Distinct clinicopathological differences between early gastric cardiac and non-cardiac carcinomas: a single-center retrospective study of 329 radical resection cases

We searched the electronic pathology database stored in the Jiangsu Province Hospital of Chinese Medicine in Nanjing, China, over the 7-year period from January 2011 to December 2017 for gastric cancer radical resection and collected 2184 consecutive cases with pathologically confirmed gastric cancer. According to the 2019 World Health Organization (WHO) diagnostic criteria [6], 443 EGC cases were identified. Two experienced pathologists reviewed histological slides of all EGC cases, 114 of which were excluded because of stump carcinoma (n = 11), synchronous carcinoma (n = 2), high-grade intraepithelial neoplasia without invasive carcinoma (n = 27), lymphoma (n = 2), and neoadjuvant chemotherapy (n = 72). As a result, 329 EGC cases were eligible for this study. The clinicopathological characteristics of all selected cases, based on pathologic and endoscopic reports and operative notes, were tabulated and analyzed, which included gender, age, tumor location, size, and gross patterns. Each case was pathologically staged, according to the 8th edition of the American Joint Committee on Cancer staging manual [7]. In this study, all patient's private information was deleted to protect the patient's privacy. The study protocol was approved by the hospital Medical Ethics Committee (Number: 2019NL-098-02).

The 5th edition WHO diagnostic criteria on gastric carcinoma were followed and EGC was defined as invasive carcinoma confined to the mucosa or submucosa [6]. EGCC referred to the tumor with its epicenter located within 3 cm below the gastroesophageal junction (GEJ) [8]. For EGNCC, the tumor epicenter was situated in the distal stomach, more than 3 cm below the GEJ either in the fundus–corpus region of the stomach or more distally in the gastric antrum–angularis–pylorus region. Tumor gross features were divided into 5 subgroups: type 0-I (polypoid/protruding), type 0-IIa (superficial elevated), type 0-IIb (flat), type 0-IIc (superficial depressed), and type 0-III (excavated) [6]. These 5 sub-subgroups were further simplified into 3 sub-groups: Types 0-I and 0-IIa were sub-grouped as the elevated type; Type 0-IIb as the flat type, and Types 0-IIc and 0-III as the depressed type, for a simplified statistical analysis. The depth of tumor invasion was divided into 4 sub-groups as follows: M2 (tumor infiltration confined to the lamina propria without the involvement of the muscularis mucosae), M3 (tumor invasion into muscularis mucosae), SM1 (tumor involvement of submucosal superficial layer with the infiltration depth < 500 μm from the muscularis mucosae), and SM2 (tumor involving the submucosal deep layer with the infiltration depth ≥ 500 μm from the muscularis mucosae). Lymphovascular invasion and perineural invasion were also recorded. In equivocal cases, routine histochemical elastic fiber staining and immunostaining for CD31 and D2-40, with valid controls, were carried out to validate the finding of lymphovascular invasion recognized on conventional hematoxylin–eosin stained sections. Guided by the WHO diagnostic criteria [6], we tabulated and analyzed tumor differentiation (well, moderate, or poor) and histopathological type (tubular adenocarcinoma, papillary adenocarcinoma, micropapillary adenocarcinoma, poorly cohesive carcinoma [PCC] including signet-ring cell carcinoma, mucinous carcinoma, mixed PCC and tubular/papillary adenocarcinoma, mixed mucinous and tubular/papillary adenocarcinoma) of EGC. Helicobacter pylori (HP) infection was confirmed by microscopic identification of the bacterium on routine hematoxylin–eosin and basic fuchsin stained sections with appropriate controls.

In most Chinese patients, endoscopic mucosal GEJ and squamous-columnar epithelial junction lines overlap at the same level [9]. Microscopically, the histologic criteria for the GEJ line were defined as the distal end of oesophageal squamous epithelium, multilayered epithelium or oesophageal submucosal glands or ducts [10]. Once the GEJ line was identified, the tumor epicenter location and the extend of tumor invasion were determined; the distance of oesophageal invasion was measured microscopically with the assistance of an ocular scale bar. In addition, distal oesophageal columnar metaplasia, intestinal metaplasia, pancreatic metaplasia, and dysplasia were also studied and analyzed.

Differences between groups with continuous or categorical variables were statistically compared with appropriate statistical methods, such as Student t, χ², Fisher’s exact, or Kruskal–Wallis H test. P values < 0.05 were considered statistically significant. All statistical analyses were performed with SPSS software, version 13.0 (IBM, Armonk, NY, USA).

As shown in Table 1, while overall differences in macroscopic growth patterns of EGC were significant between EGCC and EGNCC groups (P < 0.05), there were no significant variations in the elevated or flat sub-group of EGC between the two groups, despite the fact that the frequency of the elevated pattern was more commonly seen in the former (10.0%) than in the latter (7.3%). However, EGC tumors with the depressed pattern (Types 0-IIc and 0-III) were significantly less commonly seen in the EGCC group (67.1%) than in the antrum–angularis–pylorus group (81.2%) (P < 0.05), but not in the fundus–corpus sub-group of ENGCC tumors. Statistically, differences in overall tumor size and invasion depth were not significant between EGCC and ENGCC sub-groups.

In this cohort, differences in the EGC histologic type were significantly different between EGCC group and EGNCC sub-groups (P < 0.01). As displayed in Table 1, tubular and papillary (Fig. 1a) adenocarcinomas were more frequently seen in the former than in the latter, especially for papillary adenocarcinoma that was significantly more prevalent in EGCC (18.6%) than in EGNCC (5.0%) (P < 0.05). In contrast, pure PCC (Fig. 1b) was significantly less frequently observed in EGCC than in EGNCC fundus–corpus and antrum–angularis–pylorus sub-groups (P < 0.05), while mixed PCC with tubular/papillary adenocarcinoma was more commonly seen in the antrum–angularis–pylorus (P < 0.05), but not the fundus–corpus, sub-group of EGNCC. There were no significant differences in uncommon variants of EGC, such as micropapillary adenocarcinoma (Fig. 1c), pure and mixed mucinous adenocarcinomas, neuroendocrine and adenosquamous carcinomas, and carcinoma with lymphoid stroma, between EGCC and EGNCC sub-groups. In the cohort, tumor differentiation was significantly different (P < 0.05) between the EGCC and EGNCC groups. Although well differentiation in EGC was more commonly noted in EGCC (24.3%) than in EGNCC (10.0%) groups, the difference did not reach a statistically significant level. However, poor differentiation in EGC was significantly less commonly identified in EGCC (15.7%) than in EGNCC (43.6%) groups (P < 0.05). There were no significant differences between EGCC and EGNCC groups in lymphovascular invasion, perineural invasion, HP infection, and LNM.

The average number of regional lymph nodes retrieved and examined per case was 21.5 (range: 2–68). As illustrated in Table 2, the prevalence of LNM in the cohort was 5.7% (9/158) for intramucosal carcinoma and significantly increased to 23.4% (40/171) for submucosal carcinoma (P < 0.01). Surprisingly, no LNM was detected in 38 EGCC cases with the invasion depth up to superficial submucosa, ie, M2 + M3 + SM1; thus, the prevalence of LNM was significantly lower in EGCC than in EGNCC (9.2%, 15/163) groups (P < 0.05). Specifically, the percentage of LNM in EGNCC was 6.8% (4/59), 7.0% (5/71), and 18.2% (6/33) for invasion depth at M2, M3, and SM1, respectively. There was no significant difference in risk of LNM of EGC with deep submucosal invasion (SM2) between EGCC and EGNCC sub-groups.

In this study, 22 (31.4%, 22/70) EGCC tumors showed their epicenters in the gastric cardia with a small proportion of the tumor crossing the GEJ line into the distal oesophagus (Fig. 2a), extending to an average distance of 4.16 mm (range: 1–10), primarily underneath benign oesophageal squamous epithelium. No Barrett’s oesophagus was recognized in all 22 EGCC cases. In addition, high-grade intraepithelial neoplasia was observed in cardiac mucosa adjacent to invasive carcinoma in the gastric cardia (Fig. 2b), suggesting that EGCC originated in the gastric cardiac mucosa. As demonstrated in Table 3, epithelial columnar metaplasia in the distal oesophagus was seen in 50 (71.4%, 50/70) cases, among which columnar mucinous metaplasia was in 34 (68.0%, 34/50), pancreatic metaplasia was in 13 (26.0%, 13/50), and intestinal metaplasia was found only in 3 cases (6%, 3/50). No epithelial dysplasia was identified in metaplastic epithelium. Compared to EGCC cases without oesophageal involvement (68.6%, 48/70), EGCC cases with oesophageal invasion showed no significant differences in gender, age, tumor origin, epithelial metaplasia, tumor macroscopic pattern, overall size, invasion depth, differentiation, lymphovascular or perineural invasion, and LNM. Interestingly enough, the prevalence of cases with tumors larger than 2 cm in size was significantly more frequently present in EGCCs with oesophageal invasion (68.2%, 15/22) than those without (35.4%, 17/48) (P < 0.05) and the overall difference in the microscopic tumor type was also statistically significant between the two sub-groups (P < 0.01), in that EGCC tumors with oesophageal invasion showed a significantly lower proportion of tubular adenocarcinoma than those without oesophageal invasion.