SEARCH

SEARCH BY CITATION

Keywords:

  • lymphoma;
  • non-Hodgkin;
  • Hodgkin;
  • adolescent

Summary

  1. Top of page
  2. Summary
  3. Non-Hodgkin lymphoma
  4. Hodgkin lymphoma
  5. Relapsed/refractory adolescent lymphoma
  6. Adolescent lymphoma late effects
  7. Conclusion
  8. Acknowledgements
  9. References

Lymphoma is the most common malignancy among adolescents, accounting for >25% of newly diagnosed cancers in the 15–19 year age group. Hodgkin lymphoma (HL) accounts for the majority (two-thirds) of cases, while the remainder of patients have one of four subtypes of non-Hodgkin lymphoma (NHL): diffuse large B-cell lymphoma (DLBCL) including primary mediastinal B-cell lymphoma (PMBL), Burkitt lymphoma (BL), lymphoblastic lymphoma (LL) or anaplastic large cell lymphoma (ALCL). Epidemiology, histology, treatment and outcome differ between HL and NHL, as well as among the various subtypes of NHL. Adolescent lymphoma is particularly interesting because it often shares features with both childhood and adult lymphoma. As medical oncologists and paediatric oncologists often follow divergent treatment plans, disagreements may arise between practitioners as to how best treat the adolescent group. Additional complicating factors associated with the adolescent years, such as lack of insurance, issues pertaining to body image, and concerns about fertility, can also hinder prompt, appropriate medical management. This review details the complexities associated with the diagnosis and treatment of adolescent lymphoma and updates the state of the science, with particular emphasis on epidemiology, diagnosis, and proper management of HL and the various subtypes of NHL.

Adolescent lymphomas are a heterogeneous group of lymphoproliferative malignancies with differing patterns of behaviour and responses to treatment. The two main types include non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma (HL). The most recent US Surveillance, Epidemiology, and End Results (SEER) data, which analysed the distribution of cancer in adolescents 15–19 years of age, indicate that malignant lymphomas make up 26% of all cancers in this age group (Fig 1; Bleyer et al, 2006). This is significantly higher than any other cancer that occurs in this age range.

image

Figure 1.  Cancer in 15–29 year-olds, U.S. Seer, 1975–2000. From: Bleyer et al (2006).

Download figure to PowerPoint

A critical issue that arises in the treatment of adolescents and young adults (AYA), aged 15–19 years old, with cancer is which treatment approach (paediatric or medical oncology) is best used to manage them. Review of clinical trials and outcomes have shown that most U.S. cancer patients <15 years of age are treated on a National Cancer Institute (NCI) sponsored trial and most of these patients receive their medical care at an NCI affiliated institution. In contrast to this, the majority of patients >15 years old are not treated on an NCI clinical trial but rather at the discretion of the treating institution (Albritton & Bleyer, 2003). Children compared with adolescents with cancer tend to have better overall survival (OS) and better health outcomes at the end of treatment, suggesting that the difference may be related to the treatment protocol used.

A vital aspect in treating the adolescent patient is the recognition that they are at a unique point in their lives where autonomy must be balanced with guidance and support from their families and treating physicians. Important decisions with significant consequences need to be made and should actively involve the adolescent patient and encourage independence. However, adolescents often require parental involvement in dealing with medical professionals and to help with their general inexperience at making major medical decisions, especially during a time complicated by anxiety about treatment, complications, social chaos, body image and, most of all, fear of death. The importance of family involvement must also be balanced against the adolescent’s need for normalcy, independence and peer support. It is often important to complete schooling on time and for the older adolescent to maintain career planning. Issues arise regarding body image, maintaining relationships and concerns over future fertility. At a time when most adolescents are beginning to develop plans for their adult life, it can be emotionally devastating for the cancer patient to question whether this will become a reality. Another important barrier to consider is that the older adolescent often has a lapse in insurance while transitioning from parental coverage to their own insurance either from lack of resources or personal choice. This can further hinder access to the appropriate medical centre. For these reasons, it is best to have a multidisciplinary team approach for all cancer patients, but it becomes especially useful in the adolescent and young adult. This article summarizes the diagnosis, treatment and outcome of the common subtypes of adolescent lymphomas including diffuse large B-cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma (PMBL), lymphoblastic lymphoma (LL), Burkitt lymphoma (BL), anaplastic large cell lymphoma (ALCL) and classical Hodgkin lymphoma (cHL).

Non-Hodgkin lymphoma

  1. Top of page
  2. Summary
  3. Non-Hodgkin lymphoma
  4. Hodgkin lymphoma
  5. Relapsed/refractory adolescent lymphoma
  6. Adolescent lymphoma late effects
  7. Conclusion
  8. Acknowledgements
  9. References

Non-Hodgkin lymphoma is the fourth most common malignancy among adolescents in the United States and the fifth most common among those in the United Kingdom, accounting for 8% of all cancers in patients between the ages of 15 and 19 years in both countries (Birch et al, 2002; Bleyer et al, 2006). The subtypes of NHL found in the 15–19 year-old group include those most commonly found in children as well as those most often encountered in adults (Fig 2A–C). As in adults, DLBCL accounts for the largest proportion of NHL diagnoses in adolescents (Bleyer et al, 2006). BL, LL and ALCL, each more commonly found in children than in adults, are the three other predominant subtypes of NHL diagnosed during adolescence. According to SEER data from 1996 to 2002, the four major subtypes of adolescent NHL (in descending order of number of patients affected) are DLBCL, LL, BL and ALCL. An analysis of 341 adolescents with NHL treated in France also found these four subtypes to be the most common, although the frequency with which each subtype appeared was different: DLBCL was again most common (37%), followed by BL (22%), ALCL (18%) and LL (17%) (Patte et al, 2006). PMBL is a distinct clinical and pathological subtype of DLBCL recognized by the World Health Organization (WHO) that first appears around the start of adolescence and has a peak incidence during young adulthood (Harris et al, 1999; Zinzani et al, 2002). Although rare, PMBL is more aggressive than other DLBCL and occurs almost exclusively in the adolescent and younger adult populations; for these reasons, its inclusion in any discussion of adolescent NHL is warranted. Other subtypes of lymphoma rarely seen in children but occurring more commonly in adults, including indolent lymphomas, remain rare during adolescence, only beginning to occur with greater frequency in young adults (ages 20–29 years).

image

Figure 2.  Incidence of non-Hodgkin lymphoma subtypes in (A) 0–14 year age group, (B) 15–19 year age group, and (C) 20 year and older age group.

Download figure to PowerPoint

The overall incidence of NHL varies with age, increasing progressively from birth until age 80 years (Fig 3; Bleyer et al, 2006). Among adolescents, males are affected more often than females and non-Hispanic whites have the highest incidence of new diagnoses (Bleyer et al, 2006). The average annual percentage change (AAPC) in incidence of adolescent NHL underwent a significant increase from 1975 to 1999 with a greater increase occurring among males (Bleyer et al, 2006).

image

Figure 3.  Incidence of lymphoma by ICCC group, SEER 1975–2000. From: Bleyer et al (2006).

Download figure to PowerPoint

Mortality in the 15–19 year-old age group in the U.S. from 1975 to 1999 was 41 deaths per million per year, >160% higher than in the 10–14 year-old age group (Bleyer et al, 2006). Male gender is an adverse prognostic factor for adolescent NHL, even after accounting for differences in incidence between males and females (Bleyer et al, 2006). No significant differences in 5-year survival rates for adolescent NHL exist between racial or ethnic groups. For paediatric and adolescent patients with B-cell NHL enrolled on the French–American–British (FAB)/Lymphome Malins de Burkitt (LMB) 96 study, a univariate analysis of age ≥15 years versus <15 years revealed both a significantly worse 5-year event-free survival (EFS) and 5-year OS in the adolescent group compared with younger children [5-year EFS for <15 years vs. ≥15 years: 87 ± 1·1% vs. 80 ± 3·6% (P < 0·045); 5-year OS for <15 years vs. ≥15 years: 91 ± 0·03% vs. 85 ± 3·2% (P < 0·041) (Cairo et al, 2008). However, differences in outcome by age disappeared with Cox multivariate analysis and could be explained by tumour histology (DLBCL), advanced stage [bone marrow (BM)/central nervous system (CNS) involvement] and increased lactate dehydrogenase (LDH) ≥2 times upper limit of normal that occurs in adolescents versus children >15 years of age (Cairo et al, 2008).

Diffuse large B-cell lymphoma

Diffuse large B-cell lymphoma is the most common subtype of NHL in adolescents, accounting for approximately 40% of new diagnoses (Bleyer et al, 2006; Patte et al, 2006). Three major subgroups of DLBCL have been identified based on gene expression profiling: germinal centre B-cell like (GCB) DLBCL, activated B-cell like (ABC) DLBCL, and PMBL (Fig 4A and B; Alizadeh et al, 2000; Rosenwald et al, 2002, 2003; Savage et al, 2003). Amongst the genes differentially expressed by the different DLBCL subtypes are those involved in the anti-apoptotic NF-kappaB (NF-κB) signal transduction pathway (Feuerhake et al, 2005). Both ABC DLBCL and PMBL exhibit constitutive activation of the NF-κB pathway. Immunohistochemical staining for CD10 and BCL6, two markers of the GCB phenotype, and MUM1, a marker of the ABC phenotype, can be used to differentiate between GCB and ABC DLBCL (Hans et al, 2004). A recent analysis performed on tissue samples from paediatric and adolescent patients enrolled on two consecutive German studies and recent FAB study revealed the vast majority to be of the GCB subtype (Oschlies et al, 2006; Miles et al, 2008). This is in sharp contrast to adult patients, in which >50% of DLBCL are classified as the GCB subtype (Hans et al, 2004).

image

Figure 4.  Identification of a PMBL gene expression signature. (A) Hierarchical clustering identified a set of 23 PMBL signature genes that were more highly expressed in most lymphomas with a clinical diagnosis of PMBL than in lymphomas assigned to the GCB or ABC DLBCL subgroups. Each row presents gene expression measurements from a single Lymphochip microarray feature representing the genes indicated. Each column represents a single lymphoma biopsy sample. Relative gene expression is depicted according to the colour scale shown. Reproduced from The Journal of Experimental Medicine, 2003, 198:851–862. Copyright 2003 The Rockefeller University Press. (B) Relationship of PMBL to Hodgkin lymphoma. Relative gene expression is shown in primary PMBL (average of all biopsy samples), the PMBL cell line K1106, three Hodgkin lymphoma (HL) cell lines, and six GCB DLBCL cell lines. PMBL signature genes that are also expressed at high levels in Hodgkin lymphoma cell lines compared with GCB DLBCL cell lines. Reproduced from The Journal of Experimental Medicine, 2003, 198:851–862. Copyright 2003 The Rockefeller University Press.

Download figure to PowerPoint

Outcomes in paediatric DLBCL are significantly better than in adult DLBCL (Patte et al, 2001; Laver et al, 2005). Children with DLBCL (excluding PMBL) enrolled in the international FAB/LMB 96 trial had a 4-year EFS of 92% (Patte et al, 2007). Most paediatric protocols, including the LMB protocols developed by the Societe Francaise d’Oncologie Pediatrique (SFOP; Patte et al, 2001, 2007) and the Berlin–Frankfürt–Münster (BFM) protocols developed in Germany (Reiter et al, 1995, 1999), utilize a cyclophosphamide, high-dose methotrexate, cytarabine and intrathecal chemotherapy backbone for intermediate and high-risk patients. Higher dose intensity during the first month of treatment as well as intensification of therapy for lack of response by day 7 of therapy are also strategies that have led to increased survival in paediatric patients (Reiter et al, 1999; Patte et al, 2007). In contrast to their higher risk counterparts, paediatric and adolescent patients with low-risk (resected stage I or completely resected abdominal stage II) B-cell NHL do exceedingly well with reduced duration and intensity of chemotherapy. The FAB/LMB 96 study group recently reported results for 132 patients with localized B-cell NHL, the largest proportion (43%) of whom had DLBCL, and found that two courses of COPAD (cyclophophamide, vincristine, prednisolone and doxorubicin) led to a 4-year EFS and OS of 98·3% and 99·2% respectively (Gerrard et al, 2008).

Most adult DLBCL patients receive therapy with a CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) backbone. In contrast to the excellent survival seen in paediatric patients, OS in adults ranges from 30% to 40% with standard of care CHOP treatment (Fisher et al, 1993; Coiffier et al, 2002), and is improved when rituximab is included in treatment (R-CHOP; Habermann et al, 2006; Pfreundschuh et al, 2006). In an older adult (age ≥60 years) DLBCL study, CHOP therapy alone resulted in 3-year failure-free survival (FFS) of 46%, while 3-year FFS after R-CHOP was 53% (P = 0·04). Maintenance rituximab improved FFS in patients who received CHOP, but not in those who had received R-CHOP (Habermann et al, 2006). In the younger adult MabThera International Trial (MInT), the addition of rituximab to six cycles of CHOP therapy in was found to be effective, resulting in increased 3-year EFS compared with CHOP alone [79% (95%CI 75–83) vs. 59% (54–64), P < 0·0001; Pfreundschuh et al, 2006]. Furthermore, an adult phase II study of dose-adjusted (DA) EPOCH-R (etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin plus rituximab) recently reported an OS of 80% (Wilson et al, 2008). The addition of rituximab to childhood DLBCL treatment is currently being studied [Children’s Oncology group (COG) trial ANHLO1P1 (M. Cairo, Study Chair)], with preliminary results showing the addition of rituximab to FAB/LBM 96 therapy to be safe and effective in the treatment of intermediate-risk paediatric B-NHL (Goldman et al, 2008).

Even with R-CHOP therapy or DA-EPOCH-R, adult DLBCL patients continue to have worse outcomes than paediatric patients. This difference in outcome may be partly explained by differences in treatment strategy. Tumour biology may also explain some of the difference in outcome, as paediatric DLBCL is mostly of the GCB subtype, whereas in adults the ABC and GCB subtypes are more evenly distributed. Less than 7% of children and adolescents with GCB DLBCL have tumours that express the t(14;18) translocation (Poirel et al, 2008), while approximately 28% of adult tumours have been shown to possess this cytogenetic abnormality (Weiss et al, 1987), lending support to the idea that differences in DLBCL tumour biology exist between children and adults (Cairo et al, 2008; Miles et al, 2008, Oschlies et al, 2006). Among adult patients, those with GCB DLBCL have a better prognosis than those with non-GCB DLBCLs (Rosenwald et al, 2002). It remains unknown whether the biology of adolescent DLBCL more closely resembles that of tumours found in children or adults, or if it falls somewhere along the spectrum between the two. In a recent analysis of 173 DLBCL patients enrolled on three successive BFM studies,Burkhardt et al (2005) found not only a significantly lower 5-year EFS for females versus males with non-primary mediastinal DLBCL (87% vs. 97% 5-year EFS, respectively, P = 0·015), but also a significantly worse outcome in female adolescents with non-primary mediastinal DLBCL when compared with younger girls (5-year EFS of 50% in adolescent females versus 94% in age 10–14, P = 0·0005). No significant difference in outcome was found when male adolescents with non-primary mediastinal DLBCL were compared with younger boys with the same disease.

Primary mediastinal B-cell lymphoma

Primary mediastinal B-cell lymphoma is currently classified by the WHO as a distinct subtype of DLBCL (Harris et al, 1999) although there is increasing data to suggest that it is a separate disease entity that shares clinical, morphological and genetic features with both NHL and cHL (Fig 5; Rosenwald et al, 2003; Abramson & Shipp, 2005). PMBL is a rare malignancy thought to arise from mature thymic B-cells and is characterized by a diffuse proliferation of large cells with clear cytoplasm, an invasive growth pattern, and sclerosis (Seidemann et al, 2003). DNA microarrays have shown similarities between PMBL and cHL, suggesting that PMBL falls somewhere along the biological spectrum between NHL and cHL (Fig 4B; Rosenwald et al, 2003; Abramson & Shipp, 2005). In addition, several chromosomal aberrations found in PMBL, including gains in chromosome 9p [Janus kinase (JAK)-2] and 2p (c-Rel), are also amplified in cHL (Joos et al, 1996). PMBL is typically a malignancy of adolescents and young adults. In an analysis of three successive BFM studies including patients up to the age of 18 years (Burkhardt et al, 2005), 40 PMBL patients had a reported median age of onset of 13·2 years (range 1·4–17·9 years).

image

Figure 5.  DLBCL, gray zone lymphomas, and Hodgkin lymphomas. MLBCL and T-cell/histocyte–rich large B-cell lymphoma (T/HRBCL) are considered ‘gray zone lymphomas’, which share characteristics of large B-cell lymphomas and Hodgkin lymphomas (cHL and NLPHL, respectively), including increased host inflammatory response. The similarities among these entities points to a group of tumours defined, and possibly driven, by their interaction with the host microenvironment. Images provided by J. Kutok, Department of Pathology, Brigham and Women’s Hospital, Boston, MA. The samples were analyzed using an Olympus BX41 microscope equipped with 40×/0·75 and 20×/0·50 Olympus UPlanFL objective lenses (Olympus, Melville, NY). Pictures were taken using Olympus QColor3, and were analyzed with QCapture 2·60 software (QImaging, Burnaby, BC, Canada). Adobe Photoshop 6·0 was used to process images (Adobe, San Jose, CA, USA). This research was originally published in Blood (Abramson and Shipp, 2005).

Download figure to PowerPoint

Outcomes in children and adolescents with PMBL are worse than in paediatric patients with other NHL subtypes and are also inferior to those seen in adults with PMBL. Among paediatric patients with NHL treated on three successive BFM studies using the same LMB treatment backbone described above for DLBCL, those with PMBL had worse outcomes, with 5-year EFS of 65 ± 8% compared with 85 ± 1% for the entire NHL cohort (Burkhardt et al, 2005). In contrast, a study of adult patients with PMBL treated with R-CHOP reported 5-year OS of 81% (Savage et al, 2006). More recently, a study of mostly adult patients receiving DA-EPOCH-R reported OS of 100% (Dunleavy et al, 2008). It therefore appears that paediatric patients with PMBL not only have worse outcomes than adult patients with the same disease, but those in the adolescent age range may have a particularly poor prognosis when compared with other paediatric patients with PMBL treated on identical protocols. Differences in treatment, as well as differences in tumour biology, may account for the discrepancy in outcomes between children and adults. Radiotherapy has not been studied in any prospective paediatric PMBL trials(Lones et al, 2000), but considering that PBML has features in common with cHL, it is an additional treatment modality that warrants further study, especially in adolescent patients.

Lymphoblastic lymphoma

Lymphoblastic lymphoma is a disease of children, adolescents and young adults accounting for approximately 30% of childhood and young adult NHL (Cairo et al, 2005). More than 90% of LL arise from immature T-cells, while the remainder are of B-precursor cell origin. T-LL more commonly involves BM or CNS than B-LL (Cairo et al, 2005). Acute lymphoblastic leukaemia (ALL) and LL share many of the same cell surface markers, as well as many of the same cytogenetic abnormalities. Most T-LL gene rearrangements involve the genes that encode the T-cell receptors, while those in B-LL tend to involve immunoglobulin gene rearrangements (Cairo et al, 2005).

Lymphoblastic lymphoma is usually treated with ALL-based therapy, including multidrug systemic chemotherapy and CNS prophylaxis (Reiter et al, 2000). Both paediatric and adult patients have the most favourable treatment outcomes when treated with such ALL-type regimens. The NHL-BFM 90 study, which included induction, re-induction and prolonged maintenance phases and utilized the same drugs used in ALL therapy (including high-dose methotrexate, asparaginase, anthracyclines, cyclophosphamide, cytarabine and 6-mercaptopurine), reported a 5-year EFS of 90% in 105 paediatric patients with T-LL (median age 8·8 years, range 1·1–16·4 years; Reiter et al, 2000). Hyper-CVAD (fractionated cyclophosphamide, vincristine, doxorubicin and dexamethasone) therapy has been studied in adult patients, resulting in estimated 3-year progression-free survival (PFS) and OS of 66% and 70% respectively (Thomas et al, 2004). Adults tend to have worse outcomes than paediatric patients, even with the use of similar treatment regimens, suggesting that differences in tumour biology play a role in response to therapy. To evaluate differences in outcome among paediatric LL patients, Burkhardt et al (2005) conducted a multivariate analysis of potential prognostic factors for children and adolescents treated for either B- or T-LL, and found no prognostic impact of age or gender alone on T-LL outcome and a significantly improved prognosis for B-LL patients age ≥5 years (P = 0·0001). Interestingly, when looking at the combination of age and gender together, Burkhardt et al (2005) found a nearly significant worse outcome for female T-LBL patients older than age 9 years (P = 0·079). Based on these results, it appears that younger children with B-LL have better outcomes, while older age in combination with female gender may be a poor prognostic factor for T-LL. The Children’s Cancer Group (CCG) protocol CCG-E-08 analysed the cytogenetics of LL specimens from 13 paediatric patients to determine if certain abnormalities occurred with increased frequency in children and adolescents (Lones et al, 2007). They found chromosomal abnormalities in 85% of patients studied, most often involving a translocation at chromosome 14q11·2 (likely involving the TCR A/D locus), but were unable to draw any definitive conclusions based on the small number of patients studied and the multiple treatment regimens used. Data from the NHL-BFM 95 study suggests that loss of heterozygosity on chromosome 6q14-q24 may confer a high risk of relapse in paediatric patients with T-LL (Burkhardt et al, 2006). Chromosome analysis of larger numbers of additional paediatric and adolescent patients, as well as the use of gene expression profiling techniques to look for overexpression of specific pathways, may allow for the tailoring of treatment and play a role in determining prognosis in all children with LL, including adolescents.

Burkitt lymphoma

Burkitt lymphoma is the most common NHL subtype in children ages 5 to 14 years, but is less common than both DLBCL and LL in the 15 to 19 year age group according to SEER data (Bleyer et al, 2006). BL is rare in adults, accounting for <5% of all lymphomas.

Gene expression profiling can be used to distinguish BL from DLBCL, as the molecular signature of BL includes a high level of expression of c-myc target genes and low levels of expression of major-histocompatibility-complex class I genes and NF-κB genes (Dave et al, 2006; Hummel et al, 2006).

As mentioned earlier in the discussion of DLBCL, excellent EFS and OS of 98·3% and 99·2%, respectively, were recently reported for 132 paediatric patients with localized B-cell NHL, including 72 patients with BL or Burkitt-like lymphoma (BLL), treated with two cycles of COPAD (Gerrard et al, 2008). For more advanced stage disease, treatment consists of intensive, short courses of chemotherapy, usually including cyclophosphamide, high-dose methotrexate and cytarabine. Other effective drugs include doxorubicin, vincristine, etoposide, ifosfamide and corticosteroids (Patte et al, 2008). In the FAB/LMB 96 paediatric study, as in earlier large cooperative group studies, children and adolescents with BL were treated identically to those with DLBCL (Reiter et al, 1995; Patte et al, 2001, 2007; Cairo et al, 2007). Adults with BL, unlike adults with DLBCL who receive CHOP-based therapy, are also treated with intensive chemotherapy regimens (Magrath et al, 1996; Divine et al, 2005) based on the very poor survival rates (50–65% OS for BM and CNS-negative disease, <30% OS if BM or CNS-positive) seen with CHOP-based regimens (Longo et al, 1994) and improved survival with the use of paediatric regimens. Children and adolescents with BL treated on FAB/LMB 96 had 4-year EFS of 93·3%, better than in either the non-primary mediastinal DLBCL (4-year EFS 92·7%) or PMBL (4-year EFS 71·5%) groups. A multivariate analysis of the FAB/LMB data revealed a significantly worse prognosis based on tumour histology, with DLBCL patients having a higher risk ratio than those with BL [DLBCL vs. BL relative risk (RR)EFS = 1·7, P = 0·043; Cairo et al, 2008]. In a multivariate analysis of 1004 childhood and adolescent patients with BL, neither age nor gender were found to be significant independent prognostic factors (Burkhardt et al, 2005). Conversely, a multivariate analysis of 470 paediatric patients with BL and BLL treated on four consecutive CCG trials found a significant difference in outcome in patients ≥15 years versus those <15 years (4-year EFS: 34% vs. 59%, respectively (P < 0·05; Fig 6; Cairo et al, 2003).

image

Figure 6.  Comparison of event-free survival by age among 470 disseminated Burkitt’s and Burkitt-like lymphoma patients from CCG studies −551, −503, −552, and −5911. *Ages 15 years and older versus all others, 4-year EFS (34 ± 7% vs. 59 ± 2%, P = 0·002; Cairo et al 2003).

Download figure to PowerPoint

Anaplastic large cell lymphoma

Anaplastic large cell lymphoma is generally considered to be the least common of the four major subtypes of adolescent NHL (Bleyer et al, 2006). It is a distinct clinicopathological entity, first described by Stein et al (1985) and characterized by the proliferation of large pleomorphic cells of a T or null phenotype with CD30 antigen expression and a tendency to invade lymph node sinuses (Le Deley et al, 2008). A characteristic t(2;5)(p23;q35) translocation involving the anaplastic lymphoma kinase gene (ALK; chromosome 2) and the nucleophosmin gene (NPM1; chromosome 5) is associated with most childhood and adolescent ALCL (Rimokh et al, 1989; Morris et al, 1994). Two subtypes of ALCL, primary cutaneous ALCL (C-ALCL) and systemic nodal and extranodal ALCL (S-ALCL), are recognized by the WHO (Harris et al, 1999). S-ALCL is more common in adolescents; it often involves a t(2;5) translocation and is therefore frequently ALK-positive.

Anaplastic large cell lymphoma accounts for about 13% of paediatric NHL but only 2% of adult NHL (Drexler et al, 2000). The incidence in adolescents appears to be higher than in younger children, with a retrospective review of 341 adolescent NHL patients treated in France reporting that 18% had ALCL (Patte et al, 2006). There is a bimodal age distribution, with a large peak occurring in adolescents and young adults and a smaller peak in adults over the age of 50 years (Skinnider et al, 1999). Adolescents tend to have ALK-positive tumours, while older patients generally have ALK-negative disease (Gascoyne et al, 1999). In the retrospective review reported by Burkhardt et al (2005), of three NHL BFM protocols including 215 ALCL patients, 86% of the 15–18 year old group had ALK-positive disease. There was a male predominance of ALK-positive ALCL diagnosed during the second and third decades of life (M:F ratio 6·5:1; Falini et al, 1999). Most ALK-positive lymphomas present with systemic stage III–IV disease and frequently involve extranodal sites, most commonly skin, bones and soft tissues. BM involvement is uncommon (11–34%) and CNS involvement is very rare (3–5%; Stein et al, 2000). ALK-negative ALCL is associated with advanced stage disease and has a 5-year survival of approximately 40%, whereas ALK-positive disease has a more favourable prognosis with 5-year survival as high as 80–90% (Falini, 2001; Kadin & Carpenter, 2003).

Optimal treatment for S-ALCL is not yet well defined. EFS of 100% has been reported in children and adolescents with localized ALCL after 2 months of chemotherapy (dexamethasone, ifosfamide, methotrexate, cytarabine, etoposide and prophylactic intrathecal chemotherapy) (Seidemann et al, 2001). Adolescent and young adult patients with advanced stage S-ALCL are often treated with anthracycline-containing chemotherapy regimens. CHOP-based therapy lasting 6 months has been used to treat childhood S-ALCL and led to >75% 3-year EFS (Sandlund et al, 1994a,b). A Pediatric Oncology Group regimen using APO (doxorubicin, prednisone, vincristine) and cooperative European studies using BFM-NHL or SFOP HM 89–91 have shown 65–75% 3–5 year EFS in children with advanced S-ALCL (Abromowitch et al, 2002, Brugieres et al, 1998; Cairo et al, 2002; Mora et al, 2000; Reiter et al, 1994; Seidemann et al, 2001). A trend toward increasing 5-year EFS has been reported for childhood and adolescent ALCL with increasing age up to 18 years (Burkhardt et al, 2005). In a multivariate analysis including age, gender, LDH level and extranodal disease involvement (mediastinum, lung, skin), a significant improvement in prognosis was reported for ALCL in children and adolescents greater than or equal to age 10 years while lung or skin involvement was associated with a significantly worse prognosis (Burkhardt et al, 2005).

Gascoyne et al (1999) reported 79% 5-year OS for adolescent and young adult patients (median age 30 years) with ALK-positive ALCL treated with an anthracycline-containing regimen. In contrast, 5-year OS for ALK-negative patients in the same age group was only 46% (P < 0·0003). ALK-positivity, International Prognostic Index score, and serum LDH were each found to be independent predictors of improved survival. Age alone was not a significant independent predictor of survival, but correlated with ALK-positivity (Gascoyne et al, 1999). More aggressive therapy, including intensive chemotherapy, involved field radiotherapy and autologous stem cell transplantation (autoSCT) has been utilized in a subset of adult patients with advanced disease and resulted in 100% disease-free survival (DFS) and OS (Fanin et al, 1996). There is clearly room for improvement in the treatment of advanced stage adolescent S-ALCL, and further studies are needed to determine if more aggressive therapies, such as the addition of myeloablative chemotherapy followed by SCT, or immunotherapy with anti-CD30 antibodies may be warranted in certain cases.

Hodgkin lymphoma

  1. Top of page
  2. Summary
  3. Non-Hodgkin lymphoma
  4. Hodgkin lymphoma
  5. Relapsed/refractory adolescent lymphoma
  6. Adolescent lymphoma late effects
  7. Conclusion
  8. Acknowledgements
  9. References

The worldwide incidence of HL is approximately two to four new cases per 100 000 population/year. The most unusual aspect of HL is the classic bimodal age distribution with peaks at 15–35 years of age and again after 50 years. While HL represents only approximately 4–5% of all cancers in children younger than 15 years of age, this increases to approximately 16% in the adolescent, making HL the most common malignancy within this age group (15–19 years old; Bleyer et al, 2006). There is a slight overall male predominance with a male to female ratio of 1·7–2:1; however, there is no significant difference in gender within the adolescent population. Prior history with Epstein–Barr virus (EBV) infection confers a fourfold risk (Kapatai & Murray, 2007), often preceding the diagnosis of HL by years. However, whereas EBV-positive HL is often identified in younger patients with naïve immune systems as well as older patients that have decreased immune surveillance, there is a less striking association in the adolescent population despite a higher rate of infectious mononucleosis in this age group. This may represent differences in immune status among the different age groups. This also reflects the association of EBV with the mixed cellularity subtype, which is less common in adolescents.

The Revised European American Lymphoma (REAL)/WHO lymphoma classification now recognizes two major types of HL: nodular lymphocyte predominant HL (NLPHL) and cHL. NLPHL is rare in the adolescent/young adult age group as it typically presents with a peak age distribution in the 4th decade in males. Among cHL, there are four histological subtypes: nodular sclerosing, mixed cellularity, lymphocyte rich and lymphocyte depleted. There are significant differences in the distribution of subtypes by age (Fig 7; Herbertson & Hancock, 2005). Whereas mixed cellularity occurs in 30% and the lymphocyte rich subtype is seen in 10–15% of patients, both more often occur in children under 10 years of age. The most common subtype, nodular sclerosing, is seen in 40–50% of children overall but up to 80% of adolescents/young adults (Herbertson & Hancock, 2005).

image

Figure 7.  Comparative distribution of Hodgkin lymphoma in children versus adolescents versus adults. Adolescents and adults present with a higher percentage of nodular sclerosing subtype (80% vs. 62%, respectively) when compared with children younger than 15 years of age who present with a higher percentage of mixed cellularity (35%).

Download figure to PowerPoint

Five year OS depends on risk group, with low-risk associated with an estimated 5-year OS of 95% and high risk with a lower estimated 5-year OS of 85%. This is influenced in part by the use of involved field radiotherapy in combination with multiagent chemotherapy in high-risk groups and its omission in lower risk groups (Nachman et al, 2002). Overall outcome may be related to age at diagnosis. Adolescents with HL fare worse over time than children <15 years of age (Fig 8), but there are not many published reports directly comparing adolescent outcomes. In the Pediatric Oncology Group POG 8725 study looking at the addition of low-dose radiation therapy to multiagent chemotherapy in advanced stage HL patients, age ≤13 years of age at diagnosis was associated with a statistically significant improved 5 year EFS of 89% compared with 72% for age >13 years of age (Weiner et al, 1997). However, the German-Austrian multicenter trial DAL-HD-90, again using multiagent chemotherapy with low-dose radiation, reported no difference in OS or EFS among age groups 15–18 years old versus <15 years (Schellong et al, 1999). Yung et al (2004) performed a retrospective analysis on 209 patients (aged 15–17 years old) diagnosed with advanced HL in the UK, and reported a lower OS of 81% at 5 years and only 68% at 20 years. Moreover, when analysing EFS in adolescents with HL, 5 year EFS was only 50% and 20 year EFS only 41%. The low EFS emphasize an important observation, that outcome data for adolescents is more accurately measured by EFS, rather than OS. When long -term complications, particularly secondary malignancies are factored in, our success in the treatment of HL becomes less pronounced. The authors concluded the poor outcome may be attributable to adolescent treatment with more adult cancer treatment regimens rather than risk-adapted combined modality treatment being utilized by most paediatric cancer centres (Yung et al, 2004). Further support for the importance of appropriate therapy comes from the combined data from the German Hodgkin’s Study Group HD9/HD12 and CCG 59704 trials in which dose intensive chemotherapy with bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine and prednisone (BEACOPP) were utilized for high-risk HL. In these studies, a markedly better 5-year EFS for age 16–21 years of 88–93% was observed, with OS approaching 100% (Kelly et al, 2002; Diehl et al, 2003; Sposto et al, 2005).

image

Figure 8.  Survival rates for Hodgkin lymphoma, SEER 1975–1998. From: Bleyer et al (2006).

Download figure to PowerPoint

Over the past 50 years, due to the collaborative efforts of pathologists and basic scientists, incorporation of improved radiation oncology techniques and newer imaging modalities, and most importantly through the conduct of multicentre clinical trials, the progress in the treatment and overall outcome of HL has dramatically improved (Diehl, 2007). Combined modality therapy has a high HL cure rate, but has significant long-term toxicities which impact EFS, with this being a bigger issue for the adolescent than for an older adult. Whereas, ABVD is standard chemotherapy used by most adult groups around the world, there still is considerable variation among paediatric groups as to the choice of a particular multiagent chemotherapy regimen. Consequently, AYA patients are treated on many different regimens.

Perhaps most importantly, current radiation therapy practice utilizes lower amounts of overall radiation in addition to narrowing the radiation treatment field to either involved field or even involved node radiation. Lower doses of <26 Gy are now used with only involved field radiation for low and intermediate stage HL. The current COG trials are investigating whether radiation therapy can be eliminated altogether in patients who have a very good rapid early response. In addition, new imaging modalities, such as positron emission tomography scans, are being evaluated for use in predicting overall outcome such that therapy can be further reduced (Hutchings et al, 2006; Terasawa et al, 2008). Therapy reductions will be particularly helpful in reducing the risks of secondary cancers and other late effects. This further underscores the need to include adolescents and young adults on clinical trials.

Relapsed/refractory adolescent lymphoma

  1. Top of page
  2. Summary
  3. Non-Hodgkin lymphoma
  4. Hodgkin lymphoma
  5. Relapsed/refractory adolescent lymphoma
  6. Adolescent lymphoma late effects
  7. Conclusion
  8. Acknowledgements
  9. References

Pediatric patients with relapsed or refractory NHL have worse prognoses than do their newly diagnosed counterparts (Bradley & Cairo, 2008). Improvements in survival in relapsed/refractory NHL have been achieved with intensive chemotherapy followed by either autologous (Bradley & Cairo, 2008) or allogeneic bone marrow transplantation (Woessmann et al, 2006). Outcome after transplantation depends on chemosensitivity of disease as well as subtype of NHL (Bradley & Cairo, 2008). The European Blood and Marrow Transplantation (EBMT) Group reported a 5-year EFS of 48·7% for paediatric patients with poor risk B-cell NHL who received high-dose chemotherapy followed by autoSCT, while those with primary refractory disease had an EFS of only 8% (Ladenstein et al, 1997). The BFM group recently transplanted 20 paediatric patients with relapsed/refractory ALCL with myeloablative conditioning and allogeneic SCT (alloSCT) and reported a 3-year EFS of 75% (Woessmann et al, 2006). These results support the role of a graft versus lymphoma (GvLy) response in improvement in survival (Bradley & Cairo, 2008). Myeloablative autoSCT followed by reduced-intensity alloSCT has also proven successful in adult and paediatric patients with relapsed/refractory disease (Carella et al, 2000; Satwani et al, 2008). Satwani et al (2008) recently reported a 1-year OS of 66% in 17 paediatric patients (nine NHL, eight HL) who received autologous transplant followed by allogeneic transplant. Pending the results of larger studies, it therefore appears that adolescent patients with relapsed/refractory NHL may benefit from autologous, allogeneic or tandem transplants, as well as the addition of rituximab (in CD20-positive relapses).

Currently, there is a major attempt to tailor the treatment of the recurrent or refractory HL patient as well. Dismal outcomes (5–10 year OS: 20–25%) have been reported for early relapse or refractory HL after treatment with salvage chemotherapy alone (Longo et al, 1992; Johnston & Horning, 2000; Bradley & Cairo, 2008). For this reason, the standard treatment approach for primary refractory or relapsed HL has been high-dose myeloablative chemotherapy followed by autoSCT (Bradley & Cairo, 2008). Indications for high-dose therapy and autoSCT are the same for children and adults and include disease status, chemoresponsiveness to salvage chemotherapy, tumour bulk at time of SCT, remission duration, and extranodal relapse (Baker et al, 1999). Furthermore, adults and children treated with intensive chemotherapy followed by autoSCT have wide-ranging but comparable outcomes (EFS: 31–62%, OS: 43–95%; Williams et al, 1993; Bradley & Cairo, 2008). Similar to NHL, alloSCT is also effective in HL, with Anderson et al (1993) reporting a significantly lower relapse rate in relapsed/refractory HL patients who received a matched sibling alloSCT compared with autoSCT, 45% versus 76% respectively (Bradley & Cairo, 2008). As in NHL, the addition of targeted therapies and the use of tandem autologous/allogeneic transplantation may offer a survival advantage for relapsed/refractory patients with HL and are currently being investigated.

Newer agents, such as those that disrupt the NF-kB pathway or monoclonal antibodies that target not only RS tumour cells but also the benign reactive cells that surround them, are currently being investigated. Ongoing clinical trials have reported encouraging results combining anti-CD20 antibody (rituximab) with chemotherapy (Younes et al, 2003; Oki et al, 2008) and there has been an increase in the use of rituximab overall in the paediatric population, especially among adolescents. In addition, anti-CD30 agents are now being used which are targeted to the RS cells themselves, where CD30 is abundantly expressed (Bartlett et al, 2008). Anti-CD30 agents have shown promising results in adult trials and are currently being investigated in the paediatric population although no results have been reported yet. However, some of the advantages of newer agents like these are that they have fewer side effects, many of them can be taken orally and they can be administered at home, improving both ease of administration and quality of life. This becomes important in the adolescent population as it will serve to increase treatment compliance and thus outcomes. It also raises the issue of whether adolescents and young adults should be considered for enrolment in adult trials as a way of accessing some of these newer, promising agents. Currently, there is little crossover as adolescents often are not eligible for adult phase I trials and therefore do not have access to newer agents as quickly.

Adolescent lymphoma late effects

  1. Top of page
  2. Summary
  3. Non-Hodgkin lymphoma
  4. Hodgkin lymphoma
  5. Relapsed/refractory adolescent lymphoma
  6. Adolescent lymphoma late effects
  7. Conclusion
  8. Acknowledgements
  9. References

As detailed above, the majority of adolescent patients with newly diagnosed NHL have a 3–5 year EFS well-above 90%. Secondary primary malignancies and late mortality, however, remain a concern. Bluhm et al (2008) recently analysed the results of 1082 5-year NHL survivors included in the multi-institutional North American Childhood Cancer Survivor Study and found elevated rates of death more than 20 years after treatment due to the development of solid tumours, leukaemia, cardiac disease, and pneumonia. Current treatment paradigms for HL offer cure rates of >90% at 10 years with the utilization of combination chemotherapy and radiation therapy. However, this also has been at the expense of an increased RR of long-term complications. A recent review of SEER data over a 25-year follow-up period demonstrated that, unlike most other malignancies, the decline in relative survival curves do not plateau after 10 years following diagnosis of HL, but rather accelerate (Fig 9) (Brenner et al, 2008). This highlights the importance of late morbidity and mortality among survivors of lymphoma and makes lifelong follow up of the adolescent patient critical.

image

Figure 9.  Relative survival over 25 years following diagnosis of patients with HL by major age groups. Period analysis for 2000–2004. This research was originally published in Blood (Brenner et al, 2008).

Download figure to PowerPoint

The RR of subsequent myocardial ischemia after radiation therapy with 40–45 Gy in children and adolescents under 21 years of age is higher than in adults (RR = 41·5; Boivin et al, 1992; Hancock et al, 1993; Swerdlow et al, 2007). This is augmented by anthracycline exposure as part of standard chemotherapy regimens. Radiation during childhood at doses of 35–45 Gy have also been associated with increased RR of thyroid derangements, including hypothyroidism (RR = 17·1) and thyroid cancers (RR = 18; Sklar et al, 2000). Particularly devastating to adolescents and young adults is an increased incidence of infertility. These are gender dependant with males developing azoospermia while females undergo premature menopause, often requiring lifelong hormone replacement. Risk factors include cumulative alkylating agent exposure combined with direct radiation of 20–30 Gy to the testes or ovaries (Behringer et al, 2005). This raises the question of whether we should be avoiding alkylators in younger children and adolescents who are unable to sperm bank. If so, how will this affect outcomes? Of note, many males are noted to have azoospermia or oligospermia prior to starting any chemotherapy (Aslam et al, 2000). Thus, it is often difficult to counsel the adolescent patient regarding fertility issues but this frequently is the primary concern of parents upon starting treatment. It is recommended that all adolescent males who are at least Tanner Stage III participate in sperm banking, if available, even if the patient is not thought to have reached full sexual maturity (Ginsberg et al, 2008). For females, the issue of preserving fertility is more difficult, although further advances are being made in the preservation of eggs as well as cryopreservation of ovarian tissue (Behringer et al, 2005). Females are at risk for premature menopause but often are fertile for varying amounts of time after completion of therapy, which makes future family planning important (De Bruin et al, 2008). Particularly in the adolescent, it must be stressed that we can not predict long-term effects on fertility and that this must be considered if and when the patient becomes sexually active.

Second malignancies remain a significant risk factor post-treatment, especially within the adolescent age group. Survivors of HL have been consistently shown to have increased risk of developing NHL, leukaemia, gastrointestinal cancers, melanoma, thyroid cancer and breast cancer (van Leeuwen et al, 1994a,b; Boivin et al, 1995; Wolden et al, 1998; Bhatia et al, 2003; Josting et al, 2003; Schonfeld et al, 2006). The data suggests that children and adolescents are at higher risk of development of these cancers than adult survivors. This is particularly true for women who receive mantle-field radiation prior to the age of 20 years with up to a 40-fold increased risk for developing breast cancer in some studies (Hancock et al, 1993; Aisenberg et al, 1997). Beaty et al (1995) conducted a review of 499 children and adolescents with HL treated with multiagent chemotherapy plus radiation therapy. Their analysis showed that, at a median follow up of 9 years, adolescents treated for HL are at greater risk of second malignancies than younger patients. Overall, 23 of 25 second malignancies were in patients >10 years old at diagnosis, while only 2/25 occurred in patients <10 years old (P = 0·01). Adolescent females treated for recurrent HL appear to be at greatest risk, even when those with breast cancer are excluded.

Conclusion

  1. Top of page
  2. Summary
  3. Non-Hodgkin lymphoma
  4. Hodgkin lymphoma
  5. Relapsed/refractory adolescent lymphoma
  6. Adolescent lymphoma late effects
  7. Conclusion
  8. Acknowledgements
  9. References

The treatment of adolescent lymphomas over the past 25 years has served as a model of translational medicine, mutidisciplinary approaches and risk-based treatment modalities. We have seen dramatic improvements in OS and EFS and should be proud of our accomplishments in these areas. As we move forward, we must assess the long-term complications that arise as a result of the treatment of the adolescent patient as they progress into their adult life.

The first Childhood Cancer Survivor Study (Oeffinger et al, 2006), a retrospective cohort study of 10 397 cancer survivors diagnosed prior to the age of 21 years, demonstrated that 62·3% of survivors report at least one chronic condition; with 27·5% reporting severe or life-threatening conditions. The adjusted RR of a chronic condition in a survivor, when compared with siblings, was 3·3 (95% CI, 3·0 to 3·5); and for a severe or life-threatening condition, the risk was 8·2 (95% CI, 6·9 to 9·7; Oeffinger et al, 2006). When disease-specific health outcomes were looked at, both HL and NHL were found to have a cumulative incidence of chronic health conditions approaching 70–80% with severe conditions being reported in close to 50% of HL survivors. Long term health outcomes were slightly better in the NHL group but overall still represented unacceptable numbers (Oeffinger et al, 2006). Furthermore, age at diagnosis impacted long-term outcome. Adolescent survivors who received the diagnosis at an older age were more likely to report more severe (grade III–V) adverse conditions, or multiple conditions than their younger counterparts.

Newer treatment strategies must be continually investigated to address the long-term consequences and lifelong morbidities that adolescents ultimately must face when undergoing treatment for cancer. One recently published report compared adult versus paediatric protocols in the treatment of ALL within the adolescent age group and found superior EFS among those treated with a paediatric protocol (63% paediatric vs. 34% adult; Stock et al, 2008). Further prospective studies are needed to compare adult versus paediatric treatment regimens in the treatment of adolescent lymphomas and long-term outcomes. We have made significant strides in OS and now must ensure that we do not abandon efforts to further improve long-term quality of life.

Acknowledgements

  1. Top of page
  2. Summary
  3. Non-Hodgkin lymphoma
  4. Hodgkin lymphoma
  5. Relapsed/refractory adolescent lymphoma
  6. Adolescent lymphoma late effects
  7. Conclusion
  8. Acknowledgements
  9. References

The authors would like to thank Leslie Disla for her assistance in manuscript preparation. This work was supported in part by grants from the National Cancer Institute (U10CA98543), Pediatric Cancer Research Foundation (MC), Marisa Fund (MC), Sonia Scaramella Fund (MC), and Bevanmar Foundation (MC).

References

  1. Top of page
  2. Summary
  3. Non-Hodgkin lymphoma
  4. Hodgkin lymphoma
  5. Relapsed/refractory adolescent lymphoma
  6. Adolescent lymphoma late effects
  7. Conclusion
  8. Acknowledgements
  9. References
  • Abramson, J.S. & Shipp, M.A. (2005) Advances in the biology and therapy of diffuse large B-cell lymphoma: moving toward a molecularly targeted approach. Blood, 106, 11641174.
  • Abromowitch, M., Sposto, R., Perkins, S., Zwick, D. & Finlay, J. (2002) Preliminary results of CCG-5941 a pilot study in children and adolescents with anaplastic large cell lymphoma. Annals of Oncology, 13, 96 (abstract).
  • Aisenberg, A.C., Finkelstein, D.M., Doppke, K.P., Koerner, F.C., Boivin, J.F. & Willett, C.G. (1997) High risk of breast carcinoma after irradiation of young women with Hodgkin’s disease. Cancer, 79, 12031210.
  • Albritton, K. & Bleyer, W.A. (2003) The management of cancer in the older adolescent. European Journal of Cancer, 39, 25842599.
  • Alizadeh, A.A., Eisen, M.B., Davis, R.E., Ma, C., Lossos, I.S., Rosenwald, A., Boldrick, J.C., Sabet, H., Tran, T., Yu, X., Powell, J.I., Yang, L., Marti, G.E., Moore, T., Hudson, J., Jr, Lu, L., Lewis, D.B., Tibshirani, R., Sherlock, G., Chan, W.C., Greiner, T.C., Weisenburger, D.D., Armitage, J.O., Warnke, R., Levy, R., Wilson, W., Grever, M.R., Byrd, J.C., Botstein, D., Brown, P.O. & Staudt, L.M. (2000) Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature, 403, 503511.
  • Anderson, J.E., Litzow, M.R., Appelbaum, F.R., Schoch, G., Fisher, L.D., Buckner, C.D., Petersen, F.B., Crawford, S.W., Press, O.W. & Sanders, J.E. (1993) Allogeneic, syngeneic, and autologous marrow transplantation for Hodgkin’s disease: the 21-year Seattle experience. Journal of Clinical Oncology, 11, 23422350.
  • Aslam, I., Fishel, S., Moore, H., Dowell, K. & Thornton, S. (2000) Fertility preservation of boys undergoing anti-cancer therapy: a review of the existing situation and prospects for the future. Human Reproduction, 15, 21542159.
  • Baker, K.S., Gordon, B.G., Gross, T.G., Abromowitch, M.A., Lyden, E.R., Lynch, J.C., Vose, J.M., Armitage, J.O., Coccia, P.F. & Bierman, P.J. (1999) Autologous hematopoietic stem-cell transplantation for relapsed or refractory Hodgkin’s disease in children and adolescents. Journal of Clinical Oncology, 17, 825831.
  • Bartlett, N.L., Younes, A., Carabasi, M.H., Forero, A., Rosenblatt, J.D., Leonard, J.P., Bernstein, S.H., Bociek, R.G., Lorenz, J.M., Hart, B.W. & Barton, J. (2008) A phase 1 multidose study of SGN-30 immunotherapy in patients with refractory or recurrent CD30+ hematologic malignancies. Blood, 111, 18481854.
  • Beaty, III, O., Hudson, M.M., Greenwald, C., Luo, X., Fang, L., Wilimas, J.A., Thompson, E.I., Kun, L.E. & Pratt, C.B. (1995) Subsequent malignancies in children and adolescents after treatment for Hodgkin’s disease. Journal of Clinical Oncology, 13, 603609.
  • Behringer, K., Breuer, K., Reineke, T., May, M., Nogova, L., Klimm, B., Schmitz, T., Wildt, L., Diehl, V. & Engert, A. (2005) Secondary amenorrhea after Hodgkin’s lymphoma is influenced by age at treatment, stage of disease, chemotherapy regimen, and the use of oral contraceptives during therapy: a report from the German Hodgkin’s Lymphoma Study Group. Journal of Clinical Oncology, 23, 75557564.
  • Bhatia, S., Yasui, Y., Robison, L.L., Birch, J.M., Bogue, M.K., Diller, L., DeLaat, C., Fossati-Bellani, F., Morgan, E., Oberlin, O., Reaman, G., Ruymann, F.B., Tersak, J. & Meadows, A.T. (2003) High risk of subsequent neoplasms continues with extended follow-up of childhood Hodgkin’s disease: report from the Late Effects Study Group. Journal of Clinical Oncology, 21, 43864394.
  • Birch, J.M., Alston, R.D., Kelsey, A.M., Quinn, M.J., Babb, P. & McNally, R.J. (2002) Classification and incidence of cancers in adolescents and young adults in England 1979–1997. British Journal of Cancer, 87, 12671274.
  • Bleyer, W.A., O’Leary, M., Barr, R. & Ries, L.A.G. (eds) (2006) Cancer Epidemiology in Older Adolescents and Young Adults 15–29 Years of Age, Including SEER Incidence and Survival, 1975–2000. National Cancer Institute, NIH Pub. No. 06-5767 Bethesda, MD.
  • Bluhm, E.C., Ronckers, C., Hayashi, R.J., Neglia, J.P., Mertens, A.C., Stovall, M., Meadows, A.T., Mitby, P.A., Whitton, J.A., Hammond, S., Barker, J.D., Donaldson, S.S., Robison, L.L. & Inskip, P.D. (2008) Cause-specific mortality and second cancer incidence after non-Hodgkin lymphoma: a report from the Childhood Cancer Survivor Study. Blood, 111, 40144021.
  • Boivin, J.F., Hutchison, G.B., Lubin, J.H. & Mauch, P. (1992) Coronary artery disease mortality in patients treated for Hodgkin’s disease. Cancer, 69, 12411247.
  • Boivin, J.F., Hutchison, G.B., Zauber, A.G., Bernstein, L., Davis, F.G., Michel, R.P., Zanke, B., Tan, C.T., Fuller, L.M., Mauch, P. & Ultmann, J.E. (1995) Incidence of second cancers in patients treated for Hodgkin’s disease. Journal of the National Cancer Institute, 87, 732741.
  • Bradley, M.B. & Cairo, M.S. (2008) Stem cell transplantation for pediatric lymphoma: past, present and future. Bone Marrow Transplantation, 41, 149158.
  • Brenner, H., Gondos, A. & Pulte, D. (2008) Ongoing improvement in long-term survival of patients with Hodgkin disease at all ages and recent catch-up of older patients. Blood, 111, 29772983.
  • Brugieres, L., Deley, M.C., Pacquement, H., Meguerian-Bedoyan, Z., Terrier-Lacombe, M.J., Robert, A., Pondarre, C., Leverger, G., Devalck, C., Rodary, C., Delsol, G. & Hartmann, O. (1998) CD30(+) anaplastic large-cell lymphoma in children: analysis of 82 patients enrolled in two consecutive studies of the French Society of Pediatric Oncology. Blood, 92, 35913598.
  • Burkhardt, B., Zimmermann, M., Oschlies, I., Niggli, F., Mann, G., Parwaresch, R., Riehm, H., Schrappe, M. & Reiter, A. (2005) The impact of age and gender on biology, clinical features and treatment outcome of non-Hodgkin lymphoma in childhood and adolescence. British Journal Haematology, 131, 3949.
  • Burkhardt, B., Bruch, J., Zimmermann, M., Strauch, K., Parwaresch, R., Ludwig, W.D., Harder, L., Schlegelberger, B., Mueller, F., Harbott, J. & Reiter, A. (2006) Loss of heterozygosity on chromosome 6q14-q24 is associated with poor outcome in children and adolescents with T-cell lymphoblastic lymphoma. Leukemia, 20, 14221429.
  • Cairo, M.S., Krailo, M.D., Morse, M., Hutchinson, R.J., Harris, R.E., Kjeldsberg, C.R., Kadin, M.E., Radel, E., Steinherz, L.J., Morris, E., Finlay, J.L. & Meadows, A.T. (2002) Long-term follow-up of short intensive multiagent chemotherapy without high-dose methotrexate (‘Orange’) in children with advanced non-lymphoblastic non-Hodgkin’s lymphoma: a children’s cancer group report. Leukemia, 16, 594600.
  • Cairo, M.S., Sposto, R., Perkins, S.L., Meadows, A.T., Hoover-Regan, M.L., Anderson, J.R., Siegel, S.E., Lones, M.A., Tedeschi-Blok, N., Kadin, M.E., Kjeldsberg, C.R., Wilson, J.F., Sanger, W., Morris, E., Krailo, M.D. & Finlay, J.L. (2003) Burkitt’s and Burkitt-like lymphoma in children and adolescents: a review of the Children’s Cancer Group experience. British Journal Haematology, 120, 660670.
  • Cairo, M.S., Raetz, E., Lim, M.S., Davenport, V. & Perkins, S.L. (2005) Childhood and adolescent non-Hodgkin lymphoma: new insights in biology and critical challenges for the future. Pediatric Blood & Cancer, 45, 753769.
  • Cairo, M.S., Gerrard, M., Sposto, R., Auperin, A., Pinkerton, C.R., Michon, J., Weston, C., Perkins, S.L., Raphael, M., McCarthy, K. & Patte, C. (2007) Results of a randomized international study of high-risk central nervous system B non-Hodgkin lymphoma and B acute lymphoblastic leukemia in children and adolescents. Blood, 109, 27362743.
  • Cairo, M., Sposto, R., Gerrard, M., Waxman, I., Goldman, S., Harrison, L., Auperin, A., Pinkerton, R., Perkins, S., Raphael, M., McCarthy, K. & Patte, C. (2008) Tumor histology, advanced stage, and primary site, explain the increased risk of failure in adolescents (Age greater than or equal to 15 years) with newly diagnosed B-NHL: Results of the FAB/LMB 96. Pediatric Blood & Cancer, O.120, 52 (abstract) http://www3.interscience.wiley.com/homepages/106561790/SIOP-2008-Online-Abstracts.pdf
  • Carella, A.M., Cavaliere, M., Lerma, E., Ferrara, R., Tedeschi, L., Romanelli, A., Vinci, M., Pinotti, G., Lambelet, P., Loni, C., Verdiani, S., De Stefano, F., Valbonesi, M. & Corsetti, M.T. (2000) Autografting followed by nonmyeloablative immunosuppressive chemotherapy and allogeneic peripheral-blood hematopoietic stem-cell transplantation as treatment of resistant Hodgkin’s disease and non-Hodgkin’s lymphoma. Journal of Clinical Oncology, 18, 39183924.
  • Coiffier, B., Lepage, E., Briere, J., Herbrecht, R., Tilly, H., Bouabdallah, R., Morel, P., Van Den Neste, E., Salles, G., Gaulard, P., Reyes, F., Lederlin, P. & Gisselbrecht, C. (2002) CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. New England Journal of Medicine, 346, 235242.
  • Dave, S.S., Fu, K., Wright, G.W., Lam, L.T., Kluin, P., Boerma, E.J., Greiner, T.C., Weisenburger, D.D., Rosenwald, A., Ott, G., Muller-Hermelink, H.K., Gascoyne, R.D., Delabie, J., Rimsza, L.M., Braziel, R.M., Grogan, T.M., Campo, E., Jaffe, E.S., Dave, B.J., Sanger, W., Bast, M., Vose, J.M., Armitage, J.O., Connors, J.M., Smeland, E.B., Kvaloy, S., Holte, H., Fisher, R.I., Miller, T.P., Montserrat, E., Wilson, W.H., Bahl, M., Zhao, H., Yang, L., Powell, J., Simon, R., Chan, W.C. & Staudt, L.M. (2006) Molecular diagnosis of Burkitt’s lymphoma. New England Journal of Medicine, 354, 24312442.
  • De Bruin, M.L., Huisbrink, J., Hauptmann, M., Kuenen, M.A., Ouwens, G.M., Van’t Veer, M.B., Aleman, B.M. & Van Leeuwen, F.E. (2008) Treatment-related risk factors for premature menopause following Hodgkin lymphoma. Blood, 111, 101108.
  • Diehl, V. (2007) Hodgkin’s disease – from pathology specimen to cure. New England Journal of Medicine, 357, 19681971.
  • Diehl, V., Franklin, J., Pfreundschuh, M., Lathan, B., Paulus, U., Hasenclever, D., Tesch, H., Herrmann, R., Dorken, B., Muller-Hermelink, H.K., Duhmke, E. & Loeffler, M. (2003) Standard and increased-dose BEACOPP chemotherapy compared with COPP-ABVD for advanced Hodgkin’s disease. New England Journal of Medicine, 348, 23862395.
  • Divine, M., Casassus, P., Koscielny, S., Bosq, J., Sebban, C., Le Maignan, C., Stamattoulas, A., Dupriez, B., Raphael, M., Pico, J.L. & Ribrag, V. (2005) Burkitt lymphoma in adults: a prospective study of 72 patients treated with an adapted pediatric LMB protocol. Annals of Oncology, 16, 19281935.
  • Drexler, H.G., Gignac, S.M., Von Wasielewski, R., Werner, M. & Dirks, W.G. (2000) Pathobiology of NPM-ALK and variant fusion genes in anaplastic large cell lymphoma and other lymphomas. Leukemia, 14, 15331559.
  • Dunleavy, K., Pittaluga, S., Janik, J., Grant, N., Shovlin, M., Steinberg, S., Raffeld, M., Jaffe, E.S., Staudt, L.M. & WH, W. (2008) The addition of rituximab to dose-adjusted (DA)-EPOCH obviates the need for radiation in the treatment of primary mediastinal large B-cell lymphoma (PMBL): a prospective study of 58 patients. Annals of Oncology, 19(Suppl. 4), IV96 (abstract).
  • Falini, B. (2001) Anaplastic large cell lymphoma: pathological, molecular and clinical features. British Journal Haematology, 114, 741760.
  • Falini, B., Pileri, S., Zinzani, P.L., Carbone, A., Zagonel, V., Wolf-Peeters, C., Verhoef, G., Menestrina, F., Todeschini, G., Paulli, M., Lazzarino, M., Giardini, R., Aiello, A., Foss, H.D., Araujo, I., Fizzotti, M., Pelicci, P.G., Flenghi, L., Martelli, M.F. & Santucci, A. (1999) ALK+ lymphoma: clinico-pathological findings and outcome. Blood, 93, 26972706.
  • Fanin, R., Silvestri, F., Geromin, A., Cerno, M., Infanti, L., Zaja, F., Barillari, G., Savignano, C., Rinaldi, C., Damiani, D., Buffoli, A., Biffoni, F. & Baccarini, M. (1996) Primary systemic CD30 (Ki-1)-positive anaplastic large cell lymphoma of the adult: sequential intensive treatment with the F-MACHOP regimen (+/− radiotherapy) and autologous bone marrow transplantation. Blood, 87, 12431248.
  • Feuerhake, F., Kutok, J.L., Monti, S., Chen, W., LaCasce, A.S., Cattoretti, G., Kurtin, P., Pinkus, G.S., De Leval, L., Harris, N.L., Savage, K.J., Neuberg, D., Habermann, T.M., Dalla-Favera, R., Golub, T.R., Aster, J.C. & Shipp, M.A. (2005) NFkappaB activity, function, and target-gene signatures in primary mediastinal large B-cell lymphoma and diffuse large B-cell lymphoma subtypes. Blood, 106, 13921399.
  • Fisher, R.I., Gaynor, E.R., Dahlberg, S., Oken, M.M., Grogan, T.M., Mize, E.M., Glick, J.H., Coltman, Jr, C.A. & Miller, T.P. (1993) Comparison of a standard regimen (CHOP) with three intensive chemotherapy regimens for advanced non-Hodgkin’s lymphoma. New England Journal of Medicine, 328, 10021006.
  • Gascoyne, R.D., Aoun, P., Wu, D., Chhanabhai, M., Skinnider, B.F., Greiner, T.C., Morris, S.W., Connors, J.M., Vose, J.M., Viswanatha, D.S., Coldman, A. & Weisenburger, D.D. (1999) Prognostic significance of anaplastic lymphoma kinase (ALK) protein expression in adults with anaplastic large cell lymphoma. Blood, 93, 39133921.
  • Gerrard, M., Cairo, M.S., Weston, C., Auperin, A., Pinkerton, R., Lambilliote, A., Sposto, R., McCarthy, K., Lacombe, M.J., Perkins, S.L. & Patte, C. (2008) Excellent survival following two courses of COPAD chemotherapy in children and adolescents with resected localized B-cell non-Hodgkin’s lymphoma: results of the FAB/LMB 96 international study. British Journal Haematology, 141, 840847.
  • Ginsberg, J.P., Ogle, S.K., Tuchman, L.K., Carlson, C.A., Reilly, M.M., Hobbie, W.L., Rourke, M., Zhao, H. & Meadows, A.T. (2008) Sperm banking for adolescent and young adult cancer patients: sperm quality, patient, and parent perspectives. Pediatric Blood & Cancer, 50, 594598.
  • Goldman, S., Lynch, J., Davenport, V., Perkins, S., Shiramizu, B., Sanger, W., Gross, T., Harrison, L., Bancroft, M. & Cairo, M.S. (2008) Preliminary results of a phase II study of chemoimmunotherapy (rituximab + FAB chemotherapy) in children and adolescents with intermediate risk B-cell NHL: a children’s oncology group report. Annals of Oncology, 19(Suppl. 4), IV109 (abstract).
  • Habermann, T.M., Weller, E.A., Morrison, V.A., Gascoyne, R.D., Cassileth, P.A., Cohn, J.B., Dakhil, S.R., Woda, B., Fisher, R.I., Peterson, B.A. & Horning, S.J. (2006) Rituximab-CHOP versus CHOP alone or with maintenance rituximab in older patients with diffuse large B-cell lymphoma. Journal of Clinical Oncology, 24, 31213127.
  • Hancock, S.L., Tucker, M.A. & Hoppe, R.T. (1993) Breast cancer after treatment of Hodgkin’s disease. Journal of the National Cancer Institute, 85, 2531.
  • Hans, C.P., Weisenburger, D.D., Greiner, T.C., Gascoyne, R.D., Delabie, J., Ott, G., Muller-Hermelink, H.K., Campo, E., Braziel, R.M., Jaffe, E.S., Pan, Z., Farinha, P., Smith, L.M., Falini, B., Banham, A.H., Rosenwald, A., Staudt, L.M., Connors, J.M., Armitage, J.O. & Chan, W.C. (2004) Confirmation of the molecular classification of diffuse large B-cell lymphoma by immunohistochemistry using a tissue microarray. Blood, 103, 275282.
  • Harris, N.L., Jaffe, E.S., Diebold, J., Flandrin, G., Muller-Hermelink, H.K. & Vardiman, J. (1999) The World Health Organization classification of neoplastic diseases of the hematopoietic and lymphoid tissues. Report of the Clinical Advisory Committee meeting, Airlie House, Virginia, November, 1997. Annals of Oncology, 10, 14191432.
  • Herbertson, R. & Hancock, B.W. (2005) Hodgkin lymphoma in adolescents. Cancer Treatment Reviews, 31, 339360.
  • Hummel, M., Bentink, S., Berger, H., Klapper, W., Wessendorf, S., Barth, T.F., Bernd, H.W., Cogliatti, S.B., Dierlamm, J., Feller, A.C., Hansmann, M.L., Haralambieva, E., Harder, L., Hasenclever, D., Kuhn, M., Lenze, D., Lichter, P., Martin-Subero, J.I., Moller, P., Muller-Hermelink, H.K., Ott, G., Parwaresch, R.M., Pott, C., Rosenwald, A., Rosolowski, M., Schwaenen, C., Sturzenhofecker, B., Szczepanowski, M., Trautmann, H., Wacker, H.H., Spang, R., Loeffler, M., Trumper, L., Stein, H. & Siebert, R. (2006) A biologic definition of Burkitt’s lymphoma from transcriptional and genomic profiling. New England Journal of Medicine, 354, 24192430.
  • Hutchings, M., Loft, A., Hansen, M., Pedersen, L.M., Buhl, T., Jurlander, J., Buus, S., Keiding, S., D’Amore, F., Boesen, A.M., Berthelsen, A.K. & Specht, L. (2006) FDG-PET after two cycles of chemotherapy predicts treatment failure and progression-free survival in Hodgkin lymphoma. Blood, 107, 5259.
  • Johnston, L.J. & Horning, S.J. (2000) Autologous hematopoietic cell transplantation in Hodgkin’s disease. Biology of Blood and Marrow Transplantation, 6, 289300.
  • Joos, S., Otano-Joos, M.I., Ziegler, S., Bruderlein, S., Du Manoir, S., Bentz, M., Moller, P. & Lichter, P. (1996) Primary mediastinal (thymic) B-cell lymphoma is characterized by gains of chromosomal material including 9p and amplification of the REL gene. Blood, 87, 15711578.
  • Josting, A., Wiedenmann, S., Franklin, J., May, M., Sieber, M., Wolf, J., Engert, A. & Diehl, V. (2003) Secondary myeloid leukemia and myelodysplastic syndromes in patients treated for Hodgkin’s disease: a report from the German Hodgkin’s Lymphoma Study Group. Journal of Clinical Oncology, 21, 34403446.
  • Kadin, M.E. & Carpenter, C. (2003) Systemic and primary cutaneous anaplastic large cell lymphomas. Seminars in Hematology, 40, 244256.
  • Kapatai, G. & Murray, P. (2007) Contribution of the Epstein–Barr virus to the molecular pathogenesis of Hodgkin lymphoma. Journal of Clinical Pathology, 60, 13421349.
  • Kelly, K.M., Hutchinson, R.J., Sposto, R., Weiner, M.A., Lones, M.A., Perkins, S.L. & Massey, V. (2002) Feasibility of upfront dose-intensive chemotherapy in children with advanced-stage Hodgkin’s lymphoma: preliminary results from the Children’s Cancer Group Study CCG-59704. Annals of Oncology, 13(Suppl. 1), 107111.
  • Ladenstein, R., Pearce, R., Hartmann, O., Patte, C., Goldstone, T. & Philip, T. (1997) High-dose chemotherapy with autologous bone marrow rescue in children with poor-risk Burkitt’s lymphoma: a report from the European Lymphoma Bone Marrow Transplantation Registry. Blood, 90, 29212930.
  • Laver, J.H., Kraveka, J.M., Hutchison, R.E., Chang, M., Kepner, J., Schwenn, M., Tarbell, N., Desai, S., Weitzman, S., Weinstein, H.J. & Murphy, S.B. (2005) Advanced-stage large-cell lymphoma in children and adolescents: results of a randomized trial incorporating intermediate-dose methotrexate and high-dose cytarabine in the maintenance phase of the APO regimen: a Pediatric Oncology Group phase III trial. Journal of Clinical Oncology, 23, 541547.
  • Le Deley, M.C., Reiter, A., Williams, D., Delsol, G., Oschlies, I., McCarthy, K., Zimmermann, M. & Brugieres, L. (2008) Prognostic factors in childhood anaplastic large cell lymphoma: results of a large European intergroup study. Blood, 111, 15601566.
  • Van Leeuwen, F.E., Chorus, A.M., Van Den Belt-Dusebout, A.W., Hagenbeek, A., Noyon, R., Van Kerkhoff, E.H., Pinedo, H.M. & Somers, R. (1994a) Leukemia risk following Hodgkin’s disease: relation to cumulative dose of alkylating agents, treatment with teniposide combinations, number of episodes of chemotherapy, and bone marrow damage. Journal of Clinical Oncology, 12, 10631073.
  • Van Leeuwen, F.E., Klokman, W.J., Hagenbeek, A., Noyon, R., Van Den Belt-Dusebout, A.W., Van Kerkhoff, E.H., Van Heerde, P. & Somers, R. (1994b) Second cancer risk following Hodgkin’s disease: a 20-year follow-up study. Journal of Clinical Oncology, 12, 312325.
  • Lones, M.A., Perkins, S.L., Sposto, R., Kadin, M.E., Kjeldsberg, C.R., Wilson, J.F. & Cairo, M.S. (2000) Large-cell lymphoma arising in the mediastinum in children and adolescents is associated with an excellent outcome: a Children’s Cancer Group report. Journal of Clinical Oncology, 18, 38453853.
  • Lones, M.A., Heerema, N.A., Le Beau, M.M., Sposto, R., Perkins, S.L., Kadin, M.E., Kjeldsberg, C.R., Meadows, A., Siegel, S., Buckley, J., Abromowitch, M., Kersey, J., Bergeron, S., Cairo, M.S. & Sanger, W.G. (2007) Chromosome abnormalities in advanced stage lymphoblastic lymphoma of children and adolescents: a report from CCG-E08. Cancer Genetics and Cytogenetics, 172, 111.
  • Longo, D.L., Duffey, P.L., Young, R.C., Hubbard, S.M., Ihde, D.C., Glatstein, E., Phares, J.C., Jaffe, E.S., Urba, W.J. & DeVita, V.T., Jr (1992) Conventional-dose salvage combination chemotherapy in patients relapsing with Hodgkin’s disease after combination chemotherapy: the low probability for cure. Journal of Clinical Oncology, 10, 210218.
  • Longo, D.L., Duffey, P.L., Jaffe, E.S., Raffeld, M., Hubbard, S.M., Fisher, R.I., Wittes, R.E., DeVita, Jr, V.T. & Young, R.C. (1994) Diffuse small noncleaved-cell, non-Burkitt’s lymphoma in adults: a high-grade lymphoma responsive to ProMACE-based combination chemotherapy. Journal of Clinical Oncology, 12, 21532159.
  • Magrath, I., Adde, M., Shad, A., Venzon, D., Seibel, N., Gootenberg, J., Neely, J., Arndt, C., Nieder, M., Jaffe, E., Wittes, R.A. & Horak, I.D. (1996) Adults and children with small non-cleaved-cell lymphoma have a similar excellent outcome when treated with the same chemotherapy regimen. Journal of Clinical Oncology, 14, 925934.
  • Miles, R.R., Raphael, M., McCarthy, K., Wotherspoon, A., Lones, M.A., Terrier-Lacombe, M.J., Patte, C., Gerrard, M., Auperin, A., Sposto, R., Davenport, V., Cairo, M.S. & Perkins, S.L. (2008 (in press)) Pediatric diffuse large B-cell lymphoma demonstrates a high proliferation index, frequent c-Myc protein expression, and a high incidence of germinal center subtype: Report of the French-American-British (FAB) International Study Group. Pediatric Blood & Cancer, 51, 369–374.
  • Mora, J., Filippa, D.A., Thaler, H.T., Polyak, T., Cranor, M.L. & Wollner, N. (2000) Large cell non-Hodgkin lymphoma of childhood: analysis of 78 consecutive patients enrolled in 2 consecutive protocols at the Memorial Sloan-Kettering Cancer Center. Cancer, 88, 186197.
  • Morris, S.W., Kirstein, M.N., Valentine, M.B., Dittmer, K.G., Shapiro, D.N., Saltman, D.L. & Look, A.T. (1994) Fusion of a kinase gene, ALK, to a nucleolar protein gene, NPM, in non-Hodgkin’s lymphoma. Science, 263, 12811284.
  • Nachman, J.B., Sposto, R., Herzog, P., Gilchrist, G.S., Wolden, S.L., Thomson, J., Kadin, M.E., Pattengale, P., Davis, P.C., Hutchinson, R.J. & White, K. (2002) Randomized comparison of low-dose involved-field radiotherapy and no radiotherapy for children with Hodgkin’s disease who achieve a complete response to chemotherapy. Journal of Clinical Oncology, 20, 37653771.
  • Oeffinger, K.C., Mertens, A.C., Sklar, C.A., Kawashima, T., Hudson, M.M., Meadows, A.T., Friedman, D.L., Marina, N., Hobbie, W., Kadan-Lottick, N.S., Schwartz, C.L., Leisenring, W. & Robison, L.L. (2006) Chronic health conditions in adult survivors of childhood cancer. New England Journal of Medicine, 355, 15721582.
  • Oki, Y., Pro, B., Fayad, L.E., Romaguera, J., Samaniego, F., Hagemeister, F., Neelapu, S., McLaughlin, P., Goy, A. & Younes, A. (2008) Phase 2 study of gemcitabine in combination with rituximab in patients with recurrent or refractory Hodgkin lymphoma. Cancer, 112, 831836.
  • Oschlies, I., Klapper, W., Zimmermann, M., Krams, M., Wacker, H.H., Burkhardt, B., Harder, L., Siebert, R., Reiter, A. & Parwaresch, R. (2006) 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–Munster) Multicenter Trial. Blood, 107, 40474052.
  • Patte, C., Auperin, A., Michon, J., Behrendt, H., Leverger, G., Frappaz, D., Lutz, P., Coze, C., Perel, Y., Raphael, M. & Terrier-Lacombe, M.J. (2001) The Societe Francaise d’Oncologie Pediatrique 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, 97, 33703379.
  • Patte, C., Auperin, A., Sebban, C., Bergeron, C., Gisselbrecht, C., Ribrag, V., Reyes, F. & Brugieres, L. (2006) The 15–20 year old patients with NHL treated in France: data of childhood and adult databases. Pediatric Blood & Cancer, 46, 848 (abstract).
  • Patte, C., Auperin, A., Gerrard, M., Michon, J., Pinkerton, R., Sposto, R., Weston, C., Raphael, M., Perkins, S.L., McCarthy, K. & Cairo, M.S. (2007) Results of the randomized international FAB/LMB96 trial for intermediate risk B-cell non-Hodgkin lymphoma in children and adolescents: it is possible to reduce treatment for the early responding patients. Blood, 109, 27732780.
  • Patte, C., Bleyer, A. & Cairo, M.S. (ed.) (2008) Non-Hodgkin Lymphoma. Springer Verlag, Paris.
  • Pfreundschuh, M., Trumper, L., Osterborg, A., Pettengell, R., Trneny, M., Imrie, K., Ma, D., Gill, D., Walewski, J., Zinzani, P.L., Stahel, R., Kvaloy, S., Shpilberg, O., Jaeger, U., Hansen, M., Lehtinen, T., Lopez-Guillermo, A., Corrado, C., Scheliga, A., Milpied, N., Mendila, M., Rashford, M., Kuhnt, E. & Loeffler, M. (2006) CHOP-like chemotherapy plus rituximab versus CHOP-like chemotherapy alone in young patients with good-prognosis diffuse large-B-cell lymphoma: a randomised controlled trial by the MabThera International Trial (MInT) Group. Lancet Oncology, 7, 379391.
  • Poirel, H., Cairo, M., Heerema, N., Swansbury, J., A, A., Launay, E., Sanger, W., Talley, P., Perkins, S., Raphaël, M., K, M., R, S., M, G., Bernheim, A. & C, P. (2008) Specific cytogenetic abnormalities are associated with a significantly inferior outcome in children and adolescents with mature B-cell Non-Hodgkin’s Lymphoma: Results of the FAB/LMB 96 international study. Leukemia, (in press).
  • Reiter, A., Schrappe, M., Tiemann, M., Parwaresch, R., Zimmermann, M., Yakisan, E., Dopfer, R., Bucsky, P., Mann, G. & Gadner, H. (1994) Successful treatment strategy for Ki-1 anaplastic large-cell lymphoma of childhood: a prospective analysis of 62 patients enrolled in three consecutive Berlin-Frankfurt-Munster group studies. Journal of Clinical Oncology, 12, 899908.
  • Reiter, A., Schrappe, M., Parwaresch, R., Henze, G., Muller-Weihrich, S., Sauter, S., Sykora, K.W., Ludwig, W.D., Gadner, H. & Riehm, H. (1995) Non-Hodgkin’s lymphomas of childhood and adolescence: results of a treatment stratified for biologic subtypes and stage – a report of the Berlin-Frankfurt-Munster Group. Journal of Clinical Oncology, 13, 359372.
  • Reiter, A., Schrappe, M., Tiemann, M., Ludwig, W.D., Yakisan, E., Zimmermann, M., Mann, G., Chott, A., Ebell, W., Klingebiel, T., Graf, N., Kremens, B., Muller-Weihrich, S., Pluss, H.J., Zintl, F., Henze, G. & Riehm, H. (1999) Improved treatment results in childhood B-cell neoplasms with tailored intensification of therapy: a report of the Berlin–Frankfurt–Munster Group Trial NHL-BFM 90. Blood, 94, 32943306.
  • Reiter, A., Schrappe, M., Ludwig, W.D., Tiemann, M., Parwaresch, R., Zimmermann, M., Schirg, E., Henze, G., Schellong, G., Gadner, H. & Riehm, H. (2000) 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, 95, 416421.
  • Rimokh, R., Magaud, J.P., Berger, F., Samarut, J., Coiffier, B., Germain, D. & Mason, D.Y. (1989) A translocation involving a specific breakpoint (q35) on chromosome 5 is characteristic of anaplastic large cell lymphoma (‘Ki-1 lymphoma’). British Journal Haematology, 71, 3136.
  • Rosenwald, A., Wright, G., Chan, W.C., Connors, J.M., Campo, E., Fisher, R.I., Gascoyne, R.D., Muller-Hermelink, H.K., Smeland, E.B., Giltnane, J.M., Hurt, E.M., Zhao, H., Averett, L., Yang, L., Wilson, W.H., Jaffe, E.S., Simon, R., Klausner, R.D., Powell, J., Duffey, P.L., Longo, D.L., Greiner, T.C., Weisenburger, D.D., Sanger, W.G., Dave, B.J., Lynch, J.C., Vose, J., Armitage, J.O., Montserrat, E., Lopez-Guillermo, A., Grogan, T.M., Miller, T.P., LeBlanc, M., Ott, G., Kvaloy, S., Delabie, J., Holte, H., Krajci, P., Stokke, T. & Staudt, L.M. (2002) The use of molecular profiling to predict survival after chemotherapy for diffuse large-B-cell lymphoma. New England Journal of Medicine, 346, 19371947.
  • Rosenwald, A., Wright, G., Leroy, K., Yu, X., Gaulard, P., Gascoyne, R.D., Chan, W.C., Zhao, T., Haioun, C., Greiner, T.C., Weisenburger, D.D., Lynch, J.C., Vose, J., Armitage, J.O., Smeland, E.B., Kvaloy, S., Holte, H., Delabie, J., Campo, E., Montserrat, E., Lopez-Guillermo, A., Ott, G., Muller-Hermelink, H.K., Connors, J.M., Braziel, R., Grogan, T.M., Fisher, R.I., Miller, T.P., LeBlanc, M., Chiorazzi, M., Zhao, H., Yang, L., Powell, J., Wilson, W.H., Jaffe, E.S., Simon, R., Klausner, R.D. & Staudt, L.M. (2003) Molecular diagnosis of primary mediastinal B cell lymphoma identifies a clinically favorable subgroup of diffuse large B cell lymphoma related to Hodgkin lymphoma. Journal of Experimental Medicine, 198, 851862.
  • Sandlund, J.T., Pui, C.H., Roberts, W.M., Santana, V.M., Morris, S.W., Berard, C.W., Hutchison, R.E., Ribeiro, R.C., Mahmoud, H. & Crist, W.M. (1994a) Clinicopathologic features and treatment outcome of children with large-cell lymphoma and the t(2;5)(p23;q35). Blood, 84, 24672471.
  • Sandlund, J.T., Pui, C.H., Santana, V.M., Mahmoud, H., Roberts, W.M., Morris, S., Raimondi, S., Ribeiro, R., Crist, W.M. & Lin, J.S. (1994b) Clinical features and treatment outcome for children with CD30+ large-cell non-Hodgkin’s lymphoma. Journal of Clinical Oncology, 12, 895898.
  • Satwani, P., Bradley, B., Harrison, L., Tallamy, B., Garvin, J., George, D., Bhatia, M., Martin, P., Kurtzberg, J. & Cairo, M. (2008) A pilot study of myeloablative (MA) autologous stem cell (auto SCT) followed by reduced intensity allogeneic transplantation (RI allo SCT) in children with poor risk Hodgkin’s disease (HD) and non-Hodgkin’s lymphoma (NHL). Annals of Oncology, 19(Suppl. 4), iv140 (abstract 181).
  • Savage, K.J., Monti, S., Kutok, J.L., Cattoretti, G., Neuberg, D., De Leval, L., Kurtin, P., Dal Cin, P., Ladd, C., Feuerhake, F., Aguiar, R.C., Li, S., Salles, G., Berger, F., Jing, W., Pinkus, G.S., Habermann, T., Dalla-Favera, R., Harris, N.L., Aster, J.C., Golub, T.R. & Shipp, M.A. (2003) The molecular signature of mediastinal large B-cell lymphoma differs from that of other diffuse large B-cell lymphomas and shares features with classical Hodgkin lymphoma. Blood, 102, 38713879.
  • Savage, K.J., Al-Rajhi, N., Voss, N., Paltiel, C., Klasa, R., Gascoyne, R.D. & Connors, J.M. (2006) Favorable outcome of primary mediastinal large B-cell lymphoma in a single institution: the British Columbia experience. Annals of Oncology, 17, 123130.
  • Schellong, G., Potter, R., Bramswig, J., Wagner, W., Prott, F.J., Dorffel, W., Korholz, D., Mann, G., Rath, B., Reiter, A., Weissbach, G., Riepenhausen, M., Thiemann, M. & Schwarze, E.W. (1999) High cure rates and reduced long-term toxicity in pediatric Hodgkin’s disease: the German-Austrian multicenter trial DAL-HD-90. The German-Austrian Pediatric Hodgkin’s Disease Study Group. Journal of Clinical Oncology, 17, 37363744.
  • Schonfeld, S.J., Gilbert, E.S., Dores, G.M., Lynch, C.F., Hodgson, D.C., Hall, P., Storm, H., Andersen, A., Pukkala, E., Holowaty, E., Kaijser, M., Andersson, M., Joensuu, H., Fossa, S.D., Allan, J.M. & Travis, L.B. (2006) Acute myeloid leukemia following Hodgkin lymphoma: a population-based study of 35,511 patients. Journal of the National Cancer Institute, 98, 215218.
  • Seidemann, K., Tiemann, M., Schrappe, M., Yakisan, E., Simonitsch, I., Janka-Schaub, G., Dorffel, W., Zimmermann, M., Mann, G., Gadner, H., Parwaresch, R., Riehm, H. & Reiter, A. (2001) Short-pulse B-non-Hodgkin lymphoma-type chemotherapy is efficacious treatment for pediatric anaplastic large cell lymphoma: a report of the Berlin-Frankfurt-Munster Group Trial NHL-BFM 90. Blood, 97, 36993706.
  • Seidemann, K., Tiemann, M., Lauterbach, I., Mann, G., Simonitsch, I., Stankewitz, K., Schrappe, M., Zimmermann, M., Niemeyer, C., Parwaresch, R., Riehm, H. & Reiter, A. (2003) Primary mediastinal large B-cell lymphoma with sclerosis in pediatric and adolescent patients: treatment and results from three therapeutic studies of the Berlin-Frankfurt-Munster Group. Journal of Clinical Oncology, 21, 17821789.
  • Skinnider, B.F., Connors, J.M., Sutcliffe, S.B. & Gascoyne, R.D. (1999) Anaplastic large cell lymphoma: a clinicopathologic analysis. Hematological Oncology, 17, 137148.
  • Sklar, C., Whitton, J., Mertens, A., Stovall, M., Green, D., Marina, N., Greffe, B., Wolden, S. & Robison, L. (2000) Abnormalities of the thyroid in survivors of Hodgkin’s disease: data from the Childhood Cancer Survivor Study. Journal of Clinical Endocrinology and Metabolism, 85, 32273232.
  • Sposto, R., Kelly, K.M., Villaluna, D., Gilman, E., Pfistner, B. & Diehl, V. (2005) A comparison of toxicity and outcome following BEACOPP therapy in adolescents and young adults with Hodgkin’s disease (HD) by pediatric and adult oncology cooperative groups. Journal of Clinical Oncology, 23, 6599 (abstract).
  • Stein, H., Mason, D.Y., Gerdes, J., O’Connor, N., Wainscoat, J., Pallesen, G., Gatter, K., Falini, B., Delsol, G., Lemke, H., Schwating, R. & Lennert, K. (1985) The expression of the Hodgkin’s disease associated antigen Ki-1 in reactive and neoplastic lymphoid tissue: evidence that Reed-Sternberg cells and histiocytic malignancies are derived from activated lymphoid cells. Blood, 66, 848858.
  • Stein, H., Foss, H.D., Durkop, H., Marafioti, T., Delsol, G., Pulford, K., Pileri, S. & Falini, B. (2000) CD30(+) anaplastic large cell lymphoma: a review of its histopathologic, genetic, and clinical features. Blood, 96, 36813695.
  • Stock, W., La, M., Sanford, B., Bloomfield, C.D., Vardiman, J.W., Gaynon, P., Larson, R.A. & Nachman, J. (2008) What determines the outcomes for adolescents and young adults with acute lymphoblastic leukemia treated on cooperative group protocols? A comparison of children’s cancer group and cancer and leukemia group b studies. Blood, 112, 16461654.
  • Swerdlow, A.J., Higgins, C.D., Smith, P., Cunningham, D., Hancock, B.W., Horwich, A., Hoskin, P.J., Lister, A., Radford, J.A., Rohatiner, A.Z. & Linch, D.C. (2007) Myocardial infarction mortality risk after treatment for Hodgkin disease: a collaborative British cohort study. Journal of the National Cancer Institute, 99, 206214.
  • Terasawa, T., Nihashi, T., Hotta, T. & Nagai, H. (2008) 18F-FDG PET for posttherapy assessment of Hodgkin’s disease and aggressive Non-Hodgkin’s lymphoma: a systematic review. Journal of Nuclear Medicine, 49, 1321.
  • Thomas, D.A., O’Brien, S., Cortes, J., Giles, F.J., Faderl, S., Verstovsek, S., Ferrajoli, A., Koller, C., Beran, M., Pierce, S., Ha, C.S., Cabanillas, F., Keating, M.J. & Kantarjian, H. (2004) Outcome with the hyper-CVAD regimens in lymphoblastic lymphoma. Blood, 104, 16241630.
  • Weiner, M.A., Leventhal, B., Brecher, M.L., Marcus, R.B., Cantor, A., Gieser, P.W., Ternberg, J.L., Behm, F.G., Wharam, M.D., Jr & Chauvenet, A.R. (1997) Randomized study of intensive MOPP-ABVD with or without low-dose total-nodal radiation therapy in the treatment of stages IIB, IIIA2, IIIB, and IV Hodgkin’s disease in pediatric patients: a Pediatric Oncology Group study. Journal of Clinical Oncology, 15, 27692779.
  • Weiss, L.M., Warnke, R.A., Sklar, J. & Cleary, M.L. (1987) Molecular analysis of the t(14;18) chromosomal translocation in malignant lymphomas. New England Journal of Medicine, 317, 11851189.
  • Williams, C.D., Goldstone, A.H., Pearce, R., Green, S., Armitage, J.O., Carella, A. & Meloni, G. (1993) Autologous bone marrow transplantation for pediatric Hodgkin’s disease: a case-matched comparison with adult patients by the European Bone Marrow Transplant Group Lymphoma Registry. Journal of Clinical Oncology, 11, 22432249.
  • Wilson, W., Dunleavy, K., Pittaluga, S., Hegde, U., Grant, N., Steinberg, S., Raffeld, M., Gutierrez, M., Chabner, B., Staudt, L., Jaffe, E. & Janik, J. (2008) Phase II study of dose-adjusted EPOCH and rituximab in untreated diffuse large B-cell lymphoma with analysis of germinal center and post-germinal center biomarkers. Journal of Clinical Oncology, 26, 27172724.
  • Woessmann, W., Peters, C., Lenhard, M., Burkhardt, B., Sykora, K.W., Dilloo, D., Kremens, B., Lang, P., Fuhrer, M., Kuhne, T., Parwaresch, R., Ebell, W. & Reiter, A. (2006) Allogeneic haematopoietic stem cell transplantation in relapsed or refractory anaplastic large cell lymphoma of children and adolescents – a Berlin-Frankfurt-Munster group report. British Journal Haematology, 133, 176182.
  • Wolden, S.L., Lamborn, K.R., Cleary, S.F., Tate, D.J. & Donaldson, S.S. (1998) Second cancers following pediatric Hodgkin’s disease. Journal of Clinical Oncology, 16, 536544.
  • Younes, A., Romaguera, J., Hagemeister, F., McLaughlin, P., Rodriguez, M.A., Fiumara, P., Goy, A., Jeha, S., Manning, J.T., Jr, Jones, D., Abruzzo, L.V. & Medeiros, L.J. (2003) A pilot study of rituximab in patients with recurrent, classic Hodgkin disease. Cancer, 98, 310314.
  • Yung, L., Smith, P., Hancock, B.W., Hoskin, P., Gilson, D., Vernon, C. & Linch, D.C. (2004) Long term outcome in adolescents with Hodgkin’s lymphoma: poor results using regimens designed for adults. Leukaemia & Lymphoma, 45, 15791585.
  • Zinzani, P.L., Martelli, M., Bertini, M., Gianni, A.M., Devizzi, L., Federico, M., Pangalis, G., Michels, J., Zucca, E., Cantonetti, M., Cortelazzo, S., Wotherspoon, A., Ferreri, A.J., Zaja, F., Lauria, F., De Renzo, A., Liberati, M.A., Falini, B., Balzarotti, M., Calderoni, A., Zaccaria, A., Gentilini, P., Fattori, P.P., Pavone, E., Angelopoulou, M.K., Alinari, L., Brugiatelli, M., Di Renzo, N., Bonifazi, F., Pileri, S.A. & Cavalli, F. (2002) Induction chemotherapy strategies for primary mediastinal large B-cell lymphoma with sclerosis: a retrospective multinational study on 426 previously untreated patients. Haematologica, 87, 12581264.