Mortality from myelodysplastic syndromes: A multiple causes of death approach
Authors: Ugo Fedeli, Elena Schievano, Mario Saugo, Francesco Rodeghiero
Journal: American Journal of Hematology (2014)

According to the International Classification of Diseases-10th Edition (ICD-10) adopted for classifying causes of death, MDS are coded among neoplasms of uncertain behavior; by contrast in the ICD for Oncology Version 3 adopted by cancer registries, MDS have been included as malignant neoplasms. As a consequence, cancer registries are now providing incidence and survival figures for MDS: based on Surveillance, Epidemiology, and End Results Program (SEER) data 1, more than 10,000 incident cases are diagnosed yearly in the US, with a median age at diagnosis of 76 years and a median survival of about 2 years. However, cancer registries probably underestimate the real burden of MDS in the elderly 2. The majority of patients with MDS present with comorbidities at diagnosis. Although disease-based prognostic scoring systems provide the most significant classification related to prognosis, extra-hematologic comorbidities have been demonstrated to significantly affect the probability of nonleukemic death and to impact on the overall survival in cohorts of MDS patients 3. Among MDS patients identified by cancer registries, the reported cause of death was MDS in about 25% of deceased subjects, leukemia in 20%, diseases of the circulatory system in 20%, followed by other malignancies, diseases of the respiratory and of the digestive systems 4. Mortality statistics are usually limited to the underlying cause of death, as identified from all diseases reported in death certificates according to internationally adopted selection and modification algorithms. However, recent US studies analyzed MDS among all diseases mentioned in death certificates, both in Part I (conditions involved in the causal chain of events leading to death) and in Part II (other significant conditions contributing to death). This "multiple causes" approach allows a more reliable estimate of MDS-related mortality rates, and provides useful insights into nonhematologic causes of death in MDS patients 5, 6. With this approach, we analyzed mortality from MDS (ICD-10 code D46) from January 1, 2008 to December 31, 2011 in the Veneto Region (North-Eastern Italy, about 4,900,000 inhabitants), using the regional electronic archive of mortality which since January 2008 includes not only the underlying cause, but all diseases mentioned in death certificates. Overall observed mortality rates increased from 2.2 to 5.5 deaths per 100,000 population with MDS selected as the underlying cause or reported in any position of the death certificate, respectively. Figure 1 shows age-specific mortality rates in 2008–2011 comparing the underlying cause and the multiple causes analysis. It can be observed that mortality rates steeply increase with age, but are by far higher in the multiple causes approach, reaching 32 and 84 deaths per 100,000 in those aged 75–84 and ≥85 years, respectively. Among 1,056 deaths with mention of MDS in the study period, MDS were selected as the underlying cause in 41%. Other diseases frequently selected as underlying cause were leukemia (16%, mainly reported as acute myeloid, acute unspecified type, or leukemia unspecified type), diseases of the circulatory system (16%), and nonhematologic malignancies (8%). To our knowledge, this is the first report on MDS mortality by the multiple causes of death approach outside the US; the results are similar 5, 6, except that we found an even steeper increase of rates with age especially in the multiple causes analysis, and the proportion of deaths with MDS selected as the underlying cause was higher in the US. However, the distribution of other underlying causes in certificates with mention of MDS was very close to our findings, with a relevant proportion of cardiovascular deaths when MDS were not selected as the underlying cause 5. Our findings from mortality records are consistent with evidence coming from population-based cohorts in the US, where MDS were associated with an increased risk of cardiac-related events 2, and from clinical-based cohorts in Europe, where cardiac diseases were the most frequent comorbidity and the main cause of nonleukemic death in MDS patients 3. Analyses of mortality records suffer from several limits. First, MDS were almost exclusively coded as unspecified type (D46.9). Moreover, especially among elderly people where rates are highest, false positive can be included if MDS are diagnosed on a clinical basis without bone marrow examination. Last, mention of MDS can be missing in death certificates of subjects dying from acute myeloid leukemia arising from MDS, or from lymphoma or solid cancer followed by therapy-related MDS. Notwithstanding all the above limitations, the present results demonstrate that the analysis of multiple causes of death contributes to reveal the real burden of MDS-related mortality and to investigate the associated comorbidities. In conclusion, the multiple causes approach could be a useful tool in an integrated epidemiological surveillance of MDS from several sources, including mortality data, hospital and out-patients records, cancer registry data, and clinical databases. Ugo Fedeli1 Elena Schievano1 Mario Saugo1 Francesco Rodeghiero2 1SER – Epidemiological Department, Veneto Region, Padova, Italy 2Department of Cell Therapy and Hematology, San Bortolo Hospital, Vicenza, Italy