Gastric cancer (GC) accounts for 10% of all cancer-related deaths [1]. Although the reported 5-year overall survival rates in advanced GC range from 15% to 52% [23], those in early gastric cancer (EGC) range from 88% to 97% [45]. Early detection and treatment contribute to decreased mortality rates [6]. With the increased use of endoscopic treatment in EGC, the natural history of EGC must be considered in order to evaluate the efficacy of endoscopic resection and to improve treatment decision-making; this is particularly relevant for elderly patients. However, the chronological changes of GC, including whether mucosal GC can progress to advanced cancer, remain unclear due to a lack of follow-up with high-resolution endoscopic images [78910]. We present a case with prospective follow-up that provides a better understanding of the natural growth of GC.

An 85-year-old woman was referred to Shizuoka Cancer Center for evaluation of a gastric tumor in April 2007. Esophagogastroduodenoscopy (EGD) identified a 6 mm, flat-elevated lesion at the lesser curvature of the antrum. The lesion was diagnosed as Type 0-IIa EGC by endoscopy. The depth of the lesion was estimated to be intramucosal, because it was a flat-elevated lesion without nodules, remarkable depression, or fold convergence (Fig. 1A, B). Evaluation of a biopsy specimen revealed a well-differentiated tubular adenocarcinoma (Fig. 2A, B). Due to the patient's advanced age and comorbidities (rheumatoid arthritis and ischemic heart disease), she wished to receive periodic endoscopic follow-up and best supportive care without invasive treatment. Follow-up EGDs were performed at intervals of 6 months to 1 year.

From 2007 to 2009, the lesion showed no change in size or morphology. The estimated depth of the lesion remained within the mucosal layer. In order to reconfirm the initial diagnosis, a biopsy specimen was obtained from the lesion; it revealed a higher grade of cytological and structural atypia than the initial biopsy specimen (Fig. 2C, D).

In 2010 and 2011, the follow-up EGD showed that the lesion had grown to 12 mm in size. It had also developed a slight depression and a 4 mm nodule, indicating submucosal invasion (Fig. 1C, D).

In May 2012, further evaluation revealed that the lesion had an ulcer surrounded by a swollen gastric wall with clear margins. The macroscopic type was classified as Type 2 (Fig. 1E). The estimated depth of the Type 2 tumor was the muscularis propria. Six months later, the patient presented with symptoms of anemia, which was diagnosed as moderate anemia (hemoglobin 8.3 g/dL). EGD revealed oozing from the excavated ulcer of the tumor. The size of the lesion had increased to 50 mm. The advanced lesion invaded laterally without clear margins. The macroscopic type had progressed from Type 2 to Type 3. The depth of the lesion was estimated to extend to the subserosa (Fig. 1F).

In 2013, the patient complained of insufficient food intake and symptoms of anemia. Her serum albumin and hemoglobin levels were 2.6 g/dL and 8.8 g/dL, respectively. The lesion had increased to more than 100 mm in size with severe stricture, which suggested tumor penetration of the serosa (Fig. 1G). That year, 6.6 years after the initial examination, the patient died of tumor hemorrhage.

The Institutional Review Board of Shizuoka Cancer Center approved this case report (institutional code number: 25-J82-25-1-3).

The present case shows the natural history of EGC resulting in cancer-related death. At the initial examination, the lesion was classified as intramucosal cancer, and it remained in the early stage for at least 3.8 years. It could have been curatively treated by endoscopic submucosal dissection (ESD) until 2009 (2 years after the initial examination). Five years after the initial examination, the lesion finally progressed to advanced GC. The outcome may have been different if the patient had undergone ESD. In Japan, it has been reported that 87% of new lesions are detected in the early stage [1112], and 81% to 95% of these lesions meet the indications for ESD [45]. However, due to differences in the pathological diagnostic criteria for EGC between Japan and Western countries, EGC in Western countries, especially mucosal cancer, is often followed up as a pre-malignant lesion or pseudo-disease that is not expected to invade into the deeper layer [1013]. This case might represent a milestone in appreciating the importance of ESD for mucosal EGC.

A review of the literature revealed two other case reports with prospective follow-up information (Table 1) [1415]. In both cases, the morphological type progressed from Type 0-IIc to Type 3. In the present case, the morphological type progressed to Type 3 via Type 0-IIa+IIc, comparable to the data in the previous reports. The duration of time in which the cancer remained within the mucosal layer after the initial examination was 3 years in one case and unknown in the other. In the present case, the cancer also remained within the mucosal layer for 3 years after the initial examination, which suggests that mucosal cancer has the potential to invade into the submucosal layer in approximately 3 years. A previous cohort study reported that the estimated median duration of the early stage disease was 3.7 years, and that the duration of the submucosal cancer was no more than 2 years [7]. Regarding the duration of the submucosal cancer, in the presented case and in one of the previous case reports, the duration was 2 years; this indicates that tumor growth may accelerate following submucosal invasion. One reported case was followed for 8 years and the patient died of other disease, while the other case was followed for 7.9 years and the patient underwent gastrectomy. To the best of our knowledge, there have been no reports of primary cases resulting in GC-related death with long-term observation. In the present case, EGC was the cause of death 6.4 years after the initial examination. A decision to treat EGC could be made if the average life expectancy of the patient is expected to be at least 5 years from the time of EGC diagnosis.

The present case and the literature review indicate that mucosal cancer can develop into submucosal invasive cancer, remain in the submucosal layer for about 2 years, and then invade into deeper layers. EGC should be treated appropriately, because it leads to cancer-related death even if the patient is elderly. The present case emphasizes the importance of early detection and appropriate treatment.