Abstract

Background: Attenuation of the epidemic increase in non-Hodgkin's lymphoma (NHL) incidence has recently been reported in the USA and Nordic European countries. After two decades of steadily increasing NHL, this study sought to ascertain whether a similar stabilisation might have taken place in Spain in recent years.

Patients and methods: NHL cases were drawn from 13 population-based Spanish cancer registries with a record of at least 10 years of uninterrupted registration during the period 1975–2004. Overall and age-specific changes in incidence rates were evaluated using change-point Poisson models, which allow for accurate detection and estimation of trend changes.

Results: A total of 21 335 NHL cases (11 531 male and 9804 female) were identified. Although overall age- and registry-adjusted incidence rates rose by 5.74% annually among men and 6.58% among women across the period 1975–95, a statistically significant change-point was nevertheless detected in both sexes in 1996, followed by stabilisation.

Conclusions: In Spain, NHL incidence levelled off in 1996 after a sharp increase during the 1970s and 1980s. This stabilisation is, partially at least, linked to the decrease in incidence of AIDS-related lymphomas among young adults.

introduction

Non-Hodgkin's lymphomas (NHLs) are a heterogeneous group of diseases with different types of behaviour, prognosis and epidemiology. While a few risk factors for selected types of NHL have been identified, including conditions linked to the immune system [1, 2], immunodeficiency virus, HIV and hepatitis C virus [3–5], and occupational and environmental exposure [6, 7], the causes of most NHLs remain largely unknown [8].

In Spain (1998–2002), NHL is the eighth leading tumour in men and the fifth in women (3.0% of all male and 4.0% of all female cancers) [9]. Over the past 30 years, incidence of this disease has increased, particularly in industrialised countries [10–14]. While improved cancer reporting, changes in lymphoma classification and increase in AIDS-associated lymphomas have contributed to the striking escalation of disease incidence, these factors are estimated to account for only ∼50% of the increase in observed incidence [15].

Recently, an attenuation of the epidemic increase in NHL incidence has been reported in some developed countries [16, 17]. To ascertain whether a similar pattern might have taken place in Spain in recent years, this study analysed changes in NHL incidence in Spain over the period 1975–2004. In view of differences in the impact of the HIV epidemic on age-specific incidence rates, trends were also analysed separately for men and women aged 0–24, 25–39, 40–54, 55–69 and ≥70 years.

methods

data source

The number of NHLs, broken down by 5-year age group (0–4, 5–9, … , 80–84 and ≥85 years) and single year of diagnosis, was provided by 13 population-based cancer registries (Asturias, Navarre, Basque Country, La Rioja, Girona, Tarragona, Zaragoza, Albacete, Cuenca, Murcia, Granada, Mallorca and Canary Islands) which are members of the European Network of Cancer Registries and had been collecting data for at least 10 consecutive years during the designated study period (1975–2004), with data collection periods ranging from 1975–79 to 2000–04. NHL corresponded to codes C82–85 and C96 of the 10th revision of the International Classification of Diseases. Overall, the 13 registries included in this study cover ∼26% of the total Spanish population (10 109 596 persons covered in 2001), and serve 17 different Spanish provinces located mainly in the east of the country, along a band running from the northern Cantabrian coast to the southern Mediterranean area. Estimates of the mid-year populations covered by these registries during the study period were obtained from the Spanish National and Regional Institutes of Statistics.

statistical analysis

Age-standardised incidence rates (ASIRs) of NHL were calculated for each registry, sex and 5-year period (1975–79, 1980–84, 1985–89, 1990–94, 1995–99 and 2000–04) using the direct method with the European standard population taken as reference. Assuming a Poisson distribution for the number of cases broken down by registry, sex, 5-year period and age group, the ratio of age-adjusted incidence rates and its 95% confidence interval (CI) were computed for each individual registry with respect to all the registries combined, for each sex and 5-year period.

Changes in age- and registry-adjusted incidence rates over the study period were evaluated separately for men and women using transition change-point models, again assuming a Poisson distribution [18] for the number of cases in each stratum. These transition change-point models are similar to the widespread joinpoint regression [19], but, instead of assuming an overall trend made up of intersecting linear segments with an implausible sharp bend at the change-point, the proposed model allows for more gradual transitions between the linear trends. The transition change-point model provides an asymptotic test for the existence of a change-point, the estimate and 95% CI for the location of the change-point, and the estimates and 95% CIs for the annual percentage changes (APCs) in incidence rates below and above the estimated change-point. All statistical tests were two-sided, and P values <0.05 were deemed statistically significant. Further methodological details and epidemiological applications of the proposed change-point model are provided elsewhere [20, 21].

The above-described models were also used to evaluate specifically the trend in NHL incidence among men and women aged 0–24, 25–39, 40–54, 55–69 and ≥70 years.

results

A total of 21 335 incident cases (11 531 male and 9804 female) of NHL were identified in the 195 302 907 person-years covered by the 13 Spanish registries from 1975 to 2004. Overall, the ASIR increased steeply in both sexes from 3.9 cases per 100 000 person-years in 1975–79 to 12.0 cases per 100 000 person-years in 2000–04. The rate ratio between the Canary Islands and La Rioja was 2.45, indicating marked geographical differences in the incidence of this type of cancer.

Among men, the ASIR increased from 4.9 cases per 100 000 man-years in 1975–79 to 14.2 in 2000–04; and among women, the ASIR increased from 3.0 cases per 100 000 woman-years in 1975–79 to 10.1 in 2000–04. There was a substantial excess incidence of NHL among males (generally ∼40%) which remained constant across the study period (Table 1).

Table 1.

Number of cases, age-adjusted incidence rates and age-adjusted rate ratio (RR), with their 95% confidence limits (CIs), of non-Hodgkin's lymphoma (per 100 000 standard European population) by 5-year period and registry

Cancer Registry 1975–79
 
1980–84
 
1985–89
 
1990–94
 
1995–99
 
2000–04
 
 Cases Rate RRa (95% CI) Cases Rate RRa (95% CI) Cases Rate RRa (95% CI) Cases Rate RRa (95% CI) Cases Rate RRa (95% CI) Cases Rate RRa (95% CI) 
Zaragoza 1975–2003 130 3.2 0.82 (0.73, 0.93) 148 3.4 0.63 (0.55, 0.73) 281 6.0 0.86 (0.77, 0.96) 410 8.2 0.86 (0.78, 0.95) 462 8.6 0.75 (0.68, 0.82) 435 9.4 0.78 (0.70, 0.86) 
Navarre 1974–2004 123 5.1 1.31 (1.15, 1.49) 172 6.8 1.27 (1.11, 1.45) 215 7.5 1.08 (0.95, 1.23) 334 11.0 1.17 (1.05, 1.30) 388 12.2 1.06 (0.96, 1.17) 434 12.0 1.00 (0.91, 1.10) 
Tarragona 1980–2002    143 5.3 0.98 (0.85, 1.15) 178 6.1 0.87 (0.75, 1.00) 330 10.3 1.09 (0.98, 1.22) 420 12.4 1.08 (0.98, 1.19) 321 13.5 1.12 (1.00, 1.25) 
Asturias 1982–2001    249 6.8 1.28 (1.15, 1.42) 488 7.5 1.07 (0.99, 1.16) 652 9.6 1.01 (0.94, 1.09) 896 12.1 1.06 (0.99, 1.13) 376 12.3 1.02 (0.92, 1.13) 
Murcia 1983–2003    96 5.4 1.00 (0.83, 1.21) 331 7.0 1.00 (0.90, 1.10) 477 9.2 0.98 (0.90, 1.07) 606 10.5 0.91 (0.85, 0.99) 589 11.6 0.96 (0.89, 1.04) 
Granada 1985–2004       222 5.8 0.83 (0.73, 0.94) 296 7.3 0.77 (0.69, 0.86) 417 9.6 0.83 (0.76, 0.92) 444 9.5 0.79 (0.72, 0.86) 
Basque Country 1986–2004       639 7.4 1.06 (1.00, 1.14) 1144 10.0 1.06 (1.00, 1.11) 1454 11.7 1.02 (0.97, 1.07) 1670 12.3 1.02 (0.98, 1.07) 
Mallorca 1988–2000       115 9.2 1.32 (1.10, 1.59) 279 8.6 0.91 (0.81, 1.02) 404 11.4 0.99 (0.90, 1.10) 77 10.4 0.86 (0.69, 1.09) 
Girona 1994–2004          80 13.9 1.47 (1.17, 1.84) 439 13.7 1.19 (1.08, 1.31) 511 14.7 1.22 (1.12, 1.33) 
Albacete 1991–2002          127 8.5 0.89 (0.75, 1.07) 175 8.6 0.75 (0.64, 0.88) 99 7.4 0.61 (0.50, 0.76) 
Canary Islands 1993–2004          324 13.6 1.44 (1.29, 1.60) 1075 16.3 1.41 (1.34, 1.49) 1244 15.7 1.31 (1.24, 1.37) 
La Rioja 1993–2001          36 4.9 0.52 (0.37, 0.73) 121 6.9 0.60 (0.50, 0.72) 46 6.4 0.53 (0.39, 0.73) 
Cuenca 1993–2004          30 5.4 0.57 (0.39, 0.85) 81 6.7 0.58 (0.46, 0.7) 102 7.1 0.59 (0.47, 0.73) 
Men 148 4.9  431 6.2  1344 8.4  2420 11.1  3764 13.7  3424 14.2  
Women 105 3.0  377 4.6  1125 5.8  2099 8.0  3174 9.5  2924 10.1  
Both sexes 253 3.9  808 5.4  2469 7.0  4519 9.5  6938 11.5  6348 12.0  
Cancer Registry 1975–79
 
1980–84
 
1985–89
 
1990–94
 
1995–99
 
2000–04
 
 Cases Rate RRa (95% CI) Cases Rate RRa (95% CI) Cases Rate RRa (95% CI) Cases Rate RRa (95% CI) Cases Rate RRa (95% CI) Cases Rate RRa (95% CI) 
Zaragoza 1975–2003 130 3.2 0.82 (0.73, 0.93) 148 3.4 0.63 (0.55, 0.73) 281 6.0 0.86 (0.77, 0.96) 410 8.2 0.86 (0.78, 0.95) 462 8.6 0.75 (0.68, 0.82) 435 9.4 0.78 (0.70, 0.86) 
Navarre 1974–2004 123 5.1 1.31 (1.15, 1.49) 172 6.8 1.27 (1.11, 1.45) 215 7.5 1.08 (0.95, 1.23) 334 11.0 1.17 (1.05, 1.30) 388 12.2 1.06 (0.96, 1.17) 434 12.0 1.00 (0.91, 1.10) 
Tarragona 1980–2002    143 5.3 0.98 (0.85, 1.15) 178 6.1 0.87 (0.75, 1.00) 330 10.3 1.09 (0.98, 1.22) 420 12.4 1.08 (0.98, 1.19) 321 13.5 1.12 (1.00, 1.25) 
Asturias 1982–2001    249 6.8 1.28 (1.15, 1.42) 488 7.5 1.07 (0.99, 1.16) 652 9.6 1.01 (0.94, 1.09) 896 12.1 1.06 (0.99, 1.13) 376 12.3 1.02 (0.92, 1.13) 
Murcia 1983–2003    96 5.4 1.00 (0.83, 1.21) 331 7.0 1.00 (0.90, 1.10) 477 9.2 0.98 (0.90, 1.07) 606 10.5 0.91 (0.85, 0.99) 589 11.6 0.96 (0.89, 1.04) 
Granada 1985–2004       222 5.8 0.83 (0.73, 0.94) 296 7.3 0.77 (0.69, 0.86) 417 9.6 0.83 (0.76, 0.92) 444 9.5 0.79 (0.72, 0.86) 
Basque Country 1986–2004       639 7.4 1.06 (1.00, 1.14) 1144 10.0 1.06 (1.00, 1.11) 1454 11.7 1.02 (0.97, 1.07) 1670 12.3 1.02 (0.98, 1.07) 
Mallorca 1988–2000       115 9.2 1.32 (1.10, 1.59) 279 8.6 0.91 (0.81, 1.02) 404 11.4 0.99 (0.90, 1.10) 77 10.4 0.86 (0.69, 1.09) 
Girona 1994–2004          80 13.9 1.47 (1.17, 1.84) 439 13.7 1.19 (1.08, 1.31) 511 14.7 1.22 (1.12, 1.33) 
Albacete 1991–2002          127 8.5 0.89 (0.75, 1.07) 175 8.6 0.75 (0.64, 0.88) 99 7.4 0.61 (0.50, 0.76) 
Canary Islands 1993–2004          324 13.6 1.44 (1.29, 1.60) 1075 16.3 1.41 (1.34, 1.49) 1244 15.7 1.31 (1.24, 1.37) 
La Rioja 1993–2001          36 4.9 0.52 (0.37, 0.73) 121 6.9 0.60 (0.50, 0.72) 46 6.4 0.53 (0.39, 0.73) 
Cuenca 1993–2004          30 5.4 0.57 (0.39, 0.85) 81 6.7 0.58 (0.46, 0.7) 102 7.1 0.59 (0.47, 0.73) 
Men 148 4.9  431 6.2  1344 8.4  2420 11.1  3764 13.7  3424 14.2  
Women 105 3.0  377 4.6  1125 5.8  2099 8.0  3174 9.5  2924 10.1  
Both sexes 253 3.9  808 5.4  2469 7.0  4519 9.5  6938 11.5  6348 12.0  
a

Age-adjusted rate ratio (95% CI) for each registry with respect to all registries combined in the corresponding 5-year period.

Figure 1 depicts age- and registry-adjusted incidence rates of NHL by single year of diagnosis in all Spanish registries, along with the estimated time trend obtained from fitting a change-point model for all ages (A1 for men and B1 for women) and for age groups (A2 for men and B2 for women).

Figure 1.

Age- and registry-adjusted incidence rates of non-Hodgkin's lymphoma over the period 1975–2004 among men (A1, all ages; and A2, by age group) and women (B1, all ages; and B2, by age group) at all Spanish registries. The observed rates (dotted line) were obtained by using nominal categories for each year of diagnosis, and the estimated time trend (solid line) and its 95% confidence interval (CI) (dashed line) were obtained from fitting a change-point model (see Methods section).

Figure 1.

Age- and registry-adjusted incidence rates of non-Hodgkin's lymphoma over the period 1975–2004 among men (A1, all ages; and A2, by age group) and women (B1, all ages; and B2, by age group) at all Spanish registries. The observed rates (dotted line) were obtained by using nominal categories for each year of diagnosis, and the estimated time trend (solid line) and its 95% confidence interval (CI) (dashed line) were obtained from fitting a change-point model (see Methods section).

Table 2 shows trend analyses for all ages and for individual age groups. During the period 1975–2004, there was a significant annual increase in the all-age incidence rate of 3.50% in men and 3.85% in women. Although incidence of NHL increased steadily during the 1980s and 1990s, it tended to stabilise in recent years. The change-point model confirmed this result, with a gradual but statistically significant change in trend observed among men in 1996 (95% CI 1994–1998; P value for the existence of a change-point <0.001) and among women in 1995 (95% CI 1992–1999; P value for the existence of a change-point <0.001). While the NHL rate increased among men by 5.74% (95% CI 5.10% to 6.39%) per annum until 1996, followed by a gradual stabilisation thereafter (APC of –0.11%; 95% CI –0.99% to 0.78%) (Figure 1 A.1), it increased among women by 6.58% (95% CI 5.79% to 7.37%) per annum until 1995 and was likewise followed by a gradual stabilisation thereafter (APC of 0.33%; 95% CI –0.57% to 1.26%) (Figure 1, B.1).

Table 2.

Trends in age-adjusted incidence rates of non-Hodgkin's lymphoma among men and women at Spanish registries

Age group Sex Change-point
 
APC (95% CI)
 
  P value Year (95% CI) Overall Below change-point Above change-point 
All ages (years) Male <0.001 1996 (1994–1998) 3.50 (3.15, 3.85) 5.74 (5.10, 6.39) -0.11 (–0.99, 0.78) 
 Female <0.001 1995 (1992–1999) 3.85 (3.49, 4.21) 6.58 (5.79, 7.37) 0.33 (–0.57, 1.26) 
0–24 Male 1.0  0.99 (-0.18, 2.18)   
 Female 1.0  0.86 (-0.58, 2.33)   
25–39 Male <0.001 1995 (1994–1997) 3.82 (2.71, 4.93) 10.82 (8.52, 13.17) -4.74 (-7.08, –2.34) 
 Female 0.016 1999 (1994–2002) 4.85 (3.53, 6.20) 6.97 (5.07, 8.91) -3.92 (-9.14, –1.58) 
40–54 Male 0.029 1999 (1991 —)a 4.12 (3.37, 4.88) 5.54 (4.33, 6.77) -1.71 (-5.44, 2.16) 
 Female 0.013 1990 (1985–1998) 4.21 (3.25, 5.17) 9.19 (5.89, 12.60) 2.46 (1.07, 3.87) 
55–69 Male <0.001 1992 (1987–1998) 3.21 (2.59, 3.84) 6.94 (5.23, 8.68) 0.67 (-0.52, 1.87) 
 Female 0.013 1992 (1988–2000) 3.48 (2.78, 4.18) 5.92 (4.26, 7.61) 1.77 (0.55, 3.01) 
70+ Male <0.001 1994 (1988 —)a 4.00 (3.36, 4.65) 7.35 (5.81, 8.90) 0.59 (-0.86, 2.07) 
 Female <0.001 1994 (1991–1998) 4.12 (3.51, 4.73) 8.48 (6.96, 10.02) 0.051 (-1.27, 1.40) 
Age group Sex Change-point
 
APC (95% CI)
 
  P value Year (95% CI) Overall Below change-point Above change-point 
All ages (years) Male <0.001 1996 (1994–1998) 3.50 (3.15, 3.85) 5.74 (5.10, 6.39) -0.11 (–0.99, 0.78) 
 Female <0.001 1995 (1992–1999) 3.85 (3.49, 4.21) 6.58 (5.79, 7.37) 0.33 (–0.57, 1.26) 
0–24 Male 1.0  0.99 (-0.18, 2.18)   
 Female 1.0  0.86 (-0.58, 2.33)   
25–39 Male <0.001 1995 (1994–1997) 3.82 (2.71, 4.93) 10.82 (8.52, 13.17) -4.74 (-7.08, –2.34) 
 Female 0.016 1999 (1994–2002) 4.85 (3.53, 6.20) 6.97 (5.07, 8.91) -3.92 (-9.14, –1.58) 
40–54 Male 0.029 1999 (1991 —)a 4.12 (3.37, 4.88) 5.54 (4.33, 6.77) -1.71 (-5.44, 2.16) 
 Female 0.013 1990 (1985–1998) 4.21 (3.25, 5.17) 9.19 (5.89, 12.60) 2.46 (1.07, 3.87) 
55–69 Male <0.001 1992 (1987–1998) 3.21 (2.59, 3.84) 6.94 (5.23, 8.68) 0.67 (-0.52, 1.87) 
 Female 0.013 1992 (1988–2000) 3.48 (2.78, 4.18) 5.92 (4.26, 7.61) 1.77 (0.55, 3.01) 
70+ Male <0.001 1994 (1988 —)a 4.00 (3.36, 4.65) 7.35 (5.81, 8.90) 0.59 (-0.86, 2.07) 
 Female <0.001 1994 (1991–1998) 4.12 (3.51, 4.73) 8.48 (6.96, 10.02) 0.051 (-1.27, 1.40) 
a

The upper limit of the 95% confidence interval (CI) could not be estimated due to the low number of cases.

We next analysed NHL incidence trends by age group. There was no evidence of a change in trend among children and young adults aged 0–24 years. Although the incidence of NHL rose steadily among men and women aged 25–39 years from 1975 to the mid-1990s, it tended to decline in recent years. Among men, a significant and sharp downturn was detected in 1995, with incidence increasing by 10.82% per annum until 1995 and declining by –4.74% per annum thereafter. Among women, however, the downturn was detected later, i.e. in 1999, with the NHL rate increasing by 6.97% per annum until 1999 and declining by –3.92% per annum thereafter. Among men aged 40–54 years there was a significant and gradual levelling off in 1999, with an annual increase in incidence of 5.54% below this threshold, followed by a gradual stabilisation. Among women aged 40–54 years, incidence increased by 9.19% annually until 1990, followed by a gradual stabilisation.

In men and women aged 55–69 years incidence increased by 6.94% and 5.92%, respectively, until 1992, followed by a gradual stabilisation in both sexes. Lastly, among men and women aged ≥70 years, there was a significant and gradual levelling off in 1994, followed by a gradual stabilisation (Figure 1 A2 and B2).

discussion

This study describes the changing incidence trends in NHL in Spain over the last three decades, as assessed by transition change-point models. The increased incidence of NHL reported in Spain during the 30-year study period coincides with that described for other geographical areas [10, 12, 14, 22]. To understand changes in NHL incidence, it is important to consider precisely which factors might be influencing observed trends in Spain. These include: (i) incompleteness of case registration due to lack of participation or poor reporting practices by participating hospitals, particularly in the early period; (ii) changes in the definition of NHL, which meant that, in certain subtypes of NHL, cases were recruited from what were previously defined as benign lymphoid disorders, e.g. in the updated classification, angioimmunoblastic lymphadenopathy is now deemed to be a peripheral T-cell lymphoma. Moreover, a variant of lymphoma that is found in extranodal mucosa tissue was falsely classed as a pseudolymphoma [23]; (iii) changes in tumour ascertainment, which accounts for the lower proportion of cases with pathological confirmation in the earlier period; (iv) an increase in the detection of NHL cases due to widespread advances in diagnostic technology (diagnostic imaging tools) [24]. Indeed, new immunological concepts and methods developed over the past three decades have revolutionised diagnostic criteria, classification and understanding of NHL; (v) changes in the prevalence of related diseases, such as AIDS, and in other risk factors. Relative risk of NHL is high in persons with AIDS, with risk estimates of 120 for males and 190 for females in selected registration regions in Spain [25]. The effect of AIDS on the overall increase in NHL in Spain is less obvious, however. AIDS-related lymphomas represent only a small proportion of NHLs, and there is a background of increasing NHL incidence among individuals without AIDS, which is clearly visible in the oldest age group.

Our results show that the steady increase in NHL incidence observed in Spain during the 1970s and 1990s has come to a halt in recent years and that the subsequent pattern of evolution differs according to age group. Examination of NHL incidence in Spain by age group reveals that NHL rates remained stable in children and young adults (ages 0–24 years), in contrast to the results of the European ACCIS study [26], which reported a weak increase in incidence of NHL among children and adolescents. Nevertheless, it is no easy task to quantify the contribution of improvements in registration to the reported increase in NHL in Europe, and the established major risk factors do not seem to affect incidence in these young age groups.

Incidence rates of NHL among young adults aged 25–39 years rose dramatically in the mid-1980s, followed by an abrupt downturn in the mid-1990s. As noted above, the striking increase in NHL in the mid-1980s coincided with the HIV epidemic. The stabilisation and subsequent decline in NHL rates in the 1990s observed among young adults is probably also explained, to a large extent, by AIDS incidence patterns. Groups at high risk of developing HIV/AIDS tend to be males in the 25- to 49-year age range, something that may go some way to explain part of the high incidence of NHL among young adult men. The AIDS epidemic decreased sharply in most risk groups after 1996. This decline was mainly attributed to the introduction of potent antiretroviral therapies [27] that delay onset of AIDS in the HIV-infected population [28] and lengthen survival among AIDS sufferers. Furthermore, due to the predominance of drug users among AIDS patients in Spain, changes in drug-use practices aimed at avoiding risk of HIV transmission could explain the marked fall-off in AIDS incidence in recent birth cohorts [29].

The decline in NHL rates among young adults has been described in the USA [17, 22], in Nordic countries [16] and, more recently, in Catalonia [30]. The US study reports a decrease in the incidence of NHL subtypes associated with AIDS. In Catalonia, the population-attributable fraction of HIV in the incidence of NHL decreased from 20% in the period 1988–89 to 6.8% in the period 1998–99 [25].

The explanation for the slowing in the rate of increase observed for adults aged >40 years during the 1990s is more elusive. Improvements in diagnostic methods, which may explain some of the increasing incidence observed among older persons in the 1970s and 1980s, are unlikely to be related to a slowing in the trend. The tendency towards stabilisation in incidence of NHL could reflect full implementation of modern diagnostic procedures or recent saturation of general population exposure to relevant risk factors. While the possibility of a stabilisation or saturation in the exposure level to relevant risk factors is an alternative explanation, the fact that the causes of NHL are largely unknown renders it difficult to speculate just which factors may have contributed to the observed levelling-off. Among environmental exposure, pesticides have been related to the incidence of NHL [31], and the regulation of or ban on the use of chlorophenols, certain phenoxy herbicides and some ‘persistent organic pollutants’ in Spain in the 1970s [32] could have contributed to the stabilisation of NHL incidence in Spain. In line with this model, NHL rates would be expected to remain at current levels.

The results of this study are strengthened both by the inclusion of the latest available data from all population-based Spanish cancer registries with a minimum of 10 years of uninterrupted registration, resulting in ∼20 000 registered cases of NHL, and by the use of appropriate statistical methods to detect trend changes. Nevertheless, several limitations must be considered when it comes to interpreting our findings. The population covered by the registries is located mainly in the east of Spain, and thus the observed trend in NHL incidence might not be generalisable to the western and central parts of the country. Heterogeneity in data quality across registries may have adversely affected our results, particularly in the latter part of follow-up, in which the change in the previously rising trend was detected. During the 1998–2002 period, however, the percentage of histologically confirmed NHL cancer cases was high, ranging from 86% to 97%, whereas the percentage of those registered solely on the basis of death certificates ranged from 0.6% to 4.0% [9]. In addition, the fact that our study period ended in 2004 means that there is likely to be some residual reporting delay. Finally, a major limitation of these interpretations of NHL incidence trends involves disease heterogeneity. NHL comprises many histologically, and perhaps biologically, distinct lymphocyte malignancies [33–36], each with poorly understood but putatively different aetiologies [37], and it is therefore not unreasonable to infer that this and other epidemiological analyses treating NHL as a single entity may well conceal informative trends for particular subtypes [37, 38]. We analysed all NHL cases jointly so as to ensure continuity and comparability with previous studies of NHL incidence trends which reported steady increases over time.

To sum up, we describe a decline in NHL incidence rates in Spain which particularly affected the 25–39 age group. This trend is probably related to the HIV epidemic, in which exposure to and the effect of the same widespread risk factors first increased and then possibly decreased, a reason why NHL rates should be expected to continue declining in this age group in Spain. In the age strata above 40 years, however, there has been a marked attenuation of the epidemic increase in NHL in Spain. Insofar as interpretation of NHL trends is concerned, the tendency towards stabilisation in NHL incidence reflects full implementation of modern diagnostic procedures and/or a recent stabilisation or decrease in general population exposure to unknown, albeit relevant, risk factors. In line with this model, NHL rates would thus be expected to remain at their current level.

funding

This study was supported by the Consortium for Biomedical Research in Epidemiology and Public Health (CIBER en Epidemiología y Salud Pública – CIBERESP) (AC07-005 to M.P., PM07-004 to R.P.-B.), the Carlos III Institute of Health (ISCIII–CIBERESP Collaboration Agreement ‘Acción Transversal del Cancer’) and the Spanish Network of Cancer Research Groups (RTICC RD06/0020/0089).

disclosures

The authors have indicated no conflicts of interest.

We should like to thank Ms Cristina Linares for her invaluable support with the statistical analyses. Other members of the Non-Hodgkin's Lymphoma Working Group: M. Dorronsorro [Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP) and Public Health Department of Gipuzkoa, Basque Country Regional Authority, San Sebastián]; P. Giraldo (Department of Haematology, Miguel Servet University Teaching Hospital, Zaragoza); J. M. Díaz García (Cuenca Cancer Registry, Health and Social Welfare Authority, Castile–La Mancha); G. Gutiérrez (Albacete Cancer Registry, Health and Social Welfare Authority, Castile–La Mancha); L. Rodríguez (Asturias Cancer Registry, Directorate-General of Public Health and Participation, Health and Medical Services Authority, Asturias); E. Pérez de Rada [Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP) and Navarre Cancer Registry, Navarre Public Health Institute, Pamplona, Spain].

References

1.
Domingo-Domenech
E
de Sanjose
S
Gonzalez-Barca
E
, et al.  . 
Post-transplant lymphomas: a 20-year epidemiologic, clinical and pathologic study in a single center
Haematologica
 , 
2001
, vol. 
86
 (pg. 
715
-
721
)
2.
Gallagher
B
Wang
Z
Schymura
MJ
, et al.  . 
Cancer incidence in New York State acquired immunodeficiency syndrome patients
Am J Epidemiol
 , 
2001
, vol. 
154
 (pg. 
544
-
556
)
3.
de Sanjose
S
Dickie
A
Alvaro
T
, et al.  . 
Helicobacter pylori and malignant lymphoma in Spain
Cancer Epidemiol Biomarkers Prev
 , 
2004
, vol. 
13
 (pg. 
944
-
948
)
4.
de Sanjose
S
Nieters
A
Goedert
JJ
, et al.  . 
Role of hepatitis C virus infection in malignant lymphoma in Spain
Int J Cancer
 , 
2004
, vol. 
111
 (pg. 
81
-
85
)
5.
de Sanjose
S
Benavente
Y
Vajdic
CM
, et al.  . 
Hepatitis C and non-Hodgkin lymphoma among 4784 cases and 6269 controls from the International Lymphoma Epidemiology Consortium
Clin Gastroenterol Hepatol
 , 
2008
, vol. 
6
 (pg. 
451
-
458
)
6.
Kogevinas
M
Kauppinen
T
Winkelmann
R
, et al.  . 
Soft tissue sarcoma and non-Hodgkin's lymphoma in workers exposed to phenoxy herbicides, chlorophenols, and dioxins: two nested case-control studies
Epidemiology
 , 
1995
, vol. 
6
 (pg. 
396
-
402
)
7.
van Balen
E
Font
R
Cavalle
N
, et al.  . 
Exposure to non-arsenic pesticides is associated with lymphoma among farmers in Spain
Occup Environ Med
 , 
2006
, vol. 
63
 (pg. 
663
-
668
)
8.
Hartge
P
Wang
SS
Bracci
PM
, et al.  . 
Schottenfeld
D
Fraumeni
JF
Non-Hodgkin-lymphoma
Cancer Epidemiology and Prevention
 , 
2006
3rd edn
New York, NY
Oxford University Press
(pg. 
898
-
918
)
9.
Curado
MP
Edwards
B
Shin
HR
, et al.  . 
Cancer Incidence in Five Continents, Vol. IX. (IARC Scientific Publications No. 160)
 , 
2007
Lyon, France
IARC
10.
Cartwright
R
Brincker
H
Carli
PM
, et al.  . 
The rise in incidence of lymphomas in Europe 1985–1992
Eur J Cancer
 , 
1999
, vol. 
35
 (pg. 
627
-
633
)
11.
Groves
FD
Linet
MS
Travis
LB
Devesa
SS
Cancer surveillance series: non-Hodgkin's lymphoma incidence by histologic subtype in the United States from 1978 through 1995
J Natl Cancer Inst
 , 
2000
, vol. 
92
 (pg. 
1240
-
1251
)
12.
Liu
S
Semenciw
R
Mao
Y
Increasing incidence of non-Hodgkin's lymphoma in Canada, 1970–1996: age-period-cohort analysis
Hematol Oncol
 , 
2003
, vol. 
21
 (pg. 
57
-
66
)
13.
Pollan
M
Lopez-Abente
G
Moreno
C
, et al.  . 
Rising incidence of non-Hodgkin's lymphoma in Spain: analysis of period of diagnosis and cohort effects
Cancer Epidemiol Biomarkers Prev
 , 
1998
, vol. 
7
 (pg. 
621
-
625
)
14.
Adamson
P
Bray
F
Costantini
AS
, et al.  . 
Time trends in the registration of Hodgkin and non-Hodgkin lymphomas in Europe
Eur J Cancer
 , 
2007
, vol. 
43
 (pg. 
391
-
401
)
15.
Fisher
SG
Fisher
RI
The epidemiology of non-Hodgkin's lymphoma
Oncogene
 , 
2004
, vol. 
23
 (pg. 
6524
-
6534
)
16.
Sandin
S
Hjalgrim
H
Glimelius
B
, et al.  . 
Incidence of non-Hodgkin's lymphoma in Sweden, Denmark, and Finland from 1960 through 2003: an epidemic that was
Cancer Epidemiol Biomarkers Prev
 , 
2006
, vol. 
15
 (pg. 
1295
-
1300
)
17.
Clarke
CA
Undurraga
DM
Harasty
PJ
, et al.  . 
Changes in cancer registry coding for lymphoma subtypes: reliability over time and relevance for surveillance and study
Cancer Epidemiol Biomarkers Prev
 , 
2006
, vol. 
15
 (pg. 
630
-
638
)
18.
McCullagh
P
Nelder
JA
Generalized Linear Models
 , 
1989
London, UK
Chapman & Hall
19.
Kim
HJ
Fay
MP
Feuer
EJ
Midthune
DN
Permutation tests for joinpoint regression with applications to cancer rates
Stat Med
 , 
2000
, vol. 
19
 (pg. 
335
-
351
)
20.
Pastor-Barriuso
R
Guallar
E
Coresh
J
Transition models for change-point estimation in logistic regression
Stat Med
 , 
2003
, vol. 
22
 (pg. 
1141
-
1162
)
21.
Pollan
M
Pastor-Barriuso
R
Ardanaz
E
, et al.  . 
Recent Changes in Breast Cancer Incidence in Spain, 1980–2004
J Natl Cancer Inst
 , 
2009
, vol. 
101
 (pg. 
1584
-
1591
)
22.
Eltom
MA
Jemal
A
Mbulaiteye
SM
, et al.  . 
Trends in Kaposi's sarcoma and non-Hodgkin's lymphoma incidence in the United States from 1973 through 1998
J Natl Cancer Inst
 , 
2002
, vol. 
94
 (pg. 
1204
-
1210
)
23.
Saltzstein
SL
Pulmonary malignant lymphomas and pseudolymphomas classification, therapy and prognosis
Cancer
 , 
1963
, vol. 
16
 (pg. 
928
-
955
)
24.
Lázaro
P
Evaluación de Servicios Sanitarios: La alta Tecnologia Médica en España
1990
Madrid, Spain
Fondo de Investigación Sanitaria
25.
Galceran
J
Marcos-Gragera
R
Soler
M
, et al.  . 
Cancer incidence in AIDS patients in Catalonia, Spain
Eur J Cancer
 , 
2007
, vol. 
43
 (pg. 
1085
-
1091
)
26.
Izarzugaza
MI
Steliarova-Foucher
E
Martos
MC
Zivkovic
S
Non-Hodgkin's lymphoma incidence and survival in European children and adolescents (1978–1997): report from the Automated Childhood Cancer Information System project
Eur J Cancer
 , 
2006
42
(pg. 
2050
-
2063
)
27.
Collier
AC
Coombs
RW
Schoenfeld
DA
, et al.  . 
Treatment of human immunodeficiency virus infection with saquinavir, zidovudine, and zalcitabine. AIDS Clinical Trials Group
N Engl J Med
 , 
1996
, vol. 
334
 (pg. 
1011
-
1017
)
28.
Moore
RD
Chaisson
RE
Natural history of HIV infection in the era of combination antiretroviral therapy
AIDS
 , 
1999
, vol. 
13
 (pg. 
1933
-
1942
)
29.
Castilla
J
Pollan
M
Lopez-Abente
G
The AIDS epidemic among Spanish drug users: a birth cohort-associated phenomenon
Am J Public Health
 , 
1997
, vol. 
87
 (pg. 
770
-
774
)
30.
Marcos-Gragera
R
Guma
J
de Sanjose
S
Analysis of cancer incidence, survival and mortality according to the main tumoral localizations, 1985–2019: non-Hodgkinian lymphomas
Med Clin (Barc)
 , 
2008
, vol. 
131 Suppl 1
 (pg. 
72
-
77
)
31.
Fritschi
L
Benke
G
Hughes
AM
, et al.  . 
Occupational exposure to pesticides and risk of non-Hodgkin's lymphoma
Am J Epidemiol
 , 
2005
, vol. 
162
 (pg. 
849
-
857
)
32.
Porta
M
Puigdomenech
E
Ballester
F
, et al.  . 
[Studies conducted in Spain on concentrations in humans of persistent toxic compounds]
Gac Sanit
 , 
2008
, vol. 
22
 (pg. 
248
-
266
)
33.
Harris
NL
Jaffe
ES
Diebold
J
, et al.  . 
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
Ann Oncol
 , 
1999
 
10: 1419–1432
34.
Harris
NL
Jaffe
ES
Diebold
J
, et al.  . 
Lymphoma classification–from controversy to consensus: the R.E.A.L. and WHO Classification of lymphoid neoplasms
Ann Oncol
 , 
2000
 
11 Suppl 1: 3–10
35.
Marcos-Gragera
R
Vilardell
L
Izquierdo
A
, et al.  . 
Population-based incidence of lymphoid neoplasms by histological subtypes in Girona (Spain), 1994–2001
Med Clin (Barc)
 , 
2006
, vol. 
126
 (pg. 
5
-
12
)
36.
Morton
LM
Wang
SS
Devesa
SS
, et al.  . 
Lymphoma incidence patterns by WHO subtype in the United States, 1992–2001
Blood
 , 
2006
, vol. 
107
 (pg. 
265
-
276
)
37.
Herrinton
LJ
Epidemiology of the Revised European-American Lymphoma Classification subtypes
Epidemiol Rev
 , 
1998
, vol. 
20
 (pg. 
187
-
203
)
38.
Groves
FD
Linet
MS
Travis
LB
Devesa
SS
Cancer surveillance series: non-Hodgkin's lymphoma incidence by histologic subtype in the United States from 1978 through 1995
J Natl Cancer Inst
 , 
2000
, vol. 
92
 (pg. 
1240
-
1251
)

Author notes

Other members of the Non-Hodgkin's Lymphoma Working Group are listed in he Acknowledgements.