Non-Hodgkin lymphoma in children. Epidemiology and late effects

Abstract

Epidemiological studies are necessary for the understanding of diseases and their response to treatment. Accurate incidence data are crucial for epidemiological investigations and population-based data are the most reliable source. In Sweden there is excellent potential for population-based studies. The favorable prognosis of childhood non-Hodgkin lymphoma with increasing numbers of survivors who have been systematically followed for a long time makes this group of children well suited for late effect-studies. Furthermore the different classification and treatment eras offer the opportunity to carry out studies analyzing the impact of different approaches on outcome.The general aims of the studies reported in this thesis was to investigate epidemiology and endocrine late effects in non-Hodgkin lymphoma in a 20-year population-based childhood material. In addition to the hospital registry, the established registries in Sweden were searched for children in western Sweden with NHL diagnosed between 1975 and 1994. All sections from paraffin embedded blocks of tumors with a diagnosis of malignant lymphoma were collected and re-examined histopathologically and immunohistochemically. To guarantee that no cases of NHL were misdiagnosed, a re-examination of all other childhood malignancies collected from these registries during the investigation period was also performed. Median follow-up duration of surviving patients was 10 years. The annual incidence of NHL in children under 15 years of age was 9 per million children, representing 6% of all childhood malignancies during the investigation time. The male/female ratio was 4.1:1. Two patients with Ki-1-positive ALCL were originally diagnosed as histiocytosis. Treatment era was the most significant prognostic indicator with event-free survival (EFS) 19% in the pre-protocol era (1975-1979) compared with EFS 74% in the period 1980-1994. The annual incidence of NHL was found to be somewhat higher than reported in earlier investigations and has increased from 8 to 10/million children during the 20-year period. A more pronounced male predominance than in previous investigations was observed. With the introduction of intensified multiagent chemotherapy there was a dramatic improvement in survival. Treatment success can be expected in 86% of children with localized disease and in 64% of children with extensive disease.Longitudinal growth was studied in children treated for NHL and acute lymphoblastic leukemia (ALL) in order to compare growth in unirradiated versus irradiated patients. In both groups of children there was a prominent negative effect on height growth rates during the treatment. However, the final adult height was normal. These findings suggest that not only irradiation but also chemotherapy contribute to growth retardation during the treatment.Growth and growth hormone (GH) secretion, as assessed by the rate and pattern of secretion, was studied in patients in remission from childhood NHL who had been treated with corticosteroids and intense chemotherapy. None of the patients had received cranial irradiation. Spontaneous GH secretion, in terms of both secretory rate and pulsatile pattern, was evaluated by measuring integrated GH concentrations in 20-minute blood samples collected over a 24-hour period. The plasma GH concentrations were transformed into GH secretion rates using deconvolution technique. Fourier time series analysis was applied to determine possible disturbances of rhythmicity of the GH secretion. The GH secretion rate and the pulsatile pattern of secretion in the NHL patients were similar to those of the reference population of pubertal matched healthy controls. It is well known that cytotoxic agents may cause gonadal damage and the importance of assessing gonadal dysfunction in children treated for a malignant disease has increased. To detect even low prepubertal gonadotropin levels, plasma LH and FSH concentrations were measured using an ultrasensitive time-resolved immunofluorometric assay (trIFMA). Testosterone concentrations were determined by radioimmunoassay (RIA) using direct coated tube technology. There were increased levels of gonadotropins indicating that multiagent cytotoxic chemotherapy used in the treatment of childhood NHL has a major impact on gonadal function with risk of infertility.