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The incidence and mortality trends of bone lymphoma in the United States: An analysis of the Surveillance, Epidemiology, and End Results database

Highlights • The incidence rates of bone lymphoma had sharply increased for the early decades.• The incidence trend of bone lymphoma has stabilized in recent years.• The mortality had sharply increased from 1985 to 2016 without a turn point.• The incidence and mortality by various characteristics had similar patterns.


Introduction
Lymphoma can infect any tissue, with approximately one-third of patients presenting with extranodal sites [1]. Bone lymphoma, a rare extranodal form, was initially reported by Oberlin [2]. Later, some researchers considered bone lymphoma as a distinct entity, which was acknowledged to be a malignant lymphoid infiltrate of the bone [3][4][5]. According to the last version of the World Health Organization (WHO) classification of tumors of soft tissue and bone, primary lymphomas of bone (PBL) is defined as a neoplasm composed of malignant lymphoid cells, producing one or more masses within the bone, excludes regional lymph node involvement or distant sites of extranodal disease [6]. On the contrary, bone lymphoma with systemic disease and a primary soft tissue mass secondarily involving a bone both are not considered as PBL and is defined as ''secondary bone lymphoma" [7][8][9][10]. Thus, based on the current understanding, bone lymphoma has two broad categories including, primary lymphomas of bone and secondary bone Lymphoma [8,9].
Bone lymphoma is a rare tumor accounting for nearly 5% of extranodal lymphomas and between 3% and 7% of all bone malignancies [8,9]. Considering the low incidence, previous assessments relied on results from small series or single-institution. The publicly available Surveillance, Epidemiology, and End Results (SEER) database provided plenty of data for population-level studies of bone lymphoma, which focused on prognostic factors and treatment outcomes. Unfortunately, existing reports failed to particularly describe the incidence and mortality trends associated with bone lymphoma, also, such studies did not conduct systemic analyses of the trends based on various characteristics [9,11,12]. Although the level of healthcare burden has continued to heighten in the U.S. over the past decade [13], the impacts of these policies remain unclear.
Hence, relying on the large population-based cancer registries in the U.S., this study purposed to assess the incidence rates and trends of bone lymphoma using demographic and tumor characteristics between 1975 and 2016. Also, we investigated the incidence-based mortality rates and trends by these characteristics in the U.S. between 1985 and 2016. To our knowledge, this is one of the largest epidemiological studies on primary bone lymphoma across the globe.

Data source and patients selection
All data of patients were obtained from the National Cancer Institute's SEER program (https://seer.cancer.gov), which was a deidentified and public use research file [14]. We used the SEER-9 cancer incidence file maintained by the United States National Cancer Institute between 1975 and 2016. The SEER database collected cancer data from 9 high-quality, population-based registries covering nearly 10% of the U.S. population in the following regions: California (San Francisco and Oakland), Connecticut, Georgia (Atlanta), Hawaii, Iowa, Michigan (Detroit), New Mexico, Utah, and Washington (Seattle and Puget Sound region) [15]. All data in the database were retrospective, therefore, we did not have to obtain the Institutional Review Board approval for this study.
With the SEER database, we relied on pathologically confirmed diagnosis and bone location (C40.0 to C41.9) in selecting patients diagnosed between 1975 and 2016 [12]. Lymphoma Subtype Recode ICD-O-3/WHO 2008 classification from the database was directly used to identify cases with lymphoma [16]. Age-adjusted incidence rates of bone lymphoma were calculated for the years 1975 through 2016. To avoid underestimation of mortality rates in the earlier years, incidencebased mortality analysis was restricted to deaths that occurred between 1985 and 2016. All incidence rates in our study were age-adjusted to the 2000 standard US population and expressed per 100,000 population. Besides, incidence-based mortality (IBM) rates were calculated as the number of specific tumors deaths among cases diagnosed over person-time at risk among people in the SEER areas (https:// surveillance.cancer.gov/statistics). The IBM rate allowed for partitioning of mortality by variables associated with cancer onset. An accurate measure of IBM requires high-quality population-based cancer registry data and high-quality follow-up of cancer patients for vital status including the cause of death [11]. Consequently, to calculate "incidence-based mortality" rates, we captured age-adjusted population-level mortality rates by variables attributable to bone lymphoma reported to SEER registries which were expressed per 1000,000 population.

Variables selection
Demographic and tumor characteristics included: age, year of diagnosis/death recode, sex (male and female), race (white, black, others and unknown), stage (localized, regional, distant and unknown), tumor location (appendicular, axial and unknown), and histological type (diffuse large B-cell lymphoma [DLBCL], other NHL, others and unclassified). Cases were categorized into four groups based on age as follows: (1) 0-19 years; (2) 20-39 years; (3) 40-59 years; (4) ≥60 years. The stage at diagnosis was identified in SEER from 1975 to 2015 as follows: SEER Historic Stage A, as localized (limited to the bone), regional (tumor extension beyond the limits of the bone), distant (distant metastasis), and unknown [17]. Tumor location was dichotomized as either appendicular or axial [12], the appendicular skeleton included upper limbs (including scapula) and lower limbs, while the axial skeleton included the spine, head, sternum, rib, and clavicle. Histological type was recorded from 1975 to 2016, by International classification of disease for oncology (ICD-O-3), as DLBCL, other NHL (NHL excluded DLBCL), and others and unclassified (HL, composite HL and NHL, unclassified). This classification was used because the incidence and mortality of HL and composite lymphoma were too low to show the data.

Statistical analysis
The SEER software (SEER*Stat, version 8.3.6) was used to calculate cancer incidence rates and incidence-based mortality rates. All incidence rates were age-adjusted to the US standard population and expressed per 100,000 person-years, whereas all mortality rates were expressed per 1,000,000 person-years. The joinpoint regression analysis program (version 4.4.0.0 [National Cancer Institute]) was used to calculate Annual Percentage Change (APC), mean APC, and corresponding 95% CIs. Compared with zero, the statistical significance of APCs was determined by t-test. Also, we selected calendar years (joinpoints) to identify the best-fitting log-linear regression model [18]. Two-sided Pvalues < 0.05 were considered statistically significant.

Incidence and mortality by characteristics
We included 13,058 cases of patients diagnosed with bone lymphoma in the U.S. between 1975 and 2016 for incidence analysis. The case counts, incidence rates, and incidence-based mortality rates based on demographic and tumor characteristics are shown in Table 1. Of them, the elderly (above 60 years old), male, white, and DLBCL patients comprised the most cases and the highest incidence rate in cases included from 1975 to 1999. Similar results were noted from 2000 to 2009 and 2010-2016. Interestingly, the incidence of localized stage, regional stage, and distant stage was equal among the three study durations. Also, the incidence of axial site and appendicular site was equal among the three study durations.
Out of the total cases, 6888 succumbed to bone lymphoma be-tween1985 and 2016 and were identified in incidence-based mortality analysis. The largest proportion of the deaths were the elderly aged above 60 years (

Discussion
With the occurrence and advancement of public databases, in particular, the SEER database, a growing body of work was performed to study bone lymphoma, among them, ascribing the epidemiological data and analyzing the prognostic factors, which aimed at accounting for the clinical indicators [9,12]. Previous assessments, however, lost sight of the vital significance in showing the trends of incidence and mortality of bone lymphoma to identify tumor-related risk factors. To our knowledge, this is the first study to uncover the incidence and incidence-based mortality rates for bone lymphoma using epidemiological and tumor characteristics. At the same time, this study systematically compared the corresponding trends based on these features, thus may help clinicians better manage bone lymphoma tumor. Being one of the largest population-based studies, it possesses the ability to including a larger collection of cases [19]. To our knowledge, it is not until the WHO classification that pathologists and clinicians unify the diagnosis criteria of lymphoma subtypes and DLBCL as a term corresponded to the WHO classification of 2000. From our study, it is evident that the proportion of cases with unclassified subtypes from 1975 to 1999 is significantly more compared to cases between 2000 and 2009 and between 2010 and 2016. Whereas, the proportions of DLBCL cases and NPL cases between 1975 and 1999 are significantly less than cases between 2000 and 2009 and those between 2010 and 2016. Above data suggested that the occurrence of WHO classification resulted in decreased unclassified cases and increased classified cases. Additionally, we reported that the overall incidence rate from 1975 to 1999 was significantly lower than that from 2000 to 2009 and from 2010 to 2016. This could be attributed to real increase and artefactual increase; also, artefactual increase could be attributed to occurrence of WHO classification, the improved diagnosis, and completeness of cancer registries. Further detailed analysis of increased incidence rates would be provided in the next trend analysis. In our analysis, the increased trends of overall incidence and incidence-based mortality of bone lymphoma have been demonstrated for past decades, though the trend in recent years, has stabilized. A similar variational pattern with one joinpoint was e observed in most groups using various characteristics. Notably, four reasons may have contributed to the increasing trend in the early decades. First, advancement in detection methods and the subsequent emergence of early diagnosis enhanced the chance of disease detection. On the contrary, improved diagnosis can enhance the death cases of bone lymphoma registration to increase the incidence-based mortality. Second, the completeness of cancer registries in this period may result in an artefactual increase in bone lymphomas, thus may simply reflect an increase of registration rather than a factual increase [20]. Third, a change of diagnostic criteria throughout the study period, and the occurrence of diagnostic consensus between pathologists and clinicians according to WHO classification can lead to the recording of more diagnosed cases of bone lymphomas. This phenomenon might lead to a sudden increasing trend with a turning point in the early decades. However, we could observe that, in the early decades, the incidence rates exhibited a continual increase rather than a sudden increase. Furthermore, considering the standard data collection strategy, we tend to think that this might not be the main reason to potentially be attributed to the continued increase in incidence rates. Fourth, we did not exclude the possibility of a real increase of bone lymphoma patients in the general population, which was not associated with the detection at early diagnosis.
Of note, the trend of incidence-based mortality showed a significant rise without an inflection point, which mismatched the incidence trend. Also, based on the various characteristics, the trends of all sub-groups exhibited a sharply increasing trend. Over the past decade, the growing level of healthcare burden in the U.S. is of great concern [13]. Intuitively, the management and treatment of patients could be greatly improved. However, whether these enormous costs reaped the deserved outcome can be answered regarding the result of mortality. Given this, there is an urgent need to effectively improve the survival of patients with bone lymphoma. Moreover, based on the incidence and mortality cases by characteristics, the elderly, men and patients with distant metastasis or tumor occurring in axial location should be given more attention, which would be systematically analyzed in the next incidence analysis.
In this present study, the incidence and mortality rates of bone lymphoma both increased with age. Also, patients aged above 60 years accounted for more than half of bone lymphoma cases with an incidence and mortality rates rate 6 times and 15 times respectively, higher than each younger group. These findings are consistent with a previous report which ascribed a theory whereby the incidence rates exponentially rose with age in the multi-stage carcinogenic carcinogenesis of solid tumors [21]. Elsewhere, Yin et al. also reported a similar result, which only confined to extranodal diffuse large B-cell lymphoma from the SEER database between 1973 and 2015 [11]. In summary, the above observations can be explained as follows: (1) With age, the immune system in the elderly declines.
(2) The possibility of virus invasion gradually increases which further exhausts T-cell, resulting in telomere attrition and immune senescence [6,22,23]. (3) Some genes and epigenetics might change with age. (4) The level of some micromolecules and the microenvironment would be abnormal, such as BCL2 [24]. Based on our analysis, the incidence and mortality rates of male patients were higher than females. It is worth noting that the incidence trend in the male population showed a remarkable increase in recent years, whereas, in the female population, a similar trend was not observed. This phenomenon has in most cases been reported for most cancers [9,11], also, it was reminiscent of the fact that male sex often was considered as risk and prognostic factors [9,17]. Unfortunately, the underlying reasons have not been deeply evaluated. Further, we hypothesized that the differences in health awareness and lifestyle mainly contributed to the phenomenon. Smoking and social stress which have been regarded as predisposing factors for lymphoma might be the main reason [25]. In addition, females exert stronger humoral and cellular immunity, which are closely linked to lymphomagenesis [26,27]. On mortality, some treatment drugs such as rituximab offer more beneficial effects in females, thus might extend the survival time [28,29].
In terms of race, whites had the most proportion of the highest incidence and mortality rates in the U.S. in our study. However, the increasing trend in blacks was more significant than that in other races. These findings might strongly explain that in the early decades, whites comprise most populations in the U.S., and they could acquire more medical resources for tumor detection and management, therefore, whites were included in medical recode. With the rise in social and healthcare expenses, blacks were also able to get diagnosis and management into the medical record [30], which contributed to the dramatic increase in the incidence and mortality trends. Furthermore, this is reminiscent of the fact that racial diversity for most tumors was still existing and blacks were diagnosed with more advanced cancers than other races in the U.S. [11,17]. This could explain why the mortality rates in blacks were higher than that in whites from 2008.
Moreover, we found that the overall incidence rates of localized, regional, and distant diseases were similar, however, the data revealed higher overall mortality rates as the historic stages progressed. Also, distant diseases had significantly higher mortality trends compared with localized and regional diseases which was closely associated with the sharply increasing incidence trends. As such, we concluded that early detection and early treatment of bone lymphoma patients can reduce the patients with advanced stages at initial diagnosis, which could decrease the mortality rates in the U.S.
A number of previous researchers reported contradicting results on the location at which bone lymphoma occurs. For instance, in the Japanese population, bone lymphoma most occurred in the pelvis in two different series [31,32]. However, some studies ascribed that the long bones were the most common site of this tumor [33,34]. Besides, other studies in the U.S. and Britain reported the similarly equal frequency between axial and extremity sites [12,35], which was consistent with our findings. Furthermore, we found a markedly increasing trend of incidence and mortality, however, the rising trends in axial involvement were significantly more rapid than that in appendicular involvement.
DLBCL was acknowledged as the most common type of lymphoma, accounting for 59.8% [9]. In our study of bone lymphoma, our data revealed a similar result with the previous report. Considering the low incidence of other historic types, we included the other types of NPL into one group, then the PL was incorporated into an unclassified group because of the extremely low incidence. As for incidence, in recent years, the bone DLBCL exhibited a slightly decreasing trend, while other NPL showed a continuously increasing sharp trend. Also, the increased mortality trend of other NPL was significantly more rapid than that in bone DLBCL. According to our result, except for bone DLBCL, the other NPL occurring in the bone as fairly rare tumors should be deeply explored.
A few limitations existed in the present study. Firstly, because of the limitation of the SEER database, some basic information was not enrolled, including environmental exposures and other risk factors. Secondly, selection bias might exist in the retrospective trial because of its inherent flaws. Thirdly, Ann Arbor Stage is an important tumor characteristic for bone lymphoma, however, several unclassified cases in the database might affect the results, therefore, we did not estimate the incidence and incidence-based mortality rates. Fourthly, the SEER database does not have 100% coverage, and the population covered may not be the same during the study period, thus it may lack generalizability to the U.S. population. Until now, the SEER database always was reliable for assessing rare tumors in a preliminary analysis, but further study based better databases were deserved.

Conclusion
This study revealed that the incidence trend of bone lymphoma had been sharply increasing in the past decades, but has plateaued in recent years. And the joinpoint is approximately in 2009. Besides, the incidence-based mortality exhibited a sharply increasing trend between 1985 and 2016 without a turning point. Notably, these findings could help clinicians to elaborately determine the epidemiology and risk factors of bone lymphoma, and provide new insight into improving healthcare quality and better bone lymphoma management.

Funding statement
This work was supported by grants of the National Natural Science Foundation of China (No. 81871806) and Basic Public Welfare Project of Zhejiang Province (No. LGF19H060008).

Data availability statement
Publicly available datasets were analyzed in this study. This data can be found here: the Surveillance, Epidemiology and End Results database.