This study yielded four important results. First, age under 40 years was identified as an independent risk factor for survival. Second, the predominant histological type in the young group was poorly differentiated, and the typical metastatic pattern was peritoneal dissemination. Third, the proportion of patients who received third-line chemotherapy was lower in the young group than in the middle-aged group. Finally, we suggest that the survival of younger patients is worse than that of middle-aged patients.
Previous studies have reported that the prognosis of patients aged under 40 years with stage I–III GC is comparable to or better than that of patients aged ≥ 40 years [4,8–10,18]. We focused on patients with stage IV GC in this study and found that the young group had a worse prognosis than the middle-aged group. Young patients were more likely to have undifferentiated type GC, resulting in a higher incidence of peritoneal dissemination than hematogenous metastasis. Peritoneal dissemination can present with a more rapid progression than liver or lymph node metastasis, and the switch to chemotherapy is often unsuccessful. In the present study, the rate of third-line treatment in young patients was lower than that in middle-aged patients, reflecting the difficulty of treating peritoneal dissemination.
The prevalence of H. pylori infection among young Japanese people is low. Therefore, GC development in people aged under 40 years may involve carcinogenesis pathways and biological properties that are different from those of common GC secondary to atrophic gastritis. The molecular mechanisms of gastric carcinogenesis have recently been elucidated, and potential therapeutic targets have been identified based on the classification of molecular subtypes . The genomically stable GC subtype is more common in younger patients, has the highest resistance to fluorouracil, and is associated with poor prognosis . In addition, the chromosomal instability GC subtype, which is associated with extensive gastric mucosal atrophy owing to H. pylori infection, is more sensitive to chemotherapy and has less recurrence after adjuvant therapy than other subtypes . These molecular differences may be related to differences in chemotherapy efficacy and GC progression. Young patients with stage IV GC who already have distant metastasis at the time of diagnosis require shorter intervals between examinations and earlier evaluation of treatment effects.
Previous studies have shown that younger age was not a poor prognostic factor for stage I–III GC [18,21]. However, for stage IV GC, younger age indicated poorer prognosis in our study. Early-onset disease includes rare cases of rapid progression. Patient survival is short when the disease is detected at stage IV.
This study has a few limitations. First, information on H. pylori infection and genetic information (CDH1 mutation, RhoA, microsatellite instability, and loss of heterozygosity) were not collected. Second, the number of cases in the young group was small, which could interfere with the reliability of our results. However, young patients with GC are rare, and stage IV GC cases are uncommon [9,16]. In our study, young patients with stage IV GC accounted for approximately 1.5% of the entire cohort. Therefore, the results of this study are meaningful and distinct since they focused on early-onset stage IV GC.
In conclusion, younger age (under 40 years) was an independent prognostic factor for patients with stage IV GC. Although this is a rather rare population among patients with stage IV GC, further studies investigating the genomic characteristics of GC and exploring more effective chemotherapeutic agents are required.