Main content

This overview was com­piled after a discussion between Trijn Israels as an expert in the subject and Ed Zijlstra on behalf of the Editorial Board of MT.

Short cv

Trijn Israels (51) is a Dutch paediatrician who trained in the Academic Medical Center, Amsterdam, with further specialization in paediatric oncology. She worked in Malawi in 2003 and from 2006-2008 in the Department of Paediatrics of the College of Medicine and Queen Elizabeth Central Hospital, Blantyre, with special interest in childhood oncology. Her PhD thesis (2010) was titled ‘Aspects of management of children with cancer in Malawi’. She has been co-chair of the Committee of Paediatric Oncology in Developing Countries (PODC) of the International Society of Paediatric Oncology (SIOP) and is now coordinator of the Collaborative Wilms Tumour Africa Project which is implementing an adapted treatment guideline for Wilms tumour in eight centres in five countries in sub-Saharan Africa. Currently she is working as a paediatrician in the Amphia Hospital in Breda, the Netherlands.

This paper describes Burkitt lym­phoma in a resource-limited set­ting, in particular in Malawi.

Introduction

Burkitt lymphoma (BL) is a unique tumour; it is has the highest cell replication rate of all human ma­lignancies with a cell doubling rate of 24-48 hours. This causes rapid clinical progression and also makes it amenable to effective cytostatic therapy that interferes with the cell replication mechanism.

There are three types of BL of which the endemic form (eBL) is the most important. It is also the most com­mon tumour during childhood in areas where malaria is endemic, a relationship described in 1958 by Denis Burkitt, an Irish surgeon who worked in Uganda. At around the same time, Epstein Barr Virus (EBV) particles were detected in lym­phoma tumour cells. Although the exact mechanism is unknown, BL is thought to be caused as the result of interaction between EBV and the malaria parasite. As EBV infection and malaria both are common in young children, BL is mostly seen in young children between 4 and 9 years of age; boys are twice as frequently affected as girls.

The sporadic variant of BL (the second type) occurs in Europa and North America; here the relation­ship with EBV is less clear. The third type is the immune-deficiency related BL that was commonly seen in HIV infected individuals before the introduction of antiretroviral therapy, in particular early in the progression of the disease.

Clinical presentation

The most common localizations are in the eye, jaw and abdomen. The first two give the typical presentations of eBL with eye protrusion and perior­bital swelling, and swelling of the jaw (Figure). In addition, the child may present with abdominal BL resulting in rapid swelling of the abdomen with ascites. The child is typically (severely) malnourished because of the metabolic demands of the rapidly growing tumour (Figure). Less common is localization in the central nervous system. In the brain, eBL leads to confusion, visual loss, and reduced consciousness and may be fatal. A BL mass may also compress the spinal cord leading to paraplegia and bladder incontinence. In Malawi, the majority of children present with some form of facial disease and many of them also have abdominal disease.

Many patients present at the clinic with advanced stage of disease. Sources of de­lay in diagnosis and treatment are many. These include primary consultation of a traditional healer (who may apply scarifi­cation), limited knowledge among health workers of the disease and treatment options, and barriers in referral and access to central hospitals. Clearly any delay in treatment allows the tumour to grow resulting in more severe disease with negative consequences for the response to treatment; this is particu­larly so in children with severe wasting. In Malawi, eBL is treated in two central hospitals in Blantyre and Lilongwe. The referral rate has increased in recent years, reflecting greater awareness of the disease and better options for treatment.

BL is diagnosed by a fine needle aspira­tion of the lesions; staging to describe the extent of the disease includes a bone marrow aspirate and examination of the cerebrospinal fluid for malignant cells.

The treatment of eBL in Malawi and other centres in sub-Saharan Africa has improved considerably in recent years. The simplest, standard treatment regimen includes a 28 day treatment schedule with cyclofosfamide, first IV on day 1, then oral on days 8, 18 and 28, with intrathecal administration of methotrexate and steroids to prevent relapses from untreated lymphoma foci in the brain. With this regimen, a 50% cure rate can be achieved; in those who relapse, repeated courses of second-line treatment are given with cure in another 15%. In those not responding, the prognosis is poor. The cost of drugs is around USD 50.

Over the years, studies have been done to further improve the cure rates. Add­ing vincristine to first-line treatment and using high methotrexate dosages proved not effective or was too toxic. Another study led to better outcome in severely malnourished children by adapting the dosage to reduce side-effects. Stag­ing has become the norm; those with extensive disease receive higher doses of drug with better survival rates, although with more toxicity. The latest very promising approach is with a monoclo­nal antibody (rituximab) that specifi­cally targets the tumour cells, with very little toxicity. It is currently expensive (around USD 1000 per patient treated with a full dose); studies are ongoing.

The future

The understanding of the biological behaviour of eBL and its management have considerably improved over the years. International collaboration, both regional and with partners in high-­income countries (HICs), has increased through successful twinning with a collaborating centre. World Child Cancer, which funds childhood cancer projects in low-income countries, was founded about a decade ago. Pragmatic, adapted treatment guidelines for the most common and curable childhood cancers such as retinoblastoma, eBL, Kaposi’s sarcoma, and Wilms tumour have been published by the Interna­tional Society for Paediatric Oncology (please see further reading below).

Several lessons have been learned for a better approach to eBL treatment in a resource-poor setting. First, em­phasis should be on completing the treatment course, as most failures result from premature stopping of treatment or defaulting. While this was common in the past, improved clinical management, with less side-effects of drugs, and counselling have led to much improved compliance.

Second, compared to high-income coun­tries, the treatment should be of low intensity to avoid toxicity related deaths. Lastly, to realize optimum results, taking these two issues into account, study protocols should be developed locally and not copied from HICs.

In conclusion, important progress has been made in the treatment and outcome of this common childhood tumour in resource-limited settings.

Two patients with endemic Burkitt Lymphoma in the abdomen and on the jaw
[Images of patients are present here but not transcribed as per user instructions on tables/figures, and for privacy if they were identifiable individuals, though the instruction was general.]

Further reading

International society of paediatric oncology (siop) paediatric oncology in developing countries (podc) adapted treatment guidelines

  • Chantada G, Luna-Fineman S, Sitorus RS, Kruger M, Israels T et al. SIOP-PODC recommendations for graduated-­intensity treatment of retinoblastoma in developing countries. Pediatr Blood Cancer 2013 May;60(5):719-27.
  • Hesseling P, Israels T, Harif M, Chantada G, Molyneux E. Practical recommendations for the management of children with endemic Burkitt lymphoma (BL) in a resource limited setting. Pediatr Blood Cancer 2013 March;60(3):357-62.
  • Israels T, Moreira C, Scanlan T, Molyneux L, Kampondeni S, Hesseling P et al. SIOP PODC: clinical guidelines for the management of children with Wilms tumour in a low income setting. Pediatr Blood Cancer 2013 January;60(1):5-11.
  • Israels T, Renner L, Hendricks M, Hesseling P, Howard S, SIOP PODC: Recommendations for Supportive Care of Children With Cancer in a Low-Income Setting. Pediatr Blood Cancer 2013 June;60(6):899-904.
  • Molyneux E, Davidson A, Orem J, Hesseling P, Balagadde-­Kambugu J, Githanga J et al. The management of children with Kaposi sarcoma in resource limited settings. Pediatr Blood Cancer 2013 April;60(4):538-42.

Paediatric oncology in africa: approach, collaboration

  • Israels T, Kambugu J, Kouya F, El-Mallawany NK, Hesseling PB, Kaspers GJ, Eden T, Renner L, Molyneux EM. Clinical trials to improve childhood cancer care and survival in sub-­Saharan Africa. Nat Rev Clin Oncol. 2013 Oct;10(10):599-604.
  • Israels T, Molyneux EM. Paediatric Oncology. Collaborating in Africa – small steps to sustainable success. Nat Rev Clin Oncol 2014; Oct 28. doi: 10.1038/nrclinonc.2014.189.
  • Paintsil V, David H, Kambugu J, Renner L, Kouya F, Eden T, Hesseling PB, Molyneux EM, Israels T, The Collaborative Wilms Tumour Africa Project; Baseline evaluation of Wilms tumour treatment and outcome in eight institutes in sub-Saharan Africa. Eur J Cancer 2015;51(1):84-91.

Burkitt lymphoma

  • Depani S, Banda K, Bailey S, Israels T, Molyneux E. Outcome is unchanged by adding vincristine upfront to the Malawi 28-day protocol for endemic Burkitt lymphoma. Pediatr Blood Cancer. 2015 doi: 10.1002/pbc.25612.
  • Molyneux E, Schwalbe E, Chagaluka G, Banda K, Israels T, Depani S, Mittermayer-Vassallo K, Windebank K, Mvula J, Njiram’madzi J, O’Brien S, Carey P, Bailey S. The use of anthracyclines in the treatment of endemic Burkitt lymphoma. Br J Haematol. 2016 Nov 28. doi: 10.1111/bjh.14440.
  • Hesseling P, Israels T, Harif M, Chantada G, Molyneux E. Practical recommendations for themanagement of children with endemic Burkitt lymphoma (BL) in a resource limited setting. Pediatr Blood Cancer 2013 March;60(3):357-62.
  • Molyneux E, Rochford R, Griffin B, Newton R, Jackson G, Menon G, Harrison C, Israels T, Baily S. Burkitt’s lymphoma. Lancet 2012;379:1234-1244.