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Keywords:

  • secondary malignancies;
  • childhood cancer;
  • non-Hodgkin lymphoma;
  • secondary neoplasm

Summary

  1. Top of page
  2. Summary
  3. Patients and methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References

The emergence of non-Hodgkin lymphoma (NHL) during childhood and adolescence as a secondary neoplasm (SN) after previous cancer other than NHL is rare. To describe the characteristics and outcome of NHL following previous cancer other than NHL in children and adolescents, this study analysed the data of patients reported to the NHL-Berlin-Frankfurt-Münster study centre from 1986 to 2005. Out of the total of 2968 NHL-patients registered, 11 patients were assessed as having suffered from NHL as a proven SN. Four additional children had most likely suffered from NHL as an SN, but a late relapse of the first neoplasm could not be ruled out unequivocally. In the patients with proven SN, median age at diagnosis of the primary malignancy was 3·9 years (range 2–11·7). The median age at diagnosis of NHL was 7·6 years (range 4·7–18). Only lymphoblastic (= 7) and diffuse large B-cell (= 4) lymphomas were diagnosed as SN. The estimated 5-year event-free survival from time of diagnosis of NHL was 91% [95% confidence interval (CI) 74–100%] in patients with proven SNs and 84% (95% CI 63–100%) when the patients with probable SNs were included in the analysis. We concluded that secondary NHL in children and adolescents confers a favourable prognosis.

Survival rates after childhood cancer have improved substantially over recent decades, with reported 5-year survival rates of up to 80% in western countries (Gatta et al, 2002, 2003; Steliarova-Foucher et al, 2004; http://www.kinderkrebsregister.de/english/texts06_07pdf/13_28.pdf). Secondary neoplasms (SNs) are a recognized late effect of therapy among survivors of childhood and adolescent cancer. Although the lifetime incidence of SNs has not yet been defined, cumulative incidences of up to 12% for having developed an SN 20 years after diagnosis of the first cancer have been reported (Robison & Mertens, 1993; Loning et al, 2000; Neglia et al, 2001; Jenkinson et al, 2004; Cardous-Ubbink et al, 2007; MacArthur et al, 2007). Based on data collected from 1980 to 2001, the nationwide German Childhood Cancer Registry (GCCR) reported an estimated cumulative incidence of 1·8% in childhood cancer patients to develop an SN within 10 years after diagnosis of the primary malignancy. That means that within 10 years after diagnosis one out of 60 childhood cancer patients develops an SN (http://www.kinderkrebsregister.de/english/texts05pdf/23_28.pdf). The most frequent SNs reported to the GCCR were myelodysplastic syndrome, acute myeloid leukaemia (AML), and central nervous system tumours. These entities were reported to confer a dismal prognosis when diagnosed as an SN in children and adolescents (Barnard et al, 2002; Bhatia et al, 2002; Carret et al, 2006).

Non-Hodgkin lymphoma (NHL) developing during childhood and adolescence as an SN is rare and information on characteristics and outcome of NHL as an SN are scarce.

We therefore aimed to describe features and outcome of NHL as an SN after cancer other than NHL in children and adolescents by analysing data of patients registered into the Non-Hodgkin Lymphoma-Berlin-Frankfurt-Münster (NHL-BFM) database.

Patients and methods

  1. Top of page
  2. Summary
  3. Patients and methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References

The datasets of patients who suffered from NHL as an SN after previous neoplasm other than NHL, and reported to the NHL-BFM study centre between 1st October 1986 and 31st December 2005 were analysed. The NHL-BFM study centre’s database comprises data from children and adolescents from Germany, Austria, parts of Switzerland, and from the Czech Republic who suffer from all subtypes of NHL. Patients up to the age of 18 years are registered in the NHL BFM study centre registry. Children suffering from NHL as an SN were not eligible for inclusion in the ongoing trials but they were treated according to the respective referral protocol, i.e., the protocols of the consecutive trials NHL-BFM 86, 90, and 95 (Reiter et al, 1995, 1999, 2000; Seidemann et al, 2001; Woessmann et al, 2005; Burkhardt et al, 2006).

Non-Hodgkin lymphoma was classified according to the World Health Organization classification (Jaffe et al, 2001). A central reference pathology review was performed in the majority of cases. Staging was determined by physical examination, peripheral blood and bone marrow aspiration smears, lumbar puncture and examination of cerebrospinal fluid, ultrasonography, chest X-ray, cranial computed tomography and/or cranial magnetic resonance imaging, and determination of serum lactate dehydrogenase concentration. Staging was performed according to the St Jude staging system (Murphy, 1980).

Information on previous malignancy is mandatory when reporting a new patient to the NHL-BFM study centre. In case of missing information on previous malignancy the reporting institution is contacted before patient registration. In addition, the NHL-BFM study centre is promptly notified of all children and adolescents who are diagnosed with NHL by the time they are registered in the GCCR, a nationwide registry of childhood and adolescent cancer patients under the age of 15. In older children, registration in the GCCR is optional. The completeness of cancer registration within the GCCR is estimated to be 95% (General Information, located at: http://www.kinderkrebsregister.de/english/). If a patient is found to be registered by the GCCR but has not yet been reported to the NHL-BFM study centre, the institution where the child has been treated is asked to report the case to the NHL-BFM study centre and provide further information as necessary. This approach of co-operative documentation within the GCCR and the NHL-BFM study centre accounts significantly for completeness of data on patients with NHL as an SN in Germany.

For the purpose of this study, histopathological information on the first malignancy and on the SN was reviewed again to confirm the presence of a secondary malignancy in all patients reported to suffer from NHL as an SN. If required, complementary investigations for which methods had not yet been widely available at the time of diagnosis of NHL were carried out in the central reference pathology institute to ascertain secondary malignancy.

Non-Hodgkin lymphoma was considered to be a proven secondary malignancy when (i) the primary malignancy was a non-lymphoid neoplasm, (ii) acute lymphoblastic leukaemia (ALL) was the first neoplasm and NHL the second neoplasm and there was a lineage change, i.e., B lineage to T lineage and vice versa or (iii) the first malignancy was a lymphoid neoplasm and there was a change with respect to the differentiation compartment, i.e., from a precursor B (or T) neoplasm to peripheral B (or T) neoplasm or vice versa.

Patients who had an NHL as a first malignancy were not included in this analysis.

In all patients registered in the NHL-BFM study centre, follow-up status after therapy is ascertained semi-annually within the first 5 years after diagnosis and annually for the following 5 years. Thereafter follow-up status is assessed every 2 years. Standardized forms are completed by the treating institution to inform the NHL-BFM study centre on the date of the most recent contact and the status of each patient. Patients are followed at least until the age of 18 years in the paediatric institution where they were treated. In many cases follow-up through a paediatric institution even extends several years into adulthood. In case of medical care by an institution other than a paediatric hospital beyond the age of 18 years, the responsible physician was contacted for follow-up information.

The trial protocols were approved by the local ethics committees of the participating institutions and informed consent for transfer of confidential data had been obtained from the guardians.

Statistical analyses

Death for any reason, tumour failure, third malignancy, tumour progress, and relapse of the primary or of the SN were considered as events. Data on patients who were alive or lost to follow-up were censored on the date the patient was last seen. Event-free survival (EFS) was calculated from date of diagnosis of NHL to date of event respectively. Kaplan–Meier curves (Kaplan & Meier, 1958) were constructed to estimate the EFS. The time span between the diagnosis of the first and the second tumour was compared between children whose first tumour was a solid tumour and children who previously suffered from a non-solid malignancy, by the two-sided Mann–Whitney U-test. Statistical analyses were performed using the sas program (SAS, version 9.1.3; SAS Institute Inc, Cary, NC, USA). Data were updated as of June, 2007.

Results

  1. Top of page
  2. Summary
  3. Patients and methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References

Between 1st January 1986 and 31st December 2005, 2968 children and adolescents were registered in the NHL-BFM study centre’s database (median age: 9·6 years, range 0·2–18·5 years). Among them, 16 patients were reported as suffering from NHL as an SN after treatment for cancer other than NHL. Fourteen out of the total of 16 patients had a central pathology review when NHL was diagnosed.

After a detailed review of histopathological information and – where feasible – performing complementary investigations, 11 of the 16 children registered as having developed NHL after a previous neoplasm other than NHL were confirmed unequivocally to having suffered from a secondary malignancy (details in Table I).

Table I.   Characteristics, treatment and outcome in patients with proven secondary neoplasm.
Patient no.GenderPrevious neoplasm(s)Age at diagnosis of first neoplasm (years)Age at diagnosis of the secondary neoplasm (years)Latency (years)Therapy, previous neoplasm(s) with information on possible causative agents given and on radiotherapySecondary neoplasm (stage)Therapy, secondary neoplasmTherapy modificationOutcome (date of last contact in patients not lost to follow-up)
  1. B-LBL, B-lymphoblastic lymphoma; BMT, bone marrow transplantation; CR, complete remission; DLBCL, diffuse large B-cell lymphoma; f, female; LFU, lost to follow-up; m, male; MTX, methotrexate; T-LBL, T-lymphoblastic lymphoma.

  2. Therapy strategy/protocol outlined in 1COSS-82 (Winkler et al, 1988), 2COSS-86 (Winkler et al, 1990)3 HD-90 (Schellong, 1998); 4AML-BFM 98 (Creutzig et al, 2006), 5ALL-BFM 95 (Moricke et al, 2008), 6AML-BFM 93 (Creutzig et al, 2001), 7HIT 91(Timmermann et al, 2002), 8EURO-LB 02: NCT00275106 (clinicaltrials.gov).17NB-90 (Berthold et al, 2003); 18information on conditioning regimen, unfortunately not available. Characteristics of first and secondary malignancy indicating why the SN is considered a proven secondary malignancy: 9t (12;21), cytogenetics: MLL/AF4 and 10cortical T immunophenotype; 11CD19+, CD10+, TdT+ and 12TdT; 13CD19+, CD22+, TdT+ and 14TdT, BCL2+; 15CD19+, CD22+, TdT+, CD3, CD5, CD7 and 16CD1a+, CD3+, CD4+, CD8+, CD79.

 1mNeuroblastoma2·05·33·3Surgical removalT-LBL (IV)NHL-BFM 90noCR 12·5 years after diagnosis, then LFU
 2mOsteosarcoma femur, relapse with solitary pulmonary metastasis 1 7/12 years after initial diagnosis 7·416·59·2COSS 821, COSS 862(ifosfamide 3 g/m2)DLBCL (III)NHL-BFM 90reduction due to toxicity (0·5 g/m2 MTX instead of 5 g/m2 MTX)CR 5·0 years after diagnosis, then LFU
 3mHodgkin lymphoma11·717·06·2HD-903 (cyclophosfamide 2 g/m2, etoposide 1 g/m2, 25 Gy)DLBCL (III)NHL-BFM 95intensification(5 g/m2 MTX instead of 1 g MTX/m2, 2 additional courses including high-dose cytarabine and etoposide)CR 2·0 years after diagnosis, then LFU
 4mAML4·17·63·5AML-BFM 984 (cyclophosphamide 1 g/m2, etoposide 500 mg/m2, 12 Gy)B-LBL (I)NHL-BFM 95noCR 4·5 years after diagnosis (2/2007)
 5fPrecursor B-cell (common)-ALL92·55·22·7ALL-BFM 955 (cyclophosphamide 3 g/m2, ifosfamide 8 g/m2, etoposide 1 g/m2, 12 Gy)T-LBL10 (III)NHL-BFM 95intensification (additional HR-1 course, i.e., high-dose MTX and high-dose cytarabine5)CR 7·0 years after diagnosis of NHL (5/06)
 6mPrecursor B-cell (common)-ALL113·05·72·7ALL-BFM 955 (cyclophosphamide 3 g/m2)DLBCL12 (III)NHL-BFM 95noCR 7·2 years after diagnosis (7/05)
 7mPrecursor B-cell (common)-ALL132·44·7 (during maintenance therapy)2·4ALL-BFM 955 (cyclophosphamide 3 g/m2)DLBCL of the appendix14Surgical removal, ALL maintenance therapy, no further therapyreduction (only ALL maintenance therapy, no further chemotherapy)CR 5·0 years after diagnosis (9/06)
 8mAML 3/943·96·42·6AML-BFM 936 (etoposide 950  mg/m2, cyclophosphamide 1 g/m2, 30 Gy) BMT 9/9418T-LBL (IV)NHL-BFM 95noCR 6·9 years after diagnosis, then LFU
 9mNeuroblastoma3·99·35·4NB 9017 (etoposide 2 g/m2, ifosfamide 30 g/m2, DTIC 1 g/m2 etoposide 50 mg/kg, melphalan 120 mg/m2)T-LBL (III)NHL-BFM 95noCR 5·1 years after diagnosis (5/2007)
10mPNET (CNS, WHO IV)6·314·07·7HIT 917 (CCNU 600 mg/m2, 55·2 Gy)T-LBL (III)NHL-BFM 95noDied on day 33 of therapy (respiratory failure due to pulmonary aspergillosis)
11mPrecursor B-cell (common)-ALL 4/95152·611·08·4ALL-BFM 955 (cyclophosphamide 3 g/m2)T-LBL (III)16EURO-LB 028noCR 3·6 years after diagnosis (4/2007)

One patient was registered as having suffered from Hodgkin disease as the primary malignancy and from large cell anaplastic lymphoma as the secondary malignancy. Clonal identity of the first and the SN proved retrospectively the second event to be a late relapse of the first neoplasm. This case was thus excluded from all further analyses. The remaining four patients were assessed as having suffered from a SN in all probability (details in Table II). It remains possible, however, that the secondary malignancies actually represented late relapses of the initial tumour. In these four patients, unfortunately, material for complementary investigations was no longer available anymore. Unless indicated otherwise, the following analyses only refer to the 11 patients with proven diagnosis of NHL as a secondary tumour. When the four patients with probable diagnosis of an SN were included in the analyses, it was referred to as ‘all patients’.

Table II.   Characteristics, treatment and outcome in patients with probable secondary neoplasm.
Patient no.GenderPrevious neoplasm(s), histology, and siteAge at diagnosis of first previous neoplasm (years)Age at diagnosis secondary neoplasm (years)Latency (years)Therapy, Previous neoplasm(s)Secondary neoplasm (stage)Reason why diagnosis as a secondary lymphoma remains ambiguousTherapy, secondary neoplasmTherapy modificationOutcome (date of last contact in patients not lost to follow-up)
  1. B-LBL, B-lymphoblastic lymphoma; BMT, bone marrow transplantation; CR, complete remission; DLBCL, diffuse large B-cell lymphoma; f, female; LFU, lost to follow up; m, male; MTX, methotrexate; nfs, immunophenotype not further specified; T-LBL, T-lymphoblastic lymphoma.

  2. Therapy strategy/protocols outlined in 1ALL-BFM 83: (Riehm et al, 1987); 2ALL-Rez 87 (Einsiedel et al, 2005); 3ALL-Rez 90 (Dopfer et al, 1991); 4VIDE (Juergens et al, 2006); 5HD-90 (Schellong, 1998); 6ALL-VII/81 (Zintl et al, 1992).

12mPrecursor B-cell (common)-ALL (Philadelphia chromosome positive), 2* BMT3·69·66·0ALL-BFM 831, ALL-Rez 872 with BMT, ALL- Rez 903 with BMTDLBCL (III)Not examined for clonal diversity/not tested for Philadelphia chromosome/no central pathology reviewNHL-BFM 90Protocol deviation (six courses instead four courses, but no anthracycline and no etoposide)Relapse of c-ALL 4 5/12 years after diagnosis of NHL, died of complications of treatment of c-ALL relapse
13fALL, nfs2·813·610·9ALL-VII/816B-LBL (III)Not examined for clonal diversityNHL-BFM 90Intensification (two additional courses for B-NHL and two additional courses from the ALL-Rez protocol)CR 4·4 years after diagnosis of NHL, then LFU
14mEwing sarcoma14·215·51·34* VIDE4B-LBL (IV)It cannot be ruled out that the primary tumour was wrongly diagnosed as Ewing sarcomaNHL-BFM 95Reduction (high-dose MTX due to pancreatitis not given)CR 4·2 years after diagnosis (7/06)
15fHodgkin lymphoma13·314·91·6two cycles OPPA5 four cycles COPP5DLBCL (I)Not examined for clonal diversityNHL-BFM 95NoCR 7·0 years after diagnosis (1/06)

Median age at diagnosis of primary malignancy was 3·9 (range 2–11·7) years in children and adolescents with proven diagnosis of SN (3·9 years, range 2–14·2 in all children). Median age at diagnosis of NHL was 7·6 years (range 4·7–18) in the patients with proven SN and 9·6 years (range 4·7–18) in all children. One out of the 11 patients with proven SN was female and there were three female patients among all 15 children with SN.

The most common primary malignancy was acute leukaemia, accounting for 54·5% of primary neoplasms in patients with proven SN [common ALL (c-ALL) in four and AML in two patients] and for 53·3% of primary neoplasms in all patients. One patient had suffered from HL as a primary malignancy (two cases of HL among all patients). A solid tumour preceded NHL in four patients (five cases among all patients).

Only lymphoblastic lymphoma (LBL, n = 7) and diffuse large B-cell lymphoma (DLBCL) (n = 4) were diagnosed as SNs. Among the seven LBLs, six were T-LBLs. The clinical presentation in these six patients did not deviate from what would be expected in a primary precursor T-LBL. The four patients with DLBCL presented with disseminated abdominal localisation, with liver, spleen and bone involvement, with disseminated abdominal localisation and involvement of the spleen, and with localisation in the appendix only.

The median time for the development of NHL after diagnosis of the first tumour was 3·5 (range 2·4–9·2) years [3·5 (range 1·3–10·8) years in all patients]. The median time to diagnosis of NHL after diagnosis of a solid tumour was 6·6 (5·4 years in all patients) and 2·7 years after diagnosis of a non-solid tumour (3·1 years in all patients). However, this difference was not statistically significant (P = 0·16).

The treatment regimens used are listed in Tables I and II. Relevant deviation from the appropriate protocol was reported in four patients (seven patients among all patients).

One of the 11 patients diagnosed with proven SN had died of complications of NHL treatment. Of the four patients with probable SN, one patient had died of complications of treatment for a c-ALL relapse, which had occurred 5 years after successful treatment of NHL. The median duration of follow-up for the 13 survivors was 5·02 years (range 2·0–12·5) after diagnosis of NHL.

The estimated 5-year EFS from time of diagnosis of NHL was 91% [95% confidence interval (CI) 74–100%] in patients with proven SNs and 84% (95% CI 63–100%) in all patients (Figs 1 and 2).

image

Figure 1.  Event-free survival from date of diagnosis of non-Hodgkin lymphoma for patients with proven secondary neoplasm.

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Figure 2.  Event-free survival from date of diagnosis of non-Hodgkin lymphoma as a secondary neoplasm – all patients.

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Discussion

  1. Top of page
  2. Summary
  3. Patients and methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References

The diagnosis of NHL as an SN is rare. Only 11 out of the 2968 children and adolescents registered between 1986 and 2005 in the NHL-BFM study centre’s database suffered from NHL as a proven SN and four additional children most probably suffered from NHL as an SN following a first neoplasm other than NHL.

One limitation of our study is that, retrospectively, in four out of 15 patients registered with NHL as a secondary malignancy, clonal identity between the first and the second malignancy could not be ruled out. Outcome and pertinent features are therefore described for the 11 children with proven SN only and for all 15 patients, i.e., including those with probable diagnosis of secondary NHL. Comparisons between both groups, e.g., with respect to EFS, yielded some differences but the low number of patients has to be kept in mind.

Overall, these patients appeared to have a favourable prognosis, with an estimated 5-year EFS of 91% in patients with proven diagnosis and of 84% when patients with probable diagnosis of NHL as an SN were included in the analysis. Several considerations, however, must be taken into account. Firstly, in this analysis, only individuals that developed NHL as an SN below the age of 18 years are included, the majority of them being diagnosed with the first and the second malignancy within childhood. It cannot be excluded that the prognosis in older adolescents and in adults is less favourable. Secondly, in addition to the immediate risk of treatment-related morbidity and mortality through therapy of the SN, these children are at an increased risk of developing late effects such as pulmonary, cardiovascular and endocrine morbidity. Again, it might be speculated that this particularly holds true when the primary neoplasm is diagnosed in late adolescence, as late effects data show older adolescents to be at greater risk for the development of significant long-term effects than their younger counterparts. Furthermore, it has to be kept in mind that the EFS rate reported was based on a small number of patients.

The data presented contrast with the findings of Eguiguren et al (1991) who described pertinent features of 24 children and adolescents with NHL as an SN. The outcome was known in 18 patients. Only four of them were reported to be alive at 5, 6, 12 and 96 months after diagnosis respectively. The patients described in our study were diagnosed with the first malignancy between 1984 and 2001. The second malignancies were diagnosed between 1992 and 2002. The children and adolescents described by Eguiguren et al (1991) were diagnosed with the first malignancy between 1940 and 1981 and with the second neoplasm between 1973 and 1985. Differences in outcome are therefore likely to be explained by the different diagnostic and therapeutic options available within the respective time periods. To the best of our knowledge, no further publications have addressed the outcome and characteristics of NHL emerging as an SN in childhood and adolescence.

In the patients described in our study, T-LBL was the most commonly diagnosed NHL-subtype. This preponderance is not found when NHL is diagnosed as the first malignancy, where T-LBLs comprise 16% of all childhood NHLs (Burkhardt et al, 2005). One additional patient was diagnosed with B-LBL and four with DLBCL, which are both rare in primary childhood NHL [5% and 8% respectively (Burkhardt et al, 2005)]. This analysis also indicated that the time span between the first and second neoplasm seemed to be longer in patients suffering from a solid primary tumour. It remains speculative whether both of these findings indicate a biological cause or whether they are only an accidental finding in a small number of patients.

In summary, the data presented indicate a favourable prognosis if NHL is diagnosed as an SN, with EFS rates approximating those of NHL when diagnosed as a primary neoplasm. Treatment according to the reference arm of ongoing trial protocols appears reasonable, although in many cases therapy modifications, e.g., reduction in anthracycline dose after previous anthracycline therapy, may be necessary.

The number of patients described in this report is small. However, to the best of our knowledge, no further report provides updated information on children and adolescents with NHL as an SN. Our findings may therefore provide a basis for patient counselling and decision making in the rare event of NHL emerging as an SN during childhood and adolescence.

Characteristics of NHL as an SN emerging beyond adolescence in childhood cancer survivors, however, might differ and underscores the need for a systematic lifelong monitoring of childhood cancer survivors.

Acknowledgements

  1. Top of page
  2. Summary
  3. Patients and methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References

We thank the pathologists involved in establishing the diagnoses. We thank Ulrike Meyer and Bettina Paul (data management) for their expert work and especially thank the doctors, nurses and data managers at the participating hospitals who cared for these sick children and supplied data.

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  1. Top of page
  2. Summary
  3. Patients and methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References
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