Non-Hodgkin's lymphoma in childhood: clinical and epidemiological characteristics and survival analysis at a single center in Northeast Brazil

Abstracts

OBJETIVO: Descrever o perfil clínico-epidemiológico dos pacientes portadores de linfoma não-Hodgkin diagnosticados no Serviço de Oncologia Pediátrica do Instituto Materno-Infantil Professor Fernando Figueira em um período de 9 anos, bem como descrever sobrevida e possíveis associações prognósticas com as variáveis clínico-epidemiológicas estudadas. MÉTODOS: Estudo descritivo de corte transversal, realizado através da análise dos prontuários de 110 pacientes com linfoma não-Hodgkin admitidos na instituição no período de maio de 1994 a maio de 2003. As sobrevidas global e livre de doença foram analisadas através da técnica de Kaplan-Meier, e o teste de log rank foi utilizado para avaliar diferenças entre os grupos. RESULTADOS: A idade média foi de 6,1 anos, e a relação masculino-feminino, 2,4:1. O subtipo histológico mais freqüente foi o linfoma de Burkitt. A maioria dos pacientes foi diagnosticada em estádio III e IV da classificação de Murphy e provinha da zona rural. Renda familiar per capita inferior a 1/2 salário mínimo foi observada em 36,4%, e analfabetismo materno, em 12,7% dos casos. A probabilidade de sobrevida global e livre de doença aos 5 anos foi de 70±4% e 68±4%, respectivamente. Nenhuma das variáveis clínico-epidemiológicas analisadas mostrou associação estatística significante com a probabilidade de sobrevida dos pacientes (p > 0,05). CONCLUSÃO: Observamos incidência mais elevada do subtipo Burkitt e de crianças acometidas em idade mais jovem quando comparada à descrita em literatura estrangeira. A sobrevida observada aproximou-se dos resultados descritos pelos principais grupos cooperativos de tratamento de câncer infantil. As variáveis clínico-epidemiológicas analisadas não apresentaram associação prognóstica estatística significante.

Linfoma; infância; epidemiologia; câncer; sobrevida; países em desenvolvimento

ORIGINAL ARTICLE

Non-Hodgkin's lymphoma in childhood: clinical and epidemiological characteristics and survival analysis at a single center in Northeast Brazil

Márcia Ferreira Pedrosa^I; Francisco Pedrosa^II; Mecneide M. Lins^III; Nicodemos T. Pontes Neto^IV; Gilliatt Hanois Falbo^V

^IMestre. Oncologista pediatra, Unidade de Oncologia Pediátrica, Instituto Materno-Infantil Professor Fernando Figueira (IMIP), Recife, PE, Brazil

^IIEspecialista em Cancerologia Infantil. Diretor médico, Unidade de Oncologia Pediátrica, IMIP, Recife, PE, Brazil

^IIIMestre. Oncologista pediatra, Unidade de Oncologia Pediátrica, IMIP, Recife, PE, Brazil

^IVMédico pediatra

^VDoutor. Médico cirurgião pediátrico. Coordenador, Curso de Medicina, Escola Pernambucana de Medicina, Recife, PE, Brazil

^{Correspondence}

ABSTRACT

OBJECTIVE: To describe the clinical and demographic characteristics of non-Hodgkin's lymphoma patients diagnosed at the Pediatric Oncology Unit at the Instituto Materno-Infantil Professor Fernando Figueira (IMIP) over a 9-year period, and also to describe their survival rates and possible associations between the survival rates and the clinical and demographic characteristics analyzed in the study.

METHODS: This was a cross-sectional study. Data were collected by a retrospective review of the charts of all 110 patients admitted to our unit during the period of May 1994 through May 2003. Probability of survival was calculated in accordance with the techniques of Kaplan-Meier, using log rank to evaluate differences between the groups.

RESULTS: The average age was 6.1 years. The male/female ratio was 2.4:1. The most frequent histological subtype was Burkitt's lymphoma. The majority of patients had been diagnosed with advanced disease (stage III or IV of Murphy's Classification) and was from rural areas. Family income per capita was lower than 1/2 minimum wage in 36.4% of cases; maternal illiteracy was observed in 12.7% of cases. The 5-year overall survival and disease-free survival rates were 70±4% and 68.4±4%, respectively. None of the clinical-demographic characteristics had a significant association with the probability of survival (p > 0.05).

CONCLUSION: Children admitted to the IMIP seemed to be affected by non-Hodgkin lymphoma at a younger age, with a higher incidence of Burkitt's lymphoma and with survival rates similar to those described in the literature of developed countries. No clinical demographic characteristics had a statistically significant association with prognosis.

Keywords: Lymphoma, childhood, epidemiology, cancer, survival, developing countries.

Introduction

Although rare in childhood, lymphoma among children and adolescents has been receiving ever-growing attention among researchers, not just because of its growing importance from the epidemiological point of view, but also because of the major advances observed in diagnosis and treatment.

Malignant neoplasms are the second cause of child death in developed countries and the fourth cause of death among children and adolescents in Brazil, and they are the second most frequent cause of death, in our country, in the age range five to 9 years, among whom they are only less common than deaths from external causes.^1,2

In this context, lymphomas are the third most frequently diagnosed malignant neoplasm among children and adolescents in the age range 0 to 15 years, with 60% of cases being non-Hodgkin's lymphoma (NHL) and 40% being Hodgkin lymphomas.

Depending on the geographic region being studied, there are important differences in relation to the clinical and epidemiological characteristics of NHLs diagnosed during childhood.^3,4

In equatorial Africa, the Burkitt histological subtype of NHL accounts for 50% of all cancers diagnosed in the pediatric age group and has a high incidence of primary tumors involving the jaw, whereas in the rest of the world, this neoplasm accounts for less than 5% of pediatric cancers, and abdominal primary tumors are the most common presentation.^3,5 In the northeast of Brazil, a high frequency of the Burkitt histological subtype has also been reported in the past.^6,7

Among the prognostic factors of childhood NHL that have been studied, the factor with greatest consensus in the literature is the tumor burden at the time of diagnosis, normally quantified by staging and serum lactate dehydrogenase (LDH) levels. Others important prognostic factors are: the type of treatment and the location where this is carried out, with patients on more modern therapeutic schemes at centers with appropriate experience and infrastructure, exhibiting better survival rates.³

Developing countries often have inferior survival rates than developed countries, and this finding is generally related to the low social economic status in these regions, which makes early diagnosis and the use of effective treatments nonviable.⁸

It was the scarcity of existing data in the literature illustrating the behavior of NHL among the children of our region that induced us to carry out this study, with the intention of describing the clinical, epidemiological and socioeconomic characteristics of our NHL patients, assessing their survival and searching for possible prognostic associations with the variables under analysis.

Methods

This study included all patients with non-Hodgkin's lymphoma diagnosed at the Pediatric Oncology Unit at the Instituto Materno-Infantil Professor Fernando Figueira (IMIP) during its first 9 years of operations, from May, 1994 to May, 2003. Only one patient was excluded due to the fact that their data were not sufficiently complete for analysis, because they had been admitted after starting oncological treatment at another center.

This was a descriptive, cross-sectional study based on the medical records, radiology and anatomopathological findings and on the social data collected by our Social Services Department. The following data were analyzed: age, sex, nutritional status, origin, maternal educational level, total and per capita family income, histological subtype, tumor stage, serum lactate dehydrogenase (LDH) levels, duration of symptoms at time of diagnosis, primary tumor site, therapeutic scheme, response to treatment (relapse, death or remission) and length of follow-up.

In order to analyze possible associations between the probability of survival and the variables listed above, they were categorized and the patients allocated to groups (Table 1).

Nutritional status was assessed according to Z scores, using the National Center for Health Statistics growth curves as the standard, and defining patients as malnourished if any of their z scores were further than -2 SD from the median of the reference group, as recommended by the World Health Organization (WHO).⁹

Anatomopathological assessments were performed by pathologists from the Pediatric Oncology Unit at IMIP, who were using the histological classification that was most widely accepted at that time: the Working Formulation, Revised European American Lymphoma Classification or the WHO classification. Despite of the classification employed, the patients were grouped into three subtypes: Burkitt's, lymphoblastic and large cell.

From 1999 onwards, immunohistochemical assays using the markers LCA, CD20, CD3, CD48 and ALK were used to diagnose NHL and determine the B, T, non-B and non-T cell lines. ALK was used for those with anaplastic histology.

Staging was according to Murphy's classification (Saint Jude Children's Research Hospital).¹⁰

Serum LDH assays were performed within 24 hours of patient admission, being considered elevated when over 500 UI/dL (International Units per deciliter).

The therapeutic regimen was prescribed depending on histological typing and/or immunophenotype of the lymphoma and on the period during which the patient was admitted. Burkitt's and large B-cell lymphomas and/or those where the primary site was abdominal were treated with a chemotherapy protocol based on the LMB-89.¹¹ With the aim of reducing toxicity related to the intensity of the chemotherapy regimen, from 1995 to 1997 a modified LMB-89 protocol was employed, with the following changes to the original protocol:

- Reduction of methotrexate dose to 1 g/m² in groups B and C.

- No cyclophosphamide dosage to be scaled up above 500 mg/m²/day during COPADM courses.

- Substitution of the chemotherapy cycle known as CYVE by CYM, during consolidation of branch C of the protocol.

A therapeutic protocol based on the Total XIIIB-SJCRH was used for lymphoblastic lymphomas or large cell lymphomas of T cells and/or where the primary site was not abdominal.¹²

Treatment based on the LSA2L2 protocol¹³ was used for patients admitted during the first year of the service's operations, before the protocols described above were adopted.

The Kaplan-Meier method was used to estimate global survival and disease-free survival. The following were considered as events: deaths for any reason or relapse of the disease. Patients who had not suffered any event until the day when the results were analyzed were censured. No losses of follow-up were observed. The log rank test was used for comparisons between groups.¹⁴

Deaths occurring within 30 days of admission were classed as early deaths. Improvement of the rate of early deaths was evaluated by means of tendency test (np trend test).

The level of significance used for the statistical tests was 5% (p < 0.05) with 95% confidence intervals.

Data were input on a database created with Epi-Info, version 6, and statistical calculations were carried out using specialized software: SAS (Statistical Analysis System), version 8, SPSS (Statistical Package for the Social Sciences), version 11 and Stata 9.2.

This study was approved by the Human Research Ethics Committee at IMIP.

Results

During the period between May 1994 and May 2003, 110 patients with NHL were admitted to the IMIP Oncology Service.

Males predominated in a proportion of 2.4:1, and age varied from 21 months to 15 years, with a mean of 6.1±3.4 years (median of 5 years).

Twenty-five patients were defined as malnourished, which was equivalent to 22.7% of our patients.

Only 31 patients (28.2%) originated from the state capital (Recife) and the metropolitan region, with the remaining patients coming from the interior of the state or from other states.

Since the social form was only made routine in 1997, after the definitive implementation of the IMIP Pediatric Oncology Unit's Social Services Department, the data on maternal educational level, family income and family income per capita were not available for 38 (34.6%), 41 (37.2%) and 42 (38.2%) patients, respectively.

With relation to the histological subtypes, Burkitt type NHL was observed to be predominant, affecting 78.2% (86) of the patients. Immunohistochemical studies were carried out for 33 of the 47 (70.2%) patients admitted during the period from 1999 to 2003, which is equivalent to 30% of the 110 patients studied. Of the 33 patients who underwent these tests, B cell line was confirmed (CD20+) in 25 patients (75.7%), T cell line (CD3+) in 6 patients (18.2%) and non-B non-T (LCA+ with CD20- and CD3-) in 2 patients (6.1%), both with anaplastic histology and ALK positive.

Only 10 (9.1%) patients presented with localized disease (stages I and II) and 100 (90.9%) presented with advanced disease (stages III or IV) and, of these, the majority, 95 (86.4%) patients, had stage III lymphomas.

Elevated LDH levels (> 500 UI/dL) were observed in only 36 (33%) patients, and levels varied from 110 to 3,130 UI/dL, with a mean of 504.41±476.86 UI/dL (median of 364 UI/dL).

The duration of symptoms varied from 3 to 365 days, with a mean duration of 50.2±55.2 days (median of 30 days). Patients whose complaints had lasted more than 30 days accounted for 39.1% (43) of cases.

Primary abdominal tumors were the most common among our patients, affecting 80.9% (89) of them.

The LMB-89 was the most used protocol, since Burkitt lymphomas and abdominal primaries predominated in this group of patients, and was given to 89 (80.9%) patients; although 34 (30.9%) patients were on the modified version with reduced toxicity.

The mean follow-up period was 3.31±2.83 years, with a median of 2.8 years.

Ninety-four (85.4%) of the 110 patients studied achieved remission and 16 (14.6%) died within the first 30 days after diagnosis (early death), before their remission status was evaluated. Although it was not statistically significant (tendency test: p = 0.348), it was observed that the rate of early deaths reduced over the years.

Of the patients who achieved remission, seven (7.4%) have relapsed and 15 (16%) died, 11 during first remission and four after a relapse.

The overall 2 and 5 year survival rates of our study were 73%±4% and 70%±4%, respectively (Figure 1).

Disease-free survival was 70%±4% at 2 years and 68%±4%, at 5 years. None of the clinical, epidemiological or socioeconomic variables exhibited a statistically significant association with global survival or disease-free survival (p > 0.05) (Table 2).

Discussion

Little data can be found in the Brazilian medical literature relating to the behavior of NHLs in the infant and juvenile population of our region. This study describes the epidemiological, clinical and socioeconomic characteristics of children with NHLs who were treated in a region where resources are limited.

We reviewed the medical records of 110 patients admitted with diagnosis of NHL to the Pediatric Oncology Unit at the IMIP during the period from May 1994 to May 2003. This was a larger patient sample than many others that have been described, both in Portuguese and other languages, that have reported the experience of a single institution in caring for and treating these patients.

The incidence of NHL increases uniformly with age and is rarely diagnosed before 2 years.³ In our study we observed that NHL affects younger children than those described in foreign literature and this fact is compatible with other reports that have described other Brazilian experiences.^6,7,15,16 The possibility of infectious etiology, principally related to the Epstein-Barr virus,⁴ being involved in the pathogenesis of Burkitt lymphomas may be a partial explanation for the emergence of this disease in younger patients in our region, since it is believed that populations in less privileged socioeconomic situations are exposed to infectious agents earlier.

With relation to sex, a predominance of male cases was observed, in a proportion of 2.4:1, which is similar to what is described in the literature.⁴

When we compared our rate of malnutrition with other studies involving Brazilian children with malignant neoplasms, we observed that our rate was lower than the others,^15,17 which is a fact that warrants more profound analysis, since both studies used similar methodology to ours to define malnutrition.

The percentage of maternal illiteracy was lower in our group when compared with data from another research project carried out in our region,¹⁸ which makes us suppose that perhaps some children with NHL, who were the children of illiterate mothers, may have had healthcare access difficulties, because of their mothers' scant understanding of the health-disease process, among other reasons.

The fact that more than 70% of our patients were sent to us from the interior of the state reflects the wide coverage of the IMIP as a regional reference hospital. This finding, together with the high percentage of patients with extremely low family incomes, reinforces the importance of nongovernmental institutions that provide socioeconomic support to the families of children with cancer and the implementation of an active and effective Social Service, integrated with the multidisciplinary team that cares for this group of patients. In the past, before these support services existed, an important cause of treatment failure was patients abandoning treatment, to a great extent as a result of the difficulties imposed by the distances involved and the underprivileged economic conditions observed in the majority of these patients' families, making the costs of treatment away from their localities of residence nonviable.

The duration of symptoms among our patients was, on average, 50 days, which is in agreement with results found by Pollock et al.¹⁹ in a study involving 2,665 patients with solid tumors. Considering the duration of symptoms of more than 30 days as delayed diagnosis, as it has previously been defined by other authors,^20,21 we observed that around 40% of the patients on our study had a delayed diagnosis.

The high prevalence rates of advanced tumor stages in our series is probably related to, among other factors, the large number of patients with voluminous abdominal lymphomas, late diagnosis, and the predominance of primary mediastinal tumors within the lymphoblastic histological type, associated with a low frequency of NHL with more superficial primary sites, such as tumors of the head and neck and primary nodal disease, making it difficult to detect this pathology earlier in our children.

We found evidence of a high prevalence of NHL of the Burkitt histological subtype (78.2%), when compared with American and European data.³ Sandlund et al.⁶ have previously made the same observation with relation to the distribution of histological types, reporting a frequency of 94% of Burkitt's lymphoma in children with NHL in our region.

This finding suggests that, in our children, Burkitt's lymphoma has a similar pattern of frequency to African Burkitt's lymphoma,⁵ although with clinical presentation that is essentially abdominal, similar to sporadic Burkitt lymphomas.

Evidence relating certain biological characteristics of Burkitt lymphomas, such as the association with the Epstein-Barr virus (EBV) and the point at which chromosome 8 is broken, supports the view that there are pathogenetically distinct subtypes of Burkitt's lymphoma in different regions of the world,⁴ which could make us suppose that the patients in our study exhibit a type that is biologically distinct of the NHLs described in endemic (Africa) and sporadic variety (rest of world). However, in the light of current knowledge, this hypothesis cannot be confirmed, and further studies are needed into the subject in order that this question may be answered.

The survival of our patients approaches, although it remains inferior, to the results being currently presented by the major collaborative childhood cancer treatment groups, who report survival of around 80 to 90% for patients with NHL (Table 3).

However, we found that around 50% of our deaths (16 out of 31 deaths) occurred during the first 30 days after admission, being defined as early deaths that were frequently associated with comorbidities, such as metabolic, compressive and infectious complications, related to advanced disease stages. Excluding these deaths from our survival analysis, we observed a survival rate of around 80% at 2 years, close to the best results reported in the current period.

We therefore believe that efforts to reduce the rate of early deaths are essential, improving the clinical condition of these children at admission, by means of procedures such as: diagnosis during earlier phases, improved hospital infrastructure and capacitation of health professionals.

The impact of such measures has already resulted in improved survival among our acute lymphoblastic leukemia patients, as Howard et al.²⁸ have described, and maybe related to the decreasing in early death rate observed in this study over the 9 years of our analysis.

In relation to the attempt to identify prognostic factors, no statistically significant associations were demonstrated between the clinical, epidemiological and socioeconomic variables and either global survival or disease-free survival in our study, which may be due to insufficient sample size or may be related to the important socioeconomic support that the families of our patients are given by a nongovernmental institution, which has been cited above as one possible cause of the improvements in survival among children with cancer in countries with limited resources.²⁸

Finally, we suggest that further studies be carried out in order to better define prognostic factors and in order to elucidate etiopathogenic factors that could be associated with the differences in the form of presentation of NHLs among children in our region.

Acknowledgements

We are grateful to Prof. José Natal Figueroa, Professor of Biostatistics at the IMIP, for his dedicated help with the statistical analysis.

We would also like to thank Dr Raul Ribeiro (International Outreach Program, St. Jude Children's Research Hospital), Dr Scott Howard (International Outreach Program, St. Jude Children's Research Hospital), Mr. Hélio Monteiro (Pediatric Oncology Department Library, IMIP) and Dr. Beatriz Camargo (Doctorate in Medicine from the Medical Faculty of USP), for helping with designing the project and writing the article.

References

Manuscript received June 26 2007, accepted for publication Oct 17 2007.

No conflicts of interest declared concerning the publication of this article.

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Publication Dates

• Publication in this collection
  28 Jan 2008
• Date of issue
  Dec 2007

History

• Accepted
  17 Oct 2007
• Received
  26 June 2007