Primary lung signet-ring cell carcinoma: a national analysis
Original Article

Primary lung signet-ring cell carcinoma: a national analysis

Arian Mansur1, Zain Saleem2, Alexandra L. Potter3, Camille Mathey-Andrews3, Priyanka Senthil3, Chi-Fu Jeffrey Yang3

1Harvard Medical School, Boston, MA, USA; 2University of Ottawa, Ottawa, ON, Canada; 3Division of Thoracic Surgery, Department of Surgery, Massachusetts General Hospital, Boston, MA, USA

Contributions: (I) Conception and design: A Mansur, CFJ Yang; (II) Administrative support: CFJ Yang; (III) Provision of study materials or patients: AL Potter, CFJ Yang; (IV) Collection and assembly of data: A Mansur, Z Saleem, AL Potter, C Mathey-Andrews, P Senthil; (V) Data analysis and interpretation: A Mansur, Z Saleem, AL Potter, C Mathey-Andrews, P Senthil; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors.

Correspondence to: Arian Mansur, BA. Harvard Medical School, 25 Shattuck Street, Boston, MA 02115, USA. Email: arianmansur@hms.harvard.edu.

Background: Primary lung signet-ring cell carcinoma (LSRCC) is a rare form of aggressive lung cancer whose clinical features remain inadequately discerned. The objective of this study was to evaluate the clinicopathological characteristics and independent prognostic factors of primary LSRCC.

Methods: Overall survival (OS) of patients with LSRCC, lung adenocarcinoma (LAC), and lung mucinous adenocarcinoma (LMAC) in the National Cancer Database from 2004 to 2018 was evaluated using Kaplan-Meier and multivariable Cox proportional hazards modeling. Independent prognostic indicators for patients with LSRCC were determined using multivariable Cox proportional hazards analysis.

Results: A total of 1,705 LSRCC, 504,006 LAC, and 15,883 LMAC patients were included in our analysis. LSRCC histology was significantly associated with younger age, male sex, larger and more poorly differentiated tumors, later American Joint Committee on Cancer (AJCC) stage disease, higher clinical T, N, and M status, more use of chemotherapy, and less use of surgery when compared to LAC and LMAC patients. In unadjusted analysis, patients with LSRCC had significantly worse OS when compared to patients with LAC and LMAC. In multivariable analysis, patients with LSRCC experienced significantly worse OS when compared to only patients with LAC. Independent predictors of survival for patients with LSRCC were younger age, later year of diagnosis, lower Charlson/Deyo comorbidity condition scores, lower AJCC stage, higher income, smaller tumors, treatment with surgery, and receipt of chemotherapy.

Conclusions: In this national analysis, LSRCC was found to be associated with distinct clinicopathological characteristics from those of LAC.

Keywords: Signet-ring cell carcinoma; lung cancer; adenocarcinoma


Submitted Jan 17, 2024. Accepted for publication May 10, 2024. Published online Sep 26, 2024.

doi: 10.21037/jtd-24-102


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).

Figure 1 Flow diagram of study subject selection. NSCLC, non-small cell lung cancer; LSRCC, lung signet-ring cell carcinoma; LAC, lung adenocarcinoma; LMAC, lung mucinous adenocarcinoma; AJCC, American Joint Committee on Cancer.

Table 1

Clinicopathologic and demographic characteristics for patients, stratified by LSRCC versus LAC versus LMAC

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).

Figure 2 Kaplan-Meier analysis of overall survival for patients with LSRCC versus patients with LAC versus patients with LMAC. CI, confidence interval; LSRCC, lung signet-ring cell carcinoma; LAC, lung adenocarcinoma; LMAC, lung mucinous adenocarcinoma.

Table 2

Multivariable Cox proportional hazards analyses for patients, stratified by LSRCC versus LAC versus LMAC

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

Independent predictors of overall survival after Cox proportional hazards adjustment for patients with lung signet-ring cell carcinoma

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/.


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Cite this article as: Mansur A, Saleem Z, Potter AL, Mathey-Andrews C, Senthil P, Yang CFJ. Primary lung signet-ring cell carcinoma: a national analysis. J Thorac Dis 2024;16(9):5899-5908. doi: 10.21037/jtd-24-102

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