AIM: To investigate the relationship of solitary lymph node metastasis (SLNM) and age with patient survival in gastric cancer (GC).

METHODS: The medical records databases of China’s Beijing Cancer Hospital at the Peking University School of Oncology and Shanghai Tenth People’s Hospital affiliated to Tongji University were searched retrospectively to identify patients with histologically proven GC and SLNM who underwent surgical resection between October 2003 and December 2012. Patients with distant metastasis or gastric stump carcinoma following resection for benign disease were excluded from the analysis. In total, 936 patients with GC + SLNM were selected for analysis and the recorded parameters of clinicopathological disease and follow-up (range: 13-2925 d) were collected. The Kaplan-Meier method was used to stratify patients by age (≤ 50 years-old, n = 198; 50-64 years-old, n = 321; ≥ 65 years-old, n = 446) and by metastatic lymph node ratio [MLR < 0.04 (1/25), n = 180; 0.04-0.06 (1/25-1/15), n = 687; ≥ 0.06 (1/15), n = 98] for 5-year survival analysis. The significance of intergroup differences between the survival curves was assessed by a log-rank test.

RESULTS: The 5-year survival rate of the entire GC + SLNM patient population was 49.9%. Stratification analysis showed significant differences in survival time (post-operative days) according to age: ≤ 50 years-old: 950.7 ± 79.0 vs 50-64 years-old: 1697.8 ± 65.9 vs≥ 65 years-old: 1996.2 ± 57.6, all P < 0.05. In addition, younger age (≤ 50 years-old) correlated significantly with mean survival time (r = 0.367, P < 0.001). Stratification analysis also indicated an inverse relationship between increasing MLR and shorter survival time: < 0.04: 52.8% and 0.04-0.06: 51.1% vs≥ 0.06: 40.5%, P < 0.05. The patients with the shortest survival times and rates were younger and had a high MLR (≥ 0.06): ≤ 50 years-old: 496.4 ± 133.0 and 0.0% vs 50-65 years-old: 1180.9 ± 201.8 and 21.4% vs≥ 65 years-old: 1538.4 ± 72.4 and 37.3%, all P < 0.05. The same significant trend in shorter survival times and rates for younger patients was seen with the mid-range MLR group (0.04-0.06), but the difference between the two older groups was not significant. No significant differences were found between the age groups of patients with MLR < 0.04. Assessment of clinicopathological parameters identified age group, Borrmann type, histological type and tumor depth as the most important predictors of the survival rates and times observed for this study population.

CONCLUSION: GC patients below 51 years of age with MLR of SLNM above 0.06 have shorter life expectancy than their older counterparts.

Gastric carcinoma (GC) is one of the most commonly diagnosed cancers in China. The elderly (65 years and older) represent over one-half of these cases, and occurrence of GC in individuals younger than 40-years-old is relatively rare (approximately 5% of total reported cases)[1,2]. Studies of age-related GC progression and prognosis have yielded inconsistent findings. The collective data in the literature indicate both distinctly unfavorable outcomes for the younger patient population (citing more advanced disease at diagnosis and/or faster disease progression) and a seemingly paradoxical favorable overall survival (with early disease stage cases possibly providing a confounding subgroup effect); in addition, other studies have demonstrated a lack of age-related impact on GC prognosis[3-8].

Regardless of patient age, lymph node metastasis is a well-established critical prognostic factor and predictor of recurrence in GC. Histological detection of metastatic lymph nodes (MLNs) is strongly correlated with a high risk of recurrence, and this is an especially critical clinical finding for patients diagnosed in the early stages of GC to help design effectively robust, but safe, clinical management strategies[9-12]. While calculation of the metastatic lymph node ratio (MLR; single positive lymph nodes per total number of lymph nodes harvested) improves the sensitivity of predicting GC recurrence, minimizing the number of lymph node dissection is necessary to reduce the corresponding side effects, such as lymphedema[13-15].

A major clinical challenge in GC evaluation is determining the appropriate extent of lymph node dissection that is capable of detecting single lymph node metastasis (SLNM). The gastric lymphatic drainage system is particularly complex, and not all cases of SLNM are localized to the perigastric node area and are detectable by standard D2 lymphadenectomy. MLR, however, can help to overcome this limitation.

In this study, the differential prognostic features of younger and older GC patients with SLNM were investigated using MLR to gain further insights into the particular clinicopathological features and surgical outcomes of these two patient populations.

Some studies have indicated that a younger age of diagnosis may correspond to worse prognosis of GC[16]. From a histological perspective, GC in younger patients is more likely to be diffuse type, rather intestinal or mixed, and with disseminated morphology[17-19]. These features may underlie a more aggressive behavior of GC in this patient population or merely reflect a trend in diagnosis being made at a later disease state[4]; nevertheless, both of these issues are associated with poorer prognosis and may help to explain a key pathological difference between younger and older GC patients.

As cited in the Introduction, the collective research to date has yet to define the precise age-related epidemiological and clinicopathological characteristics of GC. For example, in a study of old and young GC patients matched by tumor stage, Moreira et al[20] found that younger age was associated with a more favorable outcome. Similarly, in a study of elderly and middle-aged GC patients matched for tumor extension, Kitamura et al[21] found that older age was associated with poorer overall survival and death within 30 d after surgery. Indeed, the increased risk of complications and death from surgery in general is well recognized, and a study of surgically-treated GC patients showed markedly better 5-year postoperative survival at all tumor stages[22].

It has been reported that younger (middle-aged) patients have better prognosis following curative resection of stage I tumors than their elderly counterparts[6]. Other reports, however, have demonstrated that younger age provides no benefit to survival when the GC is present in more advanced stages and that the most important prognostic factor in young patients is advanced nodal involvement[23-25]. Regardless of whether or not there is a distinctive malignant trait related to age, a key means towards improving survival rates is early diagnosis and timely application of curative resection.

The results from the current study confirmed the view that the relationship between GC prognosis and patient age is complicated. In general, the mean age of GC diagnosis falls within the 5^th decade of life and cases younger than 50 years old are relatively rare[26,27]; however, by searching a large patient database we were able to analyze a patient population that equally represented young and old GC sufferers. The current study population showed a poorer prognosis for younger (≤ 50 years old) patients, as evidenced by both cumulative and 5-year survival rates. Moreover, the younger patients had fewer surgery-related complications (data not shown) that may have benefited their recovery and prognosis.

Another important finding for the current study’s population of patients with GC + SLNM was the relationship between age and mean survival days after surgery. The younger patients, who also had more aggressive tumors by histological analysis, survived for a significantly shorter duration following the resection treatment. This finding agrees with another study of GC patients that found diffuse cancers more likely to occur in younger patients and to be associated with poorer prognosis.

Depth of invasion and presence of MLNs are well-established and essential prognostic factors of GC[28], and nodal involvement is considered an especially significant clinical finding in early GC. Ten-year overall survival in node-positive patients has been reported at 27%, compared to the estimated 92% for node-negative patients[29]. Incomplete removal of MLNs, which harbor residual tumor cells, represents an increased risk of disease spread or recurrence. Indeed, studies of post-gastrectomy survival in GC patients have shown that survival rates improve in conjunction with number of lymph nodes removed for examination[30-32].

The benefit of lymphadenectomy was related to extent; however, it remains to be precisely determined. Both the Union for International Cancer Control and the American Joint Commission for Cancer have recommended that at least 15 lymph nodes be examined for correct assessment node metastatic status in GC (7^th edition TNM system). Moreover, dissection of ≥ 15 lymph nodes in resections with curative intent has been reported to significantly improve prognosis of patients with GC + MLN[33]. Yet, while the useful prognostic impact of this lower-limit criteria has been validated in several large clinical studies[34,35], no study to date has systematically evaluated the risk to benefit ratio of precise numbers of lymph nodes for GC or its myriad of histological parameters.

The association of SLNM with depth of tumor invasion and its prognostic significance in GC are well established. Furthermore, it is generally accepted that GC patients with SLNM have a worse survival rate than those without SLNM (zero positive lymph nodes). The estimates of GC cases with single nodal metastasis distributed beyond the perigastric area range from 12.6%-29.0%, and it is hypothesized that this feature may be related to (caused by) complicated lymphatic drainage from the stomach[36-38]. However, a comparative study of patients with and without skip metastasis after standard D2 lymphadenectomy found no significant difference in survival between the two groups[39]. Sentinel node mapping with a visible tracer or radio-guided approach has limited accuracy in GC patients. Therefore, the current study evaluated the age-related 5-year survival rates of follow-up GC + SLNM patients using an array of clinicopathological parameters, and found that Borrmann type, histological type, and tumor status were significantly different among the groups and were related to patient survival.

MLR calculation is considered a simpler and (possibly) more effective method for prognosing patients with GC who undergo curative or radical resections[40-42], compared to the conventional lymph node staging systems. In particular, MLR could supplement the conventional N staging system when a limited number of lymph nodes are obtained, thus providing more accurate prognostic stratification in advanced GC[40,43-45]. Herein, as in some related previous studies, MLR was shown to be a better prognostic factor than the other clinicopathological parameters examined; however, no consensus has been made on the optimal categorization of MLR, as each study has used different standardization. In the current study, the GC + SLNM patients were categorized according to the number of harvested lymph nodes, and the data indicated that 5-year survival rates were associated with SLNM per lymph node harvested. Specifically, younger patients with MLR ≥ 0.06 and 0.06-0.04 had lower survival than older patients.

As discussed above, young adults may be more likely to present for diagnosis at an advanced disease stage. In the absence of an effective predictive marker, surveillance endoscopy of patients with positive family histories seems to be the only way to detect early stage GC. Such patients should also be educated on the signs and symptoms of GC, and more attention should be paid to younger patients with upper gastrointestinal symptoms, to improve their rate of early diagnosis. Multivariate analyses have indicated that younger patients undergoing curative resection have longer survival[46]. As D2 lymphadenectomy leads to the examination of more nodes, and improves prognostic accuracy in patients with or without MLNs[47], wider use of D2 lymphadenectomy may be essential for patients with GC, especially those of younger age.

In conclusion, among the GC + SLNM patients examined in this study, younger patients tended to have shorter survival than their older counterparts. In particular, younger patients with the highest MLR had the worst prognosis. Thus, the field should strive towards improving earlier detection rates for GC patients to help improve prognosis of these patients. For younger patients, who may be at greater risk of disease-related mortality but at less risk of surgery-related morbidities, D2 lymphadenectomy may be considered because it allows sampling of many more lymph nodes.