Indian Journal of Medical and Paediatric Oncology

ORIGINAL ARTICLE
Year
: 2019  |  Volume : 40  |  Issue : 1  |  Page : 41--47

Clinical profile and outcomes of Non-Hodgkin's lymphoma in children: A report from a tertiary care hospital from India


Jagdish Prasad Meena, Aditya Kumar Gupta, Mansingh Parihar, Rachna Seth 
 Department of Pediatrics, Division of Pediatric Oncology, All India Institute of Medical Sciences, New Delhi, India

Correspondence Address:
Aditya Kumar Gupta
Department of Pediatrics, Division of Pediatric Oncology, All India Institute of Medical Sciences, New Delhi - 110 029
India

Abstract

Background: Non-Hodgkin's lymphoma (NHL) is an aggressive malignancy. Its outcome has improved over the past decades. Although it accounts for 8%–10% of all childhood cancers, very less information about its clinical presentation and outcomes is available from India. Our objective was to study the clinical presentation and outcomes in children (<15 years) with NHL at our center. Methodology: We retrospectively analyzed 26 children diagnosed with NHL at our center from August 2008 to June 2014 and followed them up to May 2017. Results: The median age at the time of diagnosis was 7.7 years (2.5–13 years). Abdominal distension and an abdominal lump were the most common presenting features occurring in 75%, followed by fever (73.8%) and weight loss (46.2%). Most patients had advanced-stage (Stage III/IV, 92.3%) disease at presentation. The primary presentation was extranodal in 57.7%, nodal in 26.9%, and combined in 15.4%. Burkitt's lymphoma (BL) was the most common subtype (46.2%), followed by T-lymphoblastic lymphoma, diffuse large B-cell lymphoma, and anaplastic large-cell lymphoma. Three patients did not take treatment. The median follow-up of patients was 48 months (36–99 months). Nineteen patients achieved remission and four had progressive disease. Significantly better event-free survival (EFS) was found with younger age and lower stage of presentation. The EFS did not significantly differ with sex, group of disease, lactate dehydrogenase levels, and presenting features. Conclusions: Our cohort of patients with NHL showed characteristics similar to those reported from other developing countries. NHL occurred at a younger age, with a higher incidence of BL. The outcome for patients aged >10 years was poor. The outcome of NHL was comparable to that of other centers in the world.



How to cite this article:
Meena JP, Gupta AK, Parihar M, Seth R. Clinical profile and outcomes of Non-Hodgkin's lymphoma in children: A report from a tertiary care hospital from India.Indian J Med Paediatr Oncol 2019;40:41-47


How to cite this URL:
Meena JP, Gupta AK, Parihar M, Seth R. Clinical profile and outcomes of Non-Hodgkin's lymphoma in children: A report from a tertiary care hospital from India. Indian J Med Paediatr Oncol [serial online] 2019 [cited 2019 Aug 24 ];40:41-47
Available from: http://www.ijmpo.org/text.asp?2019/40/1/41/256184


Full Text

 Introduction



Malignant lymphomas (including non -Hodgkin's lymphoma [NHL] and HL) are the third most common group of malignancies in children after leukemias and brain tumors. They account for 15% of all childhood malignancies in children younger than 20 years.[1] Approximately 60% of pediatric lymphomas are NHL, whereas the rest are HL.[2]

Most NHLs in children present as an aggressive disseminated disease. Potential clinical emergencies in patients with NHL prior to diagnosis are superior/inferior vena cava obstruction, acute airway obstruction, spinal cord compression, pericardial tamponade, intussusception/intestinal obstruction, and central nervous system (CNS) complications. The outcome of childhood NHL has improved progressively over the past decade to about 80%–90% with intensive risk-adapted multiagent therapy.[3],[4],[5]

In developing countries, there are many obstacles to the treatment of childhood lymphomas. The most important are late diagnosis, low socioeconomic status, and poor nutrition.[6],[7],[8] The lack of awareness at primary care level, universal health-care provision, and poor socioeconomic status lead to late presentations with advanced stage disease, thus influencing outcomes.

There is a scarcity of data on the clinical profile and outcomes of treatment of childhood NHL in India. Here, we present the experience in the management of childhood NHL from a single tertiary center in a large metropolitan urban setting, focusing specifically on the clinical profile and outcome of these children.

 Methodology



Eligibility, staging, and diagnosis

The data of children younger than 15 years diagnosed with NHL at the All India Institute of Medical Sciences, New Delhi, diagnosed with NHL over 6 years from August 2008 to June 2014, were retrospectively analyzed. The study was approved by our Institutional Ethics Committee. Twenty-six patients who had been diagnosed with NHL during this period were identified, and data regarding clinical features, diagnostic and staging workup, and treatment outcomes were collected.

The workup for all patients included a detailed history; physical examination; standard blood tests including lactate dehydrogenase (LDH); computed tomography (CT) scan of the primary site along with neck, chest, abdomen, and pelvis; and bone marrow (BM) aspiration and biopsy. NHL was staged according to St Jude/Murphy staging system[9] before treatment initiation.

The diagnosis was on the basis of either ultrasound or CT-guided core needle or excisional biopsy. The presence of neoplastic cells in the cerebrospinal fluid and the clinical sign of CNS involvement defined CNS disease. To evaluate malnutrition, the Z-scores were used for each patient's weight for age (undernutrition), height for age (stunting), and weight for height (wasting) (WHO Z-scores in children <5 years of age[10] and Indian Academy of Pediatrics Z-scores in children >5 years of age).[11]

Stratification

Therapy was stratified into three risk groups[3] according to the following criteria: risk Group 1 (R1) was defined as patients having lymphoma with initial complete resection; risk Group 2 (R2) was defined as patients diagnosed with lymphoma with no or incomplete resection and involvement of only extra-abdominal sites and LDH level <500 U/L, measured before starting chemotherapy; and risk Group 3 (R3) was defined as patients diagnosed with lymphoma, with no or incomplete resection of abdominal lymphoma and LDH ≥500 U/L, all patients with BM involvement and/or CNS disease, and/or multifocal bone involvement.

Treatment

The patients were stratified by risk factors (stage and LDH level) and treated with the NHL-Berlin–Frankfurt–Münster (BFM 90) protocol.[3],[12] At diagnosis, all patients were treated with vigorous hydration and allopurinol to prevent tumor lysis syndrome (TLS). All patients received a cytoreductive phase with prednisone and cyclophosphamide. After the 5th day of prephase, the first course of chemotherapy was initiated the next day depending on the condition of the patient. In our patients' group, no one was in Group R1. Patients in Group R2 received four courses of multiagent chemotherapy (AA-BB-AA-BB). Patients in Group R3 received six courses, i.e., AA-BB-AA-BB-AA-BB. Conditions for starting the subsequent course of therapy were as follows: platelets >100,000/μL and neutrophils >1000/μL after the nadir of postchemotherapeutic cytopenia. The minimal interval between the two successive courses was at least 4 weeks.

Patients in risk groups R2 and R3 who had a residual tumor after two therapy courses received therapy course CC. Patients were re-evaluated after course CC. If no viable lymphoma tissue was found, therapy was continued with three more courses (AA-BB-CC).

Patients of lymphoblastic lymphoma (LBL) were treated with the International Network for Cancer Treatment and Research (INCTR), an unpublished study protocol for LBL/lymphoma and the MCP 841 protocol.

Response evaluation

Physical examination of all clinically documented sites of disease was performed prior to the initiation of each cycle. All patients underwent a CT scan of the neck, chest, and abdomen upfront. A CT or positron emission tomography (PET) scan study was performed after the first two cycles of chemotherapy. Follow-up evaluations included history, physical examination, and laboratory examinations every 3 months during the 1st year after the end of the therapy and at 4–6-month intervals during the following 3 years and yearly thereafter. PET or CT scans were performed when clinically indicated. Progression was defined as a recurrence of tumor documented by clinical examination, X-rays, ultrasound, and CT scan or PET scan studies. Patients with initial BM and CNS involvement were evaluated with punctures of BM and CNS until clearing of blasts. Complete response was defined as the complete disappearance of clinical and radiological lesions. Disease progression was defined as increase by ≥25% of at least one measurable lesion, or by the appearance of a new lesion. Event-free survival (EFS) was determined as the time from the initiation of treatment to progression, death, or the most recent follow-up examination.

Statistical analysis

Data were statistically described as frequencies (number of cases) and percentages where appropriate. Descriptive statistics were used to calculate the relative frequencies of age, sex, histopathologic types, and clinical and laboratory features. Survival curves were plotted using the Kaplan–Meier method, and comparison was made using the log-rank test. P < 0.05 was considered to be statistically significant. The statistical analysis was performed using SPSS statistics version 16.0 for analysis (SPSS Inc. Released 2007. SPSS for Windows, Version 16.0. Chicago, SPSS Inc).

 Results



Patient characteristics and presentation

There were 26 patients of NHL who were treated at our center during the above period. The median age at the time of diagnosis was 7.7 years (2.5–13 years). There were 21 males. The presenting clinical characteristics of patients are shown in [Table 1]. The abdominal distension/lump was the most common presenting feature occurring in twenty patients (76.9%), followed by fever (73.1%), weight loss (46.2%), breathlessness (34.6%), pallor (34.6%), lymphadenopathy (26.9%), and bone pain (19.2%). The physical/radiological findings of the cohort are shown in [Table 2]. An abdominal mass (69.2%) was the most common finding. Pleural effusion was present in 46% of patients and about 19% of the patients presented with a superior mediastinum syndrome/superior vena cava syndrome.{Table 1}{Table 2}

Disease localization and staging

Highly elevated serum LDH (LDH ≥1000 IU/L) was seen in 50% of patients. Nineteen patients (73.1%) were in Group R3 and seven patients (26.9%) were in R2 risk group. The primary presentation was extranodal in 57.7%, followed by nodal (26.9%) and combined (15.4%). The most common nodal presentation was cervical lymphadenopathy (46.2%), and the most common extranodal presentation was gastrointestinal tract (69.2%) followed by liver and BM (15.4% each).

Types of non-Hodgkin's lymphoma

Burkitt's lymphoma (BL) was the most common NHL subtype (46.2%), followed by T-LBL (T-LBL), diffuse large B-cell lymphoma (DLBCL), and anaplastic large-cell lymphoma (ALCL), accounting for 15.4%, 7.7%, and 3.8% of the cases, respectively. Seven patients (26.9%) could not be classified in specific subtype [Table 3].{Table 3}

Treatment

Fifteen patients (57.7%) received chemotherapy alone. Three patients (11.5%) (T-LBL) received a combination of chemotherapy and radiotherapy (cranial radiation therapy). Five patients (19.2%) received combined therapy of chemotherapy and surgery. Two patients (BL) required surgery for residual tumor. Three patients required surgery for intestinal obstruction (1 BL, 1 DLBCL, and 1 B-cell-NHL [B-NHL] [unclassified]). Eighteen patients (69.2%) were treated with NHL-BFM protocol, four patients of T-LBL were treated with INCTR (n = 3) and MCP 841 (n = 1) protocol, and one patient of peripheral T-cell lymphoma was treated with four chemotherapy cycles of cyclophosphamide, doxorubicin, vincristine, etoposide, and prednisone. Three patients did not take treatment. Five patients (21.7%) out of 23 who received treatment had TLS (4, BL and 1, T-LBL); out of them, two required recombinant urate oxidase (rasburicase) and hemodialysis.

Survival outcomes

The median follow-up in patients was 48 months (36–99 months). A total of 19 patients achieved complete remission and 4 (17.4%) patients had progressive disease. The 3-year EFS rate of our study was 82.6% [Figure 1]. The 3-year EFS compared between the age groups of <10 years and ≥10 years was statistically significant (94.1% vs. 66.7%; P = 0.008) [Figure 2]. The sex of the patient, risk group, LDH levels, and primary presentation characteristics did not significantly affect the EFS.{Figure 1}{Figure 2}

 Discussion



The outcome of NHL in children has improved considerably over the years with the risk stratification and treatment modifications. NHL in children is an aggressive malignancy and requires early intervention and intensive chemotherapy. Data about the clinical profile and outcomes of childhood NHL from many developing countries, including India, are scanty. This study included NHL patients <15 years old diagnosed at our department from August 2008 to June 2014. Our hospital is a tertiary care hospital and referral bias cannot be excluded.

Lymphomas are the third most common malignancy in children, accounting for 15% of all childhood malignancies in children younger than 20 years.[1] In contrast to a NHL/HL ratio of 3:2 in Western countries, it is either equal or often reversed in India.[1],[13]

In our study, BL was the most common lymphoma and constituted 46.2% of the cases, similar to what has been reported by other authors.[14],[15],[16] Other studies from India[17],[18],[19],[20] have shown that LBL is more common than BL. The incidence of BL varies markedly worldwide, being predominantly high in Equatorial Africa, which is likely due to early infection by Epstein–Barr virus (EBV) and chronic exposure to malaria. The exposure to EBV is commonly seen in the lower socioeconomic strata, and BL is commonly associated with EBV worldwide.[21]

LBL was the second most common subtype of NHL, comprising 15.4% of all NHLs similar to other studies.[14],[22],[23],[24] In a Brazilian epidemiologic study, LBL represented 36% of all NHLs and T-LBL was the most prevalent (60%) followed by B-LBL (25%) and the remaining (15%) were unclassified.[25] The overall frequency of T-LBL (6%–7.2%) in India[26],[27] has been reported to be slightly higher than that in other countries. The cause for this high frequency may be due to the role of genetic factors and environmental factors in developing countries.[28] There are studies for the possible association between T-LBL in children and risk factors such as EBV infection[29],[30] and methylene tetrahydrofolate reductase gene polymorphisms.[31]

DLBCL constituted 7.7% of all NHLs in our study. The frequency of DLBCL was higher in other studies at 21.6%.[16],[24],[32] Occasionally, differentiation of BL can be difficult from high-grade DLBCL. Childhood DLBCL is biologically different from adult and has a good prognosis. The good prognosis of DLBCL is accredited to the fact that most of the childhood DLBCLs are of the germinal center phenotype and lack the (8:14) translocation.[33] In our study, ALCL constituted about 3.8% of all NHLs.

NHL in children is generally considered to be a widely disseminated disease from the beginning. In the present study, 92.3% of NHL patients had advanced stage (Stage III/IV) disease; similar results were reported by several previous studies.[16],[22],[24],[32] Multiple reasons may be responsible for presentation in an advanced stage, and they include lack of early referral, insufficient knowledge about the disease, and wide use of alternative medicine, which may delay seeking proper medical advice. In this study, three patients received prior antitubercular drug, one patient had got methylprednisolone and intravenous immunoglobulin, and one patient received alternative medicine prior coming to our center.

NHL in children is commonly found extranodally and is more difficult to diagnose, clinically as well as histopathologically, in comparison to HL.[34] In our study of 26 patients with NHL, abdominal involvement was the most common presentation (69.2%), followed by cervical lymph node involvement (46.2%), whereas BM infiltration (15.4%) was the most common site of metastasis. In other studies, the abdominal involvement was the most common presentation (73.2%), followed by mediastinal involvement (16.2%).[16],[22] The incidence of TLS (21.7%) and mucositis (23.7%) in our study was similar to that reported by Alavi et al. at 23.7%[35] and Tiwari et al. at 26.1%, respectively.[36]

The 3-year EFS in the present study was 82.6%. The survival of our patients is comparable with the results presented by the international treatment groups, reporting a survival rate of ~80–90% for patients with NHL.[12],[15],[22],[37],[38] With regard to prognostic factors, no statistically significant associations were observed between gender, LDH, risk stratification groups, and primary presentations. The difference in 3-year EFSs between the age groups of <10 years and ≥10 years was significant. Similarly, Hwang et al.[23] reported that the overall survival for patients in the age group of 21–31 years was significantly inferior to that of the other younger age group in Korea (P = 0.014).

 Conclusions



Our cohort of pediatric patients with NHL showed characteristics that were similar to those reported from other developing countries. NHL occurs at a younger age among pediatric patients in India, with a higher incidence of BL and the most common presentation of abdominal involvement. The outcome for patients with higher age (>10 years) was poor. Age (>10 years) might serve as a criterion for risk stratification in these subtypes of NHL. The outcome of NHL in our center was satisfactory, approaching the international rates although most patients presented in advanced stage of the disease. This study may help to establish baseline data for future studies, which may serve as a guideline for the management and may help improve the outcome for children with NHL in India.

Some limitations in our study were the small sample size and retrospective design; future prospective studies with larger sample size are needed to confirm our study results.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

References

1Allen CE, Kamdar KY, Bollard CM, Gross TG. Malignant non-Hodgkin lymphomas in children. In: Pizzo PA, Poplack DG, eds. Principles and Practice of Pediatric Oncology. 7th ed. Philadelphia Pa: Lippincott Williams & Wilkins; 2016. p. 587-603.
2Shende A. Non Hodgkins lymphoma. In: Lanzkowsky P, editor. Manual of Pediatric Hematology/Oncology. 3rd ed. San Diego, California: Academic Press; 2000.
3Reiter A, Schrappe M, Tiemann M, Ludwig WD, Yakisan E, Zimmermann M, et al. Improved treatment results in childhood B-cell neoplasms with tailored intensification of therapy: A report of the Berlin-Frankfurt-Münster group trial NHL-BFM 90. Blood 1999;94:3294-306.
4Patte C, Auperin A, Michon J, Behrendt H, Leverger G, Frappaz D, et al. The Société Française D'oncologie Pédiatrique LMB89 protocol: Highly effective multiagent chemotherapy tailored to the tumor burden and initial response in 561 unselected children with B-cell lymphomas and L3 leukemia. Blood 2001;97:3370-9.
5Cairo MS, Sposto R, Perkins SL, Meadows AT, Hoover-Regan ML, Anderson JR, et al. Burkitt's and Burkitt-like lymphoma in children and adolescents: A review of the children's cancer group experience. Br J Haematol 2003;120:660-70.
6van Hasselt EJ, Broadhead R. Burkitt's lymphoma: A case file study of 160 patients treated in Queen Elizabeth central hospital from 1988 to 1992. Pediatr Hematol Oncol 1995;12:277-81.
7Ertem U, Duru F, Pamir A, Taçyildiz N, Daǧdemir A, Akçayöz A, et al. Burkitt's lymphoma in 63 Turkish children diagnosed over a 10 year period. Pediatr Hematol Oncol 1996;13:123-34.
8Hesseling PB. The SIOP Burkitt lymphoma pilot study in Malawi, Africa. Med Pediatr Oncol 2000;34:142.
9Murphy SB. Classification, staging and end results of treatment of childhood non-Hodgkin's lymphomas: Dissimilarities from lymphomas in adults. Semin Oncol 1980;7:332-9.
10WHO Multicentre Growth Reference Study Group. WHO child growth standards based on length/height, weight and age. Acta Paediatr Suppl 2006;450:76-85.
11Indian Academy of Pediatrics Growth Charts Committee, Khadilkar V, Yadav S, Agrawal KK, Tamboli S, Banerjee M, et al. Revised IAP growth charts for height, weight and body mass index for 5- to 18-year-old Indian children. Indian Pediatr 2015;52:47-55.
12Reiter A, Schrappe M, Parwaresch R, Henze G, Müller-Weihrich S, Sauter S, et al. Non-Hodgkin's lymphomas of childhood and adolescence: Results of a treatment stratified for biologic subtypes and stage – A report of the Berlin-Frankfurt-Münster group. J Clin Oncol 1995;13:359-72.
13Banerjee CK, Srinivas M, Goswami KC, Pathak IC, Walia BN. Non-Hodgkin's lymphoma in children – Histopathologic classification in relation to age and sex. Indian J Pediatr 1983;50:511-4.
14Wright D, McKeever P, Carter R. Childhood non-Hodgkin lymphomas in the United Kingdom: Findings from the UK children's cancer study group. J Clin Pathol 1997;50:128-34.
15Burkhardt B, Zimmermann M, Oschlies I, Niggli F, Mann G, Parwaresch R, et al. The impact of age and gender on biology, clinical features and treatment outcome of non-Hodgkin lymphoma in childhood and adolescence. Br J Haematol 2005;131:39-49.
16Fadoo Z, Belgaumi A, Alam M, Azam I, Naqvi A. Pediatric lymphoma: A 10-year experience at a tertiary care hospital in Pakistan. J Pediatr Hematol Oncol 2010;32:e14-8.
17Manipadam MT, Nair S, Viswabandya A, Mathew L, Srivastava A, Chandy M, et al. Non-Hodgkin lymphoma in childhood and adolescence: Frequency and distribution of immunomorphological types from a tertiary care center in South India. World J Pediatr 2011;7:318-25.
18Bharatnur SS, Amirtham U, Premalata CS, Kumar RV. Distribution of non-Hodgkin lymphoma in children and adolescents. A study from a regional cancer centre in South India. IOSR J Dent Med Sci 2016;15:7-12.
19Srinivas V, Soman CS, Naresh KN. Study of the distribution of 289 non-Hodgkin lymphomas using the WHO classification among children and adolescents in India. Med Pediatr Oncol 2002;39:40-3.
20Advani S, Pai S, Adde M, Vaidya S, Vats T, Naresh K, et al. Preliminary report of an intensified, short duration chemotherapy protocol for the treatment of pediatric non-Hodgkin's lymphoma in India. Ann Oncol 1997;8:893-7.
21Magrath IT. African Burkitt's lymphoma. History, biology, clinical features, and treatment. Am J Pediatr Hematol Oncol 1991;13:222-46.
22Sherief LM, Elsafy UR, Abdelkhalek ER, Kamal NM, Youssef DM, Elbehedy R, et al. Disease patterns of pediatric non-Hodgkin lymphoma: A study from a developing area in Egypt. Mol Clin Oncol 2015;3:139-44.
23Hwang IG, Yoo KH, Lee SH, Park YH, Lim TK, Lee SC, et al. Clinicopathologic features and treatment outcomes in malignant lymphoma of pediatric and young adult patients in Korea: Comparison of Korean all-ages group and Western younger age group. Clin Lymphoma Myeloma 2007;7:580-6.
24Mobark NA, Tashkandi SA, Shakweer WA, Saidi KA, Fataftah S, Nemer MM, et al. Pediatric non-Hodgkin lymphoma: A retrospective 7-year experience in children and adolescents with non-Hodgkin lymphoma treated in King Fahad Medical City (KFMC). J Cancer Ther 2015;6:299-314.
25Gualco G, Klumb CE, Barber GN, Weiss LM, Bacchi CE. Pediatric lymphomas in Brazil. Clinics (Sao Paulo) 2010;65:1267-77.
26Naresh KN, Srinivas V, Soman CS. Distribution of various subtypes of non-Hodgkin's lymphoma in India: A study of 2773 lymphomas using R.E.A.L. And WHO classifications. Ann Oncol 2000;11 Suppl 1:63-7.
27Naresh KN, Agarwal B, Nathwani BN, Diebold J, McLennan KA, Muller-Hermelink KH, et al. Use of the World Health Organization (WHO) classification of non-Hodgkin's lymphoma in Mumbai, India: A review of 200 consecutive cases by a panel of five expert hematopathologists. Leuk Lymphoma 2004;45:1569-77.
28Naresh KN, Advani S, Adde M, Aziz Z, Banavali S, Bhatia K, et al. Report of an international network of cancer treatment and research workshop on non-Hodgkin's lymphoma in developing countries. Blood Cells Mol Dis 2004;33:330-7.
29Sasikala PS, Nirmala K, Sundersingh S, Mahji U, Rajkumar T. Frequency and distribution of Epstein-Barr virus infection and its association with P53 expression in a series of primary nodal non-Hodgkin lymphoma patients from South India. Int J Lab Hematol 2010;32:56-64.
30Sehgal S, Mujtaba S, Gupta D, Aggarwal R, Marwaha RK. High incidence of Epstein Barr virus infection in childhood acute lymphocytic leukemia: A preliminary study. Indian J Pathol Microbiol 2010;53:63-7.
31Sadananda Adiga MN, Chandy S, Ramachandra N, Appaji L, Aruna Kumari BS, Ramaswamy G, et al. Methylenetetrahydrofolate reductase gene polymorphisms and risk of acute lymphoblastic leukemia in children. Indian J Cancer 2010;47:40-5.
32Nakagawa A, Nakamura S, Nakamine H, Yoshino T, Takimoto T, Horibe K, et al. Pathology review for paediatric non-Hodgkin's lymphoma patients in Japan; a report from the Japan Association of Childhood Leukaemia study (JACLS). Eur J Cancer 2004;40:725-33.
33Oschlies I, Klapper W, Zimmermann M, Krams M, Wacker HH, Burkhardt B, et al. Diffuse large B-cell lymphoma in pediatric patients belongs predominantly to the germinal-center type B-cell lymphomas: A clinicopathologic analysis of cases included in the German BFM (Berlin-Frankfurt-Münster) multicenter trial. Blood 2006;107:4047-52.
34Perkins SL. Work-up and diagnosis of pediatric non-Hodgkin's lymphomas. Pediatr Dev Pathol 2000;3:374-90.
35Alavi S, Arzanian MT, Abbasian MR, Ashena Z. Tumor lysis syndrome in children with non-Hodgkin lymphoma. Pediatr Hematol Oncol 2006;23:65-70.
36Tiwari P, Thomas MK, Pathania S, Dhawan D, Gupta YK, Vishnubhatla S, et al. Serum creatinine versus plasma methotrexate levels to predict toxicities in children receiving high-dose methotrexate. Pediatr Hematol Oncol 2015;32:576-84.
37Seidemann K, Tiemann M, Schrappe M, Yakisan E, Simonitsch I, Janka-Schaub G, et al. Short-pulse B-non-Hodgkin lymphoma-type chemotherapy is efficacious treatment for pediatric anaplastic large cell lymphoma: A report of the Berlin-Frankfurt-Münster group trial NHL-BFM 90. Blood 2001;97:3699-706.
38Link MP, Shuster JJ, Donaldson SS, Berard CW, Murphy SB. Treatment of children and young adults with early-stage non-Hodgkin's lymphoma. N Engl J Med 1997;337:1259-66.