Eighth edition of the American Joint Committee on Cancer staging system: are we getting closer to the ideal classification for gastric cancer?

For patients diagnosed with cancer, the outcomes are mainly determined by the stage of the disease; while it establishes the risk of progression and the median survival, it also serves as a guide when planning the treatment. Tumor extension and metastases to lymph nodes (LNs) have been proven as the most important prognostic factors; in this regard, the tumor-node-metastasis (TNM) classification is currently recognized as the standard tool for staging malignant solid tumors (1,2). Nevertheless, it is not a perfect system as it has limitations; specifically, in gastric cancer, the 7th edition was criticized for failing to incorporate the two N3 subclassifications into the final stratification despite reports of significant differences (1,3,4). The 8th edition published in 2017 included this key change to the pathologic grouping, dividing the N3 category into N3a (7–15 positive LNs) and N3b (≥16 positive LNs). As a result, stage shifts occurred: on one side, some tumors were upstaged (T1N3bM0 from IIB to IIIB, T2N3bM0 from IIIA to IIIB and T3N3bM0 from IIIB to IIIC); on the other hand, others were downstaged (T4aN2M0 from IIIB to IIIA and T4aN3aM0 and T4bN2M0 from IIIC to IIIB) (5). At first sight, this enabled a widening of the distance between the survival curves and therefore entailed an apparently better classification (2,6); however, the cohort of patients used in creating the new edition might not represent all the populations around the world, since 84.8% of the cases came from Japan and Korea and just 8.8% were from western countries (6).

Multiple studies serving as external validations have been done, the majority of them in Asia (particularly China) but only a few in Europe and the United States. As aforementioned, the modification impacted predominantly patients in stage III and thus they are the focus of the revisions. In general, the most frequent effect was the downstaging of groups (range: 7.9%–37.1%), what could raise concern about an underestimation of their prognosis (1,2,4-8); yet, for subjects who migrated stage, the survival curves had no significant difference compared to those of the classification in which they remained (1,4). Furthermore, N3a and N3b do represent distinctive severities of the disease; with the latter having worse outcomes (2,3,5,7). Data provided by Huang et al. showed that the 8th edition grades more orderly locally advanced gastric cancers; uniformly poorer survival rates were observed for all stages III: the median survival was 49, 27 and 15 months for subgroups A, B and C, respectively (per the 7th edition it was 62, 30 and 18 months) (9). Still the results are mixed; even though it has been demonstrated to offer a more accurate stratification (it has better homogeneity, discriminatory ability and monotonicity of gradients; besides, series have concluded its validity for western nations) (4,6,10), Lu et al. found that its superiority was only evident when ≥30 LNs are examined (they even propose a new model that depends on the number of LNs harvested) (6,7).

Unfortunately, an adequate lymphadenectomy is not always performed; in fact, the TNM system does not define a minimum number of LNs that should be retrieved during the surgery, but solely recommends that at least 15 LN are studied to distinguish the N3 categories. This flaw can lead to wrongly staging 10–15% of cases (11-13). Another tool to overcome the issue must be adopted; the lymph node ratio (LNR), defined as the positive LNs divided by the total LNs examined, has been suggested as a promising alternative. In previous studies, it was attested as an independent prognostic factor that correlated with poorer survival as the score increased, reflecting the tumor’s worse biology (11,14). Wu et al. concluded that its maximum usefulness was observed for stage III patients; in whom a further separation of survival rates was evident, not so for the rest of the groups (11). Meanwhile, Zhao et al. established that this improvement was significant only when the number of LNs was not the optimal (13). The authors of the current paper analyzed its performance in the N3b set and effectively demonstrated it was the most powerful independent indicator of disease behavior (9). All the same, it has limitations as the ideal cutoff values haven’t been well determined: on this occasion, the investigators of the article used 0.35 and 0.79; some series have employed 0.20 and 0.50 and others 0.15 and 0.40 (9,11,13). Its addition to the TNM classification may yield enhancements in the accuracy of the staging process (the novel scheme showed a larger concordance index and a smaller Akaike information criterion values) (13-15). Even so, it is important to always remember that no instrument can replace a satisfactory surgical dissection.

In summary, the 8th edition has been validated for its implementation in both eastern and western populations; moreover, research has confirmed it is superior to the previous versions by providing a better stratification of patients with a more precise prognosis (this benefit is mainly noticed in locally advanced cancer as Huang et al. stipulated). Now, since the N stage varies according to the amount of LNs obtained by the surgeon and the minimum number required has not been formally standardized, different models should be applied. In this manner, the LNR improves the effectiveness of the TNM system; although the authors evaluated its utility for the N3b category, others have verified its value when <15 LNs are examined. Noteworthy, the available literature continues to have limitations as all the studies are retrospective and consequently are subject to bias; also, some of the subgroups had very few patients and no supplementary tests could be made.

Acknowledgements

None.

Footnote

Conflicts of Interest: The authors have no conflicts of interest to declare.

References

1. Zhao B, Zhang J, Zhang J, et al. Assessment of the 8th edition of TNM staging system for gastric cancer: the results from the SEER and a single-institution database. Future Oncol 2018;14:3023-35.
2. Ji X, Bu ZD, Yan Y, et al. The 8th edition of the American Joint Committee on Cancer tumor node metastasis staging system for gastric cancer is superior to the 7th edition: results from a Chinese mono institutional study of 1663 patients. Gastric Cancer 2018;21:643-52.
3. Fang WL, Huang KH, Chen MH, et al. Comparative study of the 7th and 8th AJCC editions for gastric cancer patients after curative surgery. PLoS One 2017;12:e0187626. [Crossref] [PubMed]
4. Wang H, Guo W, Hu Y, et al. Superiority of the 8th edition of the TNM staging system for predicting overall survival in gastric cancer: Comparative analysis of the 7th and 8th editions in a monoinstitutional cohort. Mol Clin Oncol 2018;9:423-31.
5. Lu J, Zheng CH, Cao LL, et al. Validation of the American Joint Commission on Cancer (8th edition) changes for patients with stage III gastric cancer: survival analysis of a large series from a Specialized Eastern Center. Cancer Med 2017;6:2179-87.
6. In H, Solsky I, Palis B, et al. Validation of the 8th Edition of the AJCC TNM Staging System for Gastric Cancer using the National Cancer Database. Ann Surg Oncol 2017;24:3683-91.
7. Lu J, Zheng CH, Cao LL, et al. The effectiveness of the 8th American Joint Committee on Cancer TNM classification in the prognosis evaluation of gastric cancer patients: a comparative study between the 7th and 8th editions. Eur J Surg Oncol 2017;43:2349-56.
8. Lu J, Zheng CH, Cao LL, et al. Comparison of the 7th and 8th editions of the American joint committee on cancer TNM classification for patients with stage III gastric cancer. Oncotarget 2017;8:83555-62.
9. Huang SF, Chien TH, Fang WL, et al. The 8th edition American Joint Committee on gastric cancer pathological staging classification performs well in a population with high proportion of locally advanced disease. Eur J Surg Oncol 2018;44:1634-9.
10. Graziosi L, Marino E, Donini A. Survival comparison in gastric cancer patients between 7th and 8th edition of the AJCC TNM staging system: The first western single center experience. Eur J Surg Oncol 2018. [Epub ahead of print].
11. Wu XJ, Miao RL, Li ZY, et al. Prognostic value of metastatic lymph node ratio as an additional tool to the TNM stage system in gastric cancer. Eur J Surg Oncol 2015;41:927-33. [Crossref] [PubMed]
12. Wang H, Xing XM, Ma LN, et al. Metastatic lymph node ratio and Lauren classification are independent prognostic markers for survival rates of patients with gastric cancer. Oncol Lett 2018;15:8853-62. [PubMed]
13. Zhao LY, Li CC, Jia LY, et al. Superiority of lymph node ratio-based staging system for prognostic prediction in 2575 patients with gastric cancer: validation analysis in a large single center. Oncotarget 2016;7:51069-81. [PubMed]
14. Chen S, Rao H, Liu J, et al. Lymph nodes ratio based nomogram predicts survival of resectable gastric cancer regardless of the number of examined lymph nodes. Oncotarget 2017;8:45585-96. [PubMed]
15. Hung YS, Chang SC, Liu KH, et al. A prognostic model based on lymph node metastatic ratio for predicting survival outcome in gastric cancer patients with N3b subclassification. Asian J Surg 2019;42:85-92. [Crossref] [PubMed]