Cancer Epidemiology 58 (2019) 8–11 Contents lists available at ScienceDirect Cancer Epidemiology journal homepage: www.elsevier.com/locate/canep Population-based incidence of lymphoid neoplasms: Twenty years of T epidemiological data in the Girona province, Spain ⁎ Marta Solansa,b,c, , Anna Fàbregac, David Moreac, Carmen Auñon-Sanzd, Isabel Granadae, Josep Maria Roncerof, Antonio Blancof, Nicholas Kelleherf, Joan Buchf, Marc Saeza,b, Rafael Marcos-Grageraa,b,c a Centro de Investigación Biomédica en Red: Epidemiología y Salud Pública (CIBERESP), Av. Monforte de Lemos 3-5, 28029 Madrid, Spain b Research Group on Statistics, Econometrics and Health (GRECS), University of Girona, C/ Universitat de Girona 10, 17003 Girona, Spain c Epidemiology Unit and Girona Cancer Registry, Oncology Coordination Plan, Catalan Institute of Oncology, Carrer del Sol 15, 17004 Girona, Spain d Radiation Oncology Service, Josep Trueta University Hospital, Catalan Institute of Oncology, Avinguda de França, S/N, 17007 Girona, Spain e Hematological Laboratory Service, Germans Trias i Pujol University Hospital, Catalan Institute of Oncology, Josep Carreras Leukaemia Research Institute, Ctra. de Can Ruti Camí de les Escoles S/N, 8916 Badalona, Spain f Hematological Service, Josep Trueta University Hospital, Catalan Institute of Oncology, Avinguda de França, S/N, 17007 Girona, Spain A R T I C LE I N FO A B S T R A C T Keywords: Background: The aim of this study was to describe incidence patterns of lymphoid neoplasms in the Girona Lymphoid neoplasms province (Spain) (1996–2015), and to predict the number of cases in Spain during 2020. Population-based Methods: Data were extracted from the Girona cancer registry. Incident cases were classified using the ICD-O-3, Incidence third revision, and grouped according to the WHO 2008 classification scheme. Age-adjusted incidence rates to WHO 2008 the European standard population (ASRE) were estimated and incidence trends were modeled using Joinpoint. Spain Results: 4367 lymphoid neoplasms were diagnosed in the Girona province. The ASRE for overall lymphoma was 37.1 (95% CI: 36.0; 38.2), with a marked male predominance in almost all subtypes. During 1996–2015, in- cidence trends remained stable for broader lymphoma categories. According to our predictions, 17,950 new cases of LNs will be diagnosed in Spain in 2020. Conclusions: This ‘real-world’ data will provide valuable information to better inform etiological hypotheses and plan future health-care services. 1. Introduction 2. Material and methods Lymphoid neoplasms (LNs) are a heterogeneous group of hemato- Data were extracted from the population-based Girona cancer reg- logical malignancies presenting diverse etiology, presentation and istry, covering a population of 738,976 inhabitants in 2015. Incident outcomes [1]. Changing classification schemes [i.e. the Working For- cases were registered using the International Classification of Diseases mulation (WF-1982), the Revised European-American Lymphoma for Oncology, third edition (ICD-O-3) and grouped according to the (REAL, 1994) and the World Health Organization (WHO, 2001, 2008 WHO 2008 classification scheme. Age-adjusted incidence rates to the and 2016) classifications] and scarcity of subtype-specific epidemiolo- European standard population (ASRE) were estimated and Joinpoint gical data hamper international comparisons. The aim of this study was regression modeling was used to examine temporal trends in age- to describe incidence patterns of LNs in the Girona province (Spain) standardized rates. Sex- and age-specific projections of cases in Spain in (1996–2015) according to the WHO 2008 classification, and to predict 2020 were estimated, based on the National Statistics Institute of Spain the number of LNs in Spain during 2020. projections of population. Abbreviations: ASRE, age-adjusted incidence rate to the European population; APC, annual percent change; ICD-O-3, International Classification of Diseases for Oncology, third edition; LN, lymphoid neoplasm; WHO, World Health Organization ⁎ Corresponding author at: Campus de Montilivi, Carrer de la Universitat de Girona 10, 17003 Girona, Spain. E-mail address: martasolans@gmail.com (M. Solans). https://doi.org/10.1016/j.canep.2018.11.001 Received 27 September 2018; Received in revised form 31 October 2018; Accepted 1 November 2018 Available online 10 November 2018 1877-7821/ © 2018 Elsevier Ltd. All rights reserved. Table 1 Lymphoid neoplasms incidence rates by subtype in Girona, Spain (1996–2015). Subtype ICD-O-3 codes N % Annual N Median age (years) CR ASRE13 (CI 95%) Sex ratio1 M. Solans et al. Lymphoid neoplasm, total 4367 100.00 218 67.6 33.42 37.08 (35.98; 38.21) 1.54 1) Hodgkin lymphoma 364 8.34 18 39.7 2.79 2.72 (2.44; 3.02) 1.59 1.1 Classical Hodgkin lymphoma 336 92.31 17 39.1 2.57 2.50 (2.24; 2.79) 1.55 1.1.1 Lymphocyte-rich classical Hodgkin lymphoma 9651 21 6.25 1 34.4 0.16 0.15 (0.09; 0.23) 6.25 1.1.2 Nodular sclerosis classical Hodgkin lymphoma 9663-9667 214 63.69 11 36.7 1.64 1.56 (1.36; 1.79) 1.13 1.1.3 Mixed cellularity classical Hodgkin lymphoma 9652 66 19.64 3 46.4 0.51 0.51 (0.39; 0.65) 2.57 1.1.4 Lymphocyte-depleted classical Hodgkin lymphoma 9653-9655 5 1.49 0 52.5 0.04 0.04 (0.01; 0.09) NA 1.1.5 Classical Hodgkin lymphoma, NOS 9650,9661-9662 30 8.93 2 53.3 0.23 0.24 (0.16; 0.35) 2.06 1.2 Nodular lymphocyte predominant Hodgkin lymphoma 9659 28 7.69 1 43.8 0.21 0.22 (0.15; 0.32) 2.07 Non-Hodgkin lymphoma 3886 88.99 194 68.6 29.74 33.35 (32.3; 34.42) 1.54 2) Precursor lymphoid neoplasms 210 4.81 10 25 1.61 1.64 (1.42; 1.88) 1.53 2.1 B-lymphoblastic leukemia/lymphoma 9728, 9811-9818, 9836 138 65.71 7 18.2 1.06 1.08 (0.91; 1.28) 1.25 2.2 T-lymphoblastic leukemia/lymphoma 9729, 9837 46 21.90 2 20 0.35 0.34 (0.25; 0.46) 3.53 2.3 Lymphoblastic leukemia/lymphoma, NOS 9727, 9835 26 12.38 1 80 0.20 0.22 (0.14; 0.32) 1.37 3) Mature B-cell neoplasms 3413 78.15 171 69.7 26.12 29.5 (28.51; 30.51) 1.48 3.1 Chronic lymphocytic leukemia/small lymphocytic lymphoma 9670, 9823 751 22.00 38 72.4 5.75 6.62 (6.15; 7.11) 1.77 3.2 B-cell prolymphocytic leukemia 9833 – – – – – – – 3.3 Mantle cell lymphoma 9673 105 3.08 5 68.1 0.80 0.92 (0.75; 1.12) 4.37 3.4 Lymphoplasmacytic lymphoma/ Waldenström’s Macroglobulinemia 9671, 9761 128 3.75 6 73.5 0.98 1.13 (0.94; 1.34) 2.16 3.5 Diffuse large B-cell lymphoma 9678-9680,9688, 9684, 9712, 9735, 733 21.48 37 66.3 5.61 6.18 (5.74; 6.65) 1.4 9737,9738 3.6 Burkitt lymphoma/leukemia 9687, 9826 60 1.76 3 37.9 0.46 0.47 (0.36; 0.61) 1.91 3.7 Marginal lymphoma 339 9.93 17 68.7 2.59 2.92 (2.62; 3.25) 1.09 3.7.1 Splenic marginal zone lymphoma 9689 67 19.76 3 69.2 0.51 0.58 (0.45; 0.74) 1.46 3.7.2 Extranodal marginal zone lymphoma 9699 (excluding C77.0-C77.9) 243 71.68 12 68 1.86 2.09 (1.83; 2.37) 1.07 9 3.7.3 Nodal marginal zone lymphoma 9699 (C77.0-C77.9) 29 8.55 1 75.8 0.22 0.25 (0.17; 0.36) 0.60 3.8 Follicular lymphoma 9597, 9690, 9691, 9695, 9698 441 12.92 22 62.1 3.37 3.74 (3.4; 4.11) 1.07 3.9 Hairy cell leukemia 9940 32 0.94 2 58.8 0.24 0.26 (0.18; 0.37) 6.86 3.10 Plasma cell neoplasms 820 24.03 41 72.7 6.27 7.22 (6.73; 7.73) 1.41 3.10.1 Solitary plasmocytoma of bone 9731 36 4.39 2 69 0.28 0.31 (0.22; 0.43) 2.10 3.10.2 Extraosseus plasmocytoma 9734 13 1.59 1 76.9 0.10 0.12 (0.07; 0.2) 2.25 3.10.3 Plasma cell myeloma/leukemia 9732-9733 771 94.02 39 72.8 5.90 6.79 (6.32; 7.29) 1.38 3.11 Heavy chain disease 9762 – – – – – – – 3. 12 B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and classical 9596 4 0.12 0 44.5 0.03 0.03 (0.01; 0.08) 1.33 HL 4) Mature-T-cell and NK-cell neoplasms 263 6.02 13 64.7 2.01 2.22 (1.96; 2.51) 2.59 4.1 Mycosis fungoides/Sezary syndrome 9700, 9701 81 30.80 4 64.2 0.62 0.69 (0.55; 0.86) 2.78 4.2 Peripheral T/NK-cell lymphoma 130 49.43 6 60.50 0.99 1.08 (0.91; 1.30) 2.95 4.2.1 Peripheral T-cell lymphoma, NOS 9702 60 46.15 3 64.2 0.46 0.5 (0.38; 0.65) 2.52 4.2.2 Angioimmunoblastic T-cell lymphoma 9705 29 22.31 1 70.6 0.22 0.26 (0.17; 0.37) 3.23 4.2.3 Subcutaneous panniculitis-like T-cell lymphoma 9708 2 1.54 0 42 0.02 0.01 (0.00; 0.05) 0 4.2.4 Anaplastic large cell lymphoma, ALK-positive 9714 18 13.85 1 37 0.14 0.14 (0.08; 0.22) 8.33 4.2.5 Hepatosplenic T-cell lymphoma 9716 3 2.31 0 42.5 0.02 0.02 (0.00; 0.07) NA 4.2.6 Enteropathy-associated T-cell lymphoma 9717 1 0.77 0 62.5 0.01 0.01 (0.00; 0.05) 0 4.2.7 Primary cutaneous gamma-delta T-cell lymphoma 9726 – – – – – – – 4.2.8 Primary cutaneous T-cell lymphoma, NOS 9709 16 12.31 1 73 0.12 0.13 (0.07; 0.22) 3.14 4.2.9 Systemic EBV-positive T-cell lymphoproliferative disease of childhood 9724 – – – – – – – 4.2.10 Hydroa vacciniforme-like lymphoma 9725 1 0.77 0 17.5 0.01 0.01 (0.00; 0.05) NA 4.3 Adult T-cell leukemia/lymphoma 9827 3 1.14 0 82.5 0.02 0.02 (0.00; 0.07) 0.67 4.4 Extranodal NK/Tcell lymphoma, nasal type 9719 11 4.18 1 66.2 0.08 0.09 (0.04; 0.17) 1.86 4.5 T-cell large granular lymphocytic leukemia 9831 22 8.37 1 65 0.17 0.19 (0.12; 0.29) 2.25 4.6 T-cell prolymphocytic leukemia 9834 3 1.14 0 62.5 0.02 0.03 (0.01; 0.08) 0 4.7 Aggressive NK cell leukemia 9948 1 0.38 0 22.5 0.01 0.01 (0.00; 0.05) NA 4.8 Primary cutaneous CD30 + T-cell lymphoproliferative disorders 9718 12 4.56 1 70 0.09 0.10 (0.05; 0.18) 2.33 (continued on next page) Cancer Epidemiology 58 (2019) 8–11 M. Solans et al. Cancer Epidemiology 58 (2019) 8–11 Sex ratio1 Table 2 Trends in lymphoid neoplasms incidence rates by major subtypes in Girona, 1.42 Spain (1996–2015). Period APC CI 95% 1.01 (0.83; 1.21) ASRE13 (CI 95%) Lymphoid neoplasms 1996-2015 0.1 (-0.6; 0.8) Hodgkin lymphoma 1996-2015 0.7 (-1.4; 2.9) Precursor lymphoid neoplasms 1996-2015 −1.5 (-4.1; 1.2) Mature B-cell neoplasms 1996-2015 0.3 (-0.5; 1.2) Chronic lymphocytic leukemia/small 1996-2015 −0.1 (-1.4; 1.3) lymphocytic lymphoma Mantle cell lymphoma 1996-2015 1.8 (-2.8; 6.6) 0.90 Lymphoplasmacytic lymphoma/ 1996-2015 1.2 (-1.3; 3.9) CR Waldenström’s macroglobulinemia Diffuse large B-cell lymphoma 1996-2015 0.5 (-1.1; 2.0) Median age (years) Burkitt lymphoma/leukemia 1996-2015 −3.3 (-7.9; 1.6) Marginal lymphoma 1996-2015 0.4 (-0.9; 1.7) Follicular lymphoma 1996-2015 1.2 (-1.2; 3.6) Plasma cell neoplasms 1996-2015 0.3 (-1.4; 1.9) 77.9 Mature T-cell and NK-cell neoplasmns 1996-2015 1.7 (-1.9; 5.6) Lymphoid neoplasms, NOS 1996-2015 −7.4* (-11.2; -3.3) Annual N APC, annual percent change; NOS, not otherwise specified. Calculated only for major lymphoma categories and most incident mature B-cell 6 neoplasms. * p-value < 0.05. 2.68 % 3. Results 117 N 4367 LNs incident cases (59.7% men) were diagnosed in the Girona province. Among them, 364 (8.3%) were Hodgkin-lymphoma, 210 (4.8%) precursor lymphoid neoplasms, 3413 (78.2%) mature B-cell neoplasms, 263 (6.0%) mature T-cell and NK-cell neoplasms, and 117 (2.7%) lymphoid neoplasms not otherwise specified (NOS). Detailed 9590, 9591, 9820, 9970, 9971 information can be found in Table 1. In brief, the median age at diag- N, total cases; CR, crude rate; ASRE, age-standardized incidence rate using European 2013 standard population. nosis ranged from 25 to 77.9 years according to the major LNs subtypes. Overall in both sexes, the top five most frequent entities were: plasma cell neoplasm (820), chronic lymphocytic leukemia/small lymphocytic lymphoma (751), diffuse large B-cell lymphoma (733), follicular lym- ICD-O-3 codes phoma (441) and marginal lymphoma (339). The LNs crude rate (CR) was 33.4 and ASRE was 37.1 (95% confidence interval (CI): 36.0; 38.2), 45.7 (95% CI: 43.9; 47.6) in men and 29.7 (95% CI: 28.4; 31.1) in women. There was a marked male predominance; the incidence sex ratio (male/female) ranged from 1.1 for follicular and marginal lym- phomas to 6.9 for hairy cell leukemia. During 1996–2015, no statistically significant variations in in- cidence trends were found for LNs [annual percentage change (APC): 0.1 (95% CI: −0.6; 0.8)], nor for broader lymphoma categories (Table 2). Only the LNs NOS subtype category decreased, evidencing the improved diagnostic specificity for these malignancies during the last years. According to our predictions, 17,950 new cases of LNs will be di- agnosed in Spain in 2020, of which 1264 cases will be Hodgkin lym- phoma, 738 precursor lymphoid neoplasms, 14,361 mature B-cell neoplasms (i.e. 3248 chronic lymphocytic leukemia/small lymphocytic lymphoma, 445 mantle cell lymphoma, 544 lymphoplasmacytic lym- phoma/Waldenström's macroglobulinemia, 3025 diffuse large B-cell lymphoma, 221 Burkitt lymphoma/leukemia, 1394 marginal lym- phoma, 1811 follicular lymphoma, 129 hairy cell leukemia, and 3531 Sex ratio (M/F) based on ASRE. plasma cell neoplasms), 1067 mature T-cell and NK-cell neoplasms and 5) Lymphoid neoplasms, NOS 521 LNs NOS (data not shown). 4. Discussion Table 1 (continued) This paper presents epidemiological data of LNs in the province of Girona (Spain) during a 20-year period. Incidence rates for the most Subtype frequent subtypes were in accordance with those reported in France (1980–2009) [2], United Kingdom (2004–2014) [3], Europe (2000–2002) [4], and generally lower in comparison to those from the 1 10 M. Solans et al. Cancer Epidemiology 58 (2019) 8–11 United States (projected incidence in 2016) [5] or Australia information to better inform etiological hypotheses and plan future (1982–2006) [6]. Regarding specific entities, we reported higher rates health-care services. of mantel cell lymphoma (ASRE = 0.92), to the date only linked to few genetic and environmental risk factors (i.e. atopy, allergy or farm life) Author contribution [7], which merit further research. In the same vein, Burkitt lymphoma/ leukemia incidence (ASRE = 0.47) was particularly high in our region, • Study conception and design: RMG, MSo a pattern largely reported in other Southern European regions, yet • Acquisition of data: RMG, AF, IG, JMR, AB, NK, JB unexplained by well-stablished etiological factors [8]. Similarly, we • Analysis of data: AF, DM reported higher rates of chronic lymphocytic leukemia/small lympho- • Interpretation of data: MSo, RMG, AF, DM, CA, MSa cytic lymphoma (ASRE = 6.62), mainly attributable to a higher com- • Manuscript writing: MSo pleteness of our cancer registry for this entity rather than to a real peak • Critical review of the article and final approval of the article: all of incidence in our region. Chronic lymphocytic leukemia – as well as authors Waldenström's macroglobulinemia – have been shown to be under- reported by cancer registries given that they are prone to be indolent Funding and their diagnosis is not based on tissue pathology [9]. To ensure a complete coverage of all chronic lymphocytic leukemia cases in our This work was supported by the Spanish Ministry of Health (FIS region, we recently performed review of alternative sources of in- PI15/00966) and by CIBERESP (PhD contract to MS). formation (e.g. flow cytometry and hematologists databases) and evi- denced a 18.2% of underreported cases during 1998–2013 [10]. Non- Conflict of interest specialized cancer registries thus, should make additional efforts to ensure the surveillance of these malignancies is entirely accurate. None. 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