2.1 Data Source

The SEER program was used in this study [13]. In this study, we estimated the incidence rates and annual percent changes (APCs) of NHL using the SEER 22 database [14]. The access to this database was established under the terms of the SEER research data use agreement for the 1975–2020 Data [15]. In this study, we specifically utilized data from the SEER program covering the years 2000–2020.

2.2 Definitions

The APC, which indicates trends in cancer rates over time, is determined by assuming that cancer rates change by a constant percentage relative to the rate of the previous year. To summarize the average APCs over multiple years, the average annual percent change (AAPC) is calculated as a weighted average of the APCs derived from the joinpoint model, with the weights corresponding to the length of each APC interval. This study analyzed three primary categories based on race/ethnicity: Non-Hispanic White (NHW), Non-Hispanic Black (NHB), and Hispanic. Due to the limited number of cases, data from American Indian/Alaska Native, Native Hawaiian, and Asian/Pacific Islander populations were only included in the overall estimates.

We used the Lymphoid Neoplasms Recode 2021 revision for classification [16], which is the preferred classification system according to SEER 22 [13]: “2(a). Non-Hodgkin lymphoma, B-cell; 2(a)1. Precursor Non-Hodgkin lymphoma, B-cell; 2(a)2. Mature Non-Hodgkin lymphoma, B-cell; 2(a)3. Non-Hodgkin lymphoma, B-cell, NOS; 2(b). Non-Hodgkin lymphoma, T-cell; 2(b)1. Precursor Non-Hodgkin lymphoma, T-cell; 2(b)2. Mature Non-Hodgkin lymphoma, T-cell; and 2(c). Non-Hodgkin lymphoma, unknown lineage”.

2.3 Statistical Analysis

We report overall trends using the age-standardized incidence rate (ASIR), which reflects incidence adjusted for age across the population. For age-specific trends, we report incidence rates for defined age groups and refer to these as ‘incidence rates’ to maintain clarity and conciseness [14, 17]. The cases included in the study are those with a diagnosis of malignant cancer with known age. The estimations of APCs, AAPCs [18], Jointpoint regression modeling, parallelism test and coincidence tests for ASIR [19, 20] were run by the Jointpoint Regression Program, version 5.0.2 [19]. To avoid bias in the cancer incidence estimates, data from the year 2020 was excluded from the joinpoint trend analysis and was only presented in illustrations [21]. The ASIRs of NHL and their APCs were calculated by fitting least-squares regression lines to the natural logarithm of the ASIR, using diagnosis year as the regressor variable. Model selection was performed using the weighted Bayesian Information Criteria technique [17]. The 95% confidence intervals (CIs) were determined using the empirical quartile method [22].

3.1 Non-Hodgkin Lymphoma

From 2000 to 2019, a total of 962 535 cases of NHL were reported in the US across all age groups. B-cell NHL was the most prevalent subtype, accounting for 93.59% of cases (Table 1). The majority of cases were identified among NHWs at 73.31%, with a significant proportion occurring in individuals aged 70–79 years (25.94%) (Table 1 and Figure 1). The ASIRs, per 100 000 population, were 55.58 (55.43, 55.73) for men and 36.00 (35.89, 36.11) for women. Both sexes had an increase in AAPCs (Men: 0.45% [0.33, 0.62]; Women: 0.38% [0.21, 0.57]) (Table 1 and Figure 1).

Between 2015 and 2019, a total of 281 641 cases of NHL were reported. The majority of these cases were identified among NHWs, accounting for 69.67%, and in individuals aged 60–69 years, who represented 27.16% of cases (Table S1). NHW men had the highest ASIR (per 100 000 population) among all racial and ethnic groups, at 59.66 (95% CI: 59.30, 60.02) (Table S1). Importantly, there was a significant decline in ASIRs per 100 000 population during this period for both men (AAPC: −0.94% [95% CI: −1.61, −0.51]) and women (AAPC: −0.60% [95% CI: −1.36, −0.01]) (Table S1). Additional details on the similar and parallel trends of NHL can be found in Tables S2 and S3.

The number of incident cases rose with age, reaching its highest point in the 65–69 age group for men and the 70–74 age group for women. Both sexes experienced peak incidence rates in the 80–84 age category (Figure S1).

3.2 COVID-19 Impacts

There was a notable decline in the ASIRs per 100 000 population across all races and both sexes, regardless of age, with an overall percentage change (PC) of −10.52% (95% CI: −11.60, −9.45) (Table 2). This decrease was also significant for males (PC: −10.72% [95% CI: −12.15, −9.28]) and females (PC: −10.19% [95% CI: −11.83, −8.56]) from 2019 to November 2020 (Table 2).

3.3 B-Cell Non-Hodgkin Lymphoma

From 2000 to 2019, there were 900 791 B-cell NHL cases. The most common subtype was mature B-cell NHL (92.35%). The majority of cases were men (55.33%), NHWs (73.95%), and between 70 and 79 years (26.34%) (Table 3). The ASIR per 100 000 population was 51.93 (51.79, 52.08) for men and 33.76 (33.66, 33.87) for women (Table 3, Figures S2–S4).

From 2000 to 2019, there was an increase in incident cases of B cell NHL in both sexes, reaching a peak at 65–69 and 70–74 in men and women, respectively. Incidence rates increased to reach the highest at the age of 80–84 in both sexes (Figure S5).

3.4 Precursor B-Cell Non-Hodgkin Lymphoma

A total of 18 786 cases of precursor B-cell non-Hodgkin lymphoma (PBNHL) were documented. Most cases were found in males (54.08%), NHWs (54.20%), and in individuals aged 20–29 years (17.04%). The ASIR, per 100 000 population, was recorded at 1.00 (0.98, 1.01) for men and 0.76 (0.75, 0.78) for women (Table 4). Notably, Hispanic men exhibited the highest ASIR among all groups, standing at 1.61 (1.54, 1.67) per 100 000 population (Table 4 and Figures S6–S8).

There was a reduction in the incident cases of PBNHL among men from 20–24 to 30–34, followed by a minimal increase to 60–64, after which there was a decline. For women, there was an overall increase from 25–29 to 55–59, which was preceded by a decline to 80–84 (Figure S9).

3.5 Mature B-Cell Non-Hodgkin Lymphoma

Overall, 831 875 cases of mature B-cell Non-Hodgkin lymphoma (MBNHL) were reported. The majority were in men (55.53%), NHWs (74.31%), and aged 70–79 years (26.61%) (Table 5). Both sexes experienced a significant incline in ASIRs (per 100 000 population) over 2000–2019 (AAPC: 0.37% [0.29, 0.45] for men, and AAPC: 0.30% [0.19, 0.46] for women). NHW men had the highest ASIR per 100 000 population (51.52 [51.35, 51.69]) (Table 5 and Figures S10–S12).

Among men, the incident cases and rates peaked at 65–69 and 80–84 age groups, respectively. For women, the cases and rates peaked at 70–74 and 80–84, respectively. Men had a higher incidence rate compared to women (Figure S13).

3.6 B-Cell Non-Hodgkin Lymphoma Not Otherwise Specified

There were 50 130 B-cell non-Hodgkin lymphoma not otherwise specified (BNHL-NOS), mostly in men (52.41%), NHWs (75.45%), and aged 80+ years (28.75%). NHW men had the highest ASIR per 100 000 population among other groups (3.00 [2.96, 3.05]) (Table 6 and Figures S14–S16).

The incident cases of BNHL-NOS increased to 75–79 age groups in men, followed by a slight decrease. Women followed a similar pattern; however, the incidence of BNHL-NOS peaked in the 85+ group (Figure S17).

3.7 T-Cell Non-Hodgkin Lymphoma

There were 60 259 T-cell NHL, mostly in men (57.93%), NHWs (63.93%), and between 60 and 69 years (22.15%). NHB men had the highest ASIR per 100 000 population (4.77 [4.62, 4.92]) and the greatest AAPC (2.99% [1.50, 4.92]) (Table 7 and Figures S18–S20).

There was a marked exponential rise in T-cell NHL incidence for both sexes, reaching its highest levels in the 65–69 age group, after which a decline was observed (Figure S21).

3.8 Precursor T-Cell Non-Hodgkin Lymphoma

From 2000 to 2019, there were 3223 cases of precursor T-cell non-Hodgkin lymphoma (PTNHL) in the US. It mostly affected men (67.83%), NHWs (56.22%), and those aged 20–29 years (30.04%) (Table 8). NHB men had the highest ASIR per 100 000 population (0.30 [0.27, 0.34]). The AAPCs for men and women were 12.33% (2.39, 22.68) and 10.50% (1.89, 21.69), respectively (Table 8 and Figures S22–S24).

There was almost a decrease in the incident cases of PTNHL in both sexes. PTNHL incidence rates declined between 20–24 and 60–64, after which they increased to the 80–84 age group. For women, the incidence rates had minimal fluctuations (Figure S25).

3.9 Mature T-Cell Non-Hodgkin Lymphoma

From 2000 to 2019, there were 57 036 cases of mature T-cell non-Hodgkin lymphoma (MTNHL) reported in the US, with a higher incidence among men (57.38%), NHWs (64.37%), and those aged 60–69 years (22.81%) (Table 9). The ASIR per 100 000 people was 3.33 (3.30, 3.37) for men and 2.10 (2.07, 2.12) for women. NHB men had the highest ASIR per 100 000 population (4.47 [4.33, 4.61]) (Table 9). The AAPCs for men and women were 1.11% (0.60, 1.63) and 1.74% (0.79, 2.94), respectively (Table 9 and Figures S26–S28).

There was an incline in MTNHL incident cases among men aged 20–24 to 65–69, after which it began to decline. In a similar fashion, women followed the same pattern. (Figure S29).

3.10 Non-Hodgkin Lymphoma of Unknown Lineage

There were a total of 1485 reported cases of non-Hodgkin lymphoma of unknown lineage (NHL-U) in the US. Predominantly, these cases affected men (66.13%), NHW individuals (70.03%), and individuals aged 70–79 years (22.63%). The ASIR per 100 000 people was 0.10 (0.10, 0.11) for men and 0.04 (0.04, 0.05) for women (Table 10 and Figures S30–S32).

There was a substantial rise in incident cases between 50–54 and 70–74, the age group in which the NHL-UL reached its peak in men. Women had a minimal increase beginning from the 60–64 age group, after which it remained almost constant (Figure S33).

4.1 Main Findings

From 2000 to 2014, adult NHL incidence rates significantly increased, followed by a notable decline from 2014 to 2019. B-cell NHL was the predominant subtype, accounting for 93.59% of cases, with mature B-cell NHL being the most common. ASIRs (per 100 000 population) were consistently higher in men than women; men experienced rising rates from 2000 to 2014 and a decline thereafter, while women showed no significant ASIR changes from 2004 to 2019. NHL ASIRs increased with age across all groups, with the 20–29 age group showing the highest AAPCs.

Racially, NHW men had the highest ASIRs, whereas NHB women exhibited the greatest increase. NHL rates in NHWs rose until 2015 and declined from 2015 to 2019; NHBs showed trend variations but experienced an overall decline from 2011 to 2019. Hispanic rates remained relatively stable from 2004 to 2019. Following the COVID-19 pandemic, ASIRs declined significantly across all races, ethnicities, and sexes. For subtypes, both B-cell and T-cell lymphoma incidence rates increased between 2000 and 2015, followed by a decline from 2015 to 2019.

4.2 Overall Patterns of Adult NHL

In recent years, adult NHL incidence in the US has shown fluctuations. Earlier studies reported approximately 77 200 new cases in 2020, accounting for 4.3% of all cancer diagnoses and ranking NHL as the seventh most common cancer [5]. In 2017, the incidence rate was 18.6 per 100 000, marking a 168% increase from 11.1 per 100 000 in 1975 [5]. Shiels et al., using SEER data (1992–2009), reported that NHL rates nearly doubled between 1974 and 2009, with a sharp increase in the early 1990s followed by stabilization. The increase continued for men until the early 1990s and for women until the early 2000s before plateauing [23]. These trends highlight a significant long-term rise in NHL diagnoses. Our results showed a similar pattern, with incidence rates rising until 2014 and then declining significantly between 2014 and 2019.

Globally, comparable trends have been observed. Ho et al. [24], using the Global Burden of Disease (GBD) 2019 data, analyzed lymphoma and leukemia subtypes in Australia and Oceania, reporting an increase in NHL incidence. Similarly, Su et al. [25] found a rising trend in ASIRs of NHL in China from 1990 to 2019. These findings, consistent with our SEER-based analysis in the US, reflect an increasing global burden of NHL. However, differences in population demographics, healthcare systems, and data sources between SEER and GBD registries should be considered when interpreting cross-national trends.

4.3 Age and Sex Patterns

Previous research has shown that the overall age ASIR of NHL in the US is higher in men (23.9 per 100 000) than in women (16.4 per 100 000) [26], consistent with our findings. Globally, men have more than double the lifetime risk of developing NHL, and in countries with high human development index, are 39% more likely to be diagnosed and 60% more likely to die from the disease. In our study, ASIRs increased in both sexes, with an AAPC of 0.45% in men and 0.38% in women. This aligns with projections of increasing NHL incidence through 2040 [23] and with Cai et al., who reported rising rates from 1990 to 2019 with APCs of 0.78 in men and 0.25 in women [26].

NHL incidence increased with age in our analysis. Prior studies reported a mean diagnosis age of 65, varying by histological subtype [27]. Age-related immune system changes [23] and increased t(11;14) translocations [28] may contribute to this trend.

Wasifuddin et al. [29] found a declining incidence of DLBCL in adolescents and young adults (AYAs) from 2000 to 2020 using the SEER data, while Zhang et al. [30] also observed declining NHL rates. Our study, which analyzed B-cell NHL as a whole rather than by subtype, showed an increasing trend in adults from 2000 to 2019. Although we did not focus exclusively on AYAs, our joinpoint analysis included individuals aged 20–39. We found a significant increase in incidence among those aged 20–29 (APC = 0.37%, p < 0.05), while the 30–39 age group showed a non-significant decline. These discrepancies may reflect methodological differences in age stratification and subtype classification. Notably, our findings suggest potential intra-group variations within the AYA category. Further research focusing on B-cell NHL subtypes and age-stratified AYA analyses is warranted.

4.4 COVID-19 Impacts on Adult NHL

The COVID-19 pandemic in 2020 caused significant interruptions in healthcare services throughout the US [31]. This led to a reduction in face-to-face primary care consultations and cancer screenings [31]. Our study showed a significant decrease in NHL incidence rate during the COVID-19 pandemic. A study by Mariotto et al. on the SEER database also indicated that NHL age-standardized, delay-adjusted incidence rates in men and women in 2019 and 2020 had decreased from 23.3 to 21.5 (PC: −7.7%) and 16.1 to 14.7 (PC: −8.4%), respectively [32]. There were similar decreasing patterns for myeloma, as well as kidney and renal pelvis cancers, following the COVID-19 pandemic in the US [33, 34]. The drop in incidence was likely caused by less access to healthcare and fewer diagnoses during the pandemic. More research is needed to find out if the decrease was only due to delays in detection or if other factors, like changes in disease risk, how people used healthcare, or how cases were reported, also played a part.

4.5 Histological Subtypes

B-cell lymphomas account for approximately 95% of all lymphomas [35], with an incidence of about 20 new cases per 100 000 individuals annually in high-income countries [36]. Several factors may explain their higher prevalence compared to T-cell lymphomas in the US, including better 5-year relative survival rates [37] and genetic variants that may predispose B cells to malignant transformation [38].

DLBCL, classified under mature B-cell neoplasms, was the most common aggressive lymphoma in 2016 [39, 40] and is consistently reported as the most prevalent B-cell lymphoma subtype [13, 41]. Our findings align with other studies recommending that mature B-cell NHL be identified as the most frequent subtype [39], likely due to its varied cellular origins, genetic heterogeneity, and distinct clinical behavior compared to other B-cell neoplasms [42]. While Howlader et al. noted a decline in B-cell NHL subtype incidence after 2003, peripheral T-cell lymphoma rates remained stable from 2006 to 2011 [43].

4.6 Race/Ethnicity

In the US, NHW individuals face the highest likelihood of developing NHL, while those from Asian/Pacific Islander, American Indian, and Black communities have the lowest susceptibility [5]. Our findings confirmed that NHW men had the highest ASIR, while NHB women showed the most substantial increase in ASIRs over the study period. Environmental pollutants and lifestyle factors may contribute to the rising NHL incidence among African Americans. Exposure to pollutants such as polychlorinated biphenyls, dichlorodiphenyltrichloroethane, and pesticides has been linked to NHL development [30], and urban environments—more common among NHBs—are associated with higher incidence [44]. Blansky et al., using the SEER data, found that urban residence correlated with increased DLBCL incidence in Hispanics and chronic lymphocytic leukemia in NHBs. After adjusting for demographic and socioeconomic variables, DLBCL incidence remained higher in metropolitan areas, especially among Hispanics [44].

Our analysis showed that among Hispanics, adult NHL incidence rose from 2000 to 2004, then plateaued until 2009. Miller et al. reported NHL among the leading cancer sites for both incidence and mortality in US Hispanics, estimating approximately 4700 and 4200 new cases in Hispanic men and women, respectively, in 2021 [45]. Subtype distribution also differs: Portillo et al. found significantly higher rates of B-cell NHL subtypes (DLBCL, follicular lymphoma, Burkitt lymphoma) and T-cell subtypes (NK/T-cell and anaplastic lymphoma) among Hispanics compared to non-Hispanics [46]. Additionally, studies in Texas and Florida showed comparable outcomes in peripheral T-cell lymphomas between Hispanics and non-Hispanics, despite differences in demographics such as age and insurance coverage [47]. These findings highlight ethnic variation in NHL subtype distribution and demographic profiles, underscoring the need for further research to clarify these associations and temporal trends across racial and ethnic groups.

4.7 Limitations and Strengths

This study has several limitations. First, it did not account for major NHL risk factors, such as Epstein–Barr virus prevalence. Second, potential misclassification of cases or histological subtypes within the database may have introduced inaccuracies. Variability in healthcare access and diagnostic services across regions and demographics could have influenced incidence reporting. Additionally, changes in diagnostic criteria and improvements in detection over the two-decade span may affect data consistency. While this study focused on incidence trends, future research should incorporate survival and treatment-specific outcomes, especially in the context of emerging therapies like chimeric antigen receptor (CAR) T-cell therapy. Finally, findings based on the SEER database may not be generalizable to other populations or healthcare systems, limiting external validity.

Despite these limitations, the study has notable strengths. The SEER database provides high-quality, nationally representative data on adult NHL in the US. Covering the period from 2000 to 2020, it allows for a robust analysis of long-term trends. The inclusion of data reflecting the impact of the COVID-19 pandemic adds contemporary relevance. However, it is important to note that some of the observed declines in incidence during the pandemic period may not necessarily reflect true changes in cancer trends, but rather reduced detection due to limited healthcare access. Furthermore, the use of standardized and precise histologic criteria ensured accurate classification of NHL subtypes.