The Chinese Society of Clinical Oncology (CSCO): Clinical guidelines for the diagnosis and treatment of gastric cancer, 2021

. 2021 Jul 1;41(8):747–795. doi: 10.1002/cac2.12193

	Grade I recommendations
Sample type	Gross examination	Light microscopic examination	Grade II recommendations	Grade III recommendations
Biopsy specimen^*	Evaluation of the size and number of fragments	Confirm the histopathology of the lesion: • Cancerous/non‐cancerous • Benign/malignant • Histological subtype • Depth of invasion (if possible)	Immunohistochemical assessment for diagnosis if needed^j	Evaluate the status of Helicobacter pylori infection^m (Evidence 1B)
Endoscopic resection specimen^a (EMR/ESD)	• Tumor site^b • Tumor size (cm³)	Intra‐epithelial neoplasm/adenoma (high grade) Invasive carcinoma: • Histological subtype^d/Lauren classification^e • Histological grade • The depth of penetration into wall • The proximal/distal margin and the deep margin • Vascular and lymphatic invasion	• Immunohistochemical assessment for diagnosis if needed^j • Gastric cancer with the early stage^k	Evaluate the status of Helicobacter pylori infection^m (Evidence 1B)
Surgical resection specimens for those without neoadjuvant therapy	• Type of the surgical specimen • Tumor site • Tumor size (cm³) • Distance of tumor from the proximal and distal margin from tumor • The stations and number and of lymph nodes retrieved (at least 16 lymph nodes and/or preferentially >30 lymph nodes to be retrieved)^c	• Histological subtype/Lauren classification/Histological grade (G1, G2, G3) • The depth of penetration into the gastric wall (pT classification)^f • Vascular, lymphatic, and perineural invasion • Proximal/distal margin^f • Involvement of the esophagus/duodenum (if resected) • Number of positive lymph nodes and total number of lymph nodes examined (pN classification) • Number of lesions^g • Distant metastasis (pM stage)^h • pTNM stage (8^th AJCC/UICC edition)	• Immunohistochemical assessment for diagnosis if needed^j • Gastric cancer with the advanced stage^l	Evaluate the status of Helicobacter pylori infection^m (Evidence 1B)
Surgical resection specimens for those who had neoadjuvant therapy	• Type of the surgical specimen • Tumor site • Tumor size (cm³) • Distance of tumor from the proximal and distal margin from tumor • The stations and number and of lymph nodes retrieved (at least 16 lymph nodes and/or preferentially >30 lymph nodes to be retrieved)^c (If lesion is not evident, careful examination and multipoint sampling should be made to avoid misdiagnosis or down staging)	• Histological subtype/Lauren classification/Histological grade (G1, G2, G3) • The depth of penetration into the gastric wall (pT classification)^f • Vascular, lymphatic, and perineural invasion • Proximal/distal margin^f • Involvement of the esophagus/duodenum (if resected) • Number of positive lymph nodes and total number of lymph nodes examined (pN classification) • Number of lesions^g	• Immunohistochemical assessment for diagnosis if needed^j • Gastric cancer with the advanced stage^l	Evaluate the status of Helicobacter pylori infection^m (Evidence 1B)
		• Distant metastasis (pM stage)^h • pTNM stage (8^th AJCC/UICC edition) • TRGⁱ • ypTNM stage (8^th AJCC/UICC edition)

^*When diagnosis cannot be made via biopsy, cytological brushings or lavage fluid can be used to confirm the presence of tumor. For unresectable advanced gastric cancer, exfoliative cytological examination of their peritoneal ascites or pleural effusion and biopsy of distant metastases can be used for pathological diagnosis.

Abbreviations: EMR, endoscopic mucosal resection; ESD, endoscopic submucosal dissection; pT, pathological tumor depth invasion classification; pN, pathological nodal classification; pM, pathological distant metastasis classification; ypTNM, post neoadjuvant pathological tumor‐node‐metastasis classification; AJCC/UICC, American Joint Cancer Committee/Union Internationale Contre le Cancer;

Notes:

^aEndoscopic mucosal resection (EMR)/endoscopic submucosal dissection (ESD) has become the new alternative treatment for early‐stage gastric cancer [16, 17]. EMR/ESD specimens should be meticulously resected, collected, and prepared, based on standard protocols, by the endoscopists or surgeons. All samples are recommended to be sectioned at intervals of 2‐3 mm and perpendicular to the mucosal surface [18, 19, 20].

^bAccording to the 8th edition of the AJCC/UICC staging system for gastric cancer, esophageal cancer, and EGJ carcinoma [5], the staging criteria for EGJ carcinoma or gastric‐cardia carcinoma are defined as follows: 1) if the tumor has invaded the gastroesophageal boundary and the tumor's epicenter is <2 cm proximal from the EGJ (Siewert I and II), staging criteria for esophageal cancer should be used; 2) if the tumor has invaded the gastroesophageal boundary but its epicenter is located ≥2 cm distal from the EGJ (Siewert III), the staging criteria for gastric cancer should be used. Therefore, it is very important to accurately determine the location of the gastroesophageal boundary and assess whether it has been invaded by the tumor.

^cFor patients who underwent radical gastrectomy without neoadjuvant therapy, ≥16 lymph nodes should be pathologically evaluated for proper tumor staging. For a more accurate staging evaluation, the preferred number of lymph nodes should be >30. For clinicians to accurately determine the range of lymph node metastasis, it is recommended that surgeons and pathologists collect and group the peri‐gastric lymph nodes according to their respective stations, which should be accordingly mentioned in the postoperative pathological report in addition to providing the total number of metastatic lymph nodes and total number of lymph nodes examined.

^dThe histopathological classification of gastric cancer is referred from the “WHO classification of tumours of the digestive system (2010 edition)” [18]. For hospital with adequate amenities, the “2019 WHO classification of tumours of the digestive system” [19] can be used for the histopathological classification of gastric cancer. If pathological diagnosis is difficult at lower‐tier hospitals, it is recommended to send the specimen samples to a specialized center/hospital for further evaluation.

^eFrom the Lauren classification [21], gastric adenocarcinoma is classified as intestinal type, diffuse type, and mixed type based on its histological growth patterns. Intestinal type often manifests as intestinal metaplasia, is mainly composed of highly to moderately differentiated atypical glands, and may sometimes be poorly differentiated at the proximal location of tumor invasion. Diffuse type is composed of poorly adherent cells which can extensively infiltrate the gastric walls with little or no glandular formation. The cells are usually small, round, scattered, or clustered, with obvious interstitial fiber proliferation. The mixed type is composed of approximately the same number of intestinal type and diffuse type.

^fThis guideline defines a positive surgical margin as the presence of cancer cells within a 1 mm distance from the resected margin.

^gThe detection of carcinomatous nodules in sub‐serous adipose tissues adjacent to the primary tumor site is to be considered as regional lymph node metastasis even if there is no evidence of residual lymph node tissues [5]. It is recommended to separately record regional metastatic lymph nodes and carcinomatous nodules.

^hIf tissues obtained from non‐neighboring regions of the stomach are pathologically confirmed as metastatic, these are to be regarded as distant metastasis (pM1). These include metastatic tissues from distant lymph node stations and cancerous cells detected in other organs (including intraperitoneal washings or peritoneal seedings) [5].

ⁱPathological evaluation of the tumor regression grade (TRG) (refer to section 5.3 for detailed scoring criteria) is based on residual tumor cells and the degree of fibrosis after anti‐cancer treatment, proposed by the 8th AJCC TNM classification [5] or the National Comprehensive Cancer Network (NCCN) guidelines [22]. The 8th edition of the AJCC staging system proposed the post‐neoadjuvant pathological tumor‐node‐metastasis classification (ypTNM) system to represent the postoperative pathological staging after neoadjuvant therapy.

^jWhen a pathological diagnosis is difficult to determine, gastric cancer‐related markers can be used for differential diagnosis, prognostic evaluation, and follow‐up/treatment needs [23].

^kEarly‐stage gastric cancer is defined as gastric cancer confined to the mucosa and submucosa, regardless of evidence of regional lymph node metastasis.

^lAdvanced gastric cancer is defined as a tumor that has invaded the muscularis propria or deeper layer of the gastric wall. The Borrmann classification includes four subtypes: Type I: nodular polypoid tumor; Type II: local central, bowl‐shaped ulcer with easily identified elevated margins; Type III: infiltrating ulcerative tumor with poorly defined margins; and Type IV: poorly demarcated, infiltrative, and diffuse tumor (local Borrmann Type IV, diffuse tumor infiltration of the gastric wall [linitis plastica]).

^mThe 8^th edition of the AJCC/UICC staging system for gastric cancer requires the recording of the Helicobacter pylori infection status [5].