PAST
Signet ring cell histology is a relatively common variant of gastric adenocarcinoma that encompasses 35% to 40% of cases.1 Historically, signet ring cell histology has been considered a more aggressive subtype associated with a worse long-term prognosis.2 As a result, many clinicians favor the use of neoadjuvant or perioperative therapies to address the fact that patients may be clinically understaged and to target micrometastatic disease. However, current stage-specific data are sparse, and the optimal management strategy remains controversial. This study sought to assess the validity of a surgery-first versus a multimodality approach to clinical stage 1 gastric adenocarcinoma with signet ring cell histology.3
PRESENT
The current National Comprehensive Cancer Network (NCCN) guidelines do not comment on specific histologic subtypes of gastric adenocarcinoma, although upfront surgery is recommended for localized clinical stage 1 disease. Given the aggressive tumor biology associated with signet ring cell histology, many clinicians offer preoperative therapy, even in the context of clinical stage 1 disease. This decision is grounded largely in landmark clinical trials (MAGIC and FLOT-4), although their applicability to clinical stage 1 gastric adenocarcinoma with signet ring cell histology should be carefully considered.4,5 This retrospective analysis of 1018 patients from the National Cancer Database demonstrates that a surgery-first strategy is associated with improved 5-year overall survival (OS) (surgery-first [71%] vs perioperative chemotherapy [58%] vs neoadjuvant therapy [38%] vs adjuvant therapy [52%]; all p < 0.01). Furthermore, 37% of clinical stage 1 patients were upstaged on final pathology. These data highlight the concern that a neoadjuvant or perioperative approach may not be efficacious, presumably due to its chemoresistant histology. A neoadjuvant or perioperative approach consequently prolongs definitive surgical management, which may result in continued disease progression and worse survival. Importantly, adjuvant therapy was able to rescue the patients upstaged on final pathology, and they experienced better outcomes than those treated preoperatively. The authors believe these data are immediately applicable to real-world clinical practice.
FUTURE
Clinicians have a tendency to overtreat this histologic variant, and the current analyses highlight the discordance between current guidelines and prevailing practice paradigms. The results of this study support adherence to NCCN guidelines for a surgery-first approach for clinical stage 1 gastric adenocarcinoma with signet ring cell histology. If patients are deemed to have pathologic stage 1 disease, no further treatment is necessary. Patients upstaged on final pathology can be offered a favorable rescue strategy with adjuvant therapy. A prospective randomized controlled trial is warranted to validate these findings.
ACKNOWLEDGMENTS
This study was supported in part by the Katz Foundation, the National Center for Advancing Translational Science (Grant/Award No. UL1TR002378/TL1TR002382), and the Biostatistics and Bioinformatics Shared Resource of Winship Cancer Institute of Emory University (NIH/NCI No. P30CA138292). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Footnotes
DISCLOSURE There are no conflicts of interest.
Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
REFERENCES
- 1.Pernot S, Voron T, Perkins G, Lagorce-Pages C, Berger A, Taieb J Signet ring cell carcinoma of the stomach: impact on prognosis and specific therapeutic challenge. World J Gastroenterol. 2015;21:11428–38. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Piessen G, Messager M, Leteurtre E, Jean-Pierre T, Mariette C. Signet ring cell histology is an independent predictor of poor prognosis in gastric adenocarcinoma regardless of tumoral clinical presentation. Ann Surg. 2009;250:878–87. [DOI] [PubMed] [Google Scholar]
- 3.Turgeon MK, Gamboa AC, Rupji M, et al. Should signet ring cellhistology alter the treatment approach for clinical stage 1 gastric cancer? Ann Surg Oncol. 2020. 10.1245/s10434-020-08714-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Cunningham D, Allum WH, Stenning SP, et al. Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J Med. 2006;355:11–20. [DOI] [PubMed] [Google Scholar]
- 5.Al-Batran SE, Homann N, Pauligk C, et al. Perioperative chemotherapy with fluorouracil plus leucovorin, oxaliplatin, and docetaxel versus fluorouracil or capecitabine plus cisplatin and epirubicin for locally advanced, resectable gastric or gastro-oesophageal junction adenocarcinoma (FLOT4): a randomised, phase 2/3 trial. Lancet. 2019;393:1948–57. [DOI] [PubMed] [Google Scholar]