Primary lung signet-ring cell carcinoma: a national analysis
Highlight box
Key findings
• Using the National Cancer Database (NCDB), we found that the clinicopathological characteristics of lung signet-ring cell carcinoma (LSRCC) are distinct from those of lung adenocarcinoma (LAC) and lung mucinous adenocarcinoma (LMAC). Patients with LSRCC had worse survival than patients with LAC and LMAC in unadjusted analysis. However, in multivariable analysis, LSRCC had worse survival when compared to only LAC.
What is known and what is new?
• In 2015, the World Health Organization removed LSRCC as a distinct histologic subtype of lung cancer in their classification system for thoracic tumors due to limited data regarding its clinical significance, instead recognizing it as a cytologic feature. The present study aids in filling this literature gap by using the NCDB to analyze LSRCC.
What is the implication, and what should change now?
• The results of this national analysis demonstrate that LSRCC is distinct from LAC and further investigations are warranted to determine if it should be re-evaluated as a distinct subtype from LAC given the implications to patient management.
Introduction
Signet-ring cell carcinoma is a rare form of mucin-producing adenocarcinoma that is highly malignant. It most commonly appears in the stomach but can arise in the esophagus, colon, rectum, breast, gallbladder, bladder, pancreas, prostate, and lung (1). Primary lung signet-ring cell carcinoma (LSRCC) was first described in 1989 by Kish et al. (2). Then, in 2004, the third edition of the World Health Organization (WHO) classification system for thoracic tumors recognized LSRCC as a distinct histologic subtype of lung cancer (3). However, due to lack of data of its clinical significant, LSRCC was discontinued as a subtype of lung adenocarcinoma (LAC) by the International Association for the Study of Lung Cancer American Thoracic Society/European Respiratory Society committee in 2011 (4). The WHO classification of thoracic tumors then discontinued LSRCC as a distinct subtype of lung cancer in 2015 and instead recognized it as a cytologic feature (5).
The majority of studies on LSRCC are single institution case reports or small retrospective analyses that limit statistical analysis, despite some hints to its potential prognostic factor (6-11). To our knowledge, there have been only three larger population-based studies on primary LSRCC of the lung, one using the California Cancer Registry (12), and two using the Surveillance, Epidemiology and End Results (SEER) database (1,13) that suggest a potential prognostic importance of LSRCC despite its discontinuation. The objective of this study, therefore, is to improve upon current evidence and investigate the clinicopathological characteristics and prognostic factors in patients diagnosed with primary LSRCC using the population-based National Cancer Database (NCDB), similar to how we recently did for primary clear cell adenocarcinoma of the lung, another discontinued rare type of lung cancer that previously lacked enough data (14). We present this article in accordance with the STROBE reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-102/rc).
Methods
Data source
The NCDB, a clinical oncology database jointly managed by the American College of Surgeons Commission on Cancer and the American Cancer Society, was queried in this study (15). The data provided by the NCDB is estimated to include approximately 72% of all newly diagnosed annual cases of lung cancer in the United States (16). The NCDB contains data from more than 1,500 cancer centers in the United States with over 30 million patient records. Variables used in the NCDB can be found online https://www.facs.org/quality-programs/cancer-programs/national-cancer-database/puf/ (17).
Study design
The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). Patients diagnosed with LSRCC from 2004 to 2018 were identified using the International Classification of Diseases for Oncology, 3rd edition (ICD-O-3) histology and topography codes 8140/3, 8480/3, 8481/3, and 8490/3, which corresponded to adenocarcinoma (not otherwise specified), mucinous adenocarcinoma, mucin-producing adenocarcinoma, and signet ring cell carcinoma, respectively. Given that ICD-O-3 is not aligned with the recent WHO classification of tumors, as detailed online https://seer.cancer.gov/tools/solidtumor/clarifications.html (18), years of diagnosis after 2015 were included in the primary analysis. However, we also performed a sensitivity analysis limited to 2014.
Only patients initially diagnosed with a single malignancy of LAC, LSRCC, or lung mucinous adenocarcinoma (LMAC) and who were diagnosed and treated at the reporting facility were included in the study. Patients who had unknown or missing American Joint Committee on Cancer (AJCC) staging were excluded. Overall survival (OS), measured from the time of diagnosis to the time of death or last follow-up, was the primary outcome.
Statistical analysis
Patients were grouped by histological type. Baseline characteristics and unadjusted outcomes were assessed using the analysis of variance (ANOVA) or Kruskal-Wallis test for continuous variables and Pearson χ2 or Fisher’s Exact test for discrete variables. Median OS and 5-year OS were assessed with the log-rank test and Kaplan-Meier product limit approach.
Multivariable Cox proportional hazards regression models were used to compare the OS across the different histologic types as well as to identify independent predictors of survival in patients with LSRCC. Variables included in the models included age, sex, race, year of diagnosis, median household income, educational attainment, insurance type, treatment facility type, distance from the facility, Charlson/Deyo comorbidity condition (CDCC) score, clinical T status, clinical N status, clinical M status, AJCC stage, tumor size, tumor location, treatment with surgery, chemotherapy, chemoradiation, and radiation.
Results
A total of 521,594 patients met the study criteria (Figure 1). Of these, 1,705 patients (0.3%) were diagnosed with LSRCC, 15,883 (3.0%) with LMAC, and 504,006 (96.6%) with LAC. Table 1 summarizes the baseline clinicopathological and demographic characteristics of the study cohort. Patients with LSRCC were more likely to be younger, have larger and more poorly differentiated tumors, higher AJCC stage IV disease, higher clinical T, N, and M status, and were more likely to undergo chemotherapy than patients with LAC or LMAC. The majority of LMAC patients underwent surgery (52.4%) as compared to LSRCC (17.3%) and LAC (26.5%) patients. Similar findings were seen when analyzing cases diagnosed before 2015 (Table S1).
Table 1
Patient characteristics | LSRCC (n=1,705) | LAC (n=504,006) | LMAC (n=15,883) | P value |
---|---|---|---|---|
Age (years), median (IQR) | 63.0 (17.0) | 67.0 (16.0) | 68.0 (16.0) | <0.001 |
Sex, n (%) | <0.001 | |||
Male | 900 (52.8) | 242,034 (48.0) | 7,378 (46.5) | |
Female | 805 (47.2) | 261,972 (52.0) | 8,505 (53.5) | |
Race, n (%) | <0.001 | |||
White | 1,401 (82.2) | 417,752 (82.9) | 13,419 (84.5) | |
Black | 208 (12.2) | 60,992 (12.1) | 1,643 (10.3) | |
Other | 83 (4.9) | 21,587 (4.3) | 688 (4.3) | |
Unknown | 13 (0.8) | 3,675 (0.7) | 133 (0.8) | |
CDCC score, n (%) | <0.001 | |||
0 | 1,127 (66.1) | 304,936 (60.5) | 9,635 (60.7) | |
1 | 395 (23.2) | 130,924 (26.0) | 4,103 (25.8) | |
2 | 139 (8.2) | 45,719 (9.1) | 1,472 (9.3) | |
3+ | 44 (2.6) | 22,427 (4.4) | 673 (4.2) | |
Tumor size (mm), median (IQR) | 35.5 (34.0) | 32.0 (30.0) | 31.0 (3.0) | <0.001 |
Grade | <0.001 | |||
Well-differentiated | 11 (0.6) | 31,757 (6.3) | 4,434 (27.9) | |
Moderately differentiated | 132 (7.7) | 98,836 (19.6) | 4,116 (25.9) | |
Poorly differentiated | 721 (42.3) | 132,334 (26.3) | 1,557 (9.8) | |
Undifferentiated | 20 (1.2) | 2,283 (0.5) | 34 (0.2) | |
Unknown | 821 (48.2) | 238,796 (47.4) | 5,742 (36.2) | |
Tumor location, n (%) | <0.001 | |||
RUL | 399 (23.4) | 155,837 (30.9) | 3,519 (22.2) | |
RML | 99 (5.8) | 21,764 (4.3) | 817 (5.1) | |
RLL | 203 (11.9) | 69,670 (13.8) | 3,739 (23.5) | |
LUL | 350 (20.5) | 111,882 (22.2) | 2,770 (17.4) | |
LLL | 174 (10.2) | 55,442 (11.0) | 2,873 (18.1) | |
Other | 119 (7.0) | 20,417 (4.1) | 522 (3.3) | |
Unknown | 361 (21.2) | 68,994 (13.7) | 1,643 (10.3) | |
NCDB analytic stage group, n (%) | <0.001 | |||
Stage 0 | 1 (0.1) | 591 (0.1) | 10 (0.1) | |
Stage I | 127 (7.4) | 115,642 (22.9) | 5,999 (37.8) | |
Stage II | 68 (4.0) | 33,647 (6.7) | 1,929 (12.1) | |
Stage III | 403 (23.6) | 92,578 (18.4) | 2,167 (13.6) | |
Stage IV | 1,105 (64.8) | 261,153 (51.8) | 5,757 (36.2) | |
Occult (lung only) | 1 (0.1) | 395 (0.1) | 21 (0.1) | |
Clinical T status, n (%) | <0.001 | |||
T1 | 346 (20.3) | 149,688 (29.7) | 5,416 (34.1) | |
T2 | 267 (15.7) | 99,026 (19.6) | 3,243 (20.4) | |
T3 | 180 (10.6) | 60,342 (12.0) | 1,827 (11.5) | |
T4 | 571 (33.5) | 126,501 (25.1) | 3,704 (23.3) | |
Unknown | 341 (20.0) | 68,449 (13.6) | 1,693 (10.7) | |
Clinical N status, n (%) | <0.001 | |||
N0 | 341 (20.0) | 180,077 (35.7) | 8,584 (54.0) | |
N1 | 110 (6.5) | 36,544 (7.3) | 807 (5.1) | |
N2 | 598 (35.1) | 142,677 (28.3) | 2,703 (17.0) | |
N3 | 366 (21.5) | 69,192 (13.7) | 1,103 (6.9) | |
Unknown | 290 (17.0) | 75,516 (15.0) | 2,686 (16.9) | |
Clinical M status, n (%) | <0.001 | |||
M0 | 629 (36.9) | 237,965 (47.2) | 9,781 (61.6) | |
M1 | 1,039 (60.9) | 250,916 (49.8) | 5,427 (34.2) | |
Unknown | 37 (2.2) | 15,125 (3.0) | 675 (4.2) | |
Insurance type, n (%) | <0.001 | |||
Uninsured | 88 (5.2) | 18,220 (3.6) | 404 (2.5) | |
Private | 642 (37.7) | 153,152 (30.4) | 5,135 (32.3) | |
Medicaid | 152 (8.9) | 38,836 (7.7) | 981 (6.2) | |
Medicare | 746 (43.8) | 276,793 (54.9) | 8,879 (55.9) | |
Other government | 28 (1.6) | 7,595 (1.5) | 175 (1.1) | |
Unknown | 49 (2.9) | 9,410 (1.9) | 309 (1.9) | |
Facility type, n (%) | <0.001 | |||
Community | 92 (5.4) | 35,360 (7.0) | 851 (5.4) | |
Comprehensive | 550 (32.3) | 204,749 (40.6) | 5,649 (35.6) | |
Academic/research | 685 (40.2) | 160,545 (31.9) | 6,060 (38.2) | |
Integrated | 317 (18.6) | 99,599 (19.8) | 3,083 (19.4) | |
Unknown | 61 (3.6) | 3,753 (0.7) | 240 (1.5) | |
Distance from facility (miles), median (IQR) | 9.8 (20.4) | 9.3 (18.4) | 9.8 (19.1) | <0.001 |
Median household income, n (%) | <0.001 | |||
Less than $40,227 | 312 (18.3) | 98,145 (19.5) | 2,606 (16.4) | |
$40,277 to $50,353 | 351 (20.6) | 108,654 (21.6) | 3,092 (19.5) | |
$50,353 to $63,332 | 346 (20.3) | 109,791 (21.8) | 3,381 (21.3) | |
$63,333 or greater | 572 (33.5) | 149,876 (29.7) | 5,529 (34.8) | |
Unknown | 124 (7.3) | 37,540 (7.4) | 1,275 (8.0) | |
Education: % without HS diploma, n (%) | <0.001 | |||
17.6% or greater | 346 (20.3) | 103,630 (20.6) | 2,928 (18.4) | |
10.9% to 17.5% | 412 (24.2) | 131,022 (26.0) | 3,796 (23.9) | |
6.3% to 10.8% | 424 (24.9) | 131,852 (26.2) | 4,309 (27.1) | |
Less than 6.3% | 402 (23.6) | 100,869 (20.0) | 3,603 (22.7) | |
Unknown | 121 (7.1) | 36,633 (7.3) | 1,247 (7.9) | |
Surgery, n (%) | <0.001 | |||
Yes | 295 (17.3) | 133,748 (26.5) | 8,322 (52.4) | |
No | 1,403 (82.3) | 368,602 (73.1) | 7,503 (47.2) | |
Unknown | 7 (0.4) | 1,656 (0.3) | 58 (0.37) | |
Chemotherapy, n (%) | <0.001 | |||
Yes | 1,031 (60.5) | 240,889 (47.8) | 6,275 (39.5) | |
No | 632 (37.1) | 251,545 (49.9) | 9,214 (58.0) | |
Unknown | 42 (2.5) | 11,572 (2.3) | 394 (2.5) | |
Chemoradiation, n (%) | <0.001 | |||
Yes | 226 (13.3) | 57,680 (11.4) | 889 (5.6) | |
No | 1,479 (86.7) | 446,326 (88.6) | 14,994 (94.4) | |
Radiation, n (%) | <0.001 | |||
Yes | 395 (23.2) | 119,646 (23.7) | 2,358 (14.9) | |
No | 970 (56.9) | 302,651 (60.1) | 11,590 (73.0) | |
Unknown | 340 (19.9) | 81,709 (16.2) | 1,935 (12.2) | |
Year of diagnosis, median (IQR) | 2,011.0 (7.0) | 2,012.0 (7.0) | 2,013.0 (7.0) | <0.001 |
LSRCC, lung signet-ring cell carcinoma; LAC, lung adenocarcinoma; LMAC, lung mucinous adenocarcinoma; IQR, interquartile range; CDCC, Charlson/Deyo comorbidity condition; RUL, right upper lobe; RML, right middle lobe; RLL, right lower lobe; LUL, left upper lobe; LLL, left lower lobe; NCDB, national cancer database; HS, high school.
OS stratified by histology subtype of lung cancer was assessed. The median follow-up time in the study was 13.9 months [interquartile range (IQR), 3.8–38.2 months]. In unadjusted analysis, patients with LSRCC were associated with significantly worse survival than those LAC and LMAC (Figure 2). In multivariable analysis, patients with LSRCC were associated with worse survival when compared to those with LAC and LMAC, but the difference in survival between patients with LSRCC and LMAC did not reach statistical significance (Table 2). Similar findings were seen when analyzing cases diagnosed before 2015 (Figure S1, Table S2).
Table 2
Patient characteristics | Hazard ratio (95% CI) | P value |
---|---|---|
Histology (ref = LSRCC) | ||
LAC | 0.81 (0.72, 0.91) | 0.001 |
LMAC | 0.89 (0.78, 1.01) | 0.063 |
Age (per year) | 1.02 (1.02, 1.02) | <0.001 |
Female vs. male | 0.81 (0.80, 0.82) | <0.001 |
Race (ref = White) | ||
Black | 0.92 (0.90, 0.95) | <0.001 |
Other | 0.76 (0.73, 0.79) | <0.001 |
Year of diagnosis (per year) | 0.96 (0.95, 0.96) | <0.001 |
Median household income (ref <$40,227) | ||
$40,277 to $50,353 | 0.94 (0.92, 0.96) | <0.001 |
$50,353 to $63,332 | 0.90 (0.88, 0.92) | <0.001 |
$63,333 or greater | 0.85 (0.83, 0.87) | <0.001 |
Education: % without HS diploma (ref >17.6%) | ||
10.9% to 17.5% | 1.03 (1.01, 1.05) | 0.003 |
6.3% to 10.8% | 1.03 (1.01, 1.06) | 0.004 |
Less than 6.3% | 0.99 (0.96, 1.01) | 0.342 |
Insurance type (ref = uninsured) | ||
Private | 0.81 (0.78, 0.84) | <0.001 |
Medicaid | 1.16 (0.92, 1.01) | 0.121 |
Medicare | 0.90 (0.86, 0.94) | <0.001 |
Other government | 0.86 (0.80, 0.92) | <0.001 |
Facility type (ref = community) | ||
Comprehensive | 0.94 (0.91, 0.96) | <0.001 |
Academic/research | 0.81 (0.79, 0.84) | <0.001 |
Integrated | 0.92 (0.89, 0.94) | <0.001 |
Distance from facility (per mile) | 1.00 (1.00, 1.00) | 0.017 |
CDCC score (ref =0) | ||
1 | 1.17 (1.15, 1.19) | <0.001 |
2 | 1.36 (1.33, 1.39) | <0.001 |
3+ | 1.65 (1.60, 1.70) | <0.001 |
Clinical T status (ref = T1) | ||
T2 | 1.21 (1.19, 1.23) | <0.001 |
T3 | 1.25 (1.22, 1.28) | <0.001 |
T4 | 1.36 (1.32, 1.39) | <0.001 |
Clinical N status (ref = N0) | ||
N1 | 1.22 (1.19, 1.25) | <0.001 |
N2 | 1.31 (1.28, 1.33) | <0.001 |
N3 | 1.43 (1.40, 1.47) | <0.001 |
Clinical M1 status (ref = M0) | 1.46 (1.37, 1.56) | <0.001 |
NCDB analytic stage group (ref = stage I) | ||
Stage II | 1.65 (1.61, 1.70) | <0.001 |
Stage III | 2.06 (2.01, 2.12) | <0.001 |
Stage IV | 2.41 (2.25, 2.57) | <0.001 |
Tumor size (per cm) | 1.00 (1.00, 1.00) | <0.001 |
Grade (ref = well differentiated) | ||
Moderately differentiated | 1.31 (1.28, 1.34) | <0.001 |
Poorly differentiated | 1.54 (1.33, 1.39) | <0.001 |
Undifferentiated | 1.44 (1.60, 1.70) | <0.001 |
Tumor location (ref = RUL) | ||
RML | 1.07 (1.04, 1.11) | <0.001 |
RLL | 1.11 (1.09, 1.13) | <0.001 |
LUL | 1.03 (1.01, 1.04) | 0.003 |
LLL | 1.07 (1.05, 1.09) | <0.001 |
Other | 1.16 (1.12, 1.20) | <0.001 |
Surgery vs. no surgery | 0.42 (0.41, 0.43) | <0.001 |
Chemotherapy vs. no chemotherapy | 0.58 (0.57, 0.59) | <0.001 |
Chemoradiation vs. no chemoradiation | 0.86 (0.84, 0.88) | <0.001 |
Radiation vs. no radiation | 0.96 (0.94, 0.98) | <0.001 |
LSRCC, lung signet-ring cell carcinoma; LAC, lung adenocarcinoma; LMAC, lung mucinous adenocarcinoma; CI, confidence interval; ref, reference; HS, high school; CDCC, Charlson/Deyo comorbidity condition; NCDB, national cancer database; RUL, right upper lobe; RML, right middle lobe; RLL, right lower lobe; LUL, left upper lobe; LLL, left lower lobe.
Multivariable Cox proportional hazards analysis showed that age, year of diagnosis, number of comorbidities, AJCC stage, income, tumor size, treatment with surgery, and treatment with chemotherapy were independent predictors of survival for patients with LSRCC (Table 3). When restricting to patients diagnosed before 2015, the independent predictors of survival were age, year of diagnosis, surgery, and radiation (Table S3).
Table 3
Patient characteristics | Hazard ratio (95% CI) | P value |
---|---|---|
Age (per year) | 1.02 (1.00, 1.04) | 0.032 |
Female vs. male | 0.89 (0.68, 1.17) | 0.396 |
Race (ref = White) | ||
Black | 1.12 (0.69, 1.81) | 0.650 |
Other | 1.18 (0.56, 2.48) | 0.654 |
Year of diagnosis (per year) | 0.94 (0.91, 0.98) | 0.002 |
Median household income (ref <$40,227) | ||
$40,277 to $50,353 | 0.72 (0.46, 1.14) | 0.162 |
$50,353 to $63,332 | 0.57 (0.35, 0.93) | 0.026 |
$63,333 or greater | 0.77 (0.45, 1.31) | 0.331 |
Education: % without HS diploma (ref >17.6%) | ||
10.9% to 17.5% | 1.40 (0.88, 2.21) | 0.150 |
6.3% to 10.8% | 1.64 (0.99, 2.73) | 0.057 |
Less than 6.3% | 1.35 (0.76, 2.39) | 0.304 |
Insurance type (ref = uninsured) | ||
Private | 0.88 (0.45, 1.72) | 0.712 |
Medicaid | 0.89 (0.41, 1.93) | 0.764 |
Medicare | 1.10 (0.53, 2.26) | 0.796 |
Other government | 0.79 (0.17, 3.66) | 0.766 |
Facility type (ref = community) | ||
Comprehensive | 0.84 (0.46, 1.51) | 0.551 |
Academic/research | 0.79 (0.44, 1.40) | 0.413 |
Integrated | 0.84 (0.46, 1.53) | 0.562 |
Distance from facility (per mile) | 1.00 (1.00, 1.00) | 0.402 |
CDCC score (ref =0) | ||
1 | 1.50 (1.09, 2.06) | 0.013 |
2 | 1.93 (1.08, 3.45) | 0.027 |
3+ | 2.31 (1.04, 5.12) | 0.039 |
Clinical T status (ref = T1) | ||
T2 | 0.98 (0.63, 1.52) | 0.939 |
T3 | 1.57 (0.95, 2.61) | 0.079 |
T4 | 1.02 (0.60, 1.75) | 0.932 |
Clinical N status (ref = N0) | ||
N1 | 1.21 (0.72, 2.04) | 0.473 |
N2 | 1.32 (0.88, 1.99) | 0.179 |
N3 | 1.03 (0.64, 1.67) | 0.900 |
Clinical M1 status (ref = M0) | 1.76 (0.76, 4.07) | 0.186 |
NCDB analytic stage group (ref = stage I) | ||
Stage II | 1.83 (0.96, 3.51) | 0.068 |
Stage III | 2.49 (1.34, 4.63) | 0.004 |
Stage IV | 2.02 (0.83, 4.99) | 0.123 |
Tumor size (per cm) | 1.00 (1.00, 1.01) | 0.312 |
Grade (ref = well differentiated) | ||
Moderately differentiated | 1.13 (0.20, 6.27) | 0.887 |
Poorly differentiated | 0.94 (0.18, 4.94) | 0.941 |
Undifferentiated | 0.77 (0.11, 5.35) | 0.790 |
Tumor location (ref = RUL) | ||
RML | 1.03 (0.62, 1.72) | 0.891 |
RLL | 0.81 (0.52, 1.26) | 0.356 |
LUL | 0.91 (0.63, 1.29) | 0.584 |
LLL | 0.73 (0.46, 1.16) | 0.185 |
Other | 1.01 (0.61, 1.65) | 0.977 |
Surgery vs. no surgery | 0.36 (0.23, 0.57) | <0.001 |
Chemotherapy vs. no chemotherapy | 0.71 (0.51, 0.99) | 0.042 |
Chemoradiation vs. no chemoradiation | 0.78 (0.48, 1.27) | 0.319 |
Radiation vs. no radiation | 0.81 (0.56, 1.17) | 0.260 |
CI, confidence interval; ref, reference; HS, high school; CDCC, Charlson/Deyo comorbidity condition; NCDB, national cancer database; RUL, right upper lobe; RML, right middle lobe; RLL, right lower lobe; LUL, left upper lobe; LLL, left lower lobe.
Discussion
In this study, we used the NCDB to investigate the clinicopathological characteristics and independent prognostic factors of LSRCC and compared the OS of patients with LSRCC of the lung to those with LAC and LMAC. While patients with LSRCC had worse survival than patients with LAC and LMAC in unadjusted analysis, LSRCC had worse survival when compared to only LAC in multivariable analysis.
A few other retrospective studies have been performed on LSRCC. Ou et al. analyzed 262 patients with LSRCC and compared them to 50,089 patients with LAC using the California Cancer Registry between 1989 and 2006 (12). The study found that LSRCC was associated with worse survival and was an independent unfavorable prognostic predictor in multivariable analysis. Wu et al. in 2018 compared the survival of 738 patients with LSRCC to signet-ring cell carcinoma cases involving other organs using the SEER database from 1988–2012 (1). The study found that survival differed based on the primary tumor location with a 5-year cause-specific survival of 11.0% in LSRCC. Cai et al. summarized the clinical and survival-related features of LSRCC using the SEER database from 2001–2015 (13). Similar to our findings, the study found that LSRCC had significantly worse median OS than LMAC (8 vs. 18 months, respectively; P<0.001) in unadjusted analysis but not multivariable analysis. While our findings are consistent with the above-mentioned studies, our study is unique in that we are the first to use the NCDB to analyze this question as well as the first to compare LSRCC to both LAC and LMAC. These findings point that LSRCC is distinct from LAC and future investigations are warranted to determine if it should be re-evaluated as a distinct subtype from LAC.
The present study has several limitations worth mentioning. First, the study is a retrospective cohort study, and there is the possibility of inherent unmeasured confounding that may influence the observed outcomes. Second, given that LSRCC is a rare tumor that is recognized as a cytologic feature, the NCDB may contain cases where a patient’s tumor should have been characterized as LSRCC but was instead misclassified, which could impact the accuracy of the results. Third, the NCDB does not contain data on patients’ performance status and pulmonary function, which limits the comprehensive understanding of how the patient’s health status impacts the findings of this study. Fourth, the three groups analyzed (LSRCC, LAC, and LMAC) in our study had unequal sample sizes, which could lead to bias in the comparative analyses. Fifth, we recognize that the study period in our study was from 2004–2018, during which AJCC staging guidelines changed; however, the patients in our study had their stage classified by the AJCC guideline that was available at the time of a patient’s diagnosis, which was not reclassified according to the 8th edition. Nonetheless, we performed sensitivity analyses limited to cases diagnosed before 2015 but acknowledge that this may not fully address the impact of the changes to the AJCC staging guidelines. Lastly, the median follow-up time of 13.9 months might not capture long-term outcomes adequately, especially for a cancer type with potential later recurrence.
Considering the limitations of retrospective data, future investigations should aim for prospective, multi-institutional studies to validate the findings of this study and minimize biases. These studies should collect more comprehensive clinical data, including performance status and pulmonary function, to enhance the accuracy of analyses. Furthermore, given the potential for late recurrence in certain cancers, extending the follow-up duration could provide a more accurate representation of survival outcomes. Findings from this study could benefit from external validation in different populations (i.e., outside of the United States) to confirm the generalizability of the results.
Conclusions
In this national analysis, LSRCC was shown to be associated with distinct clinicopathological characteristics, higher-stage disease, and worse survival when compared to LAC in both unadjusted and multivariable analyses despite its removal as a distinct pathologic subtype of adenocarcinoma. These differences were only seen in unadjusted analysis when comparing LSRCC to LMAC. Given our findings, further efforts, including prospective, multi-institutional studies, could further investigate the clinical significance of LSRCC and guide further management of the cancer.
Acknowledgments
Funding: None.
Footnote
Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-102/rc
Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-102/prf
Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-102/coif). C.F.J.Y. serves as an unpaid editorial board member of Journal of Thoracic Disease from February 2023 to January 2025. He declares honoraria from AstraZeneca for summit participation and is on the advisory boards for AstraZeneca and Genentech. The other authors have no conflicts of interest to declare.
Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013).
Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.
References
- Wu SG, Chen XT, Zhang WW, et al. Survival in signet ring cell carcinoma varies based on primary tumor location: a Surveillance, Epidemiology, and End Results database analysis. Expert Rev Gastroenterol Hepatol 2018;12:209-14. [Crossref] [PubMed]
- Kish JK, Ro JY, Ayala AG, et al. Primary mucinous adenocarcinoma of the lung with signet-ring cells: a histochemical comparison with signet-ring cell carcinomas of other sites. Hum Pathol 1989;20:1097-102. [Crossref] [PubMed]
- Travis W, Brambilla E, Muller-Hermelink H, et al. World Health Organization International Histological Classification of Tumours. Pathology and genetics of tumors of the lung, pleura, thymus and heart. Lyon: Thymus and Heart IARC Press; 2004.
- Travis WD, Brambilla E, Noguchi M, et al. International association for the study of lung cancer/american thoracic society/european respiratory society international multidisciplinary classification of lung adenocarcinoma. J Thorac Oncol 2011;6:244-85. [Crossref] [PubMed]
- Travis WD, Brambilla E, Nicholson AG, et al. The 2015 World Health Organization Classification of Lung Tumors: Impact of Genetic, Clinical and Radiologic Advances Since the 2004 Classification. J Thorac Oncol 2015;10:1243-60. [Crossref] [PubMed]
- Yang M, Yang Y, Chen J, et al. A case report of primary signet ring cell carcinoma of the lung: imaging study and literature review. Transl Lung Cancer Res 2021;10:3840-9. [Crossref] [PubMed]
- Castro CY, Moran CA, Flieder DG, et al. Primary signet ring cell adenocarcinomas of the lung: a clinicopathological study of 15 cases. Histopathology 2001;39:397-401. [Crossref] [PubMed]
- Anwar S, Acharya S, Elsayegh D, et al. Life Threatening haemoptysis in primary lung cancer-signet ring cell carcinoma. Respir Med Case Rep 2020;31:101195. [Crossref] [PubMed]
- Tsuta K, Ishii G, Yoh K, et al. Primary lung carcinoma with signet-ring cell carcinoma components: clinicopathological analysis of 39 cases. Am J Surg Pathol 2004;28:868-74. [Crossref] [PubMed]
- Wang Y, Wang Y, Li J, et al. Primary signet-ring cell carcinoma of the lung: A report of seven cases. Thorac Cancer 2020;11:3015-9. [Crossref] [PubMed]
- Iwasaki T, Ohta M, Lefor AT, et al. Signet-ring cell carcinoma component in primary lung adenocarcinoma: potential prognostic factor. Histopathology 2008;52:639-40. [Crossref] [PubMed]
- Ou SH, Ziogas A, Zell JA. Primary signet-ring carcinoma (SRC) of the lung: a population-based epidemiologic study of 262 cases with comparison to adenocarcinoma of the lung. J Thorac Oncol 2010;5:420-7. [Crossref] [PubMed]
- Cai Y, Xie Y, Xiong Y, et al. Clinicopathological characteristics and survival in lung signet ring cell carcinoma: a population-based study. Bosn J Basic Med Sci 2021;21:752-9. [Crossref] [PubMed]
- Mansur A, Saleem Z, Potter AL, et al. Primary clear cell adenocarcinoma of the lung: a national analysis. J Thorac Dis 2023;15:4248-61. [Crossref] [PubMed]
- American College of Surgeons. About the National Cancer Database. 2024. Accessed January 16th, 2024. Available online: https://www.facs.org/quality-programs/cancer-programs/national-cancer-database/about/
- Mallin K, Browner A, Palis B, et al. Incident Cases Captured in the National Cancer Database Compared with Those in U.S. Population Based Central Cancer Registries in 2012-2014. Ann Surg Oncol 2019;26:1604-12. [Crossref] [PubMed]
- American College of Surgeons. Participant User Files. Accessed October 30th, 2022. Available online: https://www.facs.org/quality-programs/cancer-programs/national-cancer-database/puf/
- Histology Coding Clarifications. 2020. Accessed January 9th, 2023. Available online: https://seer.cancer.gov/tools/solidtumor/clarifications.html