During the past 5 decades, there have been reports of increases in the incidence and mortality rates of non-Hodgkin lymphoma (NHL) in the United States and globally. The ability to address the epidemiologic diversity, prognosis and treatment of NHL depends on the use of an accurate and consistent classification system. Historically, uniform treatment for NHL has been hampered by the lack of a systematic taxonomy of non-Hodgkin lymphoma. Before 1982, there were 6 competing classification schemes with contending terminologies for NHL: the Rappaport, Lukes-Collins, Kiel, World Health Organization, British, and Dorfman systems without consensus as to which system is most satisfactory regarding clinical relevance, scientific accuracy and reproducibility and presenting a difficult task for abstractors of incidence information. In 1982, the National Cancer Institute sponsored a workshop1 that developed a working formulation designed to: 1) provide clinicians with prognostic information for the various types of NHLs, and 2) provide a common language that might be used to compare clinical trials from various treatment centers around the world. Studies imply that prognosis is dependent on tumor stage and histology rather than the primary localization per se.2 This study utilizes the National Cancer Institute PDQ adaptation of the World Health Organization’s (WHO) updated REAL (Revised European American Lymphoma) classification3 of lymphoproliferative diseases, and the SEER*Stat 8.3.6 database (released Aug 8, 2019) for diagnosis years 1975-2016. In this article, we make use of 40 years of data to examine patterns of incidence, survival and mortality, and selected cell bio-behavioral characteristics of NHL in the United States.

Objective.—To update trends in incidence and prevalence in the United States of non-Hodgkin lymphoma, examine, compare and contrast short and long-term patterns of survival and mortality, and consider the outcome impacts of anatomic location of NHL nodal and extranodal subdivisions, utilizing selected ICD-O-3 histologic oncotypes stratified by age, sex, race/ethnicity, stage, cell behavioral morphology and histologic typology, cohort entry time-period and disease duration, employing the statistical database of the National Cancer Institute SEER*Stat 8.3.6 program for diagnosis years 1975-2016.4 

Methods.—A retrospective, population-based cohort study using nationally representative data from the National Cancer Institute’s (NCI) Surveillance, Epidemiology, and End Results (SEER) program to evaluate 384,651 NHL cases for diagnosis years 1975-2016 comparing multiple variables of age, sex, race, stage, cell behavioral morphology, cohort entry time-period, disease duration and histologic oncotype. Relative survival statistics were analyzed in two cohorts: 1975-1995 and 1996-2016. Survival statistics were derived from SEER*Stat Database: Incidence – SEER 9 Regs Research Data, November 2018 Submission (1975-2016) <Katrina/Rita Population Adjustment> released April 2019, based on the November 2018 submission.

Results.—Incidence rates, relative frequency distributions, survival and mortality by age, sex, stage and cell behavioral morphology, of adult nodal (N) and extranodal (EN) NHL in 2 entrant time-periods as recorded in the SEER Program of the National Cancer Institute for diagnosis years 1975-2016 (SEER Stat 8.3.6) are summarized. Shifts in trends over time are identified, and the findings are correlated with prognosis, including short and long-term observed (actual), expected and relative survival, median observed and relative survival, mortality rates and excess death rates per 1000 people.

Conclusions.—Trends in SEER incidence, prevalence, survival and mortality by age, sex, race, stage, cell behavioral morphology, cohort entry time-period, relative frequency and percent distribution, were examined to provide a current epidemiologic and medical-actuarial risk assessment framework for nodal (N) and extranodal (EN) non-Hodgkin’s lymphoma in the 1975-2016 timeframe.

Background and Importance.—Nodal (N) and extranodal (EN) non-Hodgkin lymphomas (NHL), are a remarkably heterogeneous group of immunophenotypic, histo/morphologic and cytogenetic lymphoproliferative malignancies reflecting clinical, biologic and pathologic diversity with differing patterns of epidemiology, biologic behavior and responses to treatment.5 The 2016 revision of the World Health Organization (WHO) classification of hematopoietic and lymphoid neoplasms,6 based on morphology and cell lineage, updates the 1995 version of the REAL (Revised European American Lymphoma) system7 and represents the established guidelines for categorization and diagnosis of malignant lymphomas. Five major neoplastic classifications are recognized: 1) mature B-cell neoplasms, 2) mature T and NK neoplasms, 3) Hodgkin lymphoma, 4) posttransplant lymphoproliferative disorders [PTLD], and 5) histiocytic and dendritic cell neoplasms with approximately 95 subtypes and variants of lymphoid malignancy. Both lymphomas and lymphoid leukemias are included in this classification because both solid and circulating phases are present in many lymphoid neoplasms and distinction between them is artificial. Within the B-cell and T-cell categories, 2 subdivisions are recognized: precursor neoplasms corresponding to the earliest stages of differentiation, and more mature differentiated neoplasms. The National Cancer Institute PDQ modification of the REAL classification of lymphoproliferative diseases includes a substantive list of: 1) Plasma cell disorders, 2) Hodgkin lymphoma, 3) Indolent lymphoma/leukemia, and 4) Aggressive lymphoma/leukemia; with approximately 55 subclasses. These variant malignancies are encompassed in the National Cancer Institute (NCI) SEER*Stat 8.3.68 database (produced Aug 6, 2019) for diagnosis years 1975-2016 and facilitate this study. Continued refinements in classification and terminologies have advanced current understanding of medical risk inherent in non-Hodgkin’s lymphomas.

Nodal anatomic localizations were defined as lymph nodes, spleen, thymus and Waldeyer’s ring, and Extranodal anatomic localizations encompass other organs. Because of selection bias in defining extranodal NHL, the Comprehensive Cancer Centre West (CCCW) population-based NHL registry study, in an original article published in the Annals of Oncology in 2003,9 presented a plausible but liberal definition of primary extranodal NHL. The study included all patients who present with NHL that apparently originated at an extranodal site, even in the presence of disseminated disease, if the extranodal component is clinically dominant. Extranodal marginal zone lymphomas including the gastrointestinal tract, thyroid, lung, breast, orbit, and skin are called mucosa-associated lymphatic tissue (MALT) lymphomas10,11 Like Hodgkin lymphoma, NHL usually originates in lymphoid tissues and can spread to other organs. NHL, however, is much less predictable than Hodgkin lymphoma and has a far greater predilection to disseminate to extranodal sites.

Epidemiology.—A steady increase in the age-adjusted incidence of NHL has occurred over the last 5 decades, as reported by US and international registries. During the years 1993 to 1995, the age-adjusted incidence increased 3% per year according to data from the Surveillance, Epidemiology, and End Results (SEER) program of the National Cancer Institute.12 Some of this increased incidence can be attributed to the acquired immunodeficiency syndrome (AIDS), but this epidemic does not explain the increase of NHL before 1980. In the elderly population, there has also been a marked increase of NHL, largely the indolent bio-behavioral variants of NHLs.

The morbid importance of NHL is underscored by the estimated new cases diagnosed with NHL in the United States in 2019. Including adults and children, there are 74,200 (41,090 males and 33,110 females). About 19,970 people will die from this cancer (11,510 males and 8460 females).13 Diffuse large B-cell lymphoma (DLBCL), the most common NHL subtype, has an aggressive behavior and is more common in whites than African Americans in the United States; however, 5-year survival outcomes are worse in African Americans (see Tables 1 & 2). The BCL2 gene and rearrangement of the MYC gene or dual overexpression of the MYC gene, or both, confer a particularly poor prognosis.14 Molecular profiles of gene expression using DNA microarrays may help to stratify patients in the future for therapies directed at specific targets and to better predict survival after standard chemotherapy.15 

Table 1.

SEER Local-Regional-Distant (LRD) Anatomic Extent of Disease System Adapted to the Ann Arbor Lugano Revised Staging Classification for Primary Nodal Lymphomas

SEER Local-Regional-Distant (LRD) Anatomic Extent of Disease System Adapted to the Ann Arbor Lugano Revised Staging Classification for Primary Nodal Lymphomas
SEER Local-Regional-Distant (LRD) Anatomic Extent of Disease System Adapted to the Ann Arbor Lugano Revised Staging Classification for Primary Nodal Lymphomas
Table 2.

SEER Cancer Data 1975-2016 (SEER*Stat 8.3.6): Index Code 37a: NHL-NODAL 1983-1995 Entrants, Sex, Age & Race; All Stages & Indolent/Aggressive Combined

SEER Cancer Data 1975-2016 (SEER*Stat 8.3.6): Index Code 37a: NHL-NODAL 1983-1995 Entrants, Sex, Age & Race; All Stages & Indolent/Aggressive Combined
SEER Cancer Data 1975-2016 (SEER*Stat 8.3.6): Index Code 37a: NHL-NODAL 1983-1995 Entrants, Sex, Age & Race; All Stages & Indolent/Aggressive Combined
Table 3.

1996-2015 Entrants, Age, Sex & Race; All Stages & Indol/Aggress Grades Combined SEER Cancer Data 1975-2016 (SEER*Stat 8.3.6): Index Code 37a: NHL-NODAL

1996-2015 Entrants, Age, Sex & Race; All Stages & Indol/Aggress Grades Combined SEER Cancer Data 1975-2016 (SEER*Stat 8.3.6): Index Code 37a: NHL-NODAL
1996-2015 Entrants, Age, Sex & Race; All Stages & Indol/Aggress Grades Combined SEER Cancer Data 1975-2016 (SEER*Stat 8.3.6): Index Code 37a: NHL-NODAL

Etiology.—Most cases of aggressive NHL do not have a well-defined cause. For the NHLs that appear to have currently identifiable etiologic drivers, there are 4 groups of drivers: 1) immune suppression (both acquired and primary), 2) infectious agents, 3) toxic exposure, and 4) familial. The greatest factor involved in the worldwide increase in NHL, although lessened with the advent of highly active antiretroviral therapy (HAART), is HIV infection.16 The risk of NHL is increased by up to 300% in untreated HIV-infected patients, rising in proportion to the duration of the HIV infection. Although the risk of NHL in HIV-infected patients appears to be decreased by HAART, the relative risk of NHL remains much higher than that for those not infected with HIV.17 

Population-based frequency18 and survival19 data from SEER registries (released April 2019) were analyzed to compare and determine differences in characteristics and patterns of mortality and survival in NHL N and EN subdivisions at diagnosis by age, sex, race, cohort entry time-period, Ann Arbor stage, bio-behavioral grade, disease duration, and frequency and mean age data spanning 1983-2015 and 1975-2016 time-periods. Standard life table methodologies for converting SEER survival data to comparative mortality are described in other publications.20-23 Excluded were all death certificate only and those alive with no survival time. The percentage of microscopically confirmed malignant behavior cancers for case selections was 100%. Incidence and survival rates were obtained from the most current database of SEER Cancer Statistics Review (CSR)24 and prevalence counts are based on the average of 2015 and 2016 population estimates from the US Bureau of the Census.

Cell Behavioral Morphology (Grade equivalent) – Grade – biologic behavioral severity of disease at onset – indolent or aggressive, is inherent in NHL cell morphology/histology tumor types and are designated by using ICD-O-3 classifications facilitating subsite comparative analysis with Ann Arbor-Lugano Staging. Physician Data Query (PDQ),25 NCI’s comprehensive database modifications of the REAL classification of lymphoproliferative diseases include a complex system of 11 indolent and 12 aggressive lymphoma/leukemia histologic subsites. To simplify for the reader, selected indolent and aggressive ICD-O-3 characterizations, largely based on case frequency, are used in this analysis. B-cell, T-cell and Follicular cell morphology/histology types in the SEER program menu are noted below and are accessed using the appropriate histologic ICD-O-3 Case Selection Variable in the SEER*Stat 8.3.6 program. ICD-O-3 cell morphology/histology codes supplant Berg’s26 4 grading categories (well differentiated to undifferentiated). The PDQ behaviorally characterized and defined NHL subsite cell morphologies as either indolent or aggressive and treatment protocols remain largely based on classification systems that group diagnosis into indolent (low-grade) and aggressive (high-grade) NHL.

  • Indolent – “low grade” – grows and spreads slowly; considered to be grade 1-2 and recorded as grade 2. Indolent ICD-O-3 histologies used for the purposes of this article:

    • ○ ICD-O-3; 9690-Follicular lymphoma, NOS; Median Survival Time (MST) >20 years32.

    • ○ ICD-O-3; 9699-Marginal zone B-cell lymphoma, NOS; Median Survival Time – 10 years.

  • Indolent Definition: despite advanced stages (AJCC-Ann Arbor Stages III and IV), if median survival ranges from 8 to 15 years, the indolent designation, a scientific a priori premise, is assigned to a given NHL cell morphology/histology classification.27,28 

  • Aggressive – “high-grade” – grows and spreads quickly; considered to be grade 3-4 and recorded as grade 4; Aggressive ICD-O-3 histologies used for the purposes of this article:

    • ○ ICD-O-3; 9670 Small B lymphocytic, NOS; Median Survival Time – 5.9 years

    • ○ ICD-O-3: 9680 Large B-cell, diffuse (includes diffuse mixed-cell, immunoblastic, and T-cell rich large B-cell lymphoma); Median Survival Time – 2.0 years

    • ○ ICD-O-3: 9702 Mature T-cell lymphomas, NOS; Median Survival Time – 0.97 years

Stage–anatomic location – extent of disease at onset is the single most important determinant of prognosis, treatment and survivability. The American Joint Committee on Cancer (AJCC) along with the Union for International Cancer Control (UICC) has adopted the subsequent Lugano classification of the Ann Arbor/Cotswolds modification as the standard for classifying lymphoma tumor extent of anatomic disease.29 The SEER*Stat program menu selection variable for Stage – ‘Other’ – includes Lymphoma – Ann Arbor Stage (1983-2015). Historically, the SEER local-regional-distant (LRD) anatomic extent of disease system adapts the AJCC Ann Arbor-Lugano Revised Staging Classification for Primary Nodal Lymphomas.30,31 Ann Arbor principal stages abstracted from Ref. 30 Cheson BD et al JCO 2014 are described in Table 1.

Tonsils, Waldeyer’s ring, and spleen are considered nodal tissue. Whether stage II bulky disease is treated as limited or advanced disease may be determined by histology and several prognostic factors.

Ann Arbor Stage I and II lymphomas in the SEER system represent localized and regional disease, respectively. Ann Arbor Stage III disease was originally developed for patients with positive lymphangiograms, but with introduction of laparotomy, it has been enlarged to include patients with splenic lymphoma who should be identified with a subscript (IIIs). Ann Arbor Stage IV is restricted to those with lymph-node disease and disseminated involvement of nonlymphoid organs. Ann Arbor-Lugano stage III and IV lymphomas in the SEER program represent distant stage disease. Combining Stages I and II is termed Limited stage and Stages III and IV Advanced stage, and is used in this review to topographically classify NHL anatomic extent of disease at presentation:

Statistical significance–Standard errors are shown for survival rates in the SEER survival tables. Actuarial method: Ederer II method is used for cumulative expected survival. Ederer II method calculates the expected survival rates for patients under observation at each point of follow-up, so the matched individuals are considered to be at risk until the corresponding cancer patient dies or is censored.32 Confidence interval: Log (-Log ()) Transformation; the level is 95%. Poisson confidence intervals at the 95% level based on the number of observed deaths are used in this study but not displayed here to conserve space on the mortality tables.

Incidence.—General incidence rates are given for non-Hodgkin lymphoma (NHL) for both nodal and extranodal combined. The SEER Cancer Statistics Review for 1975-2016, Chart 1 below (derived from CSR Tables 19,1-3) indicates recent trends in the average annual percent change (AAPC) per 100,000 for non-Hodgkin lymphoma by sex, race, and ethnicity. These consisted of -0.2 per 100,000 for men, -0.6 for women, and -0.6 for both sexes combined. Negative trend rates were also seen in 2007-2016 in the Joinpoint Trend AAPC for all races, both sexes combined, -0.6 per 100,000.

In Chart 2, Age-adjusted incidence rates, examined for broader age groups, 2012-2016, increase with age and vary by race both in the United States and worldwide. Incidence is higher in males (32%) than in females, higher in whites (29%) than in blacks, and higher in the US (25%) than the average elsewhere in the world. There is a clear preponderance in non-Hodgkin lymphoma incidence in both sexes and all races in ages 65 and above and a higher incidence in the United States population at large (25%) compared to the world (WHO 2000-2025) standard million.

Chart 3, adapted from CSR Table 19.5, demonstrates age-adjusted overall progression of incidence rates (1975-2016), decennial progression (1980-2010), and annual progression (2011-2016) per 100,000 by year, race, and sex for all NHL cases in the 1975-2016 SEER database. Incidence rates from 1980 to 2016, all races and both sexes combined, rising from 12.62 per 100,000 to 19.36 per 100,000, an overall increase of 65%, but stabilized since 2000. Incidence among whites from 1980-2016 increased 36% and among blacks 47%. However, in the 2015-2016 interval, incidence rose 15% in black females while falling 5% in whites (both sexes combined) and 2% in black males. NHLs occurring in the elderly (ie, persons older than age 65 years) account for a large share of the increased incidence of lymphoma. Part of the increased incidence of specific categories of NHL may be due to environmental carcinogens (herbicide exposure), congenital & acquired immunodeficiency states, patients with Sjogren’s syndrome and other oncogenic viruses.

Prevalence.—Five-year limited duration counts, January 1, 2016, for non-Hodgkin lymphoma: All races, both sexes, 248,946; Males 135,137; Females 133,809 (CSR Table 19.25).

Mortality.—General mortality rates are given in the CSR for Non-Hodgkin’s Lymphoma (NHL) for both Nodal and Extranodal combined. In Chart 4, Age-adjusted mortality rates, examined for broader age groups, 2012-2016, increase with age and vary by race both in the United States and worldwide. Mortality is higher in males (40%) than in females, higher in whites (31%) than in blacks, and higher in the United States (46%) than the average elsewhere in the world. There is a clear preponderance in non-Hodgkin lymphoma mortality in both sexes and all races in ages 65 and above and a higher mortality in the US population at large (46%) compared to the world (WHO 2000-2025) standard million.

Chart 5, adapted from CSR Table 19.6, demonstrates age-adjusted overall progression of mortality rates (1975-2016), annual mortality increase (1980-1997), and annual mortality decline (1998-2016) per 100,000 by year, race, and sex for all NHL cases in the 1975-2016 SEER database. Mortality rates from 1980 to 1997, all races and both sexes combined, rose from 6.23 deaths per 100,000 to 8.88 per 100,000, an overall increase of 30%, but then began a steady decline to 5.33 deaths per 100,000 to 2016 consistent with the stabilization of incidence in the same time-period and the release of Rituximab (targeted therapy), a chimeric monoclonal antibody against the protein CD20 primarily found on the surface of immune system B cells, approved for medical use in 1997. When bound to this protein it triggers cancer cell death (apoptosis). Deaths among whites from 1980-1997 increased 30% and among blacks 37%. However, in the 1997-2016 interval, deaths fell in whites and blacks 39% and 40%, respectively.

SEER Nodal & Extranodal Case Statistics. There is a total of 384,651 cases of non-Hodgkin lymphoma in the 1975-2016 SEER frequency database distributed by age, sex, stage and grade. The total number included 261,144 nodal-NHL (67.9%) and 123,507 (32.1%) extranodal-NHL cases.

Case Characteristics – Chart 6.FAMA: Relative frequency and mean age (FAMA) distributions by age, sex and race for Nodal and Extranodal NHL, along with, Ann Arbor stage distributions & cell bio-behavioral grade frequencies (indolent-aggressive) are shown in Chart 6. A total of 261,144 patient-cases of nodal non-Hodgkin’s lymphoma (67.9% of all NHL cases) in the 1975-2016 SEER frequency database with a median age of 63 years are included in the study. Frequency and mean age (FAMA) in males are 142,456 (54.6%) and 62 years respectively, and 118,688 (45.4%) with mean age 66 years in females. Also included in this study are a total of 123,507 patient-cases of extranodal NHL in the 1975-2016 SEER frequency database with a median age of 63.5 years. FAMA in males are 66,930 (54.2%) and 62 years respectively, and female FAMA are 56,577 (45.8%) with mean age 65 years. Nodal frequency by race at presentation; 87% of cases were white, black 7%, other 6%, and unknown 6.7%, and mean ages in years were white 64.5, black 56.3, other 62.3 and unknown 57.8, respectively. Extranodal frequency by race at presentation; 82% of cases were white, 8% black, 8% other and 2% unknown, and mean age in years were 64.4, 54.4, 61.9 and 56.4, respectively.

Figure 1 (NHL-Nodal Frequency by Sex), the zenith of cumulative diagnostic frequency by attained age in males occurred at quinquennial age 65-69 (62.2%) and then declined to ages 85+ years. Females reached their zenith at quinquennial ages 75-79 (78.7%) then rapidly declined to ages 85+ years. However, females had a higher percentage of cases with advancing quinquennial ages 65-85+ years than males.
Figure 1.

NHL-Nodal: Diagnostic Frequency at Attained Age 1975-2016.

Figure 1.

NHL-Nodal: Diagnostic Frequency at Attained Age 1975-2016.

Close modal
Figure 2 (NHL-Extranodal Frequency by Sex), the zenith of cumulative diagnostic frequency by attained age in males occurred at quinquennial age 65-69 (61.6%) and then declined to ages 85+ years. Females reached their zenith at quinquennial ages 70-74 (66.1%) then slowly declined to ages 85+ years. However, females had a higher percentage of cases with advancing quinquennial ages 65-85+ than males. Although NHL nodal and extranodal total patient-case frequency counts differ by 47%, cumulative percent frequencies by quinquennial attained ages are proportionally similar for each subset.
Figure 2.

NHL-Extranodal: Diagnostic Frequency at Attained Age 1975-2016.

Figure 2.

NHL-Extranodal: Diagnostic Frequency at Attained Age 1975-2016.

Close modal

NHL-NodalStaged Cases: Shown in Chart 6, Ann Arbor staging extended from 1983 to 2015 in the SEER frequency database (Ref. 18), totaled 212,455 staged cases; of these however, only 56,154 (26.4%) were available for survival and mortality analysis from the SEER survival database (Ref. 19) for 1996-2015 entrants (Table 8). NHL-N & EN staged cases for mortality and survival analysis for the 1996-2015 cohort are displayed in Tables 8 and 16, respectively. Limited staging at presentation (Stages I & II combined) for the 1983-2015 cohort displayed in Chart 6 accounted for 76,317 cases (36%) and advanced staging (Stages III & IV combined) accounted for 136,138 cases (64%) of the staged NHL-nodal subdivision. Of the 1983-2015 grand total of all cases staged and unknown stage, 22,422 cases or 9.6% were of unknown stage.

NHL-Extranodal Staged Cases: Also shown in Chart 6, Ann Arbor criteria for staging (1983-2015) in the SEER frequency database (Ref. 18) totaled 91,044 staged cases; of these however, only 25,222 Ann Arbor staged cases (27.7%) were available for survival and mortality analysis from the SEER survival database for 1996-2015 entrants (Table 16). There were more than twice as many total NHL-Nodal than extranodal cases available for survival and mortality analysis from the SEER survival database, see Tables 8 and 16, respectively. Paradoxically, limited staging at presentation (Stages I & II combined) for the 1983-2015 cohort accounted for 63,538 cases (70%) and advanced staging (Stages III & IV combined) accounted for 27,506 cases (30%) of the staged NHL-extranodal subset. Of the 1983-2015 grand total of all cases staged and unknown stage, 8286 cases (8.3%) were of unknown stage.

Note: When a stage distribution is presented, the percentage given for each stage is the number of cases in a particular stage divided by the total number X 100 of staged cases only. However, overall, all stages known and unknown combined, NHL-EN demonstrates modestly improved mortality & survival outcomes, suggesting that NHL extranodal subsites may exert varying but possibly beneficial biologic behavioral influences on extent-of-disease and prognosis at presentation. Further research is needed to understand the biologic and socioeconomic underpinnings that may explain these NHL stage and grading disparities.

Graded Cases: Shown in Chart 6 from the SEER frequency database for the selected ICD-O-3 indolent and aggressive cell histo/morphology counts:

  • NHL-Nodal cases were 23,443 (18%) and 104,424 (82%), respectively,

  • Paradoxically, NHL-Extranodal indolent-aggressive cases proportionally were 21,902 (31%) and 47,793 (69%), respectively.

Chart 7 is the SEER Site/Histology Validation List for the selected Nodal and Extranodal NHL bio-behavioral grades employed in this study.

Follow-up (FU). Standard FU procedures were used by the 9 SEER Registries, with only a minimal loss to FU, according to the Cancer Statistics Review.

Nodal Nhl: Mortality and Survival

Results.Note well: In the 1975-2016 SEER*Stat 8.3.6 database, Ann Arbor staging data extends only from 1983-2015 and is reflected in this report in all NHL Nodal and Extranodal Tables exhibiting staging data; therefore, Ann Arbor Staged data in the 1975-1995 and 1996-2016 cohort entry-periods actually spans only the 1983-1995 and 1996-2015 time-periods respectively. For ease of NHL-Nodal and Extranodal mortality and survival comparability, Table formats are the same for both nodal and extranodal subdivisions, Tables (2-9) and Tables (10-16), respectively.

Table 2; 20-year FU in the 1983-1995 cohort by age, sex and race, (all stages and indolent & aggressive grades combined) is divided into 6 duration intervals 0-1, 1-2, 2-5, 5-10, 10-15 & 15-20 years. In this cohort, excess death rates (EDRs) in both sexes are extremely high in the 1st duration in all age groups but diminish with duration. EDR also increases with age; in males in the 1st duration, the EDR in age group 65 up is 361 vs female 374 per 1000 per year. In the first year, EDR is in the range of 269 to 361 per 1000 per year in males, and 198 to 374 in females. In 1983-1995, all ages combined, the preponderance of EDR in males over females, is evident. The corresponding MR values in the first year are extremely high: over 4000% in females and 3300% in males in patients under age 65. However, by duration 15-20 years EDR has decreased to about 18 in males at entry-age <65 and to 14 in females but MR values remain relatively high. EDR results are similar in both sexes, but MRs are higher in females, all ages combined because of lower expected deaths. Median survival, all ages combined, is higher in females than males, approximately 3-years vs 2.6-years, respectively. Five-year survival ratios (SR) are about 46% and 48% in males and females respectively, all ages combined. In males, SR diminishes from 53% in age group <65 to 37% in age group >65, and in females, SR diminishes from 61% in age group <65 to 39% in those age >65. Overall data available by race show EDR values higher and 5-year SR and median survival lower in non-white than in white patients.

Table 3 shows patterns of excess mortality in the 1996-2015 cohort for the same age groups in both sexes are consistent but of much lesser magnitude than in Table 1, reflecting earlier diagnosis and more suitable therapy in the latter entry-period. In males, all first-year EDRs are lower than they are in the 1983-1995 cohort. The highest EDR of 281 per 1000 per year is in the 65 up age group. This was based on 2597 (33%) deaths in 7773 entrants, and the EDR of 281 is significantly lower than the EDR of 361 in 1983-95 but significantly higher than the other male EDRs of 155 and 214 (all ages combined) in the 1996-2015 cohort (95% confidence level). EDRs increase with age but diminish with advancing duration in all age groups. EDR values in females (all ages combined) are always lower than the corresponding male age group; EDRs also increase with age but decrease with advancing duration. At duration 5-10 years, EDR values in all age/sex groups in 1996-2015 are consistently lower than their counterparts in 1983-1995. Excess mortality is lower in all white patients than in all non-white patients. Median survival and 5-year SR are lower in non-whites but significantly higher than in the 1983-95 cohort.

Table 4 shows results for the 1983-1995 cohort by Ann Arbor Stage for age groups <65 and 65 up, grade & both sexes combined. Excess mortality (EDR) increases from the local to the regional to the distant stage and is substantially higher in patients aged 65 and up. With over 61% of the staged cases of NHL-N classified as distant (Stages III & IV combined), EDR in the patients under 65 ranged from 323 in the first year to 21 per 1000 per year after 15 years. First year excess mortality was even higher in the patients 65 years and older, with an EDR of 437 and an MR of 922%, extremely high for these older patients.

Table 4.

1983-1995 Entrants, Age, Stage; Indolent/Aggressive Grades* & Sex Combined SEER Cancer Data 1975-2016 (SEER*Stat 8.3.6) Index Code 37a: NHL-NODAL

1983-1995 Entrants, Age, Stage; Indolent/Aggressive Grades* & Sex Combined SEER Cancer Data 1975-2016 (SEER*Stat 8.3.6) Index Code 37a: NHL-NODAL
1983-1995 Entrants, Age, Stage; Indolent/Aggressive Grades* & Sex Combined SEER Cancer Data 1975-2016 (SEER*Stat 8.3.6) Index Code 37a: NHL-NODAL

Table 5 shows results for the 1996-2015 cohort by Ann Arbor Stage, EDRs were consistently lower than they were in the corresponding stage/age/duration counterparts in the 1983-1995 cohort. The same trends prevailed by stage, by age, and by duration to 15-20 years. For all ages and stages, 5-year survival ratios (SR), median observed and relative survival were significantly higher, and mortality ratios lower than the earlier cohort.

Table 5.

1996-2015 Entrants, Age, Stage; Indolent/Aggressive Grades* & Sex Combined SEER Cancer Data 1975-2016 (SEER*Stat 8.3.6) Index Code 37a: NHL-NODAL

1996-2015 Entrants, Age, Stage; Indolent/Aggressive Grades* & Sex Combined SEER Cancer Data 1975-2016 (SEER*Stat 8.3.6) Index Code 37a: NHL-NODAL
1996-2015 Entrants, Age, Stage; Indolent/Aggressive Grades* & Sex Combined SEER Cancer Data 1975-2016 (SEER*Stat 8.3.6) Index Code 37a: NHL-NODAL

Table 6 contains results for durations 0-5 and 5-10 years, all male ages combined, by combination of Ann Arbor stage with other factors, such as cell grade/bio-behavioral morphology-indolent vs aggressive for each cohort, and by T cell and B cell morphology in the 1996-2015 cohort. For each combination, data for the 1983-95 and 1996-2015 cohorts are also contrasted. In the local and regional stages, (Ann Arbor Stages I and II, respectively), morphology/histology bio-behavioral severity determinants, indolent ICD-O-3 9690, 9699 combined & aggressive ICD-O-3 9670, 9680, 9702 combined are seen to be effective prognostic risk predictors: EDR and MR values are higher when tumor cells are bio-behaviorally classified aggressive instead of indolent. In the 1996-2015 cohort, all stages known and unknown combined, at both 5-years and 10-years duration, T-cell cases had a higher EDR but lower MR than the earlier cohort but made up only approximately 5% of the cases. The overall results of Table 5 confirm the results in Tables 1-4, showing a consistent reduction in mortality and improvement in survival, by stage from the earlier to the later cohort. Comparative mortality and survival are also shown in Table 5 for the unstaged cases, and for all cases staged and unknown stages combined. For 6528 NHL cases in 1983-95 cohort, all stages known & unknown and all cell bio-morphology grades combined, the 5-year overall EDR was 166 per 1000 per year; in 1996-2015 16,752 cases were diagnosed, and the EDR was at 98. Although the decrease in EDR is small it is statistically significant at the 95% level because of the very large numbers of deaths involved. In the 1996-2015 cohort the overall EDR for T-cell cases was 206, and for B-cell cases, 116.

Table 6.

Male, Cohort, Stage, Grade-Cell Morph/Hist*, Durations 0-5 & 5-10 Years; All Ages Combined SEER Cancer Data 1975-2016 (SEER*Stat 8.3.6). Index Code IC37a: NHL-NODAL

Male, Cohort, Stage, Grade-Cell Morph/Hist*, Durations 0-5 & 5-10 Years; All Ages Combined SEER Cancer Data 1975-2016 (SEER*Stat 8.3.6). Index Code IC37a: NHL-NODAL
Male, Cohort, Stage, Grade-Cell Morph/Hist*, Durations 0-5 & 5-10 Years; All Ages Combined SEER Cancer Data 1975-2016 (SEER*Stat 8.3.6). Index Code IC37a: NHL-NODAL

Results for duration 5-10 years, 1996-2015, by stage, bio-behavioral grade and cohort. Stage I (local stage) indolent grade cases; EDR was 8 per 1000 with 50 deaths (14%) in 352 entrants; aggressive grade, EDR 18 per 1000 with 250 deaths in 1343 entrants (19%); Stage II (regional stage) indolent grade, EDR 19 per 1000 in 180 entrants with 32 deaths (18%); aggressive grade, EDR 19 per 1000 in 1,063 entrants with 180 deaths (17%); also, an EDR of 31 and 38 per 1000 respectively for indolent and aggressive cases in stages III and IV combined (advanced stage). Indolent and aggressive cases combined in the unknown stage category (1996-2015) had an EDR of 21 per 1000, and for all known and unknown stages and for all morphology/histology bio-behavioral categories (IATB) combined, an EDR of 28 per 1000. In each of these categories, (T-cell excepted with only 198 cases and 16 deaths), EDR was lower in 1996-2015 than in the 1983-95 cohort.

Table 7 displays comparative mortality and survival for all female cases at duration 0-5 and 5-10 years and is identical in format to Table 5 for males. For females as for males, the same differences in EDR are observed: EDR increases by stage and is higher in aggressive bio-behavioral grade cases in the 1983-1995 time-period than in the 1996-2015 cohort, and in T-cell than in B-cell cases in local and regional stages, as well as T-cells in the 1996-2015 cohort. As was evident in Tables 2-5, excess mortality is consistently lower than in male NHL cases. In the 1983-1995 time-period, overall EDR for all stages known and unknown was 155 per 1000 per year, lower than the EDR of 166 in males. In females in 1996-2015 the EDR (94 per 1000) had also fallen to a level lower than the EDR of 98 in males. With very large numbers of deaths, all of these differences are significant at more than the 95% confidence level. In the 1996-2015 cohort the overall EDR (all stages known and unknown) for T-cell cases was 200, and 119 for B-cell cases. EDR in females at 5-10 years in 1996-2015, all stages known and unknown and cell bio-morphology grades IATB combined was 24, in B-cell cases 18, and in T-cell cases 40 (higher than the male counterpart T-cell EDR of 17 per 1000).

Table 7.

Female, Cohort, Stage, Grade-Cell Morph/Hist*, Durations 0-5 & 5-10 Years; All Ages Combined SEER Cancer Data 1975-2016 (SEER*Stat 8.3.6). Index Code IC37a: NHL-NODAL

Female, Cohort, Stage, Grade-Cell Morph/Hist*, Durations 0-5 & 5-10 Years; All Ages Combined SEER Cancer Data 1975-2016 (SEER*Stat 8.3.6). Index Code IC37a: NHL-NODAL
Female, Cohort, Stage, Grade-Cell Morph/Hist*, Durations 0-5 & 5-10 Years; All Ages Combined SEER Cancer Data 1975-2016 (SEER*Stat 8.3.6). Index Code IC37a: NHL-NODAL

Table 8 shows NHL-Nodal 20-year mortality and survival results by Ann Arbor Stage distribution, 1996-2015, all ages, grades, and both sexes combined. In the SEER survival database, there were a total of 56,154 staged patient-cases of Nodal-NHL with 19,818 (35.3%) limited stage, and 36,336 (64.7%) advanced stage cases. Excess mortality increased in magnitude with stage progression, and observed, relative and median survival diminished with advancing stages I to IV.

Table 8.

NHL-NODAL, 1996-2015, Ann Arbor Stages I-IV & Unknown;Sex & All Ages Combined SEER Cancer Data 1975-2016 (SEER*Stat 8.3.6). Index Code IC37a: NHL-NODAL

NHL-NODAL, 1996-2015, Ann Arbor Stages I-IV & Unknown;Sex & All Ages Combined SEER Cancer Data 1975-2016 (SEER*Stat 8.3.6). Index Code IC37a: NHL-NODAL
NHL-NODAL, 1996-2015, Ann Arbor Stages I-IV & Unknown;Sex & All Ages Combined SEER Cancer Data 1975-2016 (SEER*Stat 8.3.6). Index Code IC37a: NHL-NODAL

Limited Stage: In 19,818 (35.%) limited stage patient-cases (Ann Arbor Stages I & II combined), there were 2806 deaths (15%) in the 1st duration, MR 528%, and EDR ranged from 115 to 13 per 1000 per year after 15 years duration with 5-year observed & relative survival 69% & 79% respectively; median observed and relative survival ranged from 12 to >20 years.

Advanced Stage: In 36,336 patient-cases (Ann Arbor Stages III & IV combined), there were 9001 deaths (25%) in the 1st interval, MR 948%, and EDR ranged from 222 to18 per 1000 per year after 15 years with 5-year observed and relative survival 55% and 62%, respectively; median observed and relative survival ranged from 6 to 11 years. Overall excess mortality for Nodal NHL, all stages known & unknown, is very high because regional and distant stages (advanced stage) predominate, and many cases of unknown stage (2,832) have high mortality persisting beyond 15 years of FU duration. In general, mortality was approximately twice the magnitude in advanced stage relative to limited stage NHL-Nodal disease.

Unknown Stage: Mortality is intermediate when the stage is unknown (not reported).

Table 9: Utilizing 14 selected cell subtypes, both indolent and aggressive grades, Table 9 shows a side-by-side comparative mortality and survival analysis for both NHL-N & EN subdivisions by bio-behavioral ICD-O-3 histology code at 0-5 and 5-10-years duration, all ages and both sexes combined. This kind of typing was generally not done in the earlier cohort, so results are only for the 1996-2016 cohort. It will be seen that most of the cell subtypes are small in number especially in the extranodal subdivision.

Table 9.

1996-2016 Entrants: NHL-N & EN Comparative Mortality & Survival by Bio-behavioral Grade & Duration; All Ages and Stages Combined SEER Cancer Data (SEER*Stat 8.3.6). Index Code 37: Non-Hodgkin’s Lymphoma - Nodal and Extranodal

1996-2016 Entrants: NHL-N & EN Comparative Mortality & Survival by Bio-behavioral Grade & Duration; All Ages and Stages Combined SEER Cancer Data (SEER*Stat 8.3.6). Index Code 37: Non-Hodgkin’s Lymphoma - Nodal and Extranodal
1996-2016 Entrants: NHL-N & EN Comparative Mortality & Survival by Bio-behavioral Grade & Duration; All Ages and Stages Combined SEER Cancer Data (SEER*Stat 8.3.6). Index Code 37: Non-Hodgkin’s Lymphoma - Nodal and Extranodal

NHL-N Indolentgrades in Table 9 totaled 17,786 patient-cases including rare cell types consisting of 251 patient-cases (1.4%). The lowest subtype groups were ICD-O-3 9679 (Mediastinal large B-cell lymphoma) with 63 cases (0.4%) and ICD-O-3 9729 (Precursor T-cell lymphoblastic lymphoma, NOS) with 188 cases (1.1%). Comprehensive annualized EDRs, MRs, and SRs as well as median observed and relative survival data are shown for each of the cell categories. In indolent cases, EDR per 1000 per year at 0-5 years ranged from a minimum of 17 per 1000 per year in mediastinal large B-cell lymphomas to a maximum of 96 in precursor T-cell lymphoblastic lymphoma, NOS cases. Median observed and relative survival ranged from approximately 11 to >20 years in marginal zone B-cell lymphoma, NOS cases to approximately 16 to >20 years in grades 1 & 2 follicular lymphoma cases.

NHL-N Aggressive grades totaled 31,598 patient cases. The overall number of selected indolent & aggressive cell types for the NHL-Nodal subdivision totaled 49,384 patient cases, more than twice the number of equivalent selected cell type cases present in the NHL-Extranodal subdivision. The largest cell type group was diffuse large B-cell, NOS (DLBCL) with 21,272 patient cases (67% of NHL-Nodal aggressive grade cases) and the least was angioimmunoblastic T-cell lymphoma with 586 patient-cases. EDR results correlate well with the indolent “low-grade” and aggressive “high grade” designations used in this prognostic/histological classification; the aggressive category has an EDR minimum of 57 per 1000 (lymphoplasmacytic lymphoma) to 205 and higher (angioimmunoblastic and peripheral T-cell lymphomas) to indolent of 17 per 1000 to 96 per 1000 per year in the 0-5 years durational interval.

NHL-EN Indolent grades in Table 9 totaled 8117 patient cases including rare cell types amounted to only 250 patient-cases (mediastinal large B-cell lymphoma – 241 cases, and precursor T-cell lymphoblastic lymphoma, NOS – 9 patient-cases). In indolent cases, EDR per 1000 per year at 0-5 years ranged from a minimum of 2 per 1000 per year in follicular lymphoma, grade 1 to a maximum of 83 in precursor T-cell lymphoblastic lymphoma, NOS cases. Median observed and relative survival ranged from approximately 16 to >20 years. The largest cell type category of patient-cases, marginal zone B-cell lymphoma, NOS (MALT lymphomas) with 5234 patient cases in the 0-5-year interval (64% of indolent grade cases) displayed an EDR of 11 per 1000 per year and relative survival (SR) of 95% compared to its nodal counterpart with 2353 patient-cases (13% of indolent nodal cases), EDR of 37 per 1000 per year, and SR of 83%.

NHL-EN Aggressive grades in Table 9 totaled 14,215 patient-cases. The overall number of selected indolent and aggressive cell types for the NHL-Extranodal subdivision totaled 22,332 patient cases, just 45% of the total number of NHL-N cases. The most frequent cell type was DLBCL with 11,478 patient-cases (81% of NHL-EN aggressive grade cases): EDR 111 per 1000 per year, observed and relative survival (SR) 54% and 62% respectively, like DLBCL in the nodal subdivision.

Extranodal Nhl: Mortality and Survival

Results. In Table 10; 20-year FU in the 1983-1995 cohort by age, sex and race, (all stages and indolent-aggressive grades combined) is divided into six duration intervals 0-1, 1-2, 2-5, 5-10, 10-15 & 15-20 years. In this cohort, excess death rates (EDRs) in both sexes are extremely high in the 1st duration in all age groups but diminish with duration. EDR also increases with age, but in males in the 1st duration of age group 65 up, the EDR is 324 vs 332 per 1000 in females, following the same pattern as in the nodal subdivision (Table 2). Below age group 65, first year EDR in males is 348 per 1000 and 179 in females with corresponding MR values of 4566% in males and 3606% in female patients. However, by duration 15-20 years EDR has decreased to about 24 in males at entry-age <65 and to 17 in females. For all ages combined, the preponderance of EDR in males over females, is evident with 1st year male EDR of 337 per 1000 and 276 in females with MR values of 1185% and 967% respectively. EDR results are similar in both sexes, but MRs are higher in females, at ages below and above 65-years because of lower expected deaths. Median observed and relative survival, all ages combined, is higher in females than males, 4.9 to 8.4-years vs approximately 2.8 to 4.6 years, respectively. Five-year survival ratios are about 49% and 58% in males and females, respectively, all ages combined. In males, SR diminishes from 50% in cases age <65 to 48% in those age >65, and in females, SR diminishes from 69% in cases age <65 to 50% in those age >65. Overall data available by race show EDR values higher and 5-year SR & median survival lower in non-white than in white patients.

Table 10.

1983-1995 Entrants, Age, Sex & Race; All Stages & Indol/Aggress Grades Combined SEER Cancer Data 1975-2016 (SEER*Stat 8.3.6): Index Code 37b: NHL-EXTRANODAL

1983-1995 Entrants, Age, Sex & Race; All Stages & Indol/Aggress Grades Combined SEER Cancer Data 1975-2016 (SEER*Stat 8.3.6): Index Code 37b: NHL-EXTRANODAL
1983-1995 Entrants, Age, Sex & Race; All Stages & Indol/Aggress Grades Combined SEER Cancer Data 1975-2016 (SEER*Stat 8.3.6): Index Code 37b: NHL-EXTRANODAL

Table 11 shows that patterns of excess mortality in the 1996-2015 cohort for the same age groups in both sexes are consistent but of much lesser magnitude than in Table 2 reflecting earlier diagnosis and more suitable therapy in the latter entry-period. In males all first-year EDRs are lower than they are in 1983-1995. The highest EDR of 249 per 1000 per year is in the 65 up age group. This was based on 1,303 deaths (30%) in 4,274 entrants, and the EDR of 249 is significantly lower than the EDR of 324 in 1983-95 but significantly higher than the other male EDRs of 155 and 201 (all ages combined) in the 1996-2015 cohort (95% confidence level). EDRs increase with age but diminish with advancing duration in all age groups. Females EDR values (all ages combined) are always lower than the corresponding male age group, and EDRs increase with age but decrease with advancing duration. At duration 5-10 years EDR values in all age/sex groups in 1996-2015 are consistently lower than in their counterparts in 1983-1995. Excess mortality is lower in all white patients than in all non-white patients. Median observed survival is higher in non-whites (10.3 years) than whites (9 years) and 5-year SR are lower in non-whites but significantly higher than in the 1983-95 cohort.

Table 11.

1996-2015 Entrants, Age, Sex & Race; All Stages & Indol/Aggress Grades Combined SEER Cancer Data 1975-2016 (SEER*Stat 8.3.6): Index Code 37b: NHL-EXTRANODAL

1996-2015 Entrants, Age, Sex & Race; All Stages & Indol/Aggress Grades Combined SEER Cancer Data 1975-2016 (SEER*Stat 8.3.6): Index Code 37b: NHL-EXTRANODAL
1996-2015 Entrants, Age, Sex & Race; All Stages & Indol/Aggress Grades Combined SEER Cancer Data 1975-2016 (SEER*Stat 8.3.6): Index Code 37b: NHL-EXTRANODAL

Table 12 shows results for the 1983-1995 cohort by Ann Arbor Stage for age groups <65 and 65 up, indolent and aggressive grade & both sexes combined. Excess mortality (EDR) increases from the local to the regional and distant stages and is substantially higher in patients age 65 and up in the regional and distant stages. With 23% of the staged cases of NHL-EN classified as distant (stages III & IV combined), EDR in the patients under 65 ranged from 406 per 1000 per year in the first year to 34 per 1000 per year after 15 years. First year excess mortality was even higher in the patients 65 years and older, with an EDR of 485 and an MR of 1036%, extremely high for these older patients, higher than their NHL-N counterparts.

Table 12.

1983-1995 Entrants, Age, Stage*; Indolent/Aggressive Grades & Sex Combined SEER Cancer Data 1975-2016 (SEER*Stat 8.3.6) Index Code 37b: NHL-EXTRANODAL

1983-1995 Entrants, Age, Stage*; Indolent/Aggressive Grades & Sex Combined SEER Cancer Data 1975-2016 (SEER*Stat 8.3.6) Index Code 37b: NHL-EXTRANODAL
1983-1995 Entrants, Age, Stage*; Indolent/Aggressive Grades & Sex Combined SEER Cancer Data 1975-2016 (SEER*Stat 8.3.6) Index Code 37b: NHL-EXTRANODAL

Table 13 shows results for the 1996-2015 cohort by Ann Arbor Stage, EDRs were consistently lower than they were in the corresponding stage/age/duration counterparts in the 1983-1995 cohort (but higher than the NHL-N Counterpart-Table 4). The same trends prevailed by stage, by age, and by duration to 15-20 years. For all ages and stages, 5-year survival ratios (SR), median observed and relative survival were significantly higher, and mortality ratios lower than the earlier cohort.

Table 13.

1996-2015 Entrants, Age, Stage; Indolent/Aggressive* & Sex Combined SEER Cancer Data 1975-2016 (SEER*Stat 8.3.6). Index Code IC37b: NHL-EXTRANODAL

1996-2015 Entrants, Age, Stage; Indolent/Aggressive* & Sex Combined SEER Cancer Data 1975-2016 (SEER*Stat 8.3.6). Index Code IC37b: NHL-EXTRANODAL
1996-2015 Entrants, Age, Stage; Indolent/Aggressive* & Sex Combined SEER Cancer Data 1975-2016 (SEER*Stat 8.3.6). Index Code IC37b: NHL-EXTRANODAL

Table 14 contains results for durations 0-5 and 5-10 years, all male ages combined, by combination of Ann Arbor Stage with other factors, including cell grade/bio-behavioral morphology-indolent vs aggressive each cohort, and by T cell and B cell morphology in the 1996-2015 cohort. For each combination, data for the 1983-95 and 1996-2015 cohorts are also contrasted. In the local and regional stages, (Ann Arbor Stages I and II respectively), morphology/histology bio-behavioral severity determinants, indolent (ICD-O-3 9690, 9699 combined) and aggressive ICD-O-3 9670, 9680, 9702 combined) are seen to be effective prognostic risk predictors: EDR and MR values are higher when tumor cells are bio-behaviorally classified aggressive instead of indolent. In the 1996-2015 cohort (all stages combined) and unlike their NHL-N counterpart, T-cell cases had a lower EDR & lower MR than the earlier cohort, but made up only approximately 4% of the cases. The overall results of Table 14 confirm the results in Tables 10-13, showing a consistent reduction in mortality and improvement in survival, by stage from the earlier to the later cohort. Comparative mortality and survival are also shown in Table 13 for the unstaged cases, and for all cases staged and unknown stages combined. For 2848 NHL cases in 1983-95 cohort (all stages known & unknown and all cell bio-morphology grades (IATB) combined, the 5-year overall EDR was 156 per 1000 per year; in 1996-2015, 8830 cases were diagnosed, and the EDR was at 81. Although the decrease in EDR is small, it is statistically significant at the 95% level because of the very large numbers of deaths involved. In the 1996-2015 cohort, the overall EDR for T-cell cases was 139, and for B-cell cases it was 112.

Table 14.

Male, Cohort, Stage, Grade-Cell Morph/Hist*, Durations 0-5, 5-10 Years, All Ages Combined SEER Cancer Data 1975-2016 (SEER*Stat 8.3.6). Index Code IC37b: NHL-EXTRANODAL

Male, Cohort, Stage, Grade-Cell Morph/Hist*, Durations 0-5, 5-10 Years, All Ages Combined SEER Cancer Data 1975-2016 (SEER*Stat 8.3.6). Index Code IC37b: NHL-EXTRANODAL
Male, Cohort, Stage, Grade-Cell Morph/Hist*, Durations 0-5, 5-10 Years, All Ages Combined SEER Cancer Data 1975-2016 (SEER*Stat 8.3.6). Index Code IC37b: NHL-EXTRANODAL

Results for duration 5-10 years are given by stage, bio-behavioral grade and cohort. EDR in 1996-2015 was 14 per 1000 per year in stage I (local stage) indolent cases and 17 in aggressive grade cases, 16 in 152 entrants in stage II (regional stage) indolent cases with 23 deaths, and interestingly, (EDR) 23 in 550 aggressive stage II cases with 101 deaths; also, an EDR of 18 and 32 per 1000 respectively for indolent and aggressive cases in stages III and IV combined (distant stage). Indolent and aggressive cases combined in the unknown stage category had an EDR of 27 per 1000, and for all known and unknown stages and for all morphology/histology bio-behavioral categories (IATB) combined, an EDR of 19 per 1000. In each of these categories EDR was lower in 1996-2015 than in the 1983-95 cohort.

Table 15 displays comparative mortality and survival for all female cases at duration 0-5 and 5-10 years and is identical in format to Table 14 for males. For females as for males the same differences in EDR are observed: EDR increases by stage and is higher in aggressive bio-behavioral grade cases in the 1983-1995 time-period than in the 1996-2015 cohort. In 1996-2015 stage I, EDR in T-cell cases is 68 per 1000, lower than the 88 per 1000 in B-cell cases. In the regional stage (II), T-cell EDR in the 1996-2015 cohort is 179 per 1000, however, with only 28 entrants and 15 deaths. As was evident in Tables 10-13, excess mortality is consistently lower than in male NHL cases. In the 1983-1995 time-period, overall (all stages known & unknown), EDR was 118 per 1000 per year, lower than the EDR of 156 in males. In females in 1996-2015, the EDR (68) had fallen to a level also lower than the EDR of 81 in males. With very large numbers of deaths, all of these differences are significant at more than the 95% confidence level. In the 1996-2015 cohort, the overall EDR (all stages known and unknown) for T-cell cases was 126 and 107 for B-cell cases. EDR in females at 5-10 years in 1996-2015, all stages known and unknown and cell bio-morphology grades IATB combined was 19, in B-cell cases 22, and in T-cell cases 21.3.

Table 15.

Female, Cohort, Stage, Grade-Cell Morph/Hist*, Durations 0-5, 5-10 Years, All Ages Combined SEER Cancer Data 1975-2016 (SEER*Stat 8.3.6). Index Code IC37b: NHL-EXTRANODAL

Female, Cohort, Stage, Grade-Cell Morph/Hist*, Durations 0-5, 5-10 Years, All Ages Combined SEER Cancer Data 1975-2016 (SEER*Stat 8.3.6). Index Code IC37b: NHL-EXTRANODAL
Female, Cohort, Stage, Grade-Cell Morph/Hist*, Durations 0-5, 5-10 Years, All Ages Combined SEER Cancer Data 1975-2016 (SEER*Stat 8.3.6). Index Code IC37b: NHL-EXTRANODAL

Table 16 shows NHL-Extranodal 20-year mortality and survival results by Ann Arbor stage distribution, 1996-2015, all ages, grades, and both sexes combined. In the SEER survival database, there were 25,222 staged patient-cases of Extranodal-NHL with 17,664 (70%) limited stage and 7588 (30%) advanced stage cases. Although the proportion of NHL EN cases classified as local is much higher (13,480) than in Nodal NHL (11,056), even these cases have a very high first-year EDR – 130 per 1000 per year vs 87 per 1000 per year – with some excess mortality persisting beyond 15 years. Excess mortality increased in magnitude with stage progression, and observed, relative and median survival diminished with advancing stages I to IV. However, overall mortality for the extranodal NHL subdivision, all stages known and unknown combined, is less than nodal NHL because local and regional stages (limited stage) predominate. Limited & advanced stage patient-case frequency juxtapositions between NHL-N & EN subdivisions have been previously addressed.

Table 16.

NHL-EXTRANODAL, 1996-2015, All Ages Combined; Ann Arbor Stages I-IV & Unknown SEER Cancer Data 1975-2016 (SEER*Stat 8.3.6) Index Code 37b: NHL-EXTRANODAL 10/30/2004

NHL-EXTRANODAL, 1996-2015, All Ages Combined; Ann Arbor Stages I-IV & Unknown SEER Cancer Data 1975-2016 (SEER*Stat 8.3.6) Index Code 37b: NHL-EXTRANODAL 10/30/2004
NHL-EXTRANODAL, 1996-2015, All Ages Combined; Ann Arbor Stages I-IV & Unknown SEER Cancer Data 1975-2016 (SEER*Stat 8.3.6) Index Code 37b: NHL-EXTRANODAL 10/30/2004

Comments & Conclusions. Non-Hodgkin lymphomas (NHLs), with approximately 95-100 variant subtype diseases and considerable clinical, histologic and biologic heterogeneity are a group of lymphoproliferative cancers, of which 80% to 90% of cases arise from B-cells and the remaining from T-cells. Nodal and extranodal NHLs present a complex challenge in table design for many reasons: (1) the nature of this tissue; (2) its wide distribution in lymph nodes and other bodily sites; (3) bio-behavioral importance of cell types; (4) decades of changes including use of cytogenetic markers and immunophenotyping in tumor classification; (5) molecular profiling of gene expression in each NHL variant disease; (6) terminology modifications; (7) recent steps to merge the lymphomas with acute and chronic lymphatic leukemia. In spite of this, we utilized the National Cancer Institute PDQ practical adaptation of the World Health Organization’s (WHO) updated REAL (Revised European American Lymphoma) classification (Ref 3) of lymphoproliferative diseases, and the SEER*Stat 8.3.6 database (released 8/8/2019) for diagnosis years 1975-2016, making use of 40 years of data to examine patterns of incidence, survival and mortality, and selected cell bio-behavioral characteristics of NHL in the United States. The Ann Arbor staging classification (1983-2015), adopted by the AJCC and UICC as a standard for classifying extent of anatomic disease, allowed us to examine 32 years of NHL data by stage. The selection principles of this report refer to the impact of age, sex, race, stage, grade (biologic behavior), cohort entry time-period and disease duration determining short and long-term nodal and extranodal non-Hodgkin’s lymphoma mortality and survival.

NHL Staging Criteria: Although the SEER historic staging program remains a very important factor for displaying disease severity, it adapted its L-R-D anatomic extent of disease system to the AJCC Ann Arbor-Lugano principal stages I – IV contained in the Revised Staging Classification for Primary Nodal Lymphomas (Ref. 30, 31) as follows:

Localized (Stage I): confined to one lymphatic region above or below the diaphragm.

Regional (Stage II): more than one lymphatic region involved above or below the diaphragm.

Distant (Stage III): lymphatic regions involved on both sides of the diaphragm.

Distant (Stage IV): organs involved other than lymphoid tissue or lymph nodes. Our text and tables have shown that 68% of all nodal NHL cases were advanced staging (Stages III & IV combined) or unknown stage (5%), an overall high degree of anatomic extent of malignancy. Paradoxically, extranodal NHL cases show a juxtaposition in staging with 30% in the advanced stage and 70% in the limited stage (Stages I & II combined).

Relative Frequency & Mean Age: Relative frequency and mean age (FAMA) distributions by age, sex and race for Nodal and Extranodal NHL, and Ann Arbor stage distributions & cell bio-behavioral grade frequencies (indolent-aggressive) are shown in Chart 6. A total of 261,144 patient-cases of nodal non-Hodgkin’s lymphoma (67.9% of all NHL cases) in the 1975-2016 SEER frequency database with a mean age of 63 years are included in the study. Frequency and mean age (FAMA) in males are 142,456 (54.6%) and 62 years respectively, and 118,688 (45.4%) with mean age 66 years in females. Also included in this study are a total of 123,507 patient-cases of extranodal NHL in the 1975-2016 SEER frequency database with a mean age of 63.5 years. FAMA in males are 66,930 (54.2%) and 62 years respectively, and female FAMA are 56,577 (45.8%) with mean age 65 years.

NHL Epidemiologic Signatures (ES): Trends in population-based data on cancer burden (ES) provide insight into true cancer occurrence, over diagnosis, and treatment advances.33 Mortality and incidence patterns were examined from 1975 through 2016 for non-Hodgkin’s lymphoma in the United States. Incidence rates in the USA vary according to age, ethnicity, gender and time-period (see Charts 1 & 2). Mortality and incidence data presented here, aside from the tabular nodal and extranodal mortality displays, came from SEER Cancer Statistics Review (CSR), 1975-2016 (Ref. 24).

Much improved NHL mortality and survival indices in the 1996-2016 cohort entry time-period coincides with the 1997 release of Rituximab, a chimeric monoclonal antibody against the protein CD20 and causing cancer cell apoptosis. The NHL epidemiologic signature of stable incidence since the 1990s and declining mortality rates since 1997 corresponds with the efficacy of Rituximab targeted therapy and its addition to the anthracycline-based chemotherapeutic regimen of CHOP – cyclophosphamide, doxorubicin, vincristine and prednisone.

Mortality & Survival: Mortality is consistently higher and survival less in:

  • (1)

    NHL-Nodal vs NHL-Extranodal disease

  • (2)

    Cell type: T-cell vs B-cell

  • (3)

    Sex: males vs females

  • (4)

    Race: blacks vs whites

  • (5)

    Age: older (age >65) vs younger (age <65)

  • (6)

    Disease duration:

    • 0-5 years, consistently highest EDRs and MRs,

    • 5-20 years, consistently diminishing EDRs and MRs

  • (7)

    Stage: Advanced stage vs limited stage disease

  • (8)

    Bio-behavioral Grade: Aggressive morphology vs indolent morphology

  • (9)

    Cohort entry time-period: 1983-1995 vs 1996-2016

Further Directions: Since 1975 improved patient-outcomes shown in the 1996-2015 cohort entry time-period are attributable to advances in understanding of NHL classification and epidemiologic signatures, oncogene and tumor suppressor gene genetics, and application of immunologic and molecular techniques for refined diagnosis and targeted treatment. Patient treatment is determined by the specific type of lymphoma, with the addition of grade within the tumor type, if applicable, and clinical prognostic factors such as the International Prognostic Index (IPI).34 Recent national and international collaborations have resulted in promising randomized controlled trials that revealed significant benefits of targeted biologic therapies such as antigen receptor T-cells35,36 and adoptive T-cell therapies (ACT)37 with administration of specific antitumor immune cells. These include the use of both tumor infiltrating lymphocytes (TILs) extracted from fresh tumor samples and peripheral blood lymphocytes that can be selected and used either in their natural state or modified genetically to overcome limitations of conventional therapies. Targeted therapeutics and sustained remissions with improved progression-free survival are encouraging and lessen the disease burden of non-Hodgkin’s lymphoma.

Profound appreciation to my esteemed colleague Dr. Richard B. Singer, M.D. (deceased) for his friendship, invaluable collaboration and scholarly expertise, encouragement, and assistance in the initial (unpublished) iterations of long-term comparative mortality and survival in patients with nodal & extranodal non-Hodgkin’s lymphoma in 2003.

1.
Non-Hodgkin’s Lymphoma Pathologic Classification Project
.
National Cancer Institute sponsored study of classifications of non-Hodgkin’s lymphomas. Summary and description of a working formulation for clinical usage
.
Cancer
.
1982
;
49
:
2112
-
2135
.
2.
Economoboulos
I,
Ashrou
N,
Stathakis
N,
et al
Primary extranodal non-Hodgkin’s lymphoma in adults: clinicopathological and survival characteristics
.
Leuk Lymphoma
.
1996
;
21
:
131
-
136
.
[PUBMED Abstract]
3.
Pileri
SA,
Milani
M,
Fraternali-Orcioni
G,
et al
From the R.E.A.L. Classification to the upcoming WHO scheme: a step toward universal categorization of lymphoma entities?
Ann Oncol
.
1998
;
9
:
607
-
612
.
[PUBMED Abstract]
4.
Surveillance Research Program
,
National Cancer Institute SEER*Stat software (www.seer.cancer.gov/seerstat) version 8.3.6
.,
Built
2019
.
5.
Shankland
KR,
Armitage
JO,
Hancock
BW.
Non-Hodgkin lymphoma
.
Lancet
.
2012
;
380
:
848
-
857
.
6.
Swerdlow
SH,
Campo
E,
Pileri
SA,
et al
THE UPDATED WHO CLASSIFICATION OF HEMATOLOGICAL MALIGNANCIES: The 2016 revision of the World Health Organization classification of lymphoid neoplasms
.
Blood
.
2016
;
127
:
2375
-
2390
.
7.
Pileri
SA,
Milani
M,
Fraternali-Orcioni
G,
et al
From the R.E.A.L. Classification to the upcoming WHO scheme: a step toward universal categorization of lymphoma entities?
Ann Oncol
.
1998
;
9
:
607
-
612
.
[PUBMED Abstract]
8.
Surveillance Research Program
,
National Cancer Institute SEER*Stat software (www.seer.cancer.gov/seerstat): Latest Release: Version 8.3.6
-
2019
.
9.
Krol1
ADG,
le Cessie
S,
Snijder
JC,
et al
Primary extranodal non-Hodgkin’s lymphoma (NHL): the impact of alternative definitions tested in the Comprehensive Cancer Centre West population-based NHL registry
.
Annals of Oncology
.
2003
;
14
:
131
-
139
.
10.
Bertoni
F,
Zucca
E
:
State-of-the-art therapeutics: marginal-zone lymphoma
.
J Clin Oncol
.
2005
;
23
:
6415
-
6420
.
[PUBMED Abstract]
11.
Zucca
E,
Bertoni
F
:
The spectrum of MALT lymphoma at different sites: biological and therapeutic relevance
.
Blood
.
2016
;
127
:
2082
-
2092
.
[PUBMED Abstract]
12.
Groves
FD,
Linet
MS,
Travis
LB,
Devesa
SS.
Cancer surveillance series: non-Hodgkin’s lymphoma incidence by histologic subtype in the United States from 1978 through 1995
.
J Natl Cancer Inst
.
2000
;
92
:
1240
-
1251
.
13.
American Cancer Society: Cancer Facts and Figures
2019
.
Atlanta, Ga
:
American Cancer Society
,
2019
.
14.
Scott
DW,
King
RL,
Staiger
AM,
et al
High-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements with diffuse large B-cell lymphoma morphology
.
Blood
2018
;
131
:
2060
-
2064
.
[PUBMED Abstract]
15.
Schmitz
R,
Wright
GW,
Huang
DW,
et al
Genetics and Pathogenesis of Diffuse Large B-Cell Lymphoma
.
N Engl J Med
.
2018
;
378
:
1396
-
1407
.
[PUBMED Abstract]
16.
Cote
TR,
Biggar
RJ,
Rosenberg
PS,
et al
Non-Hodgkin’s lymphoma among people with AIDS: incidence, presentation and public health burden. AIDS/Cancer Study Group
.
Int J Cancer
.
1997
;
73
:
645
-
650
.
17.
Singer
RB,
Milano
AF.
Comparative Mortality in HIV-Infected Patients in Denmark, 1995–2005
.
J Insur Med
.
2008
;
40
:
116
-
119
.
18.
Surveillance, Epidemiology, and End Results (SEER) Program (www.seer.cancer.gov) SEER*Stat Database: Incidence - SEER 18 Regs Research Data + Hurricane Katrina Impacted Louisiana Cases, Nov 2018 Sub (1975-2016 varying) - Linked To County Attributes - Total U.S., 1969-2017 Counties, National Cancer Institute, DCCPS, Surveillance Research Program, released April 2019, based on the November 2018 submission
.
19.
Surveillance, Epidemiology, and End Results (SEER) Program (www.seer.cancer.gov) SEER*Stat Database: Incidence - SEER 9 Regs Research Data, Nov 2018 Sub (1975-2016) <Katrina/Rita Population Adjustment>- Linked To County Attributes - Total U.S., 1969-2017 Counties, National Cancer Institute, DCCPS, Surveillance Research Program, released April 2019, based on the November 2018 submission
.
20.
Singer
RB,
Kita
MW,
Avery
JR
, eds.
Medical Risks - 1991 Compend of Mortality and Morbidity
.
Westport, Conn
:
Praeger Publishers
;
1994
.
21.
Brackenridge
RDC,
Croxson
RS,
Mackenzie
R
, eds.
Medical Selection of Life Risks
. 5th ed.
New York, NY
:
Palgrave Macmillan
;
2006
:
chaps 3-5
.
22.
Pokorski
RJ.
Mortality Methodology and Analysis Seminar Text. Sponsored by the Association of Life Insurance Medical Directors of America
.
J Insur Med
.
1988
;
20
:
1
-
26
.
23.
Milano
AF,
Singer
RB.
The Cancer Mortality Risk Project – Cancer Mortality Risks by Anatomic Site: Part I – Introductory Overview; Carcinoma of the Colon: 20-Year Mortality Follow-up Derived from 1973-2013 (NCI) SEER*Stat Survival Database
.
J Insur Med
.
2017
;
47
:
65
-
94
.
24.
Howlader
N,
Noone
AM,
Krapcho
M,
et al (eds).
SEER Cancer Statistics Review
,
1975-2016
,
National Cancer Institute
.
Bethesda, MD
, https://seer.cancer.gov/csr/1975_2016/,
based on November 2018 SEER data submission, posted to the SEER web site, April 2019
.
25.
Physician Data Query (PDQ)
. https://www.cancer.gov/publications/pdq
26.
Berg
JW.
Morphologic classification of human cancer
. In:
Schottenfeld
D,
Fraumeni
JF
, eds.
Cancer Epidemiology and Prevention
.
Philadelphia: Saunders
;
1982
.
27.
Swenson
WT,
Wooldridge
JE,
Lynch
CF,
et al
Improved survival of follicular lymphoma patients in the United States
.
J Clin Oncol
.
2005
;
23
:
5019
-
5026
.
[PUBMED Abstract]
28.
Liu
Q,
Fayad
L,
Cabanillas
F,
et al
Improvement of overall and failure-free survival in stage IV follicular lymphoma: 25 years of treatment experience at The University of Texas M.D. Anderson Cancer Center
.
J Clin Oncol
.
2006
;
24
:
1582
-
1589
.
[PUBMED Abstract]
29.
Hodgkin and non-Hodgkin lymphoma
. In:
Amin
MB,
Edge
SB,
Greene
FL,
et al, eds.
AJCC Cancer Staging Manual
. 8th ed.
New York, NY
:
Springer
;
2017
:
937
-
958
.
30.
Cheson
BD,
Fisher
RI,
Barrington
SF,
et al
Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification
.
J Clin Oncol
.
2014
;
32
:
3059
-
3068
.
31.
Barrington
SF,
Mikhaeel
NG,
Kostakoglu
L,
et al
Role of imaging in the staging and response assessment of lymphoma: consensus of the International Conference on Malignant Lymphomas Imaging Working Group
.
J Clin Oncol
.
2014
;
32
:
3048
-
3058
.
32.
Cho
H,
Howlader
N,
Mariotto
AB,
Cronin
KA.
Estimating relative survival for cancer patients from the SEER Program using expected rates based on Ederer I versus Ederer II method
.
Surveillance Research Program, National Cancer Institute; 2011. Technical Report
.
2011
;
1
:
1
-
17
.
Available from
: https://surveillance.cancer.gov/reports/.
33.
Welch
HG,
Kramer
BS,
Black
WC.
Epidemiologic Signatures in Cancer
.
N Engl J Med
.
2019
;
381
:
1378
-
1386
.
34.
Harris
NL,
Jaffe
ES,
Diebold
J,
et al
Lymphoma classification—from controversy to consensus: the R.E.A.L. and WHO Classification of lymphoid neoplasms [review]
.
Ann Oncol
.
2000
;
11
(Suppl 1)
:
3
-
10
.
35.
Maud
SL,
Frey
N,
Shaw
PA,
et al
Chimeric Antigen Receptor T Cells for Sustained Remission in Leukemia
.
N Engl J Med
.
2014
;
371
:
1507
-
1517
.
36.
Kochenderfer
JN,
Dudley
ME,
Kassim
SH,
et al
Chemotherapy-refractory diffuse large B-cell lymphoma and indolent B-cell malignancies can be effectively treated with autologous T cells expressing an anti-CD19 chimeric antigen receptor
.
J Clin Oncol
.
2015
;
33
:
540
-
549
.
37.
Baruch
EN,
Berg
AL,
Besser
MJ,
et al
Adoptive T-Cell Therapy: An Overview of Obstacles and Opportunities
.
Cancer
.
2017
;
123
:
2154
-
2162
.
(2017 American Cancer Society)