Early gastric cancer: Clinical features, diagnosis, and staging

INTRODUCTION — Early gastric cancer (EGC) is defined as adenocarcinoma that infiltrates the mucosa or submucosa of the stomach with or without lymph node metastases (T1, any N) (table 1). Surgically or endoscopically curable EGCs are usually asymptomatic and detected infrequently outside of gastric cancer screening programs. (See "Gastric cancer screening".)

Gastric cancer is classified into two histologic types: intestinal and diffuse. Intestinal-type gastric cancer is the most common type, which develops through a sequence of histopathologic phases, beginning with normal mucosa and progressing to chronic gastritis, atrophic gastritis, intestinal metaplasia, dysplasia, and cancer [1]. The diagnosis and management of gastric intestinal metaplasia (a precancerous lesion in the gastric cancer cascade) is discussed separately. (See "Gastric intestinal metaplasia".)

Helicobacter pylori infection, a primary risk factor for gastric cancer, may lead to diffuse gastric mucosal inflammation and chronic gastritis. Progression of chronic gastritis to cancer is influenced by several factors, including H. pylori strain, host vulnerability, chronic inflammatory response composition, nutrition, and other environmental factors [2]. (See "Association between Helicobacter pylori infection and gastrointestinal malignancy".)

This topic will review the clinical features, diagnosis, and staging of EGC. The management and prognosis of EGC is discussed separately. (See "Early gastric cancer: Management and prognosis".)

Other issues related to gastric cancer are also discussed separately:

●Epidemiology – (See "Epidemiology of gastric cancer".)

●Risk factors, including H. Pylori infection – (See "Risk factors for gastric cancer" and "Association between Helicobacter pylori infection and gastrointestinal malignancy".)

●Pathology and molecular pathogenesis – (See "Gastric cancer: Pathology and molecular pathogenesis".)

●Clinical features and diagnosis of invasive gastric cancer – (See "Clinical features, diagnosis, and staging of gastric cancer".)

●Surgical therapy – (See "Surgical management of invasive gastric cancer".)

●Systemic therapy – (See "Initial systemic therapy for metastatic esophageal and gastric cancer" and "Second- and later-line systemic therapy for metastatic gastric and esophageal cancer".)

●Local palliation of advanced gastric cancer – (See "Local palliation for advanced gastric cancer".)

DEFINITION — EGC is defined as adenocarcinoma that is confined to the mucosa or submucosa, with or without lymph node involvement (T1, any N) (table 1). EGC has a significantly better prognosis (approximately 90 percent five-year survival rate) than invasive gastric cancer. (See "Surgical management of invasive gastric cancer".)

This definition recognizes that some patients with EGC have lymph node involvement, and it is aligned with guidance from professional societies and with data from gastric cancer screening programs [3-6].

However, nodal metastases can impact management (see "Early gastric cancer: Management and prognosis"):

●Patients with established nodal metastases or who are at high risk of developing nodal metastases (due to tumor size, macroscopic appearance, or depth of invasion) may not be suitable candidates for endoscopic resection. These patients typically undergo gastrectomy with removal of the regional nodes.

●Patients with node-positive resected EGC are candidates for adjuvant therapy. (See "Surgical management of invasive gastric cancer", section on 'Adjuvant and neoadjuvant therapy'.)

EPIDEMIOLOGY — Global and country-specific incidence rates for gastric cancer are available in the World Health Organization (WHO) GLOBOCAN database (figure 1) [7]. In 2020, there were one million new cases of gastric cancer worldwide, and gastric cancer was the leading cause of infection-associated cancer mortality [8-10]. EGC accounts for 15 to 57 percent of incident gastric cancer, and the prevalence of EGC varies by geographic region, patient population, and availability of screening programs. As an example, rates of EGC increased from 15 to 57 percent following adoption of screening programs in Japan [11-13]. EGCs account for 25 to 30 percent of gastric adenocarcinomas in Korea [14,15]. In contrast, EGCs account for 15 to 21 percent of gastric cancer cases in the United States and Europe [13,16,17]. The higher prevalence of EGC in Eastern Asian countries may be attributed to geographic variation in practice patterns by pathologists who review gastric biopsies and resection specimens to establish a histologic diagnosis. (See 'Classification' below.)

In addition, early detection strategies are common in Eastern Asian countries. These strategies include screening programs, surveillance of premalignant conditions, visual expertise in early diagnosis, and endoscopy protocols (eg, extensive photo-documentation, use of advanced imaging techniques such as image-enhanced endoscopy and chromoendoscopy) [18]. (See 'Diagnostic evaluation' below.)

CLINICAL FEATURES — Patients with EGC typically present between the ages of 62 and 72 years, and EGC is more common in males [19,20].

Most patients are asymptomatic because they are diagnosed in the context of screening programs. When symptoms are present, they are often nonspecific and may include dyspepsia, mild epigastric pain, nausea, or anorexia [16]. Signs or symptoms that suggest invasive disease, such as anemia or weight loss, occur in 5 to 15 percent and 4 to 40 percent of patients with gastric cancer, respectively [16].

The nonspecific nature of EGC symptoms and the frequency of dyspepsia from other causes may hinder the diagnosis of EGC [21]. While the prevalence of gastric cancer among patients with dyspepsia is low in the United States and other Western countries, there are no reliable clinical or laboratory features to differentiate individuals with benign causes of dyspepsia from those with early or advanced cancer. (See "Approach to the adult with dyspepsia".)

DIAGNOSTIC EVALUATION

When to suspect early gastric cancer — The diagnosis of EGC may be suspected based on endoscopic findings (eg, raised lesion with color changes [pale or reddish mucosa], with or without ulceration) but is established by histologic evaluation of gastric biopsies that demonstrate adenocarcinoma (table 2). (See "Gastric cancer: Pathology and molecular pathogenesis", section on 'Histologic classification'.)

Some patients who develop EGC may have a history of atrophic gastritis or intestinal metaplasia; these conditions are discussed separately. (See "Metaplastic (chronic) atrophic gastritis" and "Gastric intestinal metaplasia".)

Early gastric cancer may also be suspected in patients with nonhealing gastric ulcers despite medical therapy. Other features of a gastric ulcer that suggest malignancy are mass lesion, elevated irregular borders, or abnormal adjacent folds [22,23]. The diagnosis and management of patients with peptic ulcer disease, including refractory gastric ulcer, are discussed in detail separately:

●(See "Peptic ulcer disease: Clinical manifestations and diagnosis".)

●(See "Peptic ulcer disease: Treatment and secondary prevention".)

●(See "Approach to refractory peptic ulcer disease".)

Upper endoscopy with biopsy — On upper endoscopy using high-definition white light, EGC usually has the appearance of an abnormal, uneven mucosal surface (eg, superficially elevated or depressed) with color changes (pale or reddish mucosa) [4,18]. EGC may have additional characteristics, such as mucosal friability, ulceration, or lack of normal vascular pattern.

Lesion characteristics also inform the estimated depth of tumor invasion. Findings associated with tumors limited to the gastric mucosa include smooth surface protrusion or depression, slight marginal elevation, and smooth tapering of converging folds [24]. Findings suggestive of submucosal tumors include an irregular surface, markedly elevated margins, and clubbing, abrupt cutting, or fusion of converging folds [4,5,18]. Under magnification endoscopy, EGC often reveals a demarcation line and uneven vascular and structural patterns (image 1).

We take one to two biopsies from lesions that are suspicious for EGC. The diagnostic accuracy with one biopsy is nearly 88 percent, and it increases to 96 percent with two or more biopsies [18].

We use the following strategies to increase the yield of endoscopic examination:

●Endoscopic imaging techniques – We typically visualize the gastric mucosa with high-definition white light and narrow band imaging (NBI). NBI is a high-resolution endoscopic technique that enhances the fine structure of the mucosal surface without the use of dyes. We may combine NBI with magnification endoscopy to improve visualization of surface and vascular patterns. Some endoscopes have a near-focus function, including near-focus NBI, and this is an emerging alternative in centers where magnification endoscopy is not available [25-27]. (See "Magnification endoscopy".)

Indirect evidence involving patients with gastric intestinal metaplasia (a precursor to EGC) suggested that NBI had good diagnostic accuracy for detecting gastric intestinal metaplasia and neoplasia by identifying key features, such as the marginal turbid band, light blue crest, and white opaque substance [5,28-30]. The diagnosis and management of gastric intestinal metaplasia is discussed separately. (See "Gastric intestinal metaplasia".)

Alternatives to NBI include dye-based chromoendoscopy and image-enhanced endoscopy [18,31-33]. These advanced imaging techniques (eg, blue light imaging, linked color imaging) may be used in combination with white light endoscopy [34,35]. Image-enhanced endoscopy facilitates visualizing the vascular structure and mucosal surface by optical or digital technologies and by magnification techniques (eg, optical or digital zoom, near-focus) [4,5,36,37]. Image-enhanced endoscopy may overcome some limitations of white light endoscopy by detecting small gastric lesions that are difficult to distinguish from normal gastric mucosa. As an example, in a study including 1924 patients undergoing screening endoscopy for gastric cancer, linked color imaging was associated with higher accuracy for detecting EGC/high grade intraepithelial neoplasms compared with white light imaging (79 versus 68 percent) [35].

●Inspection techniques – The following techniques may optimize endoscopic visualization:

•Cleansing the mucosa – Prior to mucosal inspection, we clear bubbles on the gastric mucosa by using simethicone in the water flushes used during endoscope insertion or withdrawal [18].

•Systematic visualization – We systematically examine each anatomic area of the stomach (antrum, pylorus, incisura, lesser curve, greater curve, fundus, and cardia), and we visualize the greater curvature in direct and retroflexed views with sufficient insufflation to inspect between the gastric folds [32,38]. Other station-based protocols have been proposed, whereby each area of the stomach is viewed and photographed [39]. As an example, the systematic alphanumeric-coded endoscopic method (SACE) distinguishes each gastric station by alpha-numeric terminology and with unique endoluminal features. This protocol facilitates image reconstruction-based precision endoscopy in addition to the development of predictive models via artificial intelligence. SACE shows promise for eliminating blind spots during examination of the stomach and for use as a quality indicator of endoscopy (image 2) [33,39,40].

•Time-based strategy – We inspect the mucosa for a minimum of three minutes during withdrawal of the endoscope (ie, time from reaching the duodenum to endoscope removal) [31,32]. An alternative metric is using a minimum of seven minutes for total examination time (ie, from intubating the esophagus to removing the endoscope). Studies suggested that a time-based strategy was associated with a higher yield endoscopic examination. In a study including over 30,000 upper endoscopies comparing observation time >3 minutes with observation time <3 minutes, longer observation time was associated with higher likelihood of detecting a neoplastic lesion in the upper gastrointestinal tract (odds ratio 1.51, 95% CI 1.21-1.75) [31].

Additional testing — We evaluate all patients with lesions suspicious for EGC for Helicobacter pylori infection. We typically perform gastric biopsy to assess for H. pylori, but other methods are available. Testing strategies and management of H. pylori infection are discussed in detail separately:

●(See "Indications and diagnostic tests for Helicobacter pylori infection in adults".)

●(See "Treatment regimens for Helicobacter pylori in adults".)

Establishing the diagnosis — The diagnosis of early gastric cancer is established by histologic evaluation of gastric biopsies that demonstrate adenocarcinoma (table 2). (See "Gastric cancer: Pathology and molecular pathogenesis", section on 'Histologic classification'.)

CLASSIFICATION — Gastric cancers represent a clinically, biologically, genetically, and microscopically heterogeneous group of malignant epithelial tumors. The anatomic and histologic classification of invasive gastric cancer, in addition to molecular subtyping, is discussed in detail separately. (See "Gastric cancer: Pathology and molecular pathogenesis".)

EGCs are primarily classified based on endoscopic and histologic features. In the future, molecular markers and precision medicine may help to define classification systems that may inform treatment decisions and patient prognosis.

Endoscopic (macroscopic) features — We use the Paris classification system to categorize EGCs based on the lesion's endoscopic (macroscopic) features [41]. Superficial lesions (type 0) are classified as polypoid, nonpolypoid, or excavated (table 3 and figure 2):

●Type 0-I lesions are polypoid and are categorized as:

•Type 0-Ip – protruded, pedunculated

•Type 0-Is – protruded, sessile

●Type 0-II lesions are nonpolypoid and are categorized as:

•Type 0-IIa – slightly elevated

•Type 0-IIb – flat

•Type 0-IIc – slightly depressed

●Type 0-III lesions are excavated

Type I lesions and type IIa lesions may appear similar. However, type I lesions extend above the mucosa >2.5 mm (ie, the width of the closed cups of a biopsy forceps). Pathologically, the height of the lesion is more than twice the thickness of the adjacent mucosa. Type IIa lesions are slightly elevated, but their height is <2.5 mm.

In addition, type IIc and type III lesions may appear similar. Type IIc lesions are slightly depressed with a normal epithelial layer or superficial erosions. Type III lesions are characterized by ulceration, with loss of the mucosa and possibly submucosa [41].

For reference, an earlier classification system developed by the Japanese Gastric Cancer Association recognized four types of early endoluminal cancers (figure 3) [42]:

●Type I lesions were polypoid or protuberant and further categorized as:

•Ip – pedunculated

•Ips/sp – subpedunculated

•Is – sessile

●Type II lesions were flat and further categorized as:

•IIa – superficial elevated

•IIb – flat

•IIc – flat depressed

•IIc+IIa lesions – elevated area within a depressed lesion

•IIa+IIc lesions – depressed area within an elevated lesion

●Type III lesions were ulcerated

●Type IV lesions were lateral spreading

Histologic classification — The histologic classification of gastric cancer is challenging because of intratumoral variations in architecture and/or differentiation. In addition, consensus groups have proposed several histologic classification systems that are outlined in the table (table 2) [43]. In general, small (<2 cm) EGCs often have well-differentiated histology. As tumor size increases and submucosal invasion develops, histologic diversity with mixed or poorly differentiated components is more common. (See "Gastric cancer: Pathology and molecular pathogenesis", section on 'Histologic classification'.)

Consensus groups developed the Vienna classification of gastrointestinal epithelial neoplasia and the Padova international classification of dysplasia in an attempt to harmonize reporting schemes that have been used in different geographic regions [6,44,45]. The Vienna classification recognizes the following categories [44]:

●Category 1: Negative for dysplasia

●Category 2: Indefinite for dysplasia

●Category 3: Noninvasive low-grade neoplasia (low-grade adenoma/dysplasia)

●Category 4: High-grade neoplasia

•4.1: High-grade adenoma/dysplasia

•4.2: Noninvasive carcinoma (carcinoma in situ)

•4.3: Suspicion of invasive carcinoma

●Category 5: Invasive neoplasia

•5.1: Intramucosal carcinoma (invasion into the lamina propria or muscularis mucosa)

•5.2: Submucosal carcinoma or beyond

In addition, the World Health Organization (WHO) proposed a classification of intraepithelial gastric neoplasia using similar but not identical terms (negative for dysplasia, indefinite for dysplasia, low-grade and high-grade dysplasia, and carcinoma [invasion into the lamina propria or beyond]) [43]. (See "Gastric cancer: Pathology and molecular pathogenesis", section on 'Classification of gastric cancer'.)

POST-DIAGNOSTIC STAGING EVALUATION

General approach — The post-diagnostic staging evaluation determines the depth of tumor invasion and whether there is any unexpected lymph node involvement. These factors inform selection of therapy for patients with EGC. The evaluation includes direct endoscopic visualization of the tumor, histology of the resected specimen, contrast-enhanced computed tomography (CT) of the chest, abdomen, and pelvis, and in some patients, endoscopic ultrasound (EUS). Careful staging allows the clinician to select the most appropriate therapy, minimizes unnecessary surgery, and maximizes the likelihood of benefit from the selected treatment.

The overall incidence of lymph node metastases in clinically staged T1 EGC ranges 0 to 15 percent [46-50]. Although lymph node metastases do not affect the designation of a T1 EGC tumor, they have implications for therapy. (See "Early gastric cancer: Management and prognosis" and "Adjuvant and neoadjuvant treatment of gastric cancer".)

Tumor characteristics determine the risk of lymph node metastases and have helped to define the criteria for selecting patients for endoscopic resection [51,52]. Factors associated with lymph node metastases include larger tumor size, ulceration, diffuse (undifferentiated) or mixed (intestinal/undifferentiated) type histology, depth of invasion, and submucosal or lymphovascular invasion [48,50,53,54]. Thus, the absolute criteria for endoscopic resection of an EGC include an intramucosal, nonulcerated, differentiated tumor less than 2 cm without lymphovascular invasion. Indications for endoscopic resection are discussed in more detail separately. (See "Early gastric cancer: Management and prognosis".)

Endoscopic appearance — Endoscopic findings that suggest submucosal tumor invasion include an irregular surface, marked marginal elevation, and clubbing, abrupt cutting, or fusion of converging folds [24].

Endoscopic resection (histology) — For patients with EGC who meet criteria for endoscopic resection, histologic examination of the resected specimen informs the staging evaluation [4,55]. Methods for removing EGC endoscopically include endoscopic submucosal dissection (ESD) and endoscopic mucosal resection (EMR). Although ESD often provides en bloc, complete (R0), and curative resection, it is a more technically demanding procedure than EMR and may not be available in some centers. En bloc resection using ESD permits T staging and does not impact subsequent gastrectomy if the resection is incomplete or if there are unfavorable histologic findings, such as lymphovascular invasion that suggest higher likelihood of lymph node metastases (image 3). For specimens removed en bloc with ESD, upstaging of high grade dysplasia and EGC is common [56,57].

Smaller lesions (eg, size <10 mm) may be removed using EMR. Indications for and technical aspects of endoscopic resection of EGC are discussed in detail separately. (See "Early gastric cancer: Management and prognosis".)

Endoscopic ultrasound — Endoscopic ultrasound (EUS) has become a valuable tool for selecting patients who meet criteria for endoscopic resection [58-61]. However, an accurate EUS staging examination requires endoscopic expertise and may be impacted by some tumor features (eg, mid-gastric location, poorly differentiated tumors) [62]. In addition, use of EUS for staging varies among centers because some institutional protocols for staging rely on white light endoscopy and histology from ESD specimens for post-diagnostic staging [19,20].

●Depth of tumor invasion – Studies suggested that EUS is an accurate method for evaluating the depth of tumor invasion, particularly for T1 gastric lesions [63-65]. In a study of 955 patients with suspected EGC, EUS correctly identified the T stage in 644 patients (67 percent) [66]. Use of an EUS miniprobe (ie, small caliber ultrasound probe that is introduced through the accessory channel of a standard endoscope) has been associated with higher accuracy for staging EGC compared with conventional EUS. (See "Endoscopic ultrasound (EUS): Use of miniprobes for evaluating gastrointestinal lesions", section on 'Early gastric cancer'.)

●Lymph node involvement – EUS can detect locoregional lymph node involvement [63]. Regional nodes for tumors involving different parts of the stomach are depicted in the figure (figure 4). Involvement of other intra-abdominal nodal groups (ie, pancreatoduodenal, retropancreatic, peripancreatic, superior mesenteric, middle colic, paraaortic, and retroperitoneal) is classified as distant metastases [67].

Although EUS can reveal regional node enlargement, distinguishing between benign (reactive) perigastric inflammation and nodal metastases can be difficult. EUS fine-needle aspiration of suspicious nodes may improve diagnostic accuracy. (See "Endoscopic ultrasound-guided fine needle aspiration in the gastrointestinal tract".)

Imaging studies — We obtain post-diagnostic staging imaging with contrast-enhanced CT of the chest, abdomen, and pelvis [68]. Staging imaging studies are needed to rule out lymph node involvement and distant metastases prior to initiating therapy directed at EGC. (See "Clinical features, diagnosis, and staging of gastric cancer", section on 'Staging evaluation'.)

STAGING SYSTEMS — Gastric cancer is staged using the tumor, node, metastasis classification system of the American Joint Committee on Cancer (AJCC); the current (eighth edition, 2017) version is outlined in the table (table 1) [67]. EGCs are T1 lesions, irrespective of nodal status. (See "Clinical features, diagnosis, and staging of gastric cancer", section on 'Staging systems'.)

SCREENING — Screening methods for gastric cancer include endoscopy, radiology, and noninvasive testing (eg, H. pylori serology and serum pepsinogen testing) [69-71]. Screening for gastric cancer is discussed in detail separately. (See "Gastric cancer screening".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Gastric cancer".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topic (see "Patient education: Stomach cancer (The Basics)")

SUMMARY AND RECOMMENDATIONS

●Definition – Early gastric cancer (EGC) is defined as adenocarcinoma that is confined to the mucosa or submucosa, with or without lymph node involvement (T1, any N) (table 1). EGC has a significantly better prognosis (approximately 90 percent five-year survival rate) than invasive gastric cancer. (See 'Definition' above.)

●Clinical features – Most patients with EGC are asymptomatic because they are diagnosed in the context of screening programs. When symptoms are present, they are often nonspecific and may include dyspepsia, mild epigastric pain, nausea, or anorexia. (See 'Clinical features' above.)

●Diagnostic evaluation – The diagnosis of EGC may be suspected based on endoscopic findings (eg, superficially elevated or depressed lesion with color changes [pale or reddish mucosa], with or without ulceration). The diagnosis is established by histologic evaluation of gastric biopsies that demonstrate adenocarcinoma (table 2). (See 'Diagnostic evaluation' above and "Gastric cancer: Pathology and molecular pathogenesis", section on 'Histologic classification'.)

Some patients with EGC may have a history of any of the following:

•Atrophic gastritis – (See "Metaplastic (chronic) atrophic gastritis".)

•Gastric intestinal metaplasia – (See "Gastric intestinal metaplasia".)

•Nonhealing gastric ulcer – (See "Approach to refractory peptic ulcer disease".)

We use the following strategies to increase the yield of endoscopic examination (see 'Upper endoscopy with biopsy' above):

•Imaging techniques – Use of high-definition white light endoscopy in addition to advanced imaging methods (eg, narrow band imaging [NBI], image-enhanced endoscopy).

•Inspection techniques – We optimize endoscopic examination of the stomach by flushing the gastric mucosa and systematically inspecting each anatomic area.

●Classification – EGCs are primarily classified based on endoscopic and histologic features. We use the Paris classification system (table 3 and figure 2) to categorize EGCs based on the lesion's macroscopic features. Consensus groups have proposed several histologic classification systems that are outlined in the table (table 2). In general, small (<2 cm) EGCs often have well-differentiated histology. (See 'Classification' above.)

●Post-diagnostic staging evaluation – The post-diagnostic staging evaluation determines the depth of tumor invasion and whether there is any unexpected lymph node involvement. These factors help inform selection of therapy for patients with EGC. (See "Early gastric cancer: Management and prognosis".)

The evaluation includes direct endoscopic visualization of the tumor, histology of the resected specimen, contrast-enhanced CT of the chest, abdomen, and pelvis, and in some patients, endoscopic ultrasound (EUS). (See 'Post-diagnostic staging evaluation' above.)

●Screening – Screening methods for gastric cancer and its precursor conditions include endoscopy, radiology, and noninvasive testing (eg, H. pylori serology). Screening for gastric cancer is discussed in detail separately. (See "Gastric cancer screening".)