Using the primary site as a prognostic tool for nodal mantle cell lymphoma: a SEER-based study
Publication: Journal of Comparative Effectiveness Research
Abstract
Background: Nodal mantle cell lymphoma (NMCL) has a worse survival than extra-nodal mantle cell lymphoma. Materials & methods: A cohort study was conducted to evaluate the primary site role as a mortality predictor using data from 1983 to 2011 from the Surveillance, Epidemiology, and End Results (SEER) database. Results: Most patients had NMCL in multiple regions (71.9%). There was a significantly increased incidence of NMCL cases over years with 83.2% of them occurred between 1998 and 2011. The mean survival was 52.9 months with overall survival/cancer-specific survival rate of 29.2/42.9%, respectively. Lymph nodes of intrathoracic and multiple regions had a worse overall survival while the head, face and neck, intra-abdominal, pelvic, inguinal region and leg as well as multiple regions had worse cancer-specific survival. Conclusion: NMCL primary site can serve as a prognostic factor. We encourage adding it to MCL International Prognostic Index.
Mantle cell lymphoma (MCL) is a distinct and aggressive subtype of B cell in the lymph nodes (LNs) [1,2]. In addition to the nodal involvement, the extra-nodal involvement is common as well, representing 90% of patients including the gastrointestinal (GI) tract, spleen and a rare central nervous system involvement [3–7]. MCL accounts for 5–10% of all lymphoma cases [8,9]. Moreover, several studies have reported increasing trends of MCL in the US [10–14].
MCL patients’ show a vastly variable clinical course of the disease. In general, most of the patients show an aggressive course with a poor response to the traditional chemotherapy regimens [15–17]. It has been shown that 75% of MCL patients with advanced stages develop poor survival rates and are associated with an advanced age, male sex, white people [11,13,18]. However, the median survival rate ranges from 3 to 4 years with a 1 year survival rate for patients having an aggressive form of MCL [3,8,19–23]. Whereas a subset of MCL patients’ shows an indolent clinical course with a survival lasting more than 10 years [24].
Expressive epidemiological studies were performed based on the improvements in the classification system including data on the prognostic factors for survival, morphology, stage of differentiation, immune-phenotype, genotype and clinical features of MCL. The most clinically important prognostic factors for MCL patients’ survival are those that constitute the MCL International Prognostic Index (MIPI) score including patient’s age, performance status, white blood cells count and LDH level [25–29]. Furthermore, the Ki-67 index and p53 mutation status have been identified as other prognostic factors in MCL patients [30–32]. MCL presents as a disseminated disease with a leukemic component in 20–30% of cases, recent studies suggested an improved survival in the non-nodal type of MCL [33–36]. Samaha et al. reported that relapses occur for 75% of their population, after treatment intake with a low survival rate reached less than 1 year that magnifies the role of relapses in controlling the disease survival rate, supported by Jurczak et al. study representing 49% of the progression-associated mortality [3,37]. With the introduction of more treatment modalities to MCL, more attention was paid to prognostic criteria that would affect the choice of chemotherapeutic agents and predict the MCL survival patients after the treatment. Ambinder et al. have found a worse survival in extra-nodal MCL (NMCL) as compared with NMCL [18]. Yet, the idea that the primary site of LNs involvement can have an impact on the survival of patients with MCL has not been investigated sufficiently in the literature before. This retrospective population-based cohort study was conducted to evaluate the primary site role as a predictor of mortality from NMCL using the data from the Surveillance, Epidemiology, and End Results (SEER) database.
Materials & methods
Data source
Survival data from 1983 to 2011, was retrieved from the SEER database containing 18 registries. This database contains cancer data from 18 SEER registries including Detroit, Connecticut, Hawaii, Iowa, Utah, the Greater Bay area, Cherokee Nation, New Mexico, Greater California, Seattle-Puget, Arizona, Louisiana, Georgia, New Jersey, Alaska, Kentucky, Atlanta and Los Angeles. Moreover, these registries comprise about 28% of the US population.
Variables selection
A number of variables were retrieved from SEER database including each patient’s age, sex, year of diagnosis, race, lymphoma subtype, diagnostic confirmation method, type of follow-up, the primary site coded by SEER, radiation and surgery status, the sequence number of MCL within other tumors, the marital status at diagnosis, Ann-Arbor stage, vital status at the end of follow-up, SEER specific cause of death and the survival months.
We did not include NMCL patients diagnosed between 1973 and 1982 because their staging was not applicable at that time. Cases having NMCL were defined and listed in the SEER database in compliance with the InterLymph Consortium classification of lymphoid neoplasms for epidemiological research based on the 2008 WHO classification and according to the third edition of the International Classification of Diseases for Oncology (ICD-O-3) coding system [38,39]. NMCL patients were requested using the National Cancer Institute SEER*stat software version 8.3.4 (www.seer.cancer.gov/seerstat).
Inclusion & exclusion criteria
We included patients with no restriction regarding sex, age or race. However, we excluded patients diagnosed without a microscopic confirmation or based on a clinical diagnosis only or cases with autopsy/death certificate only or inactive follow-up. Moreover, we included individuals with one primary tumor only.
Statistical analysis
Descriptive statistics, including mean/median and standard deviation/interquartile range, were provided for continuous variables. Frequencies and percentages were used to summarize categorical variables. The skewness and kurtosis tests were used for testing the normal distribution of continuous variables. Chi-squared test (or Fisher’s exact test, as appropriate) was used for categorical data while one-way analysis of variance (ANOVA) was used for continuous variables normally distributed while Kruskal–Wallis H test was used for continuous variables not normally distributed. Kaplan–Meier (KM) curves were performed and compared by the log-rank tests.
Our data was divided into training and prediction sets in a ratio of 70:30%, respectively, for the multivariable analysis. Also, we used the multivariable analysis to get the overall survival (OS) and cancer-specific survival. The hazard ratio (HR) with its 95% CI was calculated using univariable and multivariable Cox proportional hazards regression. The prediction model discriminatory powers obtained from multivariable Cox proportional hazards regression were compared according to the area under the curve from the receiver operating characteristic and their accuracy with their sensitivities and specificities. Data were analyzed using RStudio software version 3.2.4 and MedCalc software version 14.8.1. The statistical significance was considered when the p-value was <0.05.
Results
Patients’ characteristics
A total of 4020 NMCL patients were identified. We excluded 329 patients according to our aforementioned inclusion and exclusion criteria. Finally, we included 3691 MCL patients with nodal involvement.
Of those, 2567 (69.5%) were male. The majority were white (3355, 90.9%), married (2493, 67.5%) and in stage IV (2285, 61.9%). The mean age was 65 years with the majority of patients (3214, 87.1%) older than 50 years while the median diagnosis year was 2004. A total of 385 (10.4%) NMCL patients received radiotherapy and 1340 (36.3%) had surgery.
Furthermore, most patients had MCL in multiple regions, (2654, 71.9%), followed by the head, face and neck, (441, 12%) while the intrathoracic group had the least frequency (54, 1.5%). Surprisingly, there was a significantly increased incidence of NMCL cases over years with 3070 cases (83.2%) of them occurred between 1998 and 2011 as compared with 621 cases (16.8%) occurred between 1983 and 1997 (Figure 1).
There were older and more white patients in the intrathoracic group with no significant difference. Moreover, there were more patients above 50 years old in the aforementioned group, nevertheless, there were more patients ≤50 years old in the head, face and neck group. There was a significantly increased incidence of intrathoracic NMCL between 1998 and 2011. Furthermore, there were more men in the multiple regions group while there were more women in pelvic, inguinal and leg group with no significant difference. Stage I was significantly more predominant in pelvic, inguinal and leg group (67, 46.9%) than other groups while stage IV was more predominant in multiple regions group (1838, 69.3%; p < 0.001). Noteworthy, there was only one patient in stage I from multiple regions group (Supplementary Table 2). Additionally, there were more married patients in the axilla and arm group, however, there was no significant difference. There were significantly more patients who received radiation as well as had surgery in the head, face and neck group. Noteworthy, patients having multiple regions NMCL have undergone surgery less than other groups while patients with intra-abdominal MCL have received radiation less than other groups (Table 1 & Supplementary Table 3).
| Predictor | Overall (n = 3, 691) | Head, face and neck (n = 441) | Axilla and arm (n = 111) | Intrathoracic (n = 57) | Intra-abdominal (n = 285) | Pelvic, inguinal and leg (n = 143)† | Multiple regions (n = 2, 654) | p-value‡ |
|---|---|---|---|---|---|---|---|---|
| Age | 65 (12.5) | 64.1 (13.4) | 66.2 (12.1) | 70.1 (12.9) | 67.2 (11.9) | 67.5 (12) | 64.6 (12.4) | 0.68 |
| Age groups | ||||||||
| – ≤50 | 477 (12.9) | 71 (16.1) | 11 (9.9) | 5 (8.8) | 26 (9.1) | 14 (9.8) | 350 (13.2) | 0.056 |
| – >50 | 3,214 (87.1) | 370 (83.9) | 100 (90.1) | 52 (91.2) | 259 (90.9) | 129 (90.2) | 2,304 (86.8) | |
| Diagnosis year# | 2004 (8) | 2004 (9) | 2002 (10.5) | 2005 (7) | 2003 (9) | 2004 (8) | 2005 (8) | <0.001 |
| Diagnosis year groups | ||||||||
| – 1983–1997 | 621 (16.8) | 91 (20.6) | 31 (27.9) | 7 (12.3) | 70 (24.6) | 20 (14) | 402 (15.2) | <0.001 |
| – 1998–2011 | 3,070 (83.2) | 350 (79.4) | 80 (72.1) | 50 (87.7) | 215 (75.4) | 123 (86) | 2252 (84.9) | |
| Gender, male | 2567 (69.5) | 295 (66.9) | 74 (66.7) | 37 (64.9) | 184 (64.6) | 69 (48.3) | 1881 (70.9) | 0.134 |
| Race | ||||||||
| – White | 3355 (90.9) | 398 (90.2) | 101 (91) | 53 (93) | 262 (91.9) | 131 (91.6) | 2410 (90.8) | 0.66 |
| – Black | 169 (4.6) | 22 (5) | 8 (7.2) | 1 (1.8) | 9 (3.3) | 4 (2.8) | 125 (4.7) | |
| – American Indian/Alaska native | 18 (0.5) | 2 (0.5) | 0 (0) | 1 (1.8) | 2 (0.7) | 2 (1.4) | 11 (0.4) | |
| – Asian or Pacific Islander | 149 (4) | 19 (4.3) | 2 (1.8) | 2 (3.5) | 12 (4.2) | 6 (4.2) | 108 (4.1) | |
| Stage | ||||||||
| – I | 358 (9.7) | 178 (40.4) | 36 (32.4) | 15 (26.3) | 61 (21.4) | 67 (46.9) | 1 (0.04) | <0.001 |
| – II | 336 (9.1) | 84 (19) | 13 (11.7) | 11 (19.3) | 41 (14.4) | 17 (11.99) | 170 (6.4) | |
| – III | 712 (19.3) | 28 (6.3) | 12 (10.8) | 3 (5.3) | 12 (4.2) | 12 (8.4) | 645 (24.5) | |
| – IV | 2,285 (61.9) | 151 (34.2) | 50 (45) | 28 (49.1) | 171 (60) | 47 (32.9) | 1,838 (69.3) | |
| Marital status, married | 2493 (67.5) | 294 (66.7) | 79 (71.2) | 35 (61.4) | 188 (66) | 94 (65.7) | 1803 (67.9) | 0.773 |
| Survival months | 52.9 (49.7) | 66.2 (53.9) | 71.2 (67.8) | 38.1 (36.1) | 55.7 (52.3) | 57.2 (54.5) | 49.7 (47.2) | <0.001 |
| Survival rate, %§ | 29.2/42.9 | 35.4/50.8 | 32.4/54.1 | 15.8/49.1 | 25.3/39 | 31.5/51.1 | 28.6/41 | 0.005/<0.001 |
| 5-year survival rate, %¶ | 52.5 | 63 | 64.9 | 54.4 | 50.9 | 57.3 | 50.1 | <0.001 |
| 10-year survival rate, %¶ | 44.3 | 53.3 | 58.6 | 49.1 | 41.1 | 52.5 | 42.1 | <0.001 |
| Radiation, received | 385 (10.4) | 99 (22.4) | 13 (11.7) | 10 (17.5) | 14 (4.9) | 20 (14) | 229 (8.6) | <0.001 |
| Surgery, received | 1340 (36.3) | 226 (51.2) | 52 (46.8) | 15 (26.3) | 114 (40) | 57 (39.9) | 876 (24) | <0.001 |
Significant differences are in bold. Data are presented as mean (SD) for continuous variables and as frequency (percent) for categorical variables.
†
Patients with pelvic LNs were combined into inguinal region and leg LNs group because they formed of six patients only.
‡
p-value of comparison between different nodal sites.
§
The survival rate is for overall and cancer-specific survivals, respectively.
¶
Survival rate is for cancer-specific survival.
#
Data are in median and IQR.
IQR: Interaquartile range; LN: Lymph node; SD: Standard deviation.
Survival analysis
In general, the mean (standard deviation) survival was 52.9 (49.7) months with a low OS rate of 29.2% and a cancer-specific survival rate of 42.9%. In addition to that, patients having LNs involvement of the head, face and neck had significantly better survival with a mean of 66.2 (53.9) months and OS/cancer-specific survival of 35.4/50.8%, respectively, while intrathoracic-involved patients had the least survival, with a mean of 38.1 (36.1) months and OS/cancer-specific survival of 15.8/49.1% (p < 0.05; Figures 2 & 3).
Figure 2. The Kaplan–Meier survival curves showing the overall survival for nodal mantle cell lymphoma patients.
(A) sex; (B) age; (C) race; (D) site; (E) stage; (F) diagnosis year.
KM curves revealed significantly higher OS rates in married patients, ≤50 years old, stage I, diagnosed between 1998 and 2011, received radiation and/or surgery (p < 0.05). Similar trends were found in KM curves of the cancer-specific survival (Supplementary Table 1, Figures 2 & 3 and Supplementary Table 1 & 2).
Figure 3. The Kaplan–Meier survival curves showing the cancer-specific survival for nodal mantle cell lymphoma patients.
(A) sex; (B) age; (C) race; (D) site; (E) stage; (F) diagnosis year.
Multi-variable Cox proportional hazard models
Consistently, older age, unmarried, male patients, recently diagnosed with NMCL and stage IV as compared with stages I and II were associated with a worse survival across all models (Tables 2 & 3). Moreover, American Indian/Alaska native patients had about 220% probability of more risk of overall death as compared with white patients with HR, 95% CI: 2.21, (1.21, 4.03), p = 0.01 (Table 2). In addition to that, not having surgery had a worse 5-year cancer-specific survival with HR, 95% CI: 0.86, (0.76, 0.97), p = 0.014 (Table 3).
| Predictor | Overall survival | Cancer-specific survival | ||||||
|---|---|---|---|---|---|---|---|---|
| UV Cox | MV Cox | UV Cox | MV Cox | |||||
| HR, 95% CI | p-value | HR, 95% CI | p-value | HR, 95% CI | p-value | HR, 95% CI | p-value | |
| Age, years | 1.04 (1.04, 1.05) | <0.001 | 1.04 (1.04, 1.05) | <0.001 | 1.04 (1.03, 1.04) | <0.001 | 1.04 (1.03, 1.04) | <0.001 |
| Year of diagnosis | 0.98 (0.98, 0.99) | <0.001 | 0.98 (0.97, 0.98) | <0.001 | 0.98 (0.98, 0.99) | <0.001 | 0.98 (0.97, 0.99) | <0.001 |
| Gender | ||||||||
| – Male | Reference | |||||||
| – Female | 0.998 (0.92, 1.08) | 0.955 | 0.82 (0.74, 0.91) | <0.001 | 0.98 (0.89, 1.07) | 0.649 | 0.85 (0.76, 0.96) | 0.006 |
| Race | ||||||||
| – White | Reference | |||||||
| – Black | 1.05 (0.88, 1.26) | 0.59 | 1.14 (0.92, 1.41) | 0.231 | 1 (0.81, 1.23) | 0.985 | 1.06 (0.83, 1.36) | 0.622 |
| – American Indian/Alaska native | 1.13 (0.66, 1.95) | 0.659 | 2.21 (1.21, 4.03) | 0.01 | 0.96 (0.496, 1.84) | 0.89 | 1.98 (0.98, 3.98) | 0.057 |
| – Asian or Pacific Islander | 1.03 (0.84, 1.25) | 0.795 | 1.23 (0.97, 1.56) | 0.09 | 0.91 (0.72, 1.15) | 0.445 | 1.09 (0.82, 1.44) | 0.55 |
| Primary site | ||||||||
| – Axilla and arm | Reference | |||||||
| – Intra-abdominal | 1.31 (1.004, 1.7) | 0.047 | 1.29 (0.94, 1.75) | 0.112 | 1.54 (1.13, 2.1) | 0.007 | 1.60 (1.102, 2.33) | 0.013 |
| – Head, face and neck | 0.97 (0.75, 1.25) | 0.821 | 1.23 (0.91, 1.66) | 0.172 | 1.07 (0.79, 1.45) | 0.665 | 1.46 (1.01, 2.1) | 0.043 |
| – Pelvic, inguinal and leg† | 1.18 (0.87, 1.59) | 0.288 | 1.36 (0.95, 1.95) | 0.096 | 1.21 (0.84, 1.74) | 0.296 | 1.61 (1.05, 2.49) | 0.031 |
| – Multiple regions | 1.35 (1.07, 1.7) | 0.01 | 1.402 (1.06, 1.85) | 0.018 | 1.6 (1.21, 2.11) | 0.001 | 1.61 (1.14, 2.27) | 0.006 |
| – Intrathoracic | 1.93 (1.35, 2.78) | <0.001 | 1.796 (1.17, 2.76) | 0.007 | 1.64 (1.04, 2.59) | 0.034 | 1.37 (0.77, 2.42) | 0.281 |
| Stage | ||||||||
| – I | 0.73 (0.63, 0.83) | <0.001 | 0.61 (0.504, 0.75) | <0.001 | 0.55 (0.46, 0.65) | <0.001 | 0.48 (0.38, 0.61) | <0.001 |
| – II | 0.92 (0.802, 1.05) | 0.228 | 0.79 (0.67, 0.93) | 0.006 | 0.83 (0.71, 0.97) | 0.021 | 0.77 (0.64, 0.92) | <0.001 |
| – III | 1.2 (1.09, 1.32) | <0.001 | 0.99 (0.88, 1.12) | 0.919 | 1.16 (1.04, 1.29) | 0.006 | 0.96 (0.84, 1.1) | 0.549 |
| – IV | Reference | |||||||
| Marital status | ||||||||
| – Married | Reference | |||||||
| – Not married | 1.33 (1.22, 1.44) | <0.001 | 1.3 (1.18, 1.44) | <0.001 | 1.24 (1.13, 1.36) | <0.001 | 1.23 (1.1, 1.37) | <0.001 |
| Radiation | ||||||||
| – None/unknown | Reference | |||||||
| – Received radiation | 0.78 (0.69, 0.89) | <0.001 | 1.05 (0.903, 1.23) | 0.502 | 0.77 (0.66, 0.89) | <0.001 | 1.08 (0.91, 1.29) | 0.355 |
| Surgery | ||||||||
| – No surgery | Reference | |||||||
| – Received surgery | 0.795 (0.73, 0.86) | <.001 | 0.93 (0.84, 1.03) | 0.158 | 0.77 (0.699, 0.84) | <0.001 | 0.91 (0.82, 1.02) | 0.106 |
Significant predictors are in bold.
†
Patients with pelvic LNs were combined into inguinal region and leg LNs because they were formed of six patients only.
HR: Hazard ratio; LN: Lymph node; MV: Multivariable; UV: Univariable.
| Predictor | 5-year cancer-specific survival | 10-year cancer-specific survival | ||
|---|---|---|---|---|
| HR, 95% CI | p-value | HR, 95% CI | p-value | |
| Age, years | 1.04 (1.03, 1.04) | <0.001 | 1.04 (1.03, 1.04) | <0.001 |
| Year of diagnosis | 0.98 (0.98, 0.99) | <0.001 | 0.98 (0.97, 0.99) | <0.001 |
| Gender | ||||
| – Male | Reference | |||
| – Female | 0.87 (0.77, 0.99) | 0.029 | 0.84 (0.75, 0.95) | 0.004 |
| Race | ||||
| – White | Reference | |||
| – Black | 1.07 (0.82, 1.4) | 0.605 | 1.04 (0.81, 1.34) | 0.739 |
| – American Indian/Alaska native | 1.64 (0.73, 3.68) | 0.23 | 1.7 (0.81, 3.6) | 0.163 |
| – Asian or Pacific Islander | 1.08 (0.8, 1.46) | 0.63 | 1.11 (0.84, 1.47) | 0.449 |
| Primary site | ||||
| – Axilla and arm | Reference | |||
| – Intra-abdominal | 1.63 (1.07, 2.5) | 0.024 | 1.66 (1.12, 2.46) | 0.011 |
| – Head, face and neck | 1.32 (0.87, 2.01) | 0.194 | 1.47 (0.998, 2.15) | 0.051 |
| – Pelvic, inguinal and leg† | 1.67 (1.03, 2.7) | 0.039 | 1.64 (1.04, 2.58) | 0.032 |
| – Multiple regions | 1.61 (1.09, 2.39) | 0.017 | 1.69 (1.18, 2.42) | 0.005 |
| – Intrathoracic | 1.36 (0.74, 2.51) | 0.322 | 1.43 (0.8, 2.56) | 0.23 |
| Stage | ||||
| – I | 0.51 (0.4, 0.67) | <0.001 | 0.51 (0.397, 0.65) | <0.001 |
| – II | 0.76 (0.62, 0.94) | 0.011 | 0.8 (0.67, 0.97) | 0.021 |
| – III | 0.92 (0.795, 1.06) | 0.256 | 0.97 (0.85, 1.11) | 0.637 |
| – IV | Reference | |||
| Marital status | ||||
| – Married | Reference | |||
| – Not married | 1.3 (1.15, 1.47) | <0.001 | 1.25 (1.12, 1.4) | <0.001 |
| Radiation | ||||
| – No/unknown | Reference | |||
| – Received radiation | 1.07 (0.88, 1.29) | 0.498 | 1.08 (0.904, 1.28) | 0.409 |
| Surgery | ||||
| – No surgery | Reference | |||
| – Received surgery | 0.86 (0.76, 0.97) | 0.014 | 0.91 (0.82, 1.02) | 0.114 |
Significant predictors are in bold.
†
Patients with pelvic LNs were combined into inguinal region and leg LNs because they were formed of six patients only.
HR: Hazard ratio; LN: Lymph node.
For the primary site of NMCL, intrathoracic and multiple regions groups had a worse OS as compared with the axilla and arm group with 40 and 79% probability of more risk of overall death, respectively, while the head, face and neck (46%), intra-abdominal (60%), pelvic, inguinal and leg (61%) and multiple regions (61%) had a worse cancer-specific survival (Table 2). Consistent with the cancer-specific survival, the 5- and 10-year cancer-specific survival had similar trends (Table 3).
The Cox prediction models validation
Our models had an accuracy ranged between 63.3 and 72.6% with an area under the curve of 0.67–0.75, a sensitivity of 58.6–66.3% and a specificity of 61.8–76.5% (Supplementary Table 4).
Discussion
Our current study has disclosed several factors, including age, sex, primary site, marital status, race, stage, diagnosis year and surgery influencing the survival in NMCL patients.
It was revealed that older patients had worse survival. Indeed, they are most likely to have associated comorbidities that limit the therapeutic choices. Moreover, allogeneic hematopoietic stem cells transplant is offered almost exclusively to younger patients [40,41]. Furthermore, the advanced age is associated with worse outcomes in all subsets of NHL [42,43]. Akin to that, Cohen et al. and Zhou et al. magnify a good survival in patients who are <60 and <50 years old, respectively [11,44].
Men had lower survival than women, this substantiates previous results of Chandran et al. which highlight a higher MCL mortality in men and supports our finding that sex plays an important role in controlling survival in MCL [13]. It may be due to the hormonal differences that result in promising tumor characteristics [45] and a better response to immune-chemotherapy (rituximab) since this drug has been comprehensively used in MCL [46].
On the other hand, stage IV had the worst survival across all models, similarly advanced stages (III/IV) were found to be independently associated with increased mortality [18,47, 54-56]. Murthy et al. included stage I and II patients, have found better survival in the former [49].
In addition to that, married patients had a better survival as well, this supports previous findings in other cancers [48,50–56]. Also, that discloses the optimal and significant influence that marriage, especially social support, will have on cancer detection, treatment and even survival. Aizer et al. found that unmarried patients, including those who are widowed, are at a significantly greater risk of the exhibition with metastatic cancer, under treatment and even mortality from their cancer than married patients. After adjusting for other confounders, the marriage remained associated with a decline in the mortality ranging from 12 to 33% [52,53].
We could not find that receiving the radiation reduces mortality. This may be due to the small number of patients received radiation in our study (385, 10.4%) with similar insignificant results in Ambinder et al. study (307, 8.7%) [18].
Noteworthy, we have revealed that patients who underwent surgery had a better survival across all models, however, it was only significant in 5-year cancer-specific survival and other univariable but not other multivariable analyses. Interestingly, patients who underwent surgery had better survival rates than who did not undergo, 91.5% compared with 68.8%, respectively [57]. Undeniably, performing surgery in some sites such as GI lymphomas has a perfect impact on patients’ survival and in confirming a correct pathological staging and a precise histological diagnosis [57–70]. MCL treatment varies from chemotherapy to autologous stem cell transplantation with contrary results varying from good to a bad survival rate [7,71–73]. The resistance to chemotherapy marks an aggressive incurable disease requiring special attention from clinicians [37,74–77].
We have revealed an increased incidence of NMCL. Moreover, several studies have reported increasing the trends in the US [10,12–14]. Recent studies suggested an improved survival in the non-nodal type of MCL [33–36]. Furthermore, NMCL is more common than extra-nodal MCL. Notwithstanding, the worsening in the survival of NMCL in this study is probably because most of the patients were male, in stage IV with a mean age of 65 years and the majority was above 50 years old, in addition to that there was a predominance of LNs involvement of multiple regions. A previous study has revealed a worsening in the survival of NMCL as compared with the extra-nodal involvement with 30% probability of more risk of death [51].
In addition, the disease primary site can serve as an essential prognostic factor for MCL patients’ survival. Although MCL characteristics, survival and treatment were discussed in previous studies, MCL is still an unresolved problem among clinicians. An invasion of the GI tract occurs in the advanced stage of the disease, however, primary GI MCL rarely occurs with an incidence of 2% of primary GI lymphoma [78–80]. The primary site of the disease was demonstrated before as an essential and accurate prognostic factor in other cancers such as diffuse large B-cell lymphoma [81,82].
We have found several primary sites associated with increased mortality. NMCL of multiple regions involved LNs was on the top of them followed by intrathoracic, the head, face and neck, intra-abdominal and pelvic, inguinal and leg as well. Of note, patients with multiple regions involved LNs have undergone surgery less than other groups with more males than females and a significant stage IV predominance with only one patient in stage I. Similarly, there were more married patients in the axilla and arm group that may explain their better survival. Also, there was a significantly increased incidence of intrathoracic NMCL between 1998 and 2011. Indeed, there were more patients above 50 years old in that aforementioned group.
A biological mechanism should be disclosed for these primary sites aggressiveness. Undoubtedly, the rising belief of a clonal similarity among complex lymphomas different components, including mucosa-associated lymphoid tissue lymphoma and follicular lymphoma (FL) or Hodgkin’s lymphoma (HL) and FL or MCL, paves the way to simplify the complex appearance of these tumors, which may share another subtler but a common tumor behavior [83].
It has been demonstrated that a low-grade FL could be transformed into a highly aggressive large B-cell lymphoma and that histologic transformation could be clinically associated with the abrupt explosive growth of a single LN site, leading to a median survival time of 6–20 months only [25,26]. Subsequently, the resulting composite lymphoma will have the same lineage, yet other composite lymphomas were described to have different lineages (B and T cells) or compromising HL, as well as NHL combinations [27].
Regarding the primary LNs site influence on the survival in NMCL patients, several clinicopathologic characteristics of patients with these aforementioned primary sites should be investigated to see if similarities are present that may indicate either resemblance or transformation to a more aggressive or indolent tumor type.
Thus, we strongly encourage future studies to compare NMCL patients’ survival affected by the aggressive primary sites with other unfavorable variables in MIPI. Subsequently, we strongly encourage adding the primary site, especially, the multiple NMCL in the MIPI.
It has not been investigated before the association between the primary site and NMCL. Notwithstanding, we had some limitations including its retrospective nature and quite low accuracy, sensitivity and specificity of the prediction models. However, with that large sample size and several prediction models including OS, cancer-specific survival and 5- and 10-year cancer-specific survival, these limitations may not have effects on the current analysis with nearly the same significant predictors in all prediction models. Moreover, we could not validate our new prognostic factors against the MIPI since SEER does not have this index, thus future studies need to validate our findings against the MIPI.
Conclusion
NMCL has a worse survival with an increased incidence over the years. Several predictors have been identified. Older age, unmarried, male patients, recently diagnosed with MCL and stage IV were associated with worse survival. Multiple regions, intrathoracic, the head, face and neck, intra-abdominal, as well as pelvic, inguinal and leg LNs were associated with a worse survival while axilla and arm LNs were associated with better survival, suggesting that NMCL primary site can serve as a prognostic factor. Further studies need to investigate the biological basis of these aggressive primary sites and to validate its accuracy then it is encouraged to be added to MIPI.
•
Nodal mantle cell lymphoma (NMCL) has a worse survival than extra-nodal MCL.
•
NMCL had an increased incidence over the years with a mean survival of 52.9 months and overall survival/cancer-specific survival rate of 29.2/42.9%, respectively.
•
Older age, unmarried, male patients, recently diagnosed with mantle cell lymphoma and stage IV were associated with a worse survival.
•
Multiple-involved regions, intrathoracic, the head, face and neck, intra-abdominal, as well as pelvic, inguinal region and leg lymph nodes (LNs) were associated with a worse survival while axilla and arm LNs were associated with a better survival.
•
NMCL primary site can serve as a prognostic factor.
•
Further studies need to investigate the biological basis of these aggressive primary sites and to validate its accuracy then it is encouraged to be added to MCL International Prognostic Index.
Financial & competing interests disclosure
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
No writing assistance was utilized in the production of this manuscript.
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Using the primary site as a prognostic tool for nodal mantle cell lymphoma: a SEER-based study. (2020) Journal of Comparative Effectiveness Research. DOI: 10.2217/cer-2020-0083
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