405

International Journal of

HEMATOLOGYProgress inHematology

1. Introduction

Myelodysplastic syndromes (MDS) comprise a heteroge-nous group of acquired clonal bone marrow disorders char-acterized by varying degrees of pancytopenia, morphologicaland functional abnormalities of hematopoietic cells, and anincreased risk of transformation into acute myeloid leukemia(AML). Although an advisory committee meeting of theWorld Health Organization has recently published a newclassification of MDS [1], the French-American-British(FAB) classification proposals remain the gold standard fordiagnosing and categorizing these hemopathies [2]. FABdiagnosis is primarily based on the detection of dysplasticfeatures within all hematopoietic cell lineages in optimallystained peripheral blood and bone marrow smears. The earlystages of MDS require careful differentiation from other

Epidemiological Features of MyelodysplasticSyndromes: Results From Regional Cancer

Surveys and Hospital-Based StatisticsC. Aul, A. Giagounidis, U. Germing

Medizinische Klinik II (Hämatologie, Onkologie, und Immunologie), St. Johannes-Hospital Duisburg, Duisburg, Germany

Received March 6, 2001; accepted March 14, 2001

AbstractAlthough myelodysplastic syndromes (MDS) have been increasingly diagnosed in recent years, precise data on their preva-

lence and incidence are still lacking. Due to difficulties of diagnosis and classification, large-scale population-based studies thatare required for obtaining truly representative data on the epidemiology of MDS are currently not available. Our presentknowledge of the incidence and other epidemiological characteristics of MDS is based on a few regional studies performed byauthors with a long-lasting interest in these hemopathies. Despite certain limitations, these studies have consistently shown thatMDS are relatively common hematological malignancies. Their crude incidence varies from 2.1 to 12.6 cases per 100,000 peo-ple per year. Among the age group that is mainly affected, people older than 70 years, we are now faced with incidence ratesof about 15 to 50 cases per 100,000 people per year. The recent increase in MDS incidence observed in some studies is proba-bly not the result of an actual increase in the number of cases, but reflects improvements in geriatric medical care and diag-nosis. Int J Hematol. 2001;73:405-410.©2001 The Japanese Society of Hematology

Key words: MDS; Incidence; Risk factors

Correspondence and reprint requests: Prof. Dr. Carlo Aul,Medizinische Klinik II (Hämatologie, Onkologie, undImmunologie), St. Johannes-Hospital Duisburg, An der Abtei 7-11, 47166 Duisburg, Germany; fax: 49-203-546-2479 (e-mail:med2.sjh@uni-duisburg.de).

pancytopenic disorders with known precipitating causes suchas vitamin B12 and folic acid deficiency, alcoholism, antibody-mediated cytopenias, solid tumors, and chronic inflammatorydiseases. It is now agreed that MDS are caused by an intrin-sic defect of pluripotent or multipotent hematopoietic pro-genitor cells. The clonal nature of MDS has been demon-strated by cytogenetic abnormalities, fluorescence in situhybridization analysis, X-chromosome inactivation studies,and in vitro bone marrow cultures [3]. The impaired produc-tion of mature blood cells is the result of increased apopto-sis, or programmed cell death, in the bone marrow.

Over the last 2 decades, MDS have been increasingly rec-ognized as a cause of bone marrow failure, particularly inelderly persons. Unfortunately, precise data on the incidenceand prevalence of MDS are largely lacking. More than 50years after the initial description of MDS [4], only a few stud-ies have been done to obtain epidemiological information onthese disorders. Surprisingly, epidemiology is a relativelyneglected area in medicine, although epidemiological studiescan be used to identify predisposing factors for the develop-ment of MDS and related malignancies. The aim of this arti-cle is to review current data on the descriptive epidemiologyof MDS, as reflected by published regional or hospital-basedepidemiological studies. For this purpose, journal articles

406 Aul et al / International Journal of Hematology 73 (2001) 405-410

Figure 1. Age distribution of 1759 patients with primary or secondarymyelodysplastic syndromes diagnosed at the University of Düsseldorfover a period of more than 20 years.

covered by the Science Citation Index and Medline were col-lected and reviewed. Risk factors for the development ofMDS are only briefly discussed. The interested reader isreferred to several recent reviews in which the etiologicalbasis of MDS is more thoroughly considered [5,6].

2. The MDS Problem From an Epidemiological Pointof View

Large-scale epidemiological studies of MDS have beenimpeded for several reasons. First, MDS have been differ-ently defined and classified over the past 20 to 30 years. Ourcurrent perception of MDS as neoplastic processes is notidentical with previous views of these disorders. Due to dif-ferent assumptions of the underlying pathophysiologicalmechanisms as well as the marked morphological hetero-geneity of peripheral blood and bone marrow findings, aplethora of terms was proposed to describe cases of MDS.Cole et al [7] counted at least 16 different names that wereused in the literature to designate preleukemic disorders.TheFAB classification system proposed in 1982 provided hema-tologists with the first consistent framework for morphologi-cal distinction of MDS categories [2]. Although FAB classifi-cation was an important step toward standardization of theMDS nomenclature, the FAB proposals were not integratedinto current International Classification of Diseases codingsystems used for classifying hematological malignancies.Therefore, MDS cases had to be assigned to various otherdiagnostic categories that were not always well defined.According to a Swedish investigation, cases of MDS wererecorded in cancer registries under 5 different diagnoses [8].These difficulties explain why official morbidity and mortal-ity statistics are not suited to provide representative data onthe occurrence of MDS.

Another important issue is the question of what are min-imal criteria for diagnosing cases of MDS. As demonstratedby a recent survey, even hematological experts have differentinterpretations and diagnostic criteria for MDS [9]. A morepractical problem is the well-known difficulty in making thecorrect diagnosis during the early phases of disease (refrac-tory anemia). Due to the insidious beginning of MDS, it hasto be assumed that in a substantial proportion of patientswith early-stage MDS the disease is incorrectly classified as abenign disorder such as anemia caused by a chronic disorder.Even experienced morphologists will have difficulties ascer-taining the diagnosis in complex cases. Due to these prob-lems, it cannot be expected that MDS patients have beenreliably identified as such on a large scale. At present, accu-racy of diagnosis and completeness of case registration seemto be confined to specialized registers such as regional cancersurveys and hospital-based statistics. It must be recognizedthat the information that such registers provide is alsorestricted. Limiting factors include small and ill-defined ref-erence populations, inability to detect regional variations inthe incidence of MDS, and bias due to patient referral pat-terns, which are influenced by the specialized diagnosticexpertise of the participating institutions. These variable fac-tors will necessarily lead to imprecise epidemiological data.

With these limitations in mind, we concentrate on 3 epi-demiological aspects of MDS: (1) age and sex distribution,

(2) crude and age-specific incidence rates, and (3) temporaltrends of MDS occurrence and potential factors that mayexplain changes in the frequency of these hemopathies.

3. Age and Sex Distribution of MDS

MDS is a disorder of elderly people. Figure 1 gives the agedistribution of 1759 patients at the University of Düsseldorfover a period of more than 20 years whose disease was diag-nosed as MDS.The median age at diagnosis was 71 years anddid not differ significantly between FAB subgroups. In otherseries (Table 1), the median age of patients at the time ofdiagnosis varied between 65 and 74 years [10-20]. Investiga-tors in Southeast Asia, Turkey, and Central Africa havereported that MDS patients in these areas are generallyyounger than those from Western countries [21]. The reasonfor this difference is unclear. It has been speculated that theyounger age of patients in developing countries is due to anincrease in exposure to etiologically relevant risk factorssuch as organic solvents, herbicides, insecticides, and envi-ronmental pollution.The same explanation holds true for the

Table 1.Age Distribution of Myelodysplastic Syndromes in Larger SeriesComprising at Least 100 Patients

Study Patients, n Age, median (range), y

Foucar et al [10] 109 68 (3-88)Juneja et al [11] 114 74 (48-95)Teerenhovi et al [12] 162 67 (17-90)Cunningham et al [13] 226 74 (42-93)Kerkhofs et al [14] 237 74 (27-100)Sanz et al [15] 370 68 (20-94)Morel et al [16] 408 65 (18-91)Goasguen et al [17] 503 72Maschek et al [18] 569 72 (29-99)Greenberg et al [19] 816 69 (16-96)Oguma et al [20] 838 60

Epidemiology of MDS 407

Table 2.Average Annual Crude and Age-Specific Incidence Rates ofMyelodysplastic Syndromes and Acute Myeloid Leukemia in theDüsseldorf Bone Marrow Register During the Last Quinquennium ofthe Study Period (1986 to 1990)

Total Men Women

Myelodysplastic syndromesAll ages* 4.11 3.93 4.27�49 y 0.22 0.22 0.2250-69 y 4.88 4.58 5.14�70 y 22.81 33.88 18.02

Acute myeloid leukemiaAll ages* 2.11 2.19 2.04�49 y 1.34 1.57 1.1250-69 y 1.81 2.14 1.54�70 y 6.73 7.74 6.28

*Children excluded.

younger age of patients with secondary MDS, in whom thebone marrow disease develops after previous treatment withchemotherapeutic agents or ionizing radiation. In the Düs-seldorf bone marrow register, the median age of patientswith therapy-induced MDS was on average 10 years youngerthan that of patients with primary MDS.

French authors reported that younger patients tended tohave more advanced MDS, an increased risk of transforma-tion to AML, and a higher rate of prognostically unfavorablechromosomal aberrations [22].These findings could partly beconfirmed in our own series in which 151 patients (9%) wereyounger than 50 years. Thirty-six percent of younger patientsbelonged to the refractory anemia with excess blasts in trans-formation (RAEB/T) group, whereas the respective percent-age for patients older than 50 years was only 15%. Mono-somy 7, del(7q), and complex aberrations involving at least 3cytogenetic anomalies were equally distributed between theyounger and older patient groups (21% versus 18%, respec-tively). Paradoxically, despite a higher risk of AML transfor-mation, the younger patients had much better prognoses.Their 5-year cumulative survival rate was 42% compared to24% in patients older than 50 years. This finding simplyreflects the fact that younger patients usually receivedaggressive chemotherapy in our department rather thanbeing treated with supportive care only.

MDS occurs more commonly in men than in women.Only Juneja et al [12] and Teerenhovi et al [13] reportedseries with a slight preponderance of women. In most series,the sex ratio (men:women) varied between 1.1 and 2. Thisunbalanced sex ratio, which is also found in patients withAML, suggests the importance of occupational factors in thedevelopment of MDS. Looking at separate MDS entities, thechronic myelomonocytic leukemia (CMML) group standsout because of its particularly high male-to-female ratio,which ranges from 1.5 to 3 in published series [23].There are,however, exceptions to the rule that MDS is more commonin men. One such exception is the 5q– syndrome, whichapparently affects women more often than men. On review-ing 102 patients with del(5q) and refractory anemia, Van denBerghe et al found a sex ratio of 0.5 [24]. Pedersen recentlyreviewed 324 published cases of del(5q) and found that thefemale predominance in this cytogenetic subgroup isexplained by longer survival of female patients rather thanincreased disease incidence among women [25].

4. Incidence of MDS

Until recently, only a few regional studies have examinedthe incidence of MDS. They consistently showed that MDSare much more common than previously assumed. Crudeand age-specific incidence rates were first reported by ourgroup [26], which examined the disease frequency in North-Rhine-Westfalia (Düsseldorf) over a period of 16 years (1975to 1990). The Düsseldorf bone marrow register greatly bene-fits from the fact that bone marrow samples from virtually allcases of suspected hematological malignancy are sent to theDüsseldorf University Hematology Department for cytolog-ical examination. The university medical center has the onlyspecialized hematology department among 42 other hospi-tals in the area. A morphological diagnosis of MDS was

accepted only when the bone marrow smear showed normalor increased cellularity, signs of dyshematopoiesis, and ablast-cell count below 30%. We examined cases thoroughlyfor MDS exclusion criteria including vitamin B12 and folicacid deficiencies, alcoholism, hypersplenism, paroxysmalnocturnal hemoglobinuria, antibody-mediated cytopenias,solid tumors, severe metabolic diseases, and acute toxicityfrom myelotoxic substances or ionizing ration. Analysis ofmedical charts led to the exclusion of 12% of patients whosecytological specimens had suggested a diagnosis of MDS. Forcalculating disease incidences, we had to restrict our analysisto the demographically well-defined population of the towndistrict of Düsseldorf (575,000 inhabitants). To compensatefor annual variation, we calculated the incidences of MDS by5-year calendar periods (quinquenniums), using averageannual case numbers. During the study period, the crudeannual incidences of MDS markedly increased from 1.4 casesper 100,000 inhabitants in the first 5-year period to 4.1 per100,000 in the last 5-year period.Table 2 gives both crude andage-specific incidences of MDS for the last quinquennium(1986 to 1990), during which casefindings apparently reacheda plateau. In this time period, MDS was twice as common asAML, which was chosen as a reference group for reasons ofcomparison.As expected, incidence figures of MDS rose con-stantly with increasing age of the population, amounting to4.9 for people aged 50 to 70 years and 22.8 for people olderthan 70 years. It appears likely that these figures are stillunderestimates of the true disease incidence because of thelikelihood that not all patients with suspicious blood cellfindings were subjected to bone marrow examination andbecause patients whose diseases according to trephine biop-sies were diagnosed to be hypoplastic and myelofibroticMDS, now considered important subgroups of MDS, wereexcluded from the analysis [27].

Williamson et al [28] studied the incidence of MDS in theEast Dorset Health District in England over a 10-year period(1981 to 1990). Cases were sought through investigation ofindividuals presenting with abnormal peripheral blood find-ings. Two hundred seventy-nine new cases of MDS wereidentified in a population that rose from 203,000 to 226,000over the study period. People living in the catchment areawere not excessively exposed to toxic chemicals or ionizing

408 Aul et al / International Journal of Hematology 73 (2001) 405-410

radiation. Employment of residents was mainly in serviceindustries such as tourism, banking, and insurance. Contraryto our study,Williamson et al observed no consistent trend inincidence rates from 1981 to 1990. Crude incidence of MDSwas 12.6 cases per 100,000 inhabitants per year, approxi-mately 3 times higher than in the Düsseldorf study.There wasa large preponderance of elderly patients, with 38% of thembeing 80 years or older at diagnosis. Age-specific incidencerates per 100,000 were 0.5 for patients younger than 50 years,5.3 for patients aged 50 to 59 years, 15 for patients aged 60 to69 years, 49 for patients aged 70 to 79 years, and 89 forpatients aged 80 years and older. Subtypes of MDS in theBournemouth study were different from those in our study,with very few RAEB/T cases and nearly one third of patientsbelonging to the CMML subgroup. However, because theage of patients at diagnosis does not differ significantlybetween FAB groups, this distribution of morphological enti-ties does not explain the great differences in age-specific inci-dences found in the investigation by Williamson et al com-pared with those found in other epidemiological studies.

The East Dorset Health District is incorporated into thestudy area of the Leukemia Research Fund Centre (LRF) forClinical Epidemiology in England, which also published dataon the incidence of MDS [29]. Since 1984, this institution hasaimed at complete registration of hematological and relatedneoplasms in parts of the United Kingdom. The register cov-ers a population of more than 11 million people in Englandand Wales, which is over 20% of the total UK census popula-tion in 1991. The principal source of information is directnotification from collaborating local hematologists and histo-pathologists via data clerks employed by the LRF. Cross-checks suggest that the LRF register is more than 97% com-plete for hematological and lymphoid malignancies. For thetime period of 1984 to 1986, the age-standardized incidencerate of MDS was 2.1 cases per 100,000 inhabitants per year.Age-specific incidences per 100,000 inhabitants were 2.7 forpatients aged 55 to 64 years, 7.4 for those aged 65 to 74 years,and 21.7 for those aged 75 to 84 years. The great differencesin age-specific incidences reported by the Bournemouthstudy and the LFR survey become immediately apparent.Although part of the LRF Data Collection Survey, theBournemouth figures are about 2 times higher that those inthe LRF study. However, it should be emphasized that theLRF data are not exactly comparable to those of other stud-ies, because patients with RAEB/T were excluded from thedata material.

Radlund et al [30] recently examined the incidences ofMDS and AML in the county of Jönköping in Sweden. Thecatchment area for this study is located in a rural part of Swe-den, without big cities, manufacturing industries, or otherobvious sources of toxic substances. During the study periodof 15 years (1978 to 1992), 120 cases of MDS and 146 cases ofAML were diagnosed in the reference population (about310,000 inhabitants). Throughout the study period, the crudeincidences of MDS remained almost constant (3.2 to 4.1/100,000 per year). In the last quinquennium (1988 to 1992),age-specific incidences were 0.7 for people younger than 50years, 1.6 for people aged 50 to 69 years, and 15 for people 70years and older. In people 70 years and older, MDS was morefrequent than AML (15 versus 10.2/100,000 per year).

Two French studies have published data on MDS occur-rence in France. The study by Maynadié et al [31] examinedthe disease incidence in the region of Côte d’Or, which islocated in Burgundy (about 480,000 inhabitants). Bone mar-row smears of all patients with hematological disorders wereexamined in a single cytology laboratory at the local hospitalin Dijon. During the study period (1980 to 1990), a total of167 cases of MDS were diagnosed. MDS cases accounted forabout 10% of all hematological and lymphoid malignanciesrecorded in the register. It is noteworthy that more than 40%of MDS patients were diagnosed on the basis of an inciden-tal blood count. The crude incidence rate was 3.2 cases per100,000 inhabitants per year. No significant change in inci-dence rate was observed during the 10-year study period. Asin the other studies, the disease incidence rose steeply withage, producing incidence rates of about 45 cases per 100,000inhabitants per year in men older than 80 years. In anotherstudy, Bauduer et al [32] presented the epidemiological pro-file of MDS patients living in the Basque Country of France.This region, which accommodates 290,000 residents, islocated in a rural part of France and is free of nuclear instal-lations, petrol-derived industries, and other sources of toxicchemicals. During a 4-year period (1993 to 1996), 90 newcases of MDS were diagnosed, producing an average crudeincidence of 7.7 cases per 100,000 inhabitants per year.

Outside of European countries, very little information hasbeen collected on the frequency of MDS. Virtually no dataon MDS occurrence are available from developing countries.In 1991, Japanese authors conducted a nationwide survey toestimate the prevalence and incidence of MDS in Japan [33].For this poll, clinicians working in departments of internalmedicine were asked to specify the number of MDS patientswho received medical care in their hospitals during theperiod of September 1 to 30, 1991. Of 2503 hospitals, 1493(approximately 60%) responded to the initial request, andthe total number of MDS patients reported was 1564. Basedon this data, Shimizu et al calculated an age-adjusted MDSprevalence of 3.4 cases per 100,000 men aged 15 years andolder and 2.1 cases per 100,000 women aged 15 years andolder. Prevalence rates varied 2-fold between geographicalareas (districts). The crude incidence of MDS that Shimuzuet al found in their study [33] was only 1 case per 100,000people per year and therefore was much lower than thatreported in European studies. This result might be explainedby the methodological limitations of their study.

5. Real or Apparent Increase of MDS

Despite their limitations, regional incidence studies clearlydemonstrate that MDS are common disorders.This conclusionis in contrast with previous views that considered MDS to berare malignancies.Until 1973 there were only 143 patients withMDS reported worldwide [34]. Nowadays, referral centers areable to recruit similar case numbers within a couple of years. Itis thus not surprising that most hematologists accepted a con-sensus statement that the incidence of MDS has increased byat least 100% during the past 10 to 20 years [8]. Is this consen-sus statement really supported by current studies?

A rising incidence of MDS has been demonstrated by ourstudy and recently by the LRF study [35], whereas other

Epidemiology of MDS 409

authors failed to demonstrate an increase in MDS. Our studystands out because of its long and early study period (the 16-year period from 1975 through 1990). One factor that cer-tainly contributed to the rising case numbers was the intro-duction of a new and practicable MDS classification by theFAB group in 1982 [2].This classification focused the interestof hematologists and other physicians on the new diseaseentity of MDS, which became an attractive explanation forabnormal blood findings in elderly patients. In our bone mar-row register, the rising incidence of MDS during the earlyyears of our study was accompanied by a decrease in otherhematological disorders such as pernicious anemia andaplastic anemia [36]. Furthermore, the subtype distributionof the MDS cases in our register changed in parallel with theproposals of the FAB group. For example, most patients withCMML were diagnosed after 1982, when the FAB group pro-vided valuable diagnostic criteria for this disorder [26]. Wedo not believe that CMML cases were really lacking fromour study population before 1983, but we think that at leastsome of them must have been misdiagnosed as chronicmyeloid leukemia or reactive bone marrow changes.

Extended use of diagnostic procedures in the elderly isanother factor that contributed to the rising frequency ofMDS in our register. This factor can be demonstrated by thefact that the percentage of elderly patients from which ourcytology laboratory received bone marrow smears for diag-nostic purposes rose substantially between 1975 and 1990.The proportion of patients older than 60 years among newentries to the register increased from 42% in 1975 to 54% in1990 [26]. Apparently, there was a growing interest amongphysicians in performing bone marrow biopsies in elderlypeople in order to arrive at a plausible explanation for abnor-mal hematological findings. Because MDS is essentially ageriatric disease, extended use of invasive hematologicaldiagnostics in the elderly patients will inevitably increase thenumber of MDS patients identified.

A recent update of the LRF study also described a sub-stantial increase in MDS incidence over the 10-year periodbetween 1984 and 1993 [35]. The authors described a reversetrend for AML, namely a decline in incidence figures duringthe study period.The authors concluded that the rise in MDSand decline in AML most likely reflected diagnostic changes.

Of course, other risk factors may also contribute to the ris-ing frequency of MDS. Reports in the literature haveascribed an etiological role to cytostatic treatment, ionizingradiation, and prolonged occupational exposure to organicsolvents, pesticides, herbicides and other toxins. A number ofrecent publications have confirmed the role of chemotherapywith alkylating agents and topoisomerase II inhibitors suchas epipodophyllotoxins and anthracyclines in the develop-ment of myeloid neoplasms [6,37,38]. Alkylating agentsinduce therapy-related MDS/AML after a latent period ofapproximately 5 years, whereas topoisomerase inhibitorsinduce therapy-related MDS/AML after a shorter timeperiod. The risk of MDS development after treatment withalkylating drugs is dependent on dose and duration of expo-sure. Dose effects of topoisomerase II inhibitors are lessclearly defined. Other than medical treatment, a strong rela-tionship between benzene exposure and risk of MDS/AMLdevelopment has been established by cohort studies of

workers at petrochemical manufacturing plants [39,40]. Stud-ies of more general exposures, including exposure to herbi-cides, insecticides, and air pollution and use of hair dyes, haveyielded data showing inconsistent or weak effects [41-43].Despite the known association of certain myelotoxic sub-stances with the development of MDS, there are no data sug-gesting an important role of these factors in the rising fre-quency of MDS in current epidemiological studies. In ourseries, there were only 31 (5.1%) out of 584 MDS patients forwhom a diagnosis of therapy-related secondary MDS couldbe made [26]. Although we found a slight increase in the fre-quency of therapy-related MDS over the course of our study,it is obvious that this small patient group cannot account forthe remarkable rise in the entire number of MDS cases.

In conclusion, there is only a small amount of epidemio-logical data supporting the concept of a real increase in MDSin recent years. It appears likely that the recent increase inMDS most probably reflects improved case ascertainment asa consequence of increased physician awareness, improvedgeriatric medical care, and better and more widely availablelaboratory facilities as well as expansion of invasive diagnos-tic procedures.

Acknowledgment

This publication was supported by the Bundesminis-terium für Bildung und Forschung, Kompetenznetz “Akuteund chronische Leukämien.”

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