In this study, we compared the clinicopathological features of EGC in patients younger than 40 years of age to those older than 40 years of age. YGC patients were further divided into 2 groups based on LNM. In the LN positive group, deeper invasion depth, more LVI, and decreased E-cadherin expression were observed. Multivariate analysis revealed that LVI was the only independent risk factor for LNM in the younger cohort. In terms of endoscopic treatment indications in this group, we confirmed that YGC patients fulfilling absolute indications for endoscopic resection had no LNM risk, whereas for those within extended indications, appropriate treatment should be cautiously chosen due to a potentially increased risk of LNM.
Previous reports showed the overall risk of LNM ranged from 1.4% to 5.2% for mucosal cancers, and 15% to 21.4% for submucosal cancers.[26–28] Although in our cohort, the LNM rate of early YGC rose up to 27.6% (8/29) for T1a lesions and 43.7% (7/16) for T1b lesions, which is much higher than that have been reported, the overall LNM risk in the older cohort was 13%, which is in agreement with previous studies. Takatsu et al reported that more YGC patients had involvement of 7 or more lymph nodes and suggested that the presence of LNM was a strong risk factor for their tumor recurrence and a strict follow-up should be adhered to for YGCs. However, other studies found no difference in LNM rate between younger and older patients.[12,30,31]
Histologically, most young GC patients have undifferentiated carcinoma, including SRCC, mucinous carcinoma, and poorly differentiated carcinoma. Mixed type was also common in young GC patients.[7,31] As reported previously,[5,20,35] well-differentiated, Lauren intestinal type GC originates from atrophic, IM mucosa, whereas undifferentiated, diffuse type GC originates from foveolar cells of gastric fundic glands, extending laterally along the proliferative zone. Theoretically, young patients should have less atrophy and IM than older GC patients, but in our study, as much as 82% to 84% of early YGC had gastric atrophy and IM, which was still lower than the older cohort (92–94%). We can also see that Hp infection rate in these patients was as high as 75.6%. According to the consensus statement regarding Hp in China, we recommend Hp eradication in patients younger than 45 years without alarming features, with the treatment plan including a regular dose of proton pump inhibitors (PPI), 2 antibiotics and colloidal bismuth subcitrate. But a problem lies in that most of these young patients have not had an endoscopy or previously been tested for Hp infection. The true mechanism of the prevalence of undifferentiated type of GC in the younger cohort remains to be solved. Besides, undifferentiated GC infiltrates in a vertical manner, so lymph node involvement would be more likely. However, most studies[37–39] have confirmed ESD as a feasible treatment modality for undifferentiated GC within extended criteria, which yields higher complete and curative resection rates. In undifferentiated GC, many studies have reported that SRCC has more favorable clinicopathological characteristics than other undifferentiated types.[37,40] Choi et al reported that the complete resection rate was higher in SRCC than in poorly differentiated carcinoma, 89.3% versus 75%, but the rate was not statistically significant. Kim et al also reported that the en-bloc and complete resection rates of SRCC were slightly higher than poorly differentiated type. Ha et al found SRCC was more common in young female patients and the LNM rate of SRCC was lower than other undifferentiated GC. In our study, 3 patients fulfilling expanded criteria for endoscopic resection were positive for LNM. We attribute this to the fact that the GCs in younger patients exhibit unique biological features compared to traditional GC, with higher potential for metastasis, suggesting that YGC should be stringently managed.
Perineural invasion (PNI) was reported to be associated with poor outcome and recurrence. Scartozzi et al further analyzed a subgroup of EGC patients with or without LVI/PNI, and confirmed the role of LVI/PNI in patients disease-free survival (DFS) and overall survival (OS). However, in our study, PNI of YGC was significantly lower than that of OGC, a seemingly conflicting result. However, previous reports have shown that YGC had better prognosis than OGC, and other reports have also indicated that poor prognosis of YGC was a result of delayed diagnosis. From here we can see that the lower rate of PNI of YGC maybe one of the reasons for better prognosis, which was consistent with our findings. There may be interobserver differences in the identification of PNI, due to differences in the amount of tissue obtained and amount of time taken to analyze histological sections. So, a larger cohort of younger patients with EGC is warranted.
A major limitation of our study is the small study sample. Due to lower prevalence of young gastric cancer (YGC) (3–10% of overall GC) and early stage GC (10–20%) in China, a multicenter cohort study is required in order to obtain larger numbers. In addition, our study is retrospective, involving patients from 2005 to 2015, while endoscopic resection procedures, especially ESD, are becoming more widely accepted treatment for EGC in China over the past 2 years, so a detailed endoscopic report (involving magnifying endoscopy and chromoendoscopy findings) were not available for previous cases, potentially leading to some bias. However, we have started a prospective clinical program involving all YGC patients, with focus on mechanisms of tumorigenesis in this group of patients.
Significant differences were seen between EGC in younger and older patients, indicating a more aggressive pattern of EGCs in younger patients, especially higher LNM. The only independent risk factor of LNM in this group is LVI. Besides, given the high LNM potential of younger patients with EGC, patients fulfilling extended indications for endoscopic resection should be stringently assessed with multimethod modalities, and close follow-up plan is warranted.
We gratefully thank all the staff members in the Department of Gastroenterology, General Surgery and Pathology at Linyi People's Hospital for their kind assistance and suggestions.
. Ferlay J, Soerjomataram I, Ervik M, et al. GLOBOCAN 2012 v1.0. Cancer incidence and mortality worldwide: IARC CancerBase No. 11 [Internet]. Lyon, France: International Agency for Research on Cancer; 2013. Available at: http://globocan.iarc.fr/Pages/fact_sheets_cancer.aspx
. Accessed on March 8, 2016.
. Chen W, Zheng R, Baade PD, et al. Cancer statistics in China, 2015. CA Cancer J Clin 2016;66:115–32.
. Shen L, Shan YS, Hu HM, et al. Management of gastric cancer in Asia: resource-stratified guidelines. Lancet Oncol 2013;14:e535–47.
. Bang YJ, Van Cutsem E, Feyereislova A, et al. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet 2010;376:687–97.
. Takatsu Y, Hiki N, Nunobe S, et al. Clinicopathological features of gastric cancer in young patients. Gastric Cancer 2016;19:472–8.
. Jeong O, Park YK. Clinicopathological features and surgical treatment of gastric cancer in South Korea: the results of 2009 nationwide survey on surgically treated gastric cancer patients. J Gastric Cancer 2011;11:69–77.
. Zhou F, Shi J, Fang C, et al. Gastric carcinomas in young (younger than 40 years) Chinese patients: clinicopathology, family history, and post-resection survival. Medicine 2016;95:e2873.
. Lee J, Lee MA, Kim IH, et al. Clinical characteristics of young-age onset gastric cancer in Korea. BMC Gastroenterol 2016;16:110.
. Wang Z, Xu J, Shi Z, et al. Clinicopathologic characteristics and prognostic of gastric cancer in young patients. Scand J Gastroenterol 2016;51:1043–9.
. Merchant SJ, Kim J, Choi AH, et al. A rising trend in the incidence of advanced gastric cancer in young Hispanic men. Gastric Cancer 2016;20:226–34.
. Tavares A, Gandra A, Viveiros F, et al. Analysis of clinicopathologic characteristics and prognosis of gastric cancer in young and older patients. Pathol Oncol Res 2013;19:111–7.
. Isobe T, Hashimoto K, Kizaki J, et al. Characteristics and prognosis of gastric cancer in young patients. Oncol Rep 2013;30:43–9.
. Japanese Gastric Cancer Association. Japanese classification of gastric carcinoma: 3rd English edition. Gastric Cancer 2011;14:101–12.
. Kubota H, Kotoh T, Masunaga R, et al. Impact of screening survey of gastric cancer on clinicopathological features and survival: retrospective study at a single institution. Surgery 2000;128:41–7.
. Suzuki H, Oda I, Abe S, et al. High rate of 5-year survival among patients with early gastric cancer
undergoing curative endoscopic submucosal dissection. Gastric Cancer 2016;19:198–205.
. Li X, Liu Y, Cao B, et al. Metastatic lymph node ratio and prognosis of gastric cancer at different pT stages. Hepatogastroenterology 2015;62:507–11.
. Uedo N, Iishi H, Tatsuta M, et al. Long-term outcomes after endoscopic mucosal resection for early gastric cancer
. Gastric Cancer 2006;9:88–92.
. Chiu PW, Teoh AY, To KF, et al. Endoscopic submucosal dissection (ESD) compared with gastrectomy for treatment of early gastric neoplasia: a retrospective cohort study. Surg Endosc 2012;26:3584–91.
. Gotoda T, Yanagisawa A, Sasako M, et al. Incidence of lymph node metastasis
from early gastric cancer
: estimation with a large number of cases at two large centers. Gastric Cancer 2000;3:219–25.
. Park HJ, Ahn JY, Jung HY, et al. Clinical characteristics and outcomes for gastric cancer patients aged 18-30 years. Gastric Cancer 2014;17:649–60.
. Lauren P. The two histological main types of gastric carcinoma: diffuse and so-called intestinal-type carcinoma. An attempt at a histo-clinical classification. Acta Pathol Microbiol Scand 1965;64:31–49.
. Rugge M, Correa P, Dixon MF, et al. Gastric mucosal atrophy: interobserver consistency using new criteria for classification and grading. Aliment Pharmacol Ther 2002;16:1249–59.
. Edge S, Byrd DR, Compton CC, et al. Cancer Staging Manual. 7th ed.New York: Springer-Verlag; 2010;XV, 648.
. Kurzen H, Munzing I, Hartschuh W. Expression of desmosomal proteins in squamous cell carcinomas of the skin. J Cutan Pathol 2003;30:621–30.
. Japanese Gastric Cancer Association. Japanese gastric cancer treatment guidelines 2014 (ver. 4). Gastric Cancer 2016;20:1–9.
. Kang HJ, Kim DH, Jeon TY, et al. Lymph node metastasis
from intestinal-type early gastric cancer
: experience in a single institution and reassessment of the extended criteria for endoscopic submucosal dissection. Gastrointest Endosc 2010;72:508–15.
. Kwee RM, Kwee TC. Predicting lymph node status in early gastric cancer
. Gastric Cancer 2008;11:134–48.
. Hwang CS, Ahn S, Lee BE, et al. Risk of lymph node metastasis
in mixed-type early gastric cancer
determined by the extent of the poorly differentiated component. World J Gastroenterol 2016;22:4020–6.
. Fang C, Shi J, Sun Q, et al. Risk factors of lymph node metastasis
in early gastric carcinomas diagnosed with WHO criteria in 379 Chinese patients. J Dig Dis 2016;17:526–37.
. Qiu MZ, Wang ZQ, Zhang DS, et al. Clinicopathological characteristics and prognostic analysis of gastric cancer in the young adult in China. Tumour Biol 2011;32:509–14.
. Hsieh FJ, Wang YC, Hsu JT, et al. Clinicopathological features and prognostic factors of gastric cancer patients aged 40 years or younger. J Surg Oncol 2012;105:304–9.
. Pyo JH, Shin CM, Lee H, et al. A risk-prediction model based on lymph-node metastasis for incorporation into a treatment algorithm for signet ring cell-type intramucosal gastric cancer. Ann Surg 2016;264:1038–43.
. Kim JY, Kim WG, Jeon TY, et al. Lymph node metastasis
in early gastric cancer
: evaluation of a novel method for measuring submucosal invasion and development of a nodal predicting index. Hum Pathol 2013;44:2829–36.
. Eom BW, Joo J, Park B, et al. Nomogram incorporating CD44v6 and clinicopathological factors to predict lymph node metastasis
for early gastric cancer
. PLoS One 2016;11:e0159424.
. Kong X, Wang JL, Chen HM, et al. Comparison of the clinicopathological characteristics of young and elderly patients with gastric carcinoma: a meta analysis. J Surg Oncol 2012;106:346–52.
. Chinese Society of Gastroenterology CoHPaPU. Current management of Helicobacter pylori
infection in China-Fourth Consensus Report. Chin J Gastroenterol 2012;51:358–63.
. Choi MH, Hong SJ, Han JP, et al. Therapeutic outcomes of endoscopic submucosal dissection in undifferentiated-type early gastric cancer
. Korean J Gastroenterol 2013;61:196–202.
. Bang CS, Baik GH, Shin IS, et al. Endoscopic submucosal dissection for early gastric cancer
with undifferentiated-type histology: a meta-analysis. World J Gastroenterol 2015;21:6032–43.
. Park CH, Kim EH, Kang JH, et al. Low incidence of synchronous or metachronous tumors after endoscopic submucosal dissection for early gastric cancer
with undifferentiated histology. PLoS One 2016;11:e0147874.
. Kim JH, Lee YC, Kim H, et al. Endoscopic resection
for undifferentiated early gastric cancer
. Gastrointest Endosc 2009;69:e1–9.
. Ha TK, An JY, Youn HK, et al. Indication for endoscopic mucosal resection in early signet ring cell gastric cancer. Ann Surg Oncol 2008;15:508–13.
. Deng J, You Q, Gao Y, et al. Prognostic value of perineural invasion in gastric cancer: a systematic review and meta-analysis. PLoS One 2014;9:e88907.
. Scartozzi M, Galizia E, Verdecchia L, et al. Lymphatic, blood vessel and perineural invasion identifies early-stage high-risk radically resected gastric cancer patients. Br J Cancer 2006;95:445–9.
. Smith BR, Stabile BE. Extreme aggressiveness and lethality of gastric adenocarcinoma in the very young. Arch Surg 2009;144:506–10.
. Takizawa K, Ono H, Kakushima N, et al. Risk of lymph node metastases from intramucosal gastric cancer in relation to histological types: how to manage the mixed histological type for endoscopic submucosal dissection. Gastric Cancer 2013;16:531–6.
. Miyamae M, Komatsu S, Ichikawa D, et al. Histological mixed-type as an independent risk factor for nodal metastasis in submucosal gastric cancer. Tumour Biol 2016;37:709–14.