Primary lung signet-ring cell carcinoma: a national analysis

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.

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.

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).

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 8^th 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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