3) Treatment abandonment before initiation 1 (2.8) Treatment-related details (n = 32) Surgery required for diagnosis 4 (12.5) Radiotherapy required 0 (0) Grade 3–4 mucositis 16 (50.0) Grade 3–4 cytopenias 21 (67.0) Treatment-related mortality (sepsis) 2 (6.3) Treatment abandonment during therapy 1 (3.1) Follow-up and outcomes Median follow-up duration 29 months Relapse / progressive disease 5 (15.6) 3-year event-free survival (EFS) 86.5% Families requiring financial assistance 28 (87.5) Table 4 summarizes disease stage, treatment delivery, toxicity, and outcomes. A majority of children presented with advanced-stage disease (24 children, 66.7%). Treatment was initiated at the study centre in 32 children (88.9%), while 3 children (8.3%) were referred elsewhere and 1 child (2.8%) abandoned treatment prior to initiation. Surgery was required solely for diagnostic purposes in 4 children (12.5%), and none required radiotherapy. Significant treatment-related toxicities included grade 3–4 mucositis in 16 children (50%) and cytopenias in 21 children (67%), all of which were manageable with supportive care and did not result in long-term sequelae. During therapy, 2 children (6.3%) died due to sepsis and 1 child (3.1%) abandoned treatment. With a median follow-up of 29 months, relapse or progressive disease occurred in 5 children (15.6%), yielding a 3-year event-free survival of 86.5%. Notably, 28 families (87.5%) required financial assistance to complete protocol-based therapy and supportive care. Figure 1: Kaplan-Meier survival analysis The Kaplan–Meier survival curve illustrates event-free survival among children with non-Hodgkin’s lymphoma treated at our centre over a follow-up period extending to approximately 60 months. An initial decline in survival is seen within the first 12–18 months, corresponding to early adverse events, including two treatment-related deaths due to sepsis, one case of treatment abandonment, and five instances of relapse or progressive disease among the 32 children who initiated therapy. After this early decline, the curve demonstrates a sustained plateau, indicating the absence of late events and durable remission in the majority of patients. The estimated three-year event-free survival for the cohort was 86.5%, despite 66.7% of children presenting with advanced-stage disease at diagnosis. Censored observations along the curve represent patients who remained event-free at their last follow-up, with a median follow-up duration of 29 months, suggesting that children who achieve early disease control have a high likelihood of long-term survival.

Non-Hodgkin’s lymphoma (NHL) constitutes a significant proportion of childhood malignancies, accounting for approximately 8–10% of pediatric cancers worldwide. However, data from India on the clinical profile, subtype distribution, treatment patterns, challenges in care delivery, and outcomes of pediatric NHL remain limited. The present retrospective study provides a comprehensive overview of children and adolescents diagnosed with NHL at a tertiary care center in South India and highlights not only the disease characteristics and outcomes but also the social and health system–related challenges encountered during treatment. The distribution of lymphoma subtypes varies across age groups and geographic regions [1,13]. In our center, although Hodgkin’s lymphoma was marginally more common than NHL overall during the study period, NHL constituted a substantial burden with 36 cases. This finding is comparable to data from the Madras Metropolitan Tumour Registry reported by Swaminathan et al., which showed a near-equal distribution between Hodgkin’s lymphoma and NHL [2]. Other Indian studies, such as that by Manipadam et al., have reported a slightly higher incidence of NHL compared to Hodgkin’s lymphoma, reflecting institutional and regional variability. Such differences may be influenced by referral patterns, diagnostic facilities, and population characteristics. A male predominance in pediatric NHL is well documented. In our cohort, the male-to-female ratio was 3:1, which aligns closely with both Indian and international data. Burkhardt et al. reported a male-to-female ratio of 2.7:1 in a large Western cohort [14], while Indian studies by Shankaranand et al. also reported a similar male predominance [15]. The reasons for this gender disparity remain unclear but may reflect biological susceptibility as well as sociocultural factors influencing healthcare-seeking behavior. Burkitt’s lymphoma emerged as the most common NHL subtype in our study, accounting for 38.9% of cases, followed by lymphoblastic lymphoma (25%), diffuse large B-cell lymphoma (13.9%), and anaplastic large cell lymphoma (13.9%). This pattern is largely consistent with international data from Minard-Colin et al., where Burkitt’s lymphoma constituted 50–60% of pediatric NHL cases, followed by lymphoblastic lymphoma (20–25%) and large B-cell lymphomas (10–15%) [5]. Similar trends have been reported from India by Meena et al., who also identified Burkitt’s lymphoma as the most frequent subtype [12]. However, some Indian studies have reported lymphoblastic lymphoma as more common than Burkitt’s lymphoma [15–17], underscoring regional variability and possible differences in diagnostic classification and referral bias. NHL is characteristically aggressive, with rapid dissemination and a high likelihood of extranodal involvement. In our cohort, 66.7% of children presented with advanced-stage disease (stage III or IV), a finding comparable to other studies from developing countries. Meena et al. reported advanced-stage disease in 92.3% of children [12], while Worawut et al. from Thailand reported advanced disease in 71.9% of cases [16]. Delayed presentation remains a major contributor to advanced-stage diagnosis in low- and middle-income countries. In our study, factors such as low socioeconomic status, delayed referral, misdiagnosis, and prior inappropriate treatment were evident, with some children receiving antitubercular therapy or alternative medicine before definitive diagnosis. These findings emphasize the need for increased awareness and early referral to specialized pediatric oncology centers. Extranodal involvement was common in our study, with the gastrointestinal tract being the most frequent site (20%). This observation is consistent with reports from Meena et al. and Shankaranand et al., where gastrointestinal involvement predominated [12,15]. A study by Srinivas et al. focuses primarily on the epidemiological and histopathological distribution of pediatric NHL subtypes in India using the WHO classification, without outcome or treatment protocol analysis [18]. In contrast, studies by Manipadam et al. have reported mediastinal and pleural involvement as more common extranodal sites [19], again highlighting heterogeneity in disease presentation. The wide range of extranodal sites observed in our cohort, including ovary, thyroid, paranasal sinuses, orbit, and central nervous system, underscores the diverse clinical manifestations of pediatric NHL and the potential for diagnostic delay. Treatment outcomes in our study were encouraging despite the high proportion of advanced-stage disease. Of the 32 children who initiated treatment, 29 completed therapy at our center, and the three-year event-free survival was 86.5%, as demonstrated by the Kaplan–Meier survival curve (Figure 1). This outcome is comparable to the three-year event-free survival of 82.5% reported by Meena et al.[12] and similar to outcomes reported from other low- and middle-income countries [16,20]. These findings reinforce that protocol-based, risk-adapted chemotherapy can achieve outcomes comparable to those in developed nations when delivered with adequate supportive care. Risk stratification and standardized protocols played a crucial role in achieving favorable outcomes. Children with B-cell NHL treated using the FAB LMB 96 protocol showed good early response, with most group B patients demonstrating more than 20% tumor reduction after COP prephase. The addition of rituximab for group C patients likely contributed to improved disease control, consistent with existing evidence[21,22]. Importantly, none of the children required radiotherapy, and treatment-related toxicities, although common, were manageable and did not result in long-term sequelae. A notable finding of this study is the substantial socioeconomic burden faced by families. Nearly 87.5% of families required financial assistance to complete treatment, including chemotherapy, central venous access devices, and supportive care. Financial toxicity remains a major barrier to optimal cancer care in India and directly impacts treatment adherence and outcomes. The ability to mobilize support through governmental schemes, non-governmental organizations, and charitable donors was instrumental in ensuring uniform treatment delivery in our cohort. The limitations of this study include its retrospective design, relatively small sample size, and single-center experience, which may limit generalizability. Additionally, molecular and cytogenetic data were not uniformly available for all patients. Despite these limitations, the study provides valuable insights into the real-world management of pediatric NHL in a resource-limited setting. The findings underscore that early diagnosis, standardized risk-adapted therapy, robust supportive care, and sustained financial support can yield survival outcomes comparable to those in high-income countries. Strengthening referral networks, improving awareness among primary care providers, and expanding financial protection mechanisms are critical to further improving outcomes for children with NHL in India.

This single-centre retrospective study highlights that pediatric non-Hodgkin’s lymphoma in South India commonly presents at an advanced stage with frequent extranodal involvement, particularly of the gastrointestinal tract. Despite these challenges, outcomes were favorable when children were treated using standardized, risk-adapted chemotherapy protocols with comprehensive supportive care. The three-year event-free survival of 86.5% achieved in this cohort is comparable to outcomes reported from other Indian and international studies, demonstrating that cure rates similar to those in developed countries are achievable even in resource-limited settings. Early diagnosis, uniform protocol-based management, vigilant supportive care, and timely financial assistance were key factors contributing to successful outcomes. Strengthening referral systems, improving awareness, and ensuring sustained financial and social support are essential to further improve survival and reduce treatment abandonment in children with non-Hodgkin’s lymphoma in India.

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