In this study, the prognosis of patients with diffuse mixed type gastric cancer was worse than that of patients with Intestinal type in pathological stage III. Moreover, in stage 3 patients who received postoperative adjuvant chemotherapy with S-1, patients with Signet ring cell carcinoma had a Significantly worse prognosis than patients with non-solid type poorly gastric carcinoma.
The Diffuse type was more common in women and younger patients, and it was associated with type 4 cancer and peritoneal metastases as the site of initial recurrence after surgery. A meta-analysis of 73 studies showed that patients with Diffuse type had the worst prognosis [8]. They found that the risk of death was increased by 23% regardless of race, stage, and chemotherapy. Microsatellite instability (MSI) of four genomic subtypes classified by the TCGA study of gastric cancer was mainly present in non-diffuse distal cancer, whereas chromosomal instability was seen in Diffuse type cancers [9]. In the molecular classification of the Asian Cancer Research Group (ACRG), Diffuse type corresponds to microsatellite stable and the epithelial-to-mesenchymal transition (MSS/EMT) phenotype [10]. The MSS/EMT was often observed in stage III/IV advanced gastric cancer and had the worst prognosis due to frequent peritoneal metastases. The EMT was also observed in younger patients and corresponded to Laurén’s Diffuse type [11]. Thus, diffuse gastric cancer cells appear to possess the capacity of epithelial-mesenchymal transition, which promotes peritoneal metastasis [12]. Mixed type was seen in 15% of patients, and they showed a metastatic, as well as a prognostic, pattern like predominant Sig and Por2 tumors. Chen et al examined 3071 patients with gastric cancer and divided them into three groups according to the Lauren classification: Intestinal type 46%, Diffuse type 32%, and mixed type 21%. They demonstrated that the clinical appearance and outcome of mixed type in the Lauren classification was similar to Diffuse type gastric cancer [5].
In the Diffuse type, the two histotypes of Sig and Por2 differ in their clinical and molecular features to the point of representing distinct entities [13]. Poorly differentiated carcinoma cells have the potential to convert into the EMT phenotype. On the other hand, Sig is also common in early stage cancers, and the overall prognostic impact of the presence or absence of Sig is equivocal [14–16]. Pure Sig is usually present in the intramucosal layer, while its morphology is often lost during tumor growth and transformation into poorly cohesive carcinoma [17]. Sig can easily transform into poorly cohesive carcinoma in invasive areas and is most frequent in advanced gastric cancer [18]. Piessen et al demonstrated that Sig often developed peritoneal metastasis and lymph node invasion and would often fail R0 resection, and Sig was associated with a worse prognosis than non-Sig in a group matched-controlled study [19]. Possible reasons for a poor prognosis are unsuspected peritoneal carcinomatosis and lymph node involvement, which are frequent. We previously reported that Signet ring cells themselves had the capacity to produce immune suppressive enzymes, which increased metastasis [20]. Therefore, Sig in advanced gastric cancer is associated with a poorer prognosis than the poorly differentiated type.
The predictive effect of each histological subtype on the efficacy of chemotherapy has not been definitively elucidated. A decrease in the objective response rate was found in the presence of a diffuse component of advanced gastric cancer. The Laurén Diffuse type of gastric cancer is frequently highly infiltrative and resistant to chemotherapy [21]. Yoon et al demonstrated that RhoA activity plays a critical role in maintaining cancer stem cell phenotype, and direct RhoA inhibition was effective with chemotherapy [22]. The survival rate was better in Intestinal type than in Diffuse type with regimens containing docetaxel. Subgroup analysis of JCOG9912 indicated that S-1 was more effective than 5-FU alone in the treatment of Diffuse type [23]. S-1 combined with docetaxel therapy was superior to S-1 monotherapy in patients with Diffuse type in the START trial [24]. It has recently, been reported that S-1 plus docetaxel improved efficacy in patients with stage III gastric cancer [7]. If effective intraperitoneal treatment is developed, it should be directed at patients with a high risk of peritoneal recurrence. More effective adjuvant therapy is needed, perhaps with immunotherapy or new target agents.
The limitations of this study are that it was a retrospective study in a single-institution setting. However, the subjects of this study accumulated over a period of approximately 12 years, indicating an adequate investigation. Furthermore, the impact of histology on second-line chemotherapy, which could affect OS, was not examined.