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An update on lymphoma in children and young adults
SYMPOSIUM: ONCOLOGY
An update on lymphoma in children and young adults
What’s new? C
Catherine Morley-Jacob C
Eve Gallop-Evans
in 2008, uses morphology, immunohistochemistry, genetic, molecular and clinical features, and has international consensus, due to its basis on biology and its clinical relevance, practicality, and reproducibility. The main division, particularly in children and young adults, is between Hodgkin (HL) and non-Hodgkin lymphoma (NHL), with these each being further subdivided.
Abstract Lymphoma accounts for approximately 10% of childhood cancers, but 17% in teenagers. It is divided into Hodgkin and non-Hodgkin lymphoma, with the vast majority of non-Hodgkin lymphoma in children being Burkitt lymphoma, lymphoblastic lymphoma and anaplastic large cell lymphoma. Lymphoma usually presents with painless lymphadenopathy, most commonly in the cervical region. ‘B’ symptoms are associated with more advanced disease. The diagnosis is usually made by histological examination of an excised lymph node, but can be made on pleural fluid or a bone marrow aspirate. Emergency management, particularly of the airway, may be necessary, especially in non-Hodgkin lymphoma. Lymphomas are treated with multi-drug chemotherapy regimens, stratified by risk group, with radiotherapy in selected cases. Rituximab (anti-CD20 monoclonal antibody) is used in conjunction with chemotherapy for poorer risk groups and in the relapse setting. In Hodgkin lymphoma, positron emission tomography scans are prognostic at assessment of response to therapy. The high cure rate for lymphomas (more than 90% for Hodgkin and Burkitt lymphoma) and the need to reduce late effects in children and adolescents has led to the current drive to tailor treatment according to risk group and response to initial therapy.
Epidemiology Hodgkin lymphoma (HL) is a B-cell lymphoma and, in the UK, two incidence peaks exist, one in young adults aged 20e35 years, and another in older adults, aged 70e79 years. Since the mid-1980s agestandardized incidence rates for Hodgkin’s lymphoma in Britain have remained unchanged at around three per 100,000 males and two per 100,000 females (CR-UK data). The WHO classification recognizes two major sub-classifications of HL: classical HL and nodular lymphocyte predominant HL (NLPHL). Classical Hodgkin lymphoma is subdivided into nodular schlerosing, mixed cellularity, lymphocyte-rich, and lymphocyte-depleted types. Nodular sclerosing HL accounts for nearly 60% of all newly diagnosed cases in the UK, while mixed cellularity disease is more common, especially at younger ages, in poorer countries. NLPHL constitutes only 5% of all cases. HL is unique in that the malignant Hodgkin ReedSternberg (HRS) cells account for less than 1% of the total cell population of the tumour. The clinical and pathologic features of HL reflect an abnormal immune response to HRS cells, resulting in infiltration of reactive inflammatory cells. High EBV antibody titres in up to 40% of HL suggest that EBV infection may precede the development of HL, and clonality studies indicate EBV infection precedes the expansion of the tumour cell population. This association varies with geographic location, age, sex, clinical stage and histologic type. The term Non-Hodgkin lymphoma (NHL) describes all lymphomas except HL. The incidence of NHL rises with age, with an almost static incidence until 40, from when it rises steeply. Approximately 80 children and young people are diagnosed with NHL each year in the UK (CR-UK data). The major sub-division is by cell of origin, namely B and T lymphocytes. Almost all NHL occurring in children is high grade and there are three main subtypes: Burkitt lymphoma (BL, mature B cell) 45%, lymphoblastic lymphoma (LBL, both pre-B and T cell) 35% and anaplastic large cell lymphoma (ALCL, previously malignant histiocytosis) 10%. By contrast, in adults there are more than 40 subtypes of NHL, most of which are rarely seen in children (Figure 1).
Keywords adolescent; child; diagnosis; Hodgkin; Non-Hodgkin; lymphoma; review
Definition Lymphoma is a malignant disorder of the lymphatic system, which includes lymph nodes, bone marrow, spleen, tonsils, adenoids and thymus. Lymphoma can also involve other organs, commonly the skin, liver, brain and bone. Lymphomas make up approximately 10% of childhood cancers (in those under 16, which accounts for approximately 140 cases per year in the UK), but 17% of cancer in teenagers. Lymphoma describes a diverse group of conditions, in terms of pathology, epidemiology, disease behaviour and prognosis. A number of different classification strategies have been described leading to multiple reclassifications and to new entities being described. The WHO classification, published in 2001 and updated
Catherine Morley-Jacob MRCP MRCPCH DCH MD is Consultant Paediatric Oncologist in the Department of Paediatric Oncology, Children’s Hospital for Wales, Cardiff, UK. Conflict of interest: none.
Clinical presentation
Eve Gallop-Evans PhD MRCP FRCR is Consultant Clinical Oncologist in the Department of Clinical Oncology, Velindre Hospital, Cardiff, UK. Conflict of interest: none.
PAEDIATRICS AND CHILD HEALTH 22:3
Hodgkin lymphoma e radiotherapy dependent on interim assessment of response with a PET-CT scan Relapse or refractory Non-Hodgkin lymphoma e better chance of cure with rituximab
Children with lymphoma usually present with painless lymphadenopathy, most commonly cervical, with frequent involvement of the mediastinum. B symptoms (fever more than 38 C, 10%
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Incidence by age of Hodgkin and Non-Hodgkin Lymphoma in Great Britain (CR-UK data)
Coronal view of thoracic CT from Case 1 L
50
L L
Hodgkin lymphoma
Rate per million
40
L
Tr
Non-Hodgkin lymphoma (including Burkitt lymphoma)
C
PTL
30
L 20
L Heart
10
0 0
1
2
3
4
5
6
7
8
9
10
11
12
13
L, lymph nodes; PTL – paratracheal lymphadenopathy; Tr, trachea; C, contrast in right subclavian vein
14
Age at diagnosis
Figure 2 Coronal view of thoracic CT from Case 1. Figure 1 Incidence of Hodgkin and Non-Hodgkin lymphoma under 14 years of age per million in the UK. Taken from the CR-UK website.
Case history 2
weight loss and night sweats) in the 6 months prior to presentation are associated with more advanced disease. Bulky mediastinal lymphadenopathy may cause respiratory symptoms. Unlike NHL, HL characteristically demonstrates contiguous nodal spread, while NLPHL usually affects a peripheral nodal site, and mediastinal involvement is uncommon. Extra-nodal disease (lung, liver, bone, bone marrow, testis) is much more common in NHL, and although unusual, CNS disease may occur and presents as cranial nerve palsies or with symptoms of a space-occupying lesion. Children with immunodeficiency, previous chemotherapy, Ataxia Telangiectasia, Bloom’s syndrome, HIV and other immune-modulating conditions are predisposed to lymphoma.
A 5-year-old boy initially presented with a facial palsy and was treated with steroids. A full blood count at that time was normal. When the steroids stopped, his facial palsy recurred. He then developed swinging pyrexias, with no specific findings on examination, except that he looked unwell. When his renal function began to deteriorate and a renal ultrasound showed large echogenic kidneys, he was referred to the Paediatric Nephrology team for a biopsy. As part of further investigations, in conjunction with Paediatric Oncology, he underwent bone marrow aspirates and trephines under the same anaesthetic. The diagnosis was confirmed as Burkitt lymphoma on both bone marrow and kidney biopsy. Further staging included a CT scan, which showed the enlarged kidneys (Figure 3). His full blood count remained normal, despite bone marrow involvement. His early risk of tumour lysis was extremely high, with bulky solid organ infiltration and reduced renal function. He was managed with aggressive fluid management, hyperhydration and rasburicase, and with chemotherapy: vincristine, cyclophosphamide and steroids. Within 48 h of starting treatment his renal function had returned to normal and his fevers had settled. He received 9 months of intensive chemotherapy, but remains in remission over 2 years off treatment.
Case history 1 A 16-year-old boy presented with a persistent cough and mild exertional breathlessness. He had been given a short course of steroids, which helped his symptoms significantly, but they then returned. He also had a 2-week history of drenching night sweats and had lost a stone in weight over the previous month. On examination, he was well with no signs of breathlessness at rest. He had small palpable lymph nodes in the left cervical region, but no other abnormalities to find on examination. CXR showed mediastinal widening and staging CT scan showed lymphadenopathy within the cervical and mediastinal regions (Figure 2), and a single iliac chain node of 2 cm. The biopsy confirmed classical HL, and as a stage IIIB, he was treated according to the high-risk treatment group, with OEPA chemotherapy (vincristine, etoposide, prednisolone, doxorubicin). He had a good clinical response with resolution of his B symptoms. After two cycles of chemotherapy, a CT scan showed significant reduction in the size of the nodes, and a PET scan showed no evidence of abnormal uptake, confirming remission. He went on to have four further courses of chemotherapy, but no radiotherapy, and has not required any further treatment, remaining well on follow-up at over 2 years from the end of treatment.
PAEDIATRICS AND CHILD HEALTH 22:3
Differential diagnosis The differential diagnosis depends on the distribution of the lymphadenopathy and the duration of symptoms. This is usually between the different types of lymphoma, leukaemia, infection and auto-immune phenomena. For NHL, if lymphoma cells represent greater than 25% of cells in the bone marrow, the term leukaemia is used, regardless of the level of nodal or other organ involvement. Infections, such as Staphylococcus aureus, often cause tender lymphadenopathy, while glandular fever (EpsteineBarr virus) can cause generalized lymphadenopathy, fever, weight loss and splenomegaly. If tuberculosis, atypical mycobacteria or cat scratch disease (caused by Bartonella henselae) are suspected 93
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In HL, histology reveals sparse numbers of the malignant HRS cell seen in a background of B cells, T cells, plasma cells, eosinophils and fibroblasts. In NHL, sheets of small round blue cells are seen, with the different subtypes being classified by immunohistochemistry. The diagnosis can also be made from pleural fluid or a bone marrow (BM) aspirate. Fluid samples such as these are sent for cytology, and for immunophenotyping by flow cytometry. Classical cytogenetics and molecular genetics using FISH and PCR-based techniques can be helpful for diagnosis and prognosis. In BL, translocations involving chromosome 8 are seen, most commonly t(8;14) in over 70%, and more rarely t(8;22) and t(2;8).
Coronal view of abdominal CT from Case 2
Liver
Spleen
K K
V
Investigations Full staging investigations include physical examination and imaging (ultrasound or MRI of the neck, CT of the thorax, CT or MRI of the abdomen and pelvis, and PET-CT if available for HL patients). Laboratory investigations include a full blood count, ESR, biochemical profile including ß2-microglobulin and lactate dehydrogenase (LDH). HIV and hepatitis B testing should be considered. BM biopsies are performed in advanced stage HL (stage III-IV), those with B symptoms or an abnormal blood count, and in all patients with NHL. A lumbar puncture is also required for initial staging in NHL.
Sacrum
The kidneys are enlarged; a normal kidney is equivalent to the height of 3 vertebrae. V, vertebral body; K, kidney Figure 3 Coronal view of abdominal CT from Case 2.
BM involvement
and the lymph node is to be biopsied, excision biopsy is imperative to reduce the risk of a chronically discharging tract. Juvenile idiopathic arthritis and systemic lupus erythematosus can also present with lymphadenopathy.
CSF involvement
5e25% lymphoma cells in BM e stage 4 >25% lymphoma cells in BM e in NHL, leukaemia >5 white cells (unless a traumatic tap)
Prior to starting treatment, a baseline assessment of cardiac, renal and pulmonary function is performed where relevant. Sperm cryopreservation should also be arranged if ageappropriate, and oocyte vitrification may be a feasible option.
Disease course Without treatment, some forms of lymphoma can stay indolent for years (e.g. NLPHL), while the majority would follow a fatal course in days, weeks or months.
Staging Diagnosis
Accurate staging is imperative to appropriately assign a treatment group. The Ann Arbor staging system is widely used. I Involvement of a single independent lymph node region or lymph node structure II Involvement of two or more lymph node regions on the same side of the diaphragm III Involvement of lymph node regions or lymph node structures on both sides of the diaphragm IV Diffuse extra-nodal or visceral involvement X Denotes bulky (>10 cm) disease
The diagnosis is usually made by histological examination of a lymph node. Excision biopsy is preferred, but a trucut biopsy may give adequate tissue for diagnosis. Many patients have a biopsy at their local hospital (often by ENT surgeons) and are referred with a diagnosis, but increasingly children with suspicious masses are referred to Paediatric Oncology centres for a biopsy. The tissue is divided for microbiology and histopathology. Microbiology
Histopathology
Bacterial Fungal Tuberculosis ‘Tumour touch imprints’ onto glass slides then the tissue is further subdivided as appropriate: Molecular genetics Cytogenetics
gFresh tissue
Microscopy Immunohistochemistry
gFormalin-fixed tissue
PAEDIATRICS AND CHILD HEALTH 22:3
Emergency treatment Respiratory compromise Compression of both the upper and lower airways can cause respiratory compromise in lymphoma patients. Upper airways may be compromised by tonsillar enlargement. Upper mediastinal masses are anterior to the trachea and breathing can be made easier by leaning forward. However, if this is necessary, impending tracheal compression should be suspected.
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Obstruction of the superior vena cava can also occur in patients with large mediastinal disease.
assessment of response with a second PET-CT scan. Patients with an inadequate response at this stage receive radiotherapy at the end of chemotherapy. Patients in the low risk group will have no further chemotherapy, while those in the intermediate and highrisk groups will receive another two or four cycles of chemotherapy respectively. The standard treatment arm for continuing chemotherapy is COPP (cyclophosphamide, vincristine, procarbazine and prednisolone), with a randomization to an experimental arm (COPDAC), substituting dacarbazine for procarbazine, in an attempt to reduce infertility, particularly in boys. Where radiotherapy is required, the fields encompass all the initially involved sites, with a boost to areas with a poor response. Chemotherapy on this protocol is given on a day-case basis. There are a number of options for salvage treatment in relapsed and refractory HL. These include salvage with standard dose chemotherapy, high dose chemotherapy with autologous stem cell transplant, allogeneic stem cell transplant or novel agents including the antibody-drug conjugate brentuximab vedotin.
Tumour lysis In patients with ‘bulky’ disease, NHL and especially BL, rapid cell death can precipitate tumour lysis syndrome. In BL, it is possible for this to occur prior to any treatment being given, presumably due to endogenous steroid production. However, a single dose of steroids can precipitate problems in any NHL, and occasionally in HL. Preventative measures such as hyperhydration, forced diuresis and allopurinol or rasburicase may be required on initiation of treatment, and preferably for 24 h beforehand. Allopurinol blocks the formation of uric acid, but, if there is a high tumour load, the precursors of uric acid may also form crystals. Rasburicase (recombinant urate oxidase) is used if there is a high-risk of tumour lysis, as it acts as a catalyst in the enzymatic oxidation of uric acid to allantoin, a readily excreted metabolite that is 5e10 times more soluble than uric acid. Allopurinol and rasburicase should not be used together, as allopurinol blocks the pathway ahead of the catalyst.
Burkitt lymphoma If completely excised, two courses of chemotherapy are usually given, at 21-day intervals or less. Higher stage disease is treated on chemotherapy protocols based on cyclophosphamide and high dose methotrexate, which are very intensive and result in severe immunosuppression. Most children having this treatment are based in hospital for most of the duration of their chemotherapy. Treatment intensity is important in increasing survival, with the next course of chemotherapy being given as soon as count-recovery has occurred. Children with adult-type B-cell lymphomas, such as primary mediastinal B-cell lymphoma and diffuse large B-cell lymphoma, are also treated according to this chemotherapy regime with the addition of rituximab (anti-CD20 monoclonal antibody) in selected cases.
Solid organ infiltration Solid organs can be infiltrated by lymphoma cells, increasing the tumour burden, and hence the risk of tumour lysis, and disrupting organ function. Significant hepatomegaly and/or splenomegaly are not uncommon findings in high stage lymphoma, occasionally leading to abnormal liver function tests. Kidney infiltration can lead to difficulties with excretion at a time when hyperhydration and good diuresis are necessary. Occasionally acute renal failure can occur so it is essential to monitor renal function in all patients with HL and NHL.
Treatment Lymphomas are treated with multi-drug chemotherapy regimens, stratified by risk group, with radiotherapy in selected cases. Treatment covers a spectrum from two courses of chemotherapy lasting 2 months for a completely excised BL or Stage 1 HL, through 6 months intensive chemotherapy for ALCL, to over 2 years of mostly outpatient-based chemotherapy for LBL. Autologous and allogeneic transplants are reserved for selected patients with relapsed or refractory disease. The high cure rate for lymphomas and the need to reduce late effects has led to the ongoing drive to tailor treatment according to risk group and response to initial therapy. The combination of a reduced number of chemotherapy cycles, together with a radiation strategy using smaller fields and lower radiation doses, can maintain cure rates while reducing late effects. In HL, there is evidence that early response assessment using functional imaging (PET-CT) can identify patients with a worse prognosis who would benefit from radiotherapy.
Lymphoblastic lymphoma LBL (both pre-B and T cell) has historically been treated on acute lymphoblastic leukaemia protocols, but children, particularly with T-cell LBL, have a higher relapse rate and salvage treatment is ineffective. Two German protocols, NHL-BFM-90 and 95, were designed to intensify treatment early in an attempt to reduce the relapse rate. These have shown the best survival figures to date, and are the basis of current treatment. The chemotherapy regimen at induction is relatively intensive, using prednisolone, vincristine, anthracyclines, asparaginase and intrathecal methotrexate, with a follow-up phase using thiopurines, cyclophosphamide and cytarabine (still based on standard acute lymphoblastic leukaemia [ALL] therapy), with an ALL-type outpatient maintenance regime using oral thiopurine and methotrexate to complete 2 years treatment. CNS prophylaxis, using intrathecal methotrexate, is administered to all children. CNS involvement is unusual, and is treated with extra doses of intrathecal methotrexate and cranial radiotherapy after re-induction chemotherapy. Scrotal radiotherapy is limited to those boys with biopsy-confirmed testicular involvement after 4 months of chemotherapy. Primary mediastinal B-cell LBL tends to occur in teenagers and has a poorer prognosis. It is treated with intensive chemotherapy, rituximab and radiotherapy, leading to better outcomes.
Hodgkin lymphoma A Europe-wide trial in paediatric HL, open in the UK since 2007, will be closing in 2012. This trial uses a risk-stratified and response-adapted strategy to determine optimum therapy. Following staging investigations including a PET-CT scan, patients are stratified into three risk groups (low, intermediate and high). All patients receive two cycles of OEPA chemotherapy (vincristine, etoposide, prednisolone and adriamycin) before an interim
PAEDIATRICS AND CHILD HEALTH 22:3
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Anaplastic large cell lymphoma A few patients have their lymphoma completely excised and receive 3 months of low dose chemotherapy. Children with higher stage disease are treated with multi-drug regimens, including high dose methotrexate in each course, alternating with cycles of ifosfamide/cytarabine/etoposide and cyclophospamide/ doxorubicin. This is intensive inpatient-based chemotherapy, lasting approximately 6 months, and requiring high levels of supportive care. For those who relapse, intensive chemotherapy and weekly vinblastine can be curative.
women with HL treated with supradiaphragmatic radiotherapy below the age of 35 years. Their relative risk of developing breast cancer by 25 years from radiotherapy is 1:3e1:7, depending on the age at which they were treated. Chemotherapy-alone strategies, with higher cumulative doses of anthracyclines, alkylating agents and bleomycin, also carry a significant risk of cardiopulmonary toxicity, infertility and secondary leukaemias. In NHL, patients were treated with chemotherapy and cranial irradiation, adversely affecting the child’s learning potential and increasing their chance of developing a second tumour. Cranial irradiation is now limited to highly selected cases. The effects of cardiac damage are most critical at times of high growth, at puberty and during pregnancy. The next generation of trials will continue to strive to refine treatment, stratifying treatment with dose-escalation for those with high-risk disease and reduced treatment for others. The aim is always to improve overall outcomes by reducing mortality and morbidity.
Prognosis Unsurprisingly this depends on the sub-type of lymphoma, the stage and the response to treatment. Hodgkin lymphoma The 5-year overall survival rates for all stages of HL are above 95%. Patients with refractory or relapsed disease may still be cured with salvage treatment, although response to re-induction chemotherapy and disease status at transplant are highly predictive of outcome. Patients who are refractory to salvage chemotherapy have a very poor prognosis, and allogeneic stem cell transplantation may have a role in this setting.
Learning points Refer early e suspected or after biopsy Excision biopsy (not needle biopsy) Send fresh tissue to Pathology (not in preservative) If lymphoma cells make up >25% of bone marrow cells e it is leukaemia (NHL)
Burkitt lymphoma There is a greater than 90% event-free survival at 3 years for those children with Stage III disease or lower. For those children who relapse, around 30% are salvaged, with the worst outcome for those relapsing early. Treatment is with intensive high dose chemotherapy and stem cell rescue, together with rituximab.
Emergency presentation Respiratory compromise e upper and lower airway Mediastinal mass e airway and SVC obstruction Tumour lysis syndrome e hydrate and allopurinol or rasburicase Solid organ infiltration e renal failure
Lymphoblastic lymphoma Data published by the German BFM group, on the NHL-BFM-90 and 95 trials, shows a 90% event-free survival at 5 years for T-cell LBL. All those who relapsed did so in the first year and all died. However, patients with pre-B LBL were found to relapse as late as the third and fourth year from diagnosis with three of five entering a long-term second remission. The overall survival at 10 years for pre-B LBL was 91%. Even for long-term survivors, tumour regression is frequently incomplete, although if less than 70% the risk of relapse is higher, as is the case for the presence of B symptoms.
Tissue & fluid samples
Fresh tissue
Histopathology
Cytogenetics Formalin-fixed tissue Fluid samples
Anaplastic large cell lymphoma Two broad risk groups can be identified. The high-risk group (defined by skin, mediastinal, liver, spleen or lung involvement) comprises two thirds of patients and the 3-year event-free survival is 61%. The remaining third have a 3-year event-free survival of 87%. ALK-1 positivity confers a better outcome, while poor prognostic factors include an elevated LDH and B symptoms. There are reports of cure following relapse.
Histopathology Cytology Cytogenetics
Bacterial Fungal Tuberculosis ‘Tumour touch imprints’ e glass slides Antibody panels Karotype Molecular genetics Microscopy & Immunohistochemistry Microscopy & Immunohistochemistry Karyotype Molecular genetics
A
Late effects
FURTHER READING Attias D, Hodgson D, Weitzman S. Primary mediastinal B-cell lymphoma in the pediatric patient: can a rational approach to therapy be based on adult studies? Pediatr Blood Cancer 2009; 52: 566e70. Campo E, Swerdlow SH, Harris NL, Pileri S, Stein H, Jaffe ES. The 2008 WHO classification of lymphoid neoplasms and beyond:
With high cure rates, late effects of treatment become more important. In HL, early treatment-approaches using large volumes of irradiation at high doses increased the risk of musculoskeletal hypoplasia, cardiac damage and the incidence of solid tumours. There is a national breast screening programme for girls and young
PAEDIATRICS AND CHILD HEALTH 22:3
Microbiology
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SYMPOSIUM: ONCOLOGY
evolving concepts and practical applications. Blood 2011; 117: 5019e32. Cancer backup website http://www.macmillan.org.uk/Cancerinformation/ Cancertypes/Childrenscancers/Childrenscancers.aspx Daw S, Wynn R, Wallace H. Management of relapsed and refractory classical Hodgkin lymphoma in children and adolescents. Br J Haematol 2011; 152: 249e60. Hutchings M, Loft A, Hansen M, et al. FDG-PET after two cycles of chemotherapy predicts treatment failure and progression-free survival in Hodgkin lymphoma. Blood 2006; 107: 52e9. Improving Outcomes in Children and Young People with Cancer. NICE, Guidance on Cancer Services, http://guidance.nice.org.uk/csgcyp; 2005. Le Deley MC, Reiter A, Williams D, et al. Prognostic factors in childhood anaplastic large cell lymphoma: results of a large European Intergroup Study. Blood 2008; 111: 1560e6.
PAEDIATRICS AND CHILD HEALTH 22:3
Mauz-Korholz C, Hasenclever D, Dorffel W, et al. Procarbazine-free OEPACOPDAC chemotherapy in boys and standard OPPA-COPP in girls have comparable effectiveness in pediatric Hodgkin’s lymphoma: the GPOHHD-2002 study. J Clin Oncol 2010; 28: 3680e6. Reiter A, Schrappe M, Ludwig WD, et al. Intensive ALL-type therapy without local radiotherapy provides a 90% event-free survival for children with T-cell lymphoblastic lymphoma: a BFM group report. Blood 2000; 95: 416e21. €tter R, Br€amswig J, et al. High cure rates and Schellong G, Po reduced long-term toxicity in pediatric Hodgkin’s disease: the German-Austrian multicentre trial DAL-HD-90. J Clin Oncol 1999; 17: 3736e44. SEER website http://seer.cancer.gov/csr/1975_2008/index.html Thomson AB, Wallace WHB. Treatment of paediatric Hodgkin’s disease: a balance of risks. Eur J Cancer 2002; 38: 468e77.
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Ó 2011 Elsevier Ltd. All rights reserved.
An update on lymphoma in children and young adults
What’s new? C
Catherine Morley-Jacob C
Eve Gallop-Evans
in 2008, uses morphology, immunohistochemistry, genetic, molecular and clinical features, and has international consensus, due to its basis on biology and its clinical relevance, practicality, and reproducibility. The main division, particularly in children and young adults, is between Hodgkin (HL) and non-Hodgkin lymphoma (NHL), with these each being further subdivided.
Abstract Lymphoma accounts for approximately 10% of childhood cancers, but 17% in teenagers. It is divided into Hodgkin and non-Hodgkin lymphoma, with the vast majority of non-Hodgkin lymphoma in children being Burkitt lymphoma, lymphoblastic lymphoma and anaplastic large cell lymphoma. Lymphoma usually presents with painless lymphadenopathy, most commonly in the cervical region. ‘B’ symptoms are associated with more advanced disease. The diagnosis is usually made by histological examination of an excised lymph node, but can be made on pleural fluid or a bone marrow aspirate. Emergency management, particularly of the airway, may be necessary, especially in non-Hodgkin lymphoma. Lymphomas are treated with multi-drug chemotherapy regimens, stratified by risk group, with radiotherapy in selected cases. Rituximab (anti-CD20 monoclonal antibody) is used in conjunction with chemotherapy for poorer risk groups and in the relapse setting. In Hodgkin lymphoma, positron emission tomography scans are prognostic at assessment of response to therapy. The high cure rate for lymphomas (more than 90% for Hodgkin and Burkitt lymphoma) and the need to reduce late effects in children and adolescents has led to the current drive to tailor treatment according to risk group and response to initial therapy.
Epidemiology Hodgkin lymphoma (HL) is a B-cell lymphoma and, in the UK, two incidence peaks exist, one in young adults aged 20e35 years, and another in older adults, aged 70e79 years. Since the mid-1980s agestandardized incidence rates for Hodgkin’s lymphoma in Britain have remained unchanged at around three per 100,000 males and two per 100,000 females (CR-UK data). The WHO classification recognizes two major sub-classifications of HL: classical HL and nodular lymphocyte predominant HL (NLPHL). Classical Hodgkin lymphoma is subdivided into nodular schlerosing, mixed cellularity, lymphocyte-rich, and lymphocyte-depleted types. Nodular sclerosing HL accounts for nearly 60% of all newly diagnosed cases in the UK, while mixed cellularity disease is more common, especially at younger ages, in poorer countries. NLPHL constitutes only 5% of all cases. HL is unique in that the malignant Hodgkin ReedSternberg (HRS) cells account for less than 1% of the total cell population of the tumour. The clinical and pathologic features of HL reflect an abnormal immune response to HRS cells, resulting in infiltration of reactive inflammatory cells. High EBV antibody titres in up to 40% of HL suggest that EBV infection may precede the development of HL, and clonality studies indicate EBV infection precedes the expansion of the tumour cell population. This association varies with geographic location, age, sex, clinical stage and histologic type. The term Non-Hodgkin lymphoma (NHL) describes all lymphomas except HL. The incidence of NHL rises with age, with an almost static incidence until 40, from when it rises steeply. Approximately 80 children and young people are diagnosed with NHL each year in the UK (CR-UK data). The major sub-division is by cell of origin, namely B and T lymphocytes. Almost all NHL occurring in children is high grade and there are three main subtypes: Burkitt lymphoma (BL, mature B cell) 45%, lymphoblastic lymphoma (LBL, both pre-B and T cell) 35% and anaplastic large cell lymphoma (ALCL, previously malignant histiocytosis) 10%. By contrast, in adults there are more than 40 subtypes of NHL, most of which are rarely seen in children (Figure 1).
Keywords adolescent; child; diagnosis; Hodgkin; Non-Hodgkin; lymphoma; review
Definition Lymphoma is a malignant disorder of the lymphatic system, which includes lymph nodes, bone marrow, spleen, tonsils, adenoids and thymus. Lymphoma can also involve other organs, commonly the skin, liver, brain and bone. Lymphomas make up approximately 10% of childhood cancers (in those under 16, which accounts for approximately 140 cases per year in the UK), but 17% of cancer in teenagers. Lymphoma describes a diverse group of conditions, in terms of pathology, epidemiology, disease behaviour and prognosis. A number of different classification strategies have been described leading to multiple reclassifications and to new entities being described. The WHO classification, published in 2001 and updated
Catherine Morley-Jacob MRCP MRCPCH DCH MD is Consultant Paediatric Oncologist in the Department of Paediatric Oncology, Children’s Hospital for Wales, Cardiff, UK. Conflict of interest: none.
Clinical presentation
Eve Gallop-Evans PhD MRCP FRCR is Consultant Clinical Oncologist in the Department of Clinical Oncology, Velindre Hospital, Cardiff, UK. Conflict of interest: none.
PAEDIATRICS AND CHILD HEALTH 22:3
Hodgkin lymphoma e radiotherapy dependent on interim assessment of response with a PET-CT scan Relapse or refractory Non-Hodgkin lymphoma e better chance of cure with rituximab
Children with lymphoma usually present with painless lymphadenopathy, most commonly cervical, with frequent involvement of the mediastinum. B symptoms (fever more than 38 C, 10%
92
Ó 2011 Elsevier Ltd. All rights reserved.
SYMPOSIUM: ONCOLOGY
Incidence by age of Hodgkin and Non-Hodgkin Lymphoma in Great Britain (CR-UK data)
Coronal view of thoracic CT from Case 1 L
50
L L
Hodgkin lymphoma
Rate per million
40
L
Tr
Non-Hodgkin lymphoma (including Burkitt lymphoma)
C
PTL
30
L 20
L Heart
10
0 0
1
2
3
4
5
6
7
8
9
10
11
12
13
L, lymph nodes; PTL – paratracheal lymphadenopathy; Tr, trachea; C, contrast in right subclavian vein
14
Age at diagnosis
Figure 2 Coronal view of thoracic CT from Case 1. Figure 1 Incidence of Hodgkin and Non-Hodgkin lymphoma under 14 years of age per million in the UK. Taken from the CR-UK website.
Case history 2
weight loss and night sweats) in the 6 months prior to presentation are associated with more advanced disease. Bulky mediastinal lymphadenopathy may cause respiratory symptoms. Unlike NHL, HL characteristically demonstrates contiguous nodal spread, while NLPHL usually affects a peripheral nodal site, and mediastinal involvement is uncommon. Extra-nodal disease (lung, liver, bone, bone marrow, testis) is much more common in NHL, and although unusual, CNS disease may occur and presents as cranial nerve palsies or with symptoms of a space-occupying lesion. Children with immunodeficiency, previous chemotherapy, Ataxia Telangiectasia, Bloom’s syndrome, HIV and other immune-modulating conditions are predisposed to lymphoma.
A 5-year-old boy initially presented with a facial palsy and was treated with steroids. A full blood count at that time was normal. When the steroids stopped, his facial palsy recurred. He then developed swinging pyrexias, with no specific findings on examination, except that he looked unwell. When his renal function began to deteriorate and a renal ultrasound showed large echogenic kidneys, he was referred to the Paediatric Nephrology team for a biopsy. As part of further investigations, in conjunction with Paediatric Oncology, he underwent bone marrow aspirates and trephines under the same anaesthetic. The diagnosis was confirmed as Burkitt lymphoma on both bone marrow and kidney biopsy. Further staging included a CT scan, which showed the enlarged kidneys (Figure 3). His full blood count remained normal, despite bone marrow involvement. His early risk of tumour lysis was extremely high, with bulky solid organ infiltration and reduced renal function. He was managed with aggressive fluid management, hyperhydration and rasburicase, and with chemotherapy: vincristine, cyclophosphamide and steroids. Within 48 h of starting treatment his renal function had returned to normal and his fevers had settled. He received 9 months of intensive chemotherapy, but remains in remission over 2 years off treatment.
Case history 1 A 16-year-old boy presented with a persistent cough and mild exertional breathlessness. He had been given a short course of steroids, which helped his symptoms significantly, but they then returned. He also had a 2-week history of drenching night sweats and had lost a stone in weight over the previous month. On examination, he was well with no signs of breathlessness at rest. He had small palpable lymph nodes in the left cervical region, but no other abnormalities to find on examination. CXR showed mediastinal widening and staging CT scan showed lymphadenopathy within the cervical and mediastinal regions (Figure 2), and a single iliac chain node of 2 cm. The biopsy confirmed classical HL, and as a stage IIIB, he was treated according to the high-risk treatment group, with OEPA chemotherapy (vincristine, etoposide, prednisolone, doxorubicin). He had a good clinical response with resolution of his B symptoms. After two cycles of chemotherapy, a CT scan showed significant reduction in the size of the nodes, and a PET scan showed no evidence of abnormal uptake, confirming remission. He went on to have four further courses of chemotherapy, but no radiotherapy, and has not required any further treatment, remaining well on follow-up at over 2 years from the end of treatment.
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Differential diagnosis The differential diagnosis depends on the distribution of the lymphadenopathy and the duration of symptoms. This is usually between the different types of lymphoma, leukaemia, infection and auto-immune phenomena. For NHL, if lymphoma cells represent greater than 25% of cells in the bone marrow, the term leukaemia is used, regardless of the level of nodal or other organ involvement. Infections, such as Staphylococcus aureus, often cause tender lymphadenopathy, while glandular fever (EpsteineBarr virus) can cause generalized lymphadenopathy, fever, weight loss and splenomegaly. If tuberculosis, atypical mycobacteria or cat scratch disease (caused by Bartonella henselae) are suspected 93
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In HL, histology reveals sparse numbers of the malignant HRS cell seen in a background of B cells, T cells, plasma cells, eosinophils and fibroblasts. In NHL, sheets of small round blue cells are seen, with the different subtypes being classified by immunohistochemistry. The diagnosis can also be made from pleural fluid or a bone marrow (BM) aspirate. Fluid samples such as these are sent for cytology, and for immunophenotyping by flow cytometry. Classical cytogenetics and molecular genetics using FISH and PCR-based techniques can be helpful for diagnosis and prognosis. In BL, translocations involving chromosome 8 are seen, most commonly t(8;14) in over 70%, and more rarely t(8;22) and t(2;8).
Coronal view of abdominal CT from Case 2
Liver
Spleen
K K
V
Investigations Full staging investigations include physical examination and imaging (ultrasound or MRI of the neck, CT of the thorax, CT or MRI of the abdomen and pelvis, and PET-CT if available for HL patients). Laboratory investigations include a full blood count, ESR, biochemical profile including ß2-microglobulin and lactate dehydrogenase (LDH). HIV and hepatitis B testing should be considered. BM biopsies are performed in advanced stage HL (stage III-IV), those with B symptoms or an abnormal blood count, and in all patients with NHL. A lumbar puncture is also required for initial staging in NHL.
Sacrum
The kidneys are enlarged; a normal kidney is equivalent to the height of 3 vertebrae. V, vertebral body; K, kidney Figure 3 Coronal view of abdominal CT from Case 2.
BM involvement
and the lymph node is to be biopsied, excision biopsy is imperative to reduce the risk of a chronically discharging tract. Juvenile idiopathic arthritis and systemic lupus erythematosus can also present with lymphadenopathy.
CSF involvement
5e25% lymphoma cells in BM e stage 4 >25% lymphoma cells in BM e in NHL, leukaemia >5 white cells (unless a traumatic tap)
Prior to starting treatment, a baseline assessment of cardiac, renal and pulmonary function is performed where relevant. Sperm cryopreservation should also be arranged if ageappropriate, and oocyte vitrification may be a feasible option.
Disease course Without treatment, some forms of lymphoma can stay indolent for years (e.g. NLPHL), while the majority would follow a fatal course in days, weeks or months.
Staging Diagnosis
Accurate staging is imperative to appropriately assign a treatment group. The Ann Arbor staging system is widely used. I Involvement of a single independent lymph node region or lymph node structure II Involvement of two or more lymph node regions on the same side of the diaphragm III Involvement of lymph node regions or lymph node structures on both sides of the diaphragm IV Diffuse extra-nodal or visceral involvement X Denotes bulky (>10 cm) disease
The diagnosis is usually made by histological examination of a lymph node. Excision biopsy is preferred, but a trucut biopsy may give adequate tissue for diagnosis. Many patients have a biopsy at their local hospital (often by ENT surgeons) and are referred with a diagnosis, but increasingly children with suspicious masses are referred to Paediatric Oncology centres for a biopsy. The tissue is divided for microbiology and histopathology. Microbiology
Histopathology
Bacterial Fungal Tuberculosis ‘Tumour touch imprints’ onto glass slides then the tissue is further subdivided as appropriate: Molecular genetics Cytogenetics
gFresh tissue
Microscopy Immunohistochemistry
gFormalin-fixed tissue
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Emergency treatment Respiratory compromise Compression of both the upper and lower airways can cause respiratory compromise in lymphoma patients. Upper airways may be compromised by tonsillar enlargement. Upper mediastinal masses are anterior to the trachea and breathing can be made easier by leaning forward. However, if this is necessary, impending tracheal compression should be suspected.
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Obstruction of the superior vena cava can also occur in patients with large mediastinal disease.
assessment of response with a second PET-CT scan. Patients with an inadequate response at this stage receive radiotherapy at the end of chemotherapy. Patients in the low risk group will have no further chemotherapy, while those in the intermediate and highrisk groups will receive another two or four cycles of chemotherapy respectively. The standard treatment arm for continuing chemotherapy is COPP (cyclophosphamide, vincristine, procarbazine and prednisolone), with a randomization to an experimental arm (COPDAC), substituting dacarbazine for procarbazine, in an attempt to reduce infertility, particularly in boys. Where radiotherapy is required, the fields encompass all the initially involved sites, with a boost to areas with a poor response. Chemotherapy on this protocol is given on a day-case basis. There are a number of options for salvage treatment in relapsed and refractory HL. These include salvage with standard dose chemotherapy, high dose chemotherapy with autologous stem cell transplant, allogeneic stem cell transplant or novel agents including the antibody-drug conjugate brentuximab vedotin.
Tumour lysis In patients with ‘bulky’ disease, NHL and especially BL, rapid cell death can precipitate tumour lysis syndrome. In BL, it is possible for this to occur prior to any treatment being given, presumably due to endogenous steroid production. However, a single dose of steroids can precipitate problems in any NHL, and occasionally in HL. Preventative measures such as hyperhydration, forced diuresis and allopurinol or rasburicase may be required on initiation of treatment, and preferably for 24 h beforehand. Allopurinol blocks the formation of uric acid, but, if there is a high tumour load, the precursors of uric acid may also form crystals. Rasburicase (recombinant urate oxidase) is used if there is a high-risk of tumour lysis, as it acts as a catalyst in the enzymatic oxidation of uric acid to allantoin, a readily excreted metabolite that is 5e10 times more soluble than uric acid. Allopurinol and rasburicase should not be used together, as allopurinol blocks the pathway ahead of the catalyst.
Burkitt lymphoma If completely excised, two courses of chemotherapy are usually given, at 21-day intervals or less. Higher stage disease is treated on chemotherapy protocols based on cyclophosphamide and high dose methotrexate, which are very intensive and result in severe immunosuppression. Most children having this treatment are based in hospital for most of the duration of their chemotherapy. Treatment intensity is important in increasing survival, with the next course of chemotherapy being given as soon as count-recovery has occurred. Children with adult-type B-cell lymphomas, such as primary mediastinal B-cell lymphoma and diffuse large B-cell lymphoma, are also treated according to this chemotherapy regime with the addition of rituximab (anti-CD20 monoclonal antibody) in selected cases.
Solid organ infiltration Solid organs can be infiltrated by lymphoma cells, increasing the tumour burden, and hence the risk of tumour lysis, and disrupting organ function. Significant hepatomegaly and/or splenomegaly are not uncommon findings in high stage lymphoma, occasionally leading to abnormal liver function tests. Kidney infiltration can lead to difficulties with excretion at a time when hyperhydration and good diuresis are necessary. Occasionally acute renal failure can occur so it is essential to monitor renal function in all patients with HL and NHL.
Treatment Lymphomas are treated with multi-drug chemotherapy regimens, stratified by risk group, with radiotherapy in selected cases. Treatment covers a spectrum from two courses of chemotherapy lasting 2 months for a completely excised BL or Stage 1 HL, through 6 months intensive chemotherapy for ALCL, to over 2 years of mostly outpatient-based chemotherapy for LBL. Autologous and allogeneic transplants are reserved for selected patients with relapsed or refractory disease. The high cure rate for lymphomas and the need to reduce late effects has led to the ongoing drive to tailor treatment according to risk group and response to initial therapy. The combination of a reduced number of chemotherapy cycles, together with a radiation strategy using smaller fields and lower radiation doses, can maintain cure rates while reducing late effects. In HL, there is evidence that early response assessment using functional imaging (PET-CT) can identify patients with a worse prognosis who would benefit from radiotherapy.
Lymphoblastic lymphoma LBL (both pre-B and T cell) has historically been treated on acute lymphoblastic leukaemia protocols, but children, particularly with T-cell LBL, have a higher relapse rate and salvage treatment is ineffective. Two German protocols, NHL-BFM-90 and 95, were designed to intensify treatment early in an attempt to reduce the relapse rate. These have shown the best survival figures to date, and are the basis of current treatment. The chemotherapy regimen at induction is relatively intensive, using prednisolone, vincristine, anthracyclines, asparaginase and intrathecal methotrexate, with a follow-up phase using thiopurines, cyclophosphamide and cytarabine (still based on standard acute lymphoblastic leukaemia [ALL] therapy), with an ALL-type outpatient maintenance regime using oral thiopurine and methotrexate to complete 2 years treatment. CNS prophylaxis, using intrathecal methotrexate, is administered to all children. CNS involvement is unusual, and is treated with extra doses of intrathecal methotrexate and cranial radiotherapy after re-induction chemotherapy. Scrotal radiotherapy is limited to those boys with biopsy-confirmed testicular involvement after 4 months of chemotherapy. Primary mediastinal B-cell LBL tends to occur in teenagers and has a poorer prognosis. It is treated with intensive chemotherapy, rituximab and radiotherapy, leading to better outcomes.
Hodgkin lymphoma A Europe-wide trial in paediatric HL, open in the UK since 2007, will be closing in 2012. This trial uses a risk-stratified and response-adapted strategy to determine optimum therapy. Following staging investigations including a PET-CT scan, patients are stratified into three risk groups (low, intermediate and high). All patients receive two cycles of OEPA chemotherapy (vincristine, etoposide, prednisolone and adriamycin) before an interim
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Anaplastic large cell lymphoma A few patients have their lymphoma completely excised and receive 3 months of low dose chemotherapy. Children with higher stage disease are treated with multi-drug regimens, including high dose methotrexate in each course, alternating with cycles of ifosfamide/cytarabine/etoposide and cyclophospamide/ doxorubicin. This is intensive inpatient-based chemotherapy, lasting approximately 6 months, and requiring high levels of supportive care. For those who relapse, intensive chemotherapy and weekly vinblastine can be curative.
women with HL treated with supradiaphragmatic radiotherapy below the age of 35 years. Their relative risk of developing breast cancer by 25 years from radiotherapy is 1:3e1:7, depending on the age at which they were treated. Chemotherapy-alone strategies, with higher cumulative doses of anthracyclines, alkylating agents and bleomycin, also carry a significant risk of cardiopulmonary toxicity, infertility and secondary leukaemias. In NHL, patients were treated with chemotherapy and cranial irradiation, adversely affecting the child’s learning potential and increasing their chance of developing a second tumour. Cranial irradiation is now limited to highly selected cases. The effects of cardiac damage are most critical at times of high growth, at puberty and during pregnancy. The next generation of trials will continue to strive to refine treatment, stratifying treatment with dose-escalation for those with high-risk disease and reduced treatment for others. The aim is always to improve overall outcomes by reducing mortality and morbidity.
Prognosis Unsurprisingly this depends on the sub-type of lymphoma, the stage and the response to treatment. Hodgkin lymphoma The 5-year overall survival rates for all stages of HL are above 95%. Patients with refractory or relapsed disease may still be cured with salvage treatment, although response to re-induction chemotherapy and disease status at transplant are highly predictive of outcome. Patients who are refractory to salvage chemotherapy have a very poor prognosis, and allogeneic stem cell transplantation may have a role in this setting.
Learning points Refer early e suspected or after biopsy Excision biopsy (not needle biopsy) Send fresh tissue to Pathology (not in preservative) If lymphoma cells make up >25% of bone marrow cells e it is leukaemia (NHL)
Burkitt lymphoma There is a greater than 90% event-free survival at 3 years for those children with Stage III disease or lower. For those children who relapse, around 30% are salvaged, with the worst outcome for those relapsing early. Treatment is with intensive high dose chemotherapy and stem cell rescue, together with rituximab.
Emergency presentation Respiratory compromise e upper and lower airway Mediastinal mass e airway and SVC obstruction Tumour lysis syndrome e hydrate and allopurinol or rasburicase Solid organ infiltration e renal failure
Lymphoblastic lymphoma Data published by the German BFM group, on the NHL-BFM-90 and 95 trials, shows a 90% event-free survival at 5 years for T-cell LBL. All those who relapsed did so in the first year and all died. However, patients with pre-B LBL were found to relapse as late as the third and fourth year from diagnosis with three of five entering a long-term second remission. The overall survival at 10 years for pre-B LBL was 91%. Even for long-term survivors, tumour regression is frequently incomplete, although if less than 70% the risk of relapse is higher, as is the case for the presence of B symptoms.
Tissue & fluid samples
Fresh tissue
Histopathology
Cytogenetics Formalin-fixed tissue Fluid samples
Anaplastic large cell lymphoma Two broad risk groups can be identified. The high-risk group (defined by skin, mediastinal, liver, spleen or lung involvement) comprises two thirds of patients and the 3-year event-free survival is 61%. The remaining third have a 3-year event-free survival of 87%. ALK-1 positivity confers a better outcome, while poor prognostic factors include an elevated LDH and B symptoms. There are reports of cure following relapse.
Histopathology Cytology Cytogenetics
Bacterial Fungal Tuberculosis ‘Tumour touch imprints’ e glass slides Antibody panels Karotype Molecular genetics Microscopy & Immunohistochemistry Microscopy & Immunohistochemistry Karyotype Molecular genetics
A
Late effects
FURTHER READING Attias D, Hodgson D, Weitzman S. Primary mediastinal B-cell lymphoma in the pediatric patient: can a rational approach to therapy be based on adult studies? Pediatr Blood Cancer 2009; 52: 566e70. Campo E, Swerdlow SH, Harris NL, Pileri S, Stein H, Jaffe ES. The 2008 WHO classification of lymphoid neoplasms and beyond:
With high cure rates, late effects of treatment become more important. In HL, early treatment-approaches using large volumes of irradiation at high doses increased the risk of musculoskeletal hypoplasia, cardiac damage and the incidence of solid tumours. There is a national breast screening programme for girls and young
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Microbiology
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evolving concepts and practical applications. Blood 2011; 117: 5019e32. Cancer backup website http://www.macmillan.org.uk/Cancerinformation/ Cancertypes/Childrenscancers/Childrenscancers.aspx Daw S, Wynn R, Wallace H. Management of relapsed and refractory classical Hodgkin lymphoma in children and adolescents. Br J Haematol 2011; 152: 249e60. Hutchings M, Loft A, Hansen M, et al. FDG-PET after two cycles of chemotherapy predicts treatment failure and progression-free survival in Hodgkin lymphoma. Blood 2006; 107: 52e9. Improving Outcomes in Children and Young People with Cancer. NICE, Guidance on Cancer Services, http://guidance.nice.org.uk/csgcyp; 2005. Le Deley MC, Reiter A, Williams D, et al. Prognostic factors in childhood anaplastic large cell lymphoma: results of a large European Intergroup Study. Blood 2008; 111: 1560e6.
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Mauz-Korholz C, Hasenclever D, Dorffel W, et al. Procarbazine-free OEPACOPDAC chemotherapy in boys and standard OPPA-COPP in girls have comparable effectiveness in pediatric Hodgkin’s lymphoma: the GPOHHD-2002 study. J Clin Oncol 2010; 28: 3680e6. Reiter A, Schrappe M, Ludwig WD, et al. Intensive ALL-type therapy without local radiotherapy provides a 90% event-free survival for children with T-cell lymphoblastic lymphoma: a BFM group report. Blood 2000; 95: 416e21. €tter R, Br€amswig J, et al. High cure rates and Schellong G, Po reduced long-term toxicity in pediatric Hodgkin’s disease: the German-Austrian multicentre trial DAL-HD-90. J Clin Oncol 1999; 17: 3736e44. SEER website http://seer.cancer.gov/csr/1975_2008/index.html Thomson AB, Wallace WHB. Treatment of paediatric Hodgkin’s disease: a balance of risks. Eur J Cancer 2002; 38: 468e77.
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