WM is an uncommon B-cell non-Hodgkin lymphoma, on which few epidemiological studies have been performed. In this study, the average 14-year incidence was 0.06 per 100,000 people. The incidence was stable between 1988 and 2005, at 0.3 per 100,000 people in the United States, and 0.55 per 100,000 people between 1999 and 2001 in England, which were significantly higher than the values found in this study [2, 11]. Differences in ethnicity, and geographic variations, exert a considerable influence on the lower incidence of WM in Korea. According to a previous report based on the SEER database, the incidence was higher in whites (0.41 per 100,000 people) than in nonwhites (0.20 per 100,000 people), suggesting distinct geographic differences . Additionally, similar to the results of our study, the incidence of WM in Japan (0.043 per 100,000 person-years) and Taiwan (0.031 per 100,000 person-years) between 1996 and 2003, were lower than those of Asian ethnic groups (0.10 to 0.32) based on SEER data [13, 14]. These reports provide evidence that racial differences exist in the incidence of WM, and that environmental and/or genetic factors may have an influence on the development of WM. These results are also supported by the fact that the prevalence of IgM-monoclonal gammopathy of undetermined significance (MGUS), which is a precursor state to WM, is lower in the Asian population than in the other races [15, 16]. Furthermore, genetic predisposition, and immunologic factors in the pathogenesis of WM might be the reason behind these low incidence rates [17,18,19,20,21]. Although Korea may indeed have lower incidence, it should be noted that direct comparison with these studies may not be feasible. The incidence may be affected by the data collection methods and with the lapse of time. Additionally, the diagnostic criteria applied for WM may have been influenced by the cases diagnosed in the previous epoch [2, 4]. The period of our study covered the period during which the consensus panel recommendations for the diagnostic criteria of WM, published in 2003, were applied .
The annual incidence of WM has increased from 0.03 to 0.10 per 100,000 people in our study, compared with the consistent incidence reported by previous studies [2, 11, 22]. There are some studies, which showed that geographic alterations and racial differences are associated with significant increase in annual percentage change [12, 23]. This increase would partly be because of the increasing availability of diagnostic tools, and established criteria, which allowed the diagnosis of WM cases that would not have been possible to diagnose in the previous epoch. In addition, the differences between countries, in terms of the sample size, the growth rate of the aging population, and exposure to environmental factors, might explain these phenomena [12, 23]. Based on the incidence data, a comparatively lower prevalence rate than that of other countries was expected. However, the comparison was impossible because, to the best of our knowledge, no reports for the prevalence of WM were available.
Male dominance has been continuously reported in WM. In our study, the male-to-female ratio was 3.2:1, which is slightly higher than that reported in other studies from the Europe and United States (1.7 to 2.4:1) [11, 12, 14, 24, 25]. This study revealed the vulnerability of males in Korea to WM. The male-to-female ratios for WM in Japan (3.1:1)  and in Olmsted County (3.1:1)  were similar to our value, suggesting regional differences. In regard to the age distribution, the incidence peak occurred in people aged between 75 and 79 years, which is consistent with the values reported for other countries [12, 25].
The SMR of WM patients in our study (7.57) was the highest ever reported. A recent study, conducted in Olmsted County, presented a SMR of 2.4 for the patients diagnosed with WM after 2000 . Another study reported that the SMR of asymptomatic WM was equivalent to that of the general population, while that of symptomatic patients was 5.4 .
In respect of survival, the median OS of Korean WM patients (4.5 years; 95% CI, 3.6 to 5.5 years) was significantly lower than that of Asians living in United States (7.4 years for patients diagnosed with WM between 2003 and 2009; 95% CI, 6.8 to 8.2 years), implicating an environmental effect . Considerably longer median OS (7 to 25 years) has been reported from the Europe and United States owing to ethnic disparities, epoch of diagnosis, and different study designs, such as hospital-based cohort and population-based research [4, 9, 10, 27, 28]. The OS of our study (47.5%) was also lower than the range reported in previous studies (between 57 and 62% in England and the United States) [2, 4, 11]. The OS in our study was substantially worse than those of other countries, taking into account the epoch of diagnosis, because the study periods of the others were mostly before 2010.
Although there is no standard of care established for WM, the advent of anti-CD20 monoclonal antibodies, nucleoside analogs, alkylating agents, and proteasome inhibitors have shown high response rates and have resulted in better OS [3, 29, 30]. In particular, rituximab singly or in combination has been commonly used as first-line therapy, and has contributed to better OS (62 to 97.1%) in the Western countries [31,32,33,34]. However, the HIRA does not reimburse the rituximab-based chemotherapy because of the paucity of studied data for WM patients in Korea. Exclusion from the HIRA system could therefore be the cause for the higher SMR and the poorer survival of Korean patients with WM. It would be necessary to add at least rituximab-based treatment to the reimbursement system of HIRA for improving the outcome of WM patients.
Additionally, we investigated the trends of the mortality rates in the general population to find out the reason why the OS did not improve according to the epoch of diagnosis. However, there were no notable differences of general population which could influence on the mortality of WM patients. The restrictions in the appropriate prescription of rituximab combined chemotherapy owing to reimbursement issues could have contributed to the lack of improvement. Furthermore, a relatively short follow-up period, considering the expected longer life span of WM patients , in addition to an inevitable small sample size compared to other population-based studies [4, 7], may have affected these survival results.
Our competing risk analysis showed that age was a strong factor (P < 0.01) for OS in patients with WM. The significant association between old age and poorer outcome was persistently reported in previous studies [2, 4, 11].
The main cause of death in our cohort was directly attributable to WM, and the magnitude (48.57%) was almost two times higher than that of a previous report from the SEER database (25%) . The poorer survival of Korean patients owing to obstacles in the reimbursement system to newly introduced therapies could be associated with higher WM-related deaths. The next most common cause of death was non-follicular lymphoma, which was consistent with the higher proportion of deaths due to lymphoma in the SEER database . The third most common cause was malignant plasma cell neoplasms, implicating considerable relevance to WM . Because our data based on the records archived in Statistics Korea, it was difficult to differentiate non-follicular lymphoma, and plasma cell neoplasm from WM. The possibility of misclassification should be considered.
This study had several limitations. The lack of detailed clinical information such as the symptoms, the laboratory data, or genetic features, led to restrictions on the adjustments of severity for each WM patient. Moreover, classification bias could exist because we used registry data based on physicians’ diagnoses without additional pathological confirmation. Despite these limitations, the strength of our study is the use of a nationwide population database of recent WM patients, after application of established diagnostic criteria. To the best of our knowledge, no other study has reported on the incidence, prevalence, mortality, and causes of death using a recent and nationwide data source, especially in Asia. The relatively large sample size covering the entire national population and unbiased measures used in this study could provide reliable information on WM patients.