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Epidemiological data from the registry of patients with myelodysplastic syndrome in a single hospital center of Romania
Leukemia Research 33 (2009) 1556–1561
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Epidemiological data from the registry of patients with myelodysplastic syndrome in a single hospital center of Romania Radu Gologan ∗ , Daniela Georgescu, Aurelia Tatic, Ioana Radulescu, Didona Vasilache Center of Hematology and Bone Marrow Transplantation, Fundeni Clinical Institute, 258 Fundeni Road, sector 2, Bucharest 022328, Romania
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Article history: Received 19 November 2008 Received in revised form 17 February 2009 Accepted 27 March 2009 Available online 2 May 2009 Keywords: Myelodysplastic syndrome Epidemiology
a b s t r a c t We present the first Romanian study on the epidemiological characteristics of MDS, based on the data existing in Fundeni Clinical Institute, Hematological Department, Bucharest. The files at diagnosis of the adult patients with primary MDS admitted during the period 1982–2005, recorded in the registration forms provided by the MDS Foundation (USA), represented the primary database. This study indicates an increase in the number of new MDS cases over the period of time investigated. Also, a 10 years lower median age of the patients, a noticeable proportion of young patients and a low proportion of patients ≥81years have been found, which situates our findings in the middle between the Eastern and Western epidemiological reported data on MDS. © 2009 Elsevier Ltd. All rights reserved.
1. Introduction Myelodysplastic syndrome (MDS) comprises a heterogenous group of clonal stem cell disorders characterized by ineffective haemopoiesis with varying degrees of pancytopenia, characteristic morphologic abnormalities and increased susceptibility of transformation into acute leukemia (AL). The diagnosis is based upon morphologic assessment of peripheral blood and bone marrow smears and the exclusion of other causes of cytopenia and dysplasia [1,2]. The epidemiology of MDS has been a non-negligible preoccupation of the researchers all over the world in the past 10–15 years. However, the interest in this field remained in actuality due to the difficulties encountered in establishing with accuracy the real value of the most important epidemiological parameters [3–6]. Although MDS has been increasingly diagnosed in recent years, precise reported data on their prevalence and incidence are still lacking especially in the Eastern part of Europe. We present the first Romanian study on the epidemiology and main characteristics of MDS, based on the already existing registered data of the patients from the Hematological Department of the Fundeni Clinical Institute, Bucharest. 2. Material and method The database has been established from the files of MDS patients hospitalized in the Hematological Department of Fundeni Clinical Institute, Bucharest between 1982 and 2005. The primary data were included in the electronic registration form
∗ Corresponding author. Tel.: +40213180423; fax: +40213180423. E-mail address: [email protected] (R. Gologan). 0145-2126/$ – see front matter © 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.leukres.2009.03.034
supplied by the MDS International Foundation, USA (Chairman Professor J. M. Bennett). The activity started with October 2004 and ended in December 2005. As it was stipulated in the registration form, only the new patients who died, evolved to acute leukemia or have been lost from observation in this period of time have been recorded. The hematological data were reassessed based on well-accepted minimal diagnosis and FAB classification criteria of MDS. The cases with features or overt MDS, secondary either to other disorders or to oncologic therapy, were excluded. The most part of the patients had more than one admission and, therefore, the diagnosis of MDS could be verified over the time. Chronic myelomonocytic leukemia (CMML) was analyzed as a whole entity because no separate data on the proliferative and nonproliferative clinical forms were found in the registration forms utilized. The diagnosis of MDS was established by the centralized cytological examination of smears of peripheral blood and bone marrow. The morphological features of MDS in more than 10% of cells, the percentage of blasts and of ringed sideroblasts (Perls stain) in bone marrow, associated with the blood cell counts and differential, constituted the main reference elements for diagnosis and classification. The bone marrow smears or imprints were visualized, during the whole analyzed period of time, by one trained hematocytologists in the laboratory of the Hematological Department in Fundeni Clinical Institute. The histopathological examination of the bone marrow has been used whenever the cytology was inconclusive or to exclude other diseases. The cytogenetic investigation has been performed sporadically and no conclusive data could be extracted. This test has been routinely performed in MDS in Romania only starting with the year 2008. Sex distribution, age groups, MDS subtypes and annual frequency of new cases were analyzed versus other studies from Germany (Düsseldorf), Spain (Ourense) and China (Shanghai) reported in the medical literature [3,7,8]. The statistical and graphical analysis of the data was performed by means of Excell (Microsoft). The demographic data of the whole Romanian population have been obtained from the official informations of the National Institute of Statistics.
3. Results There were analyzed 424 patients registered with the diagnosis of new primary MDS during 1982–2005. The year 1982 marks the beginning of the morphological diagnosis of MDS in Romania,
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Fig. 1. Distribution by groups of age of MDS patients in Romania versus Germany and China.
shortly after the French–American–British (FAB) group established its diagnosis and classification criteria [1,2].
3.1. Age distribution The median age was 62.3 years and this parameter places Romania in the middle between Western countries such as Germany and Spain (74.7 years) and Eastern countries such as China (49 years). Sixty-six (16.7%) cases were ≤50 years old, 41 (9%) ≤40 years and their median age was 34.7 years. The proportion of the patients over 80 years old was 3.8%. The distribution by the groups of age of the autochthonous and foreign cohorts of patients is shown in Fig. 1. As compared to the data from Germany, a preponderance of group of age <50 years, a small representation of group ≥81 years for Romanian patients and almost the same representation of the group 51–80 years for the two cohorts can be noticed. Regarding the reported Chinese data, an important to “left” deviation of group <60 years for Chinese lot, a preponderance of group 60–80 years for Romanian lot and the similar representation of group ≥81 years for the two lots can be observed. Because the Chinese authors reported a trend of younger age in rural regions of their country, an analysis of the urban/rural (U/R) distribution of the MDS patients in Romania and China has been
performed. It was found an urban preponderance in both countries, but more marked and for all the age groups in Romania (U/R ratio 1.8 versus 1.08). The age distribution of MDS subtypes in Romania versus China indicated a preponderance of RA in the group <50 years in Chinese patients, but a preponderance of RA in the group >50 years in Romanian patients (Fig. 2). 3.2. Gender distribution There was a general preponderance of males in Romanian MDS patients as compared with the other two reported cohorts of patients from Spain and China. The M/F ratio was 1.26 for Romanian, 1.18 for Spanish, and 1.35 for Chinese patients. The corroboration of gender distribution with that by FAB subtypes shows a uniform distribution of the M/F ratio, except for refractory anaemia (RA), where a slight predominance of the females was found, and for refractory anaemia with excess of blasts (AREB), where a more marked predominance of males (M/F 1.94) can be observed (Fig. 3). 3.3. The FAB subtypes distribution The distribution according to the FAB subtypes of the Romanian patients was the following: RA 129 (30.4%), refractory anaemia with ringed sideroblasts (RARS) 66 (15.5%), RAEB 97 (22.8%), RAEB
Fig. 2. Distribution by age and FAB subtypes in Romania versus China.
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Fig. 5. The temporal dynamics of the frequency of the new MDS cases.
Fig. 3. Distribution by gender of FAB subtypes.
in transformation (RAEB-T) 43 (10.1%), chronic myelomonocytic leukemia (CMML) 24 (5.6%), unclassified 71 (15.6%) (Fig. 4). A predominance of RA in the Chinese cohort (43.9%) (p = 0.007) versus Romanian (30.4%) and Spanish (29%) ones was observed. As concerns the frequency of RARS in the Romanian patients (30.4%), it appears intermediary between the Spanish (29%) and Chinese (43.9%) ones, being significantly different from both (p = 0.05). The RAEB frequency is similar in the three cohorts, but RAEB-T frequency is quite different, the Romanian value (10.1%) being placed between the Chinese (21.1%) and Spanish (5%) ones. The frequency of CMML was lower but it was similar in the Romanian (5.6%) and Chinese (5.2%) cohorts versus the Spanish one (16%) (Fig. 4). A synthesis of the characteristics of the Romanian versus West-
ern (Germany + Spain) and Eastern (China) cohorts of patients is presented in Table 1. 3.4. Long term frequency and incidence A more than 5 times increase of the annual median number of new MDS cases over the analyzed period of time (from 1.4 cases/year to 36.2 cases/year) was registered (Fig. 5). Moreover, this trend of the frequency of new cases has manifested even during the past 10 years, when this parameter has practically doubled (from an average 18.5/year to 36.2/year). The increase could not be correlated with the aging of the population because the medium age of all population in Romania has increased with only ∼5 years during the past 25 years (from 56.9 up to 62.7). As regards the temporal dynamics of the FAB subtypes, it indicates that the most evident and continuous increase of frequency
Fig. 4. The distribution of FAB subtypes in Romania versus Spain and China.
Table 1 The synthesis of the characteristics of the Romanian cohort versus those reported by Western countries (Germany + Spain) and Eastern countries (China). The characteristics closer to German and Spanish cohorts
The characteristics closer to the Chinese cohort
The characteristics appearing in the middle
The characteristics similar to the other cohorts
Similar representation in the group of 51–79 years
Higher number of cases in the group < 50 years
The median age
Distribution by gender
Similar representation of RA cases
Small representation of the group ≥80 years Reduced proportion of the CMML cases
The proportion of cases < 50 years The proportion of RARS cases
The proportion of RAEB The overall urban predominance
The proportion of RAEB-T cases
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4. Discussion
Fig. 6. The temporal trend of the frequency of FAB subtypes.
was noted for low risk subtypes (Fig. 6). For reasons unexplained yet, the frequency of the high risk subtypes has stabilized during the past decade and that of CMML increased continuously but much more slowly. The median crude annual incidence was ∼0.5/100,000 and the maximum value was of ∼1/100,000 registered in 2004. It was more marked in the age group of above 60 years and slower in the age group 16–59 (Fig. 7A and B, respectively). The increase did not appear continuously if the analyzed period was short, of 1–3 years, but it was evident when it was analyzed on decades. The value of the incidence could be diminished by bias, due to the accrual of MDS patients from the same region by other, but smaller, hospitals in Bucharest. Also, the patients in stable or good condition, admitted during 2004 and 2005 or even earlier, remained unregistered because they could not be included in any of the three situations required by the registration form used in this study.
The World Health Organization (WHO) only recently recognized MDS as a disease entity [9]. Thus, MDS became reportable in the USA by the Surveillance, Epidemiology, and End Results program (SEER) starting with the year 2001 only. The statistical data have been reported not earlier than in 2006 [10] and they were published in 2008 [11]. Also, the first study in Italy providing information on the incidence and outcome of MDS using population-based data has been reported in 2007 only [12]. Therefore, we agree with the opinion that, at least until now, the pertinent epidemiological data on MDS cannot be obtained from official statistics on morbidity and mortality, but have to be extracted from specialized registers such as regional cancer surveys and hospital-based registries [3,4,13]. Despite many limitations, the majority of the studies have consistently shown that the disorders included in MDS are common hematological malignancies of the elderly, comparable with chronic lymphocytic leukemia and multiple myeloma [14]. Moreover, all the reported data from Western countries indicate that MDS is a disease of elderly people, 75% of patients being >60 years, but the reason underlying the vulnerability of this group of age to develop MDS or the role of aging in this process is not yet explained [14]. The median age at diagnosis is 71 in Germany [3,4], 74.3 in France [15–17], 75 in Italy [12,18], 72.5 in Spain [6,7], 73 in Great Britain [19], 74 years in Sweden [20], 75 years in USA [21–23]. On the contrary, the median age is 57 in Japan [24,25], 49 in China [8,26,27], 59 in Taiwan [cit. by [28]], 56 in Thailand [27], 53 in South Korea [29,30], 44 in Turkey [31], 58 in Central Africa [32], 55 in India, where the greatest incidence of MDS was in the group 41–60 years (44.23%) [33]. A synthetic presentation of these data is made in Table 2. Other data showing lower or higher values, as a median age of 58 in Brazil [34], 64 in Argentina [35] and 64 years in Singapore [36], have to be interpreted with caution due to assumed limitations of these studies. The distribution of the mean age at diagnosis between FAB subgroups observed in Romanian patients was quite similar with the findings of the German and Spanish reports, but different from the Chinese one, which was characterized by a predominance of RA in the young age group [6,8]. This aspect has also been found in other Asian countries [24]. In the present study, the mean age of the MDS patients was 62.3 years, 10 years lower than that of the Western countries and with approximately 10 years higher than that of Eastern countries, which places Romania in the middle between these extreme regions of the world. Other intricated age-linked aspects support this assertion, namely a quite similar representation of the group of age 51–80 in patients from Romania and Germany, but an increased proportion of younger patients in Romania and especially in China,
Fig. 7. The dynamics (A) and the trend (B) of crude and by age groups incidence.
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Table 2 Synthesis of the reported data on the mean age of MDS patients in different Western and Eastern countries. Author, Country, Period, Reference
Mean age at diagnosis
Western countries Aul C et al., Germany, 1975–2000 [4] Germing U et al., Germany, 1991–2001 [3] Nisse C et al., France, 1991–1996 [15] Maynadie M et al., France, 1980–1990 [16] Bauduer F et al., France (Basque region), 1993–1996 [17] Bari A et al., Italy (Province of Modena), 1997–2005 [12] Salvi F et al., Italy (Region of Piedmont) 1999–2004 [18] Sanz GF et al., Spain, 1971–1987 [6] Iglesias Gallego M et al., Spain, 1994–1998 [7] Williamson PJ et al., Great Britain, 1981–1990 [19] Radlund A et al., Sweden, 1978–1992 [20] Matacia-Murphy GM et al., USA, 2001–2003 [21] Ma X et al., USA, 2001–2003 [22] Goldberg SL et al., USA, 2003 [23]
71 72 70 73.5 74.3 76.5 71.5 68 77.5 73 76 75 76 76
Eastern countries Matsuda A et al., Japan, 1976–1997 [25] Oguma S et al., Japan, 1984–1993 [24] Chen B et al., China, 1990–2003 [8] Zhao WL et al., China, 1989–2000 [26] Irons RD et al., China, 2003–2005 [27] Tien HP et al., Taiwan (?) [cit. by [28]] Intragumtornchai T et al., Thailand, 1992–1996 [28] Lee JH et al., South Korea, 1989–2001 [30], Lee DS et al., South Korea, 1996–1999 [29] Paydas S and Kokak R, Turkey (?) [31] Mukiibi JM et al., Central Africa, 1988–1994 [32] Dakshinamurthy AG et al., India, 2003–2004 [33]
57 60 49 50 53 59 56 57 49 44 57 55
as well as a very low representation of the ≥80 in Romanian and Chinese patients. This last finding could be explained by a lower representation of this group of age in the Romanian population and by the reduced access to specialized hematological investigation of this group of age in both countries. The urban predominance of all groups of age in Romania is in accordance with the western reports and different from the rural predominance of the young MDS patients in China [8]. The reason for these regional differences is still unclear, even if an assumed toxic effect of agrochemicals in Turkey has been advanced [37]. Because Romania has been, for the period covered by the present study, a developing country, the influence of some factors as such the exposure to organic solvents, herbicides, insecticides and environmental pollution, like those incriminated in other developing countries, could not be excluded. On the other side, the ethnic difference between Eastern and Western MDS has been assumed by other authors [38]. Ethnic and racial differences in the epidemiology of MDS have been found recently in a study comparing the incidence of MDS in Hispanics versus non-Hispanics and in Whites versus Blacks in USA [11]. This factor could be also incriminated in Romania, considering its geographical position and the oriental migrations in the past, and could explain the “intermediate position” of the main MDS epidemiological data. These particularities of development of Romania could explain the mixed epidemiological features of MDS in this country. Future studies, corroborated with similar regional ones in countries surrounding Romania, could be useful to elucidate the significance of these data and to complete the worldwide epidemiology of MDS. In most series, it has been found that MDS occurs more commonly in men than in women, the sex ratio varying between 1.1 and 2. This feature is more evident in the group of age ≥70 years [4]. The value of M/F ratio of 1.26 found in this study shows the same predominance of males in Romania despite a greater propor-
tion of young patients, where a preponderance of females has been observed [39]. Looking at separate MDS entities, a slightly higher but not statistically significant proportion of females in the group of RA and a comparatively much higher proportion of males in the RAEB group represented particular but unexplained findings in our patients. The distribution according to FAB subtypes in Romanian patients appears similar to that from Western countries concerning RA, RAEB and RAEB-T. It is intermediate between Western and Eastern countries concerning RARS and RAEB-T and lower and similar with Eastern countries concerning CMML. Actually, the predominance of RA and the lower representation of RARS and CMML are considered features of “eastern” MDS [8,24–27]. In the epidemiological studies which examined the incidence of MDS, the crude incidence varies from 2.1 to 12.6 cases per 100,000 population/year but approaches 50 cases per 100,000 in persons over age 70 [3,4,13,16,18–20]. In the USA, the prevalence is estimated to be 55,000 patients and the number of the new cases 10,000–15,000/year [40]. Almost all studies indicated an increase of the incidence of MDS over the time but, especially in the last years, this has been attributed more an improvement in geriatric medical care and diagnosis as well as a general aging of the population, than a real increase [3,4,7,13]. In the present study, the frequency of the new cases has increased 35 times, which continued even during the analyzed past 5-year period, in contrast with the German findings where the number of MDS cases did not increase significantly from the mideighties. The average number of new cases per year in our study was ∼36/year during the last analyzed seven years, close to the highest value from the German study [3]. Because the “aging” of the whole population was only 5 years during the same period of time, we suppose that other factors are involved in case of Romania, and among them, a true increase of the MDS incidence in Romania during the analyzed period was also possible. The value of the maximum incidence of 1 per 100,000 in 2004 is under the inferior limit reported in other Western European countries, but similar with that found in Japan [41]. However, these values could be underestimated due to some limitations of both studies. The low incidence of MDS found in this study, could be explained by the accrual of a part of the MDS patients from the same region by other two smaller hospitals and by underdiagnosis. In Romania, the population is predominantly rural. The rural population had poor socio-economical conditions and, therefore, the addressability of the patients, especially the elderly, to a qualified hospital was limited. Larger scale epidemiological studies, including other hospitals in Bucharest which collect patients from the same limited region South-Muntenia and some adjacent counties, will provide more representative statistical data on the MDS incidence and its dynamics in Romania. No information on the survival rate and prognosis was included because it was considered inaccurate and also not relevant enough for the aim of this study. Moreover, the survival rate did not appear as an important epidemiological parameter for MDS in Romania, because it was influenced by many factors not related to MDS, as the weight and severity of the comorbidities, the socio-economical level and the precarious therapeutical means. However, due to the recent important progress in therapy, this parameter will be more and more relevant in Romania too, encouraged by also by an improved follow-up of the MDS patients in our center, by the extended use of cytogenetics and the implementation of the International Prognostic and WHO Scoring Systems. The presented data emphasize the results of an exclusive general descriptive epidemiological study aimed to emphasize the situation of MDS in Romania, similar with other studies from non-Western countries. Other more specific epidemiological data will be detailed and reported elsewhere.
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Conflict of interest statement The authors declare no competing financial interests. Acknowledgements We thank to Professors J.M. Bennett, U. Germing and D. Bowen for useful discussions. Contributions. RG initiated the study, established the methodology, organized the material, analyzed and interpreted the data, performed the statistic analysis, wrote the manuscript; DG collected the most part of the data, contributed to the systematization and assembly of the material and to its graphic illustration, AT, IR and DV contributed to the collection of data. Work supported by Romanian Ministry of Education and Research (Contract of research CEEX-III, Nr 119/2006). References [1] Bennett JM, Catovsky D, Daniel MT, et al. Proposals for the classification of the myelodysplastic syndromes. Br J Haematol 1982;51:189–99. [2] Bennett JM, Catovsky D, Daniel MT, et al. Proposed revised criteria for the classification of acute myeloid leukemia: a report of the French-American-British Cooperative Group. Ann Int Med 1985;103:620–5. [3] Germing U, Strupp C, Kündgen A, et al. No increase in age-specific incidence of myelodysplastic syndromes. Haematologica 2004;89:905–10. [4] Aul C, Giagounidis A, Germing U. Epidemiological features of myelodysplastic syndromes: results from regional cancer surveys and hospital-based statistics. Int J Hematol 2001;73:405–10. [5] Strom SS, Gu Y, Gruschkus SK, Pierce SA, Estey EH. Risk factors of myelodysplastic syndromes: a case control study. Leukemia 2005;19:1912–8. [6] Sanz GF, Sanz MA, Vallespi T, et al. Two regression models and a scoring system for predicting survival and planning treatment in myelodysplastic syndromes: a multivariate analysis of prognostic factors in 370 patients. Blood 1989;74:409–15. [7] Iglesias Gallego M, Moral Sastre JL, Diz PG, Costa AG, Forteza SR, Santos Mayan JM. Incidence and characteristics of myelodysplastic syndromes in Ourense (Spain) between 1994–1998. Haematologica 2003;88:1197–9. [8] Chen B, Zhao W-L, Jin J, et al. Clinical and cytogenetic features of 508 Chinese patients with myelodysplastic syndrome and comparison with those in Western countries. Leukemia 2005;19:767–75. [9] Harris NL, Jaffe ES, Diebold J, et al. World Health Organization of neoplastic diseases of the hematopoietic and lymphoid tissues: report of the Clinical Advisory Committee Meeting-Arlie House, Virginia, November 1997. J Clin Oncol 1999;17:3835–49. [10] Rollison DE, Hayat M, Smith M, et al. First report of national estimates of the incidence of myelodysplastic syndromes and chronic myeloproliferative disorders from the U.S. SEER Program. In: The 48th ASH Meeting, Orlando (Florida), 2006. Abstract #247. [11] Rollison DE, Howlader N, Smith MT, et al. Epidemiology of myelodysplastic syndromes and chronic myeloproliferative disorders in the United States, 2001–2004, using data from the NAACCR and SEER programs. Blood 2008;112:45–52. [12] Bari A, Marcheselli R, Rashid I, et al. Incidence and outcome of myelodysplastic syndromes in province of Modena. The 49th ASH Annual Meeting, Atlanta (Georgia), 2007, Abstract #4610. [13] Aul C, Germing U, Gattermann N, Minning H. Increasing incidence of myelodysplastic syndromes: real or fictitious? Leuk Res 1998;22:93–100. [14] Greenberg PL. Myelodysplastic syndromes. Clinical and biological advances. Cambridge University Press; 2006. p. 81. [15] Nisse C, Haguenoer JM, Grandbastien B, et al. Occupational and environmental risk factors of the myelodysplastic syndromes in the North of France. Br J Haematol 2001;112:927–35. [16] Maynadie M, Verret C, Moskovtchenko P, et al. Epidemiological characteristics of myelodysplastic syndromes in a well-defined French population. Br J Cancer 1996;74:288–90.
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Epidemiological data from the registry of patients with myelodysplastic syndrome in a single hospital center of Romania Radu Gologan ∗ , Daniela Georgescu, Aurelia Tatic, Ioana Radulescu, Didona Vasilache Center of Hematology and Bone Marrow Transplantation, Fundeni Clinical Institute, 258 Fundeni Road, sector 2, Bucharest 022328, Romania
a r t i c l e
i n f o
Article history: Received 19 November 2008 Received in revised form 17 February 2009 Accepted 27 March 2009 Available online 2 May 2009 Keywords: Myelodysplastic syndrome Epidemiology
a b s t r a c t We present the first Romanian study on the epidemiological characteristics of MDS, based on the data existing in Fundeni Clinical Institute, Hematological Department, Bucharest. The files at diagnosis of the adult patients with primary MDS admitted during the period 1982–2005, recorded in the registration forms provided by the MDS Foundation (USA), represented the primary database. This study indicates an increase in the number of new MDS cases over the period of time investigated. Also, a 10 years lower median age of the patients, a noticeable proportion of young patients and a low proportion of patients ≥81years have been found, which situates our findings in the middle between the Eastern and Western epidemiological reported data on MDS. © 2009 Elsevier Ltd. All rights reserved.
1. Introduction Myelodysplastic syndrome (MDS) comprises a heterogenous group of clonal stem cell disorders characterized by ineffective haemopoiesis with varying degrees of pancytopenia, characteristic morphologic abnormalities and increased susceptibility of transformation into acute leukemia (AL). The diagnosis is based upon morphologic assessment of peripheral blood and bone marrow smears and the exclusion of other causes of cytopenia and dysplasia [1,2]. The epidemiology of MDS has been a non-negligible preoccupation of the researchers all over the world in the past 10–15 years. However, the interest in this field remained in actuality due to the difficulties encountered in establishing with accuracy the real value of the most important epidemiological parameters [3–6]. Although MDS has been increasingly diagnosed in recent years, precise reported data on their prevalence and incidence are still lacking especially in the Eastern part of Europe. We present the first Romanian study on the epidemiology and main characteristics of MDS, based on the already existing registered data of the patients from the Hematological Department of the Fundeni Clinical Institute, Bucharest. 2. Material and method The database has been established from the files of MDS patients hospitalized in the Hematological Department of Fundeni Clinical Institute, Bucharest between 1982 and 2005. The primary data were included in the electronic registration form
∗ Corresponding author. Tel.: +40213180423; fax: +40213180423. E-mail address: [email protected] (R. Gologan). 0145-2126/$ – see front matter © 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.leukres.2009.03.034
supplied by the MDS International Foundation, USA (Chairman Professor J. M. Bennett). The activity started with October 2004 and ended in December 2005. As it was stipulated in the registration form, only the new patients who died, evolved to acute leukemia or have been lost from observation in this period of time have been recorded. The hematological data were reassessed based on well-accepted minimal diagnosis and FAB classification criteria of MDS. The cases with features or overt MDS, secondary either to other disorders or to oncologic therapy, were excluded. The most part of the patients had more than one admission and, therefore, the diagnosis of MDS could be verified over the time. Chronic myelomonocytic leukemia (CMML) was analyzed as a whole entity because no separate data on the proliferative and nonproliferative clinical forms were found in the registration forms utilized. The diagnosis of MDS was established by the centralized cytological examination of smears of peripheral blood and bone marrow. The morphological features of MDS in more than 10% of cells, the percentage of blasts and of ringed sideroblasts (Perls stain) in bone marrow, associated with the blood cell counts and differential, constituted the main reference elements for diagnosis and classification. The bone marrow smears or imprints were visualized, during the whole analyzed period of time, by one trained hematocytologists in the laboratory of the Hematological Department in Fundeni Clinical Institute. The histopathological examination of the bone marrow has been used whenever the cytology was inconclusive or to exclude other diseases. The cytogenetic investigation has been performed sporadically and no conclusive data could be extracted. This test has been routinely performed in MDS in Romania only starting with the year 2008. Sex distribution, age groups, MDS subtypes and annual frequency of new cases were analyzed versus other studies from Germany (Düsseldorf), Spain (Ourense) and China (Shanghai) reported in the medical literature [3,7,8]. The statistical and graphical analysis of the data was performed by means of Excell (Microsoft). The demographic data of the whole Romanian population have been obtained from the official informations of the National Institute of Statistics.
3. Results There were analyzed 424 patients registered with the diagnosis of new primary MDS during 1982–2005. The year 1982 marks the beginning of the morphological diagnosis of MDS in Romania,
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Fig. 1. Distribution by groups of age of MDS patients in Romania versus Germany and China.
shortly after the French–American–British (FAB) group established its diagnosis and classification criteria [1,2].
3.1. Age distribution The median age was 62.3 years and this parameter places Romania in the middle between Western countries such as Germany and Spain (74.7 years) and Eastern countries such as China (49 years). Sixty-six (16.7%) cases were ≤50 years old, 41 (9%) ≤40 years and their median age was 34.7 years. The proportion of the patients over 80 years old was 3.8%. The distribution by the groups of age of the autochthonous and foreign cohorts of patients is shown in Fig. 1. As compared to the data from Germany, a preponderance of group of age <50 years, a small representation of group ≥81 years for Romanian patients and almost the same representation of the group 51–80 years for the two cohorts can be noticed. Regarding the reported Chinese data, an important to “left” deviation of group <60 years for Chinese lot, a preponderance of group 60–80 years for Romanian lot and the similar representation of group ≥81 years for the two lots can be observed. Because the Chinese authors reported a trend of younger age in rural regions of their country, an analysis of the urban/rural (U/R) distribution of the MDS patients in Romania and China has been
performed. It was found an urban preponderance in both countries, but more marked and for all the age groups in Romania (U/R ratio 1.8 versus 1.08). The age distribution of MDS subtypes in Romania versus China indicated a preponderance of RA in the group <50 years in Chinese patients, but a preponderance of RA in the group >50 years in Romanian patients (Fig. 2). 3.2. Gender distribution There was a general preponderance of males in Romanian MDS patients as compared with the other two reported cohorts of patients from Spain and China. The M/F ratio was 1.26 for Romanian, 1.18 for Spanish, and 1.35 for Chinese patients. The corroboration of gender distribution with that by FAB subtypes shows a uniform distribution of the M/F ratio, except for refractory anaemia (RA), where a slight predominance of the females was found, and for refractory anaemia with excess of blasts (AREB), where a more marked predominance of males (M/F 1.94) can be observed (Fig. 3). 3.3. The FAB subtypes distribution The distribution according to the FAB subtypes of the Romanian patients was the following: RA 129 (30.4%), refractory anaemia with ringed sideroblasts (RARS) 66 (15.5%), RAEB 97 (22.8%), RAEB
Fig. 2. Distribution by age and FAB subtypes in Romania versus China.
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Fig. 5. The temporal dynamics of the frequency of the new MDS cases.
Fig. 3. Distribution by gender of FAB subtypes.
in transformation (RAEB-T) 43 (10.1%), chronic myelomonocytic leukemia (CMML) 24 (5.6%), unclassified 71 (15.6%) (Fig. 4). A predominance of RA in the Chinese cohort (43.9%) (p = 0.007) versus Romanian (30.4%) and Spanish (29%) ones was observed. As concerns the frequency of RARS in the Romanian patients (30.4%), it appears intermediary between the Spanish (29%) and Chinese (43.9%) ones, being significantly different from both (p = 0.05). The RAEB frequency is similar in the three cohorts, but RAEB-T frequency is quite different, the Romanian value (10.1%) being placed between the Chinese (21.1%) and Spanish (5%) ones. The frequency of CMML was lower but it was similar in the Romanian (5.6%) and Chinese (5.2%) cohorts versus the Spanish one (16%) (Fig. 4). A synthesis of the characteristics of the Romanian versus West-
ern (Germany + Spain) and Eastern (China) cohorts of patients is presented in Table 1. 3.4. Long term frequency and incidence A more than 5 times increase of the annual median number of new MDS cases over the analyzed period of time (from 1.4 cases/year to 36.2 cases/year) was registered (Fig. 5). Moreover, this trend of the frequency of new cases has manifested even during the past 10 years, when this parameter has practically doubled (from an average 18.5/year to 36.2/year). The increase could not be correlated with the aging of the population because the medium age of all population in Romania has increased with only ∼5 years during the past 25 years (from 56.9 up to 62.7). As regards the temporal dynamics of the FAB subtypes, it indicates that the most evident and continuous increase of frequency
Fig. 4. The distribution of FAB subtypes in Romania versus Spain and China.
Table 1 The synthesis of the characteristics of the Romanian cohort versus those reported by Western countries (Germany + Spain) and Eastern countries (China). The characteristics closer to German and Spanish cohorts
The characteristics closer to the Chinese cohort
The characteristics appearing in the middle
The characteristics similar to the other cohorts
Similar representation in the group of 51–79 years
Higher number of cases in the group < 50 years
The median age
Distribution by gender
Similar representation of RA cases
Small representation of the group ≥80 years Reduced proportion of the CMML cases
The proportion of cases < 50 years The proportion of RARS cases
The proportion of RAEB The overall urban predominance
The proportion of RAEB-T cases
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4. Discussion
Fig. 6. The temporal trend of the frequency of FAB subtypes.
was noted for low risk subtypes (Fig. 6). For reasons unexplained yet, the frequency of the high risk subtypes has stabilized during the past decade and that of CMML increased continuously but much more slowly. The median crude annual incidence was ∼0.5/100,000 and the maximum value was of ∼1/100,000 registered in 2004. It was more marked in the age group of above 60 years and slower in the age group 16–59 (Fig. 7A and B, respectively). The increase did not appear continuously if the analyzed period was short, of 1–3 years, but it was evident when it was analyzed on decades. The value of the incidence could be diminished by bias, due to the accrual of MDS patients from the same region by other, but smaller, hospitals in Bucharest. Also, the patients in stable or good condition, admitted during 2004 and 2005 or even earlier, remained unregistered because they could not be included in any of the three situations required by the registration form used in this study.
The World Health Organization (WHO) only recently recognized MDS as a disease entity [9]. Thus, MDS became reportable in the USA by the Surveillance, Epidemiology, and End Results program (SEER) starting with the year 2001 only. The statistical data have been reported not earlier than in 2006 [10] and they were published in 2008 [11]. Also, the first study in Italy providing information on the incidence and outcome of MDS using population-based data has been reported in 2007 only [12]. Therefore, we agree with the opinion that, at least until now, the pertinent epidemiological data on MDS cannot be obtained from official statistics on morbidity and mortality, but have to be extracted from specialized registers such as regional cancer surveys and hospital-based registries [3,4,13]. Despite many limitations, the majority of the studies have consistently shown that the disorders included in MDS are common hematological malignancies of the elderly, comparable with chronic lymphocytic leukemia and multiple myeloma [14]. Moreover, all the reported data from Western countries indicate that MDS is a disease of elderly people, 75% of patients being >60 years, but the reason underlying the vulnerability of this group of age to develop MDS or the role of aging in this process is not yet explained [14]. The median age at diagnosis is 71 in Germany [3,4], 74.3 in France [15–17], 75 in Italy [12,18], 72.5 in Spain [6,7], 73 in Great Britain [19], 74 years in Sweden [20], 75 years in USA [21–23]. On the contrary, the median age is 57 in Japan [24,25], 49 in China [8,26,27], 59 in Taiwan [cit. by [28]], 56 in Thailand [27], 53 in South Korea [29,30], 44 in Turkey [31], 58 in Central Africa [32], 55 in India, where the greatest incidence of MDS was in the group 41–60 years (44.23%) [33]. A synthetic presentation of these data is made in Table 2. Other data showing lower or higher values, as a median age of 58 in Brazil [34], 64 in Argentina [35] and 64 years in Singapore [36], have to be interpreted with caution due to assumed limitations of these studies. The distribution of the mean age at diagnosis between FAB subgroups observed in Romanian patients was quite similar with the findings of the German and Spanish reports, but different from the Chinese one, which was characterized by a predominance of RA in the young age group [6,8]. This aspect has also been found in other Asian countries [24]. In the present study, the mean age of the MDS patients was 62.3 years, 10 years lower than that of the Western countries and with approximately 10 years higher than that of Eastern countries, which places Romania in the middle between these extreme regions of the world. Other intricated age-linked aspects support this assertion, namely a quite similar representation of the group of age 51–80 in patients from Romania and Germany, but an increased proportion of younger patients in Romania and especially in China,
Fig. 7. The dynamics (A) and the trend (B) of crude and by age groups incidence.
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Table 2 Synthesis of the reported data on the mean age of MDS patients in different Western and Eastern countries. Author, Country, Period, Reference
Mean age at diagnosis
Western countries Aul C et al., Germany, 1975–2000 [4] Germing U et al., Germany, 1991–2001 [3] Nisse C et al., France, 1991–1996 [15] Maynadie M et al., France, 1980–1990 [16] Bauduer F et al., France (Basque region), 1993–1996 [17] Bari A et al., Italy (Province of Modena), 1997–2005 [12] Salvi F et al., Italy (Region of Piedmont) 1999–2004 [18] Sanz GF et al., Spain, 1971–1987 [6] Iglesias Gallego M et al., Spain, 1994–1998 [7] Williamson PJ et al., Great Britain, 1981–1990 [19] Radlund A et al., Sweden, 1978–1992 [20] Matacia-Murphy GM et al., USA, 2001–2003 [21] Ma X et al., USA, 2001–2003 [22] Goldberg SL et al., USA, 2003 [23]
71 72 70 73.5 74.3 76.5 71.5 68 77.5 73 76 75 76 76
Eastern countries Matsuda A et al., Japan, 1976–1997 [25] Oguma S et al., Japan, 1984–1993 [24] Chen B et al., China, 1990–2003 [8] Zhao WL et al., China, 1989–2000 [26] Irons RD et al., China, 2003–2005 [27] Tien HP et al., Taiwan (?) [cit. by [28]] Intragumtornchai T et al., Thailand, 1992–1996 [28] Lee JH et al., South Korea, 1989–2001 [30], Lee DS et al., South Korea, 1996–1999 [29] Paydas S and Kokak R, Turkey (?) [31] Mukiibi JM et al., Central Africa, 1988–1994 [32] Dakshinamurthy AG et al., India, 2003–2004 [33]
57 60 49 50 53 59 56 57 49 44 57 55
as well as a very low representation of the ≥80 in Romanian and Chinese patients. This last finding could be explained by a lower representation of this group of age in the Romanian population and by the reduced access to specialized hematological investigation of this group of age in both countries. The urban predominance of all groups of age in Romania is in accordance with the western reports and different from the rural predominance of the young MDS patients in China [8]. The reason for these regional differences is still unclear, even if an assumed toxic effect of agrochemicals in Turkey has been advanced [37]. Because Romania has been, for the period covered by the present study, a developing country, the influence of some factors as such the exposure to organic solvents, herbicides, insecticides and environmental pollution, like those incriminated in other developing countries, could not be excluded. On the other side, the ethnic difference between Eastern and Western MDS has been assumed by other authors [38]. Ethnic and racial differences in the epidemiology of MDS have been found recently in a study comparing the incidence of MDS in Hispanics versus non-Hispanics and in Whites versus Blacks in USA [11]. This factor could be also incriminated in Romania, considering its geographical position and the oriental migrations in the past, and could explain the “intermediate position” of the main MDS epidemiological data. These particularities of development of Romania could explain the mixed epidemiological features of MDS in this country. Future studies, corroborated with similar regional ones in countries surrounding Romania, could be useful to elucidate the significance of these data and to complete the worldwide epidemiology of MDS. In most series, it has been found that MDS occurs more commonly in men than in women, the sex ratio varying between 1.1 and 2. This feature is more evident in the group of age ≥70 years [4]. The value of M/F ratio of 1.26 found in this study shows the same predominance of males in Romania despite a greater propor-
tion of young patients, where a preponderance of females has been observed [39]. Looking at separate MDS entities, a slightly higher but not statistically significant proportion of females in the group of RA and a comparatively much higher proportion of males in the RAEB group represented particular but unexplained findings in our patients. The distribution according to FAB subtypes in Romanian patients appears similar to that from Western countries concerning RA, RAEB and RAEB-T. It is intermediate between Western and Eastern countries concerning RARS and RAEB-T and lower and similar with Eastern countries concerning CMML. Actually, the predominance of RA and the lower representation of RARS and CMML are considered features of “eastern” MDS [8,24–27]. In the epidemiological studies which examined the incidence of MDS, the crude incidence varies from 2.1 to 12.6 cases per 100,000 population/year but approaches 50 cases per 100,000 in persons over age 70 [3,4,13,16,18–20]. In the USA, the prevalence is estimated to be 55,000 patients and the number of the new cases 10,000–15,000/year [40]. Almost all studies indicated an increase of the incidence of MDS over the time but, especially in the last years, this has been attributed more an improvement in geriatric medical care and diagnosis as well as a general aging of the population, than a real increase [3,4,7,13]. In the present study, the frequency of the new cases has increased 35 times, which continued even during the analyzed past 5-year period, in contrast with the German findings where the number of MDS cases did not increase significantly from the mideighties. The average number of new cases per year in our study was ∼36/year during the last analyzed seven years, close to the highest value from the German study [3]. Because the “aging” of the whole population was only 5 years during the same period of time, we suppose that other factors are involved in case of Romania, and among them, a true increase of the MDS incidence in Romania during the analyzed period was also possible. The value of the maximum incidence of 1 per 100,000 in 2004 is under the inferior limit reported in other Western European countries, but similar with that found in Japan [41]. However, these values could be underestimated due to some limitations of both studies. The low incidence of MDS found in this study, could be explained by the accrual of a part of the MDS patients from the same region by other two smaller hospitals and by underdiagnosis. In Romania, the population is predominantly rural. The rural population had poor socio-economical conditions and, therefore, the addressability of the patients, especially the elderly, to a qualified hospital was limited. Larger scale epidemiological studies, including other hospitals in Bucharest which collect patients from the same limited region South-Muntenia and some adjacent counties, will provide more representative statistical data on the MDS incidence and its dynamics in Romania. No information on the survival rate and prognosis was included because it was considered inaccurate and also not relevant enough for the aim of this study. Moreover, the survival rate did not appear as an important epidemiological parameter for MDS in Romania, because it was influenced by many factors not related to MDS, as the weight and severity of the comorbidities, the socio-economical level and the precarious therapeutical means. However, due to the recent important progress in therapy, this parameter will be more and more relevant in Romania too, encouraged by also by an improved follow-up of the MDS patients in our center, by the extended use of cytogenetics and the implementation of the International Prognostic and WHO Scoring Systems. The presented data emphasize the results of an exclusive general descriptive epidemiological study aimed to emphasize the situation of MDS in Romania, similar with other studies from non-Western countries. Other more specific epidemiological data will be detailed and reported elsewhere.
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Conflict of interest statement The authors declare no competing financial interests. Acknowledgements We thank to Professors J.M. Bennett, U. Germing and D. Bowen for useful discussions. Contributions. RG initiated the study, established the methodology, organized the material, analyzed and interpreted the data, performed the statistic analysis, wrote the manuscript; DG collected the most part of the data, contributed to the systematization and assembly of the material and to its graphic illustration, AT, IR and DV contributed to the collection of data. Work supported by Romanian Ministry of Education and Research (Contract of research CEEX-III, Nr 119/2006). References [1] Bennett JM, Catovsky D, Daniel MT, et al. Proposals for the classification of the myelodysplastic syndromes. Br J Haematol 1982;51:189–99. [2] Bennett JM, Catovsky D, Daniel MT, et al. Proposed revised criteria for the classification of acute myeloid leukemia: a report of the French-American-British Cooperative Group. Ann Int Med 1985;103:620–5. [3] Germing U, Strupp C, Kündgen A, et al. No increase in age-specific incidence of myelodysplastic syndromes. Haematologica 2004;89:905–10. [4] Aul C, Giagounidis A, Germing U. Epidemiological features of myelodysplastic syndromes: results from regional cancer surveys and hospital-based statistics. Int J Hematol 2001;73:405–10. [5] Strom SS, Gu Y, Gruschkus SK, Pierce SA, Estey EH. Risk factors of myelodysplastic syndromes: a case control study. Leukemia 2005;19:1912–8. [6] Sanz GF, Sanz MA, Vallespi T, et al. Two regression models and a scoring system for predicting survival and planning treatment in myelodysplastic syndromes: a multivariate analysis of prognostic factors in 370 patients. Blood 1989;74:409–15. [7] Iglesias Gallego M, Moral Sastre JL, Diz PG, Costa AG, Forteza SR, Santos Mayan JM. Incidence and characteristics of myelodysplastic syndromes in Ourense (Spain) between 1994–1998. Haematologica 2003;88:1197–9. [8] Chen B, Zhao W-L, Jin J, et al. Clinical and cytogenetic features of 508 Chinese patients with myelodysplastic syndrome and comparison with those in Western countries. Leukemia 2005;19:767–75. [9] Harris NL, Jaffe ES, Diebold J, et al. World Health Organization of neoplastic diseases of the hematopoietic and lymphoid tissues: report of the Clinical Advisory Committee Meeting-Arlie House, Virginia, November 1997. J Clin Oncol 1999;17:3835–49. [10] Rollison DE, Hayat M, Smith M, et al. First report of national estimates of the incidence of myelodysplastic syndromes and chronic myeloproliferative disorders from the U.S. SEER Program. In: The 48th ASH Meeting, Orlando (Florida), 2006. Abstract #247. [11] Rollison DE, Howlader N, Smith MT, et al. Epidemiology of myelodysplastic syndromes and chronic myeloproliferative disorders in the United States, 2001–2004, using data from the NAACCR and SEER programs. Blood 2008;112:45–52. [12] Bari A, Marcheselli R, Rashid I, et al. Incidence and outcome of myelodysplastic syndromes in province of Modena. The 49th ASH Annual Meeting, Atlanta (Georgia), 2007, Abstract #4610. [13] Aul C, Germing U, Gattermann N, Minning H. Increasing incidence of myelodysplastic syndromes: real or fictitious? Leuk Res 1998;22:93–100. [14] Greenberg PL. Myelodysplastic syndromes. Clinical and biological advances. Cambridge University Press; 2006. p. 81. [15] Nisse C, Haguenoer JM, Grandbastien B, et al. Occupational and environmental risk factors of the myelodysplastic syndromes in the North of France. Br J Haematol 2001;112:927–35. [16] Maynadie M, Verret C, Moskovtchenko P, et al. Epidemiological characteristics of myelodysplastic syndromes in a well-defined French population. Br J Cancer 1996;74:288–90.
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