Introduction

Gastric cancer is the second most common type of cancer worldwide. Approximately 800,000 new cases and 650,000 deaths are reported per year, despite a steadily declining incidence during the past 50 years.¹ There is wide variation in incidence on different continents, with the highest rates in Asia, central Europe, and South America.² In the United States, gastric cancer is the seventh most frequent cause of cancer-related death. The National Cancer Institute estimates that almost 22,000 new cases of gastric cancer will be diagnosed in 2013 and that approximately 11,000 deaths will be attributed to this disease.^2,3

The topographic distribution of gastric cancer has also changed in recent years. Since the early 1980s, the incidence of proximal gastric tumors has been on the rise. Carcinomas of the gastric cardia now represent approximately 30% of all gastric cancers.^4,5 Changes in clinical practice have also led to diagnosis of a higher percentage of early-stage cancers. The widespread increased use of upper gastrointestinal (GI) endoscopy has led to more frequent detection of superficial cancers. Early gastric cancer (EGC) now represents almost 20% of all newly diagnosed cancers in the United States, and as many as 50% in Japan.^6–9 This trend has had a dramatic impact on the mortality rate, to the point that gastric cancer is now considered potentially curable if it is detected at an early stage.

Pathogenesis

The pathogenesis of sporadic gastric carcinoma is a multifactorial process in which both environmental and host-related factors play a major role.¹⁰ The carcinogenic process involves a progression from chronic gastritis to atrophy with hypochlorhydria or achlorhydria, intestinal metaplasia, dysplasia, and, ultimately, adenocarcinoma.^10,11 Intestinal metaplasia and, subsequently, dysplasia and early adenocarcinoma develop initially in the neck region of the antral or fundic glands of the stomach, supporting the hypothesis that precursor cells are located in this region.¹²

The well-known geographic variations in incidence data, obtained from studies of changes in dietary and sanitary conditions among immigrants, have underscored the role of environmental influences in the development of the intestinal type of gastric carcinoma, which is the most common type.^13–15 Furthermore, the worldwide decrease in the incidence of intestinal-type gastric cancer has paralleled the decline in Helicobacter pylori infection, which confirms this bacterium as a major environmental cause of this type of cancer. Long-standing H. pylori infection induces chronic gastritis that gradually results in atrophy and intestinal metaplasia.^16,17 There is a fourfold to ninefold increased risk of gastric lesions among patients with H. pylori infection, particularly if infection began in early childhood.^18–20 Chronic acid suppression also increases the risk for development of atrophy in patients with H. pylori gastritis.²¹

Certain aspects of H. pylori virulence have been associated with risk of gastric cancer. For instance, strains that are positive for cytotoxin-associated gene A (CagA)produce higher levels of interleukin 8, elicit more intense inflammation, and are associated with an increased risk of gastric carcinoma.²²

However, gastric cancer does not develop in most individuals who are infected by H. pylori, and, conversely, as many as 20% of patients in whom gastric cancer develops are H. pylori seronegative. Therefore, other environmental and host factors are presumed to be important in the pathogenesis of this disease.^23,24 Diets that are rich in salt (e.g., dried and salted fish and meats, soy sauce, smoked fish, pickled foods) and contain low levels of micronutrients, vitamins, and antioxidants¹⁴ favor intraluminal formation of genotoxic agents, such as specific N-nitroso compounds (formed by nitrosation of ingested nitrates) and have been associated with the development of gastric cancer.^25–27 In contrast, diets rich in fresh vegetables, citrus fruits, and ascorbic acid are inversely associated with risk of gastric cancer.²⁷ Bile reflux has been associated with the development of adenocarcinoma in surgical stumps.²⁸ With regard to host factors, polymorphisms of the interleukin 1 gene have been associated with an increased risk of gastric cancer in H. pylori–infected individuals. Furthermore, the presence of a proinflammatory interleukin 1 genotype, which plays a role in hypochlorhydria and atrophy, is clearly associated with an increased risk of the intestinal type, but not the diffuse type, of gastric cancer.²⁹

In contrast to the intestinal type of gastric cancer, the diffuse type is more common in younger individuals and is observed with equal incidence in both high- and low-risk geographic regions. Its development is more regulated by genetic factors than is intestinal-type gastric cancer.^14,30 The importance of genetic factors is also underscored by the existence of familial clustering³¹ and by the increased incidence of atrophic gastritis in relatives of patients with gastric cancer (see Genetic Predisposition and Hereditary Tumor Syndromes).

Histologic Precursors of Gastric Cancer

In most instances, the development of gastric adenocarcinoma represents the culmination of an inflammation–metaplasia–dysplasia–carcinoma sequence, known as the Correa cascade of multistep gastric carcinogenesis.³² Mucosal atrophy and intestinal metaplasia confer a high risk for the development of gastric cancer; however, gastric epithelial dysplasia (or adenoma, if it is a polypoid lesion) represents a direct neoplastic precursor lesion.^32,33 Almost all gastric epithelial dysplasias (or adenomas) have an “intestinal” phenotype (type I), resembling colonic adenomas. Another, less common, histologic variant is hyperplastic (type II) dysplasia.³⁴ Finally, the exceedingly rare tubule neck (or globoid) dysplasia is believed to be a precursor of diffuse-type gastric carcinoma.³⁵

Anatomic Distribution: Cardia Cancer

There has been an important epidemiologic shift in the location and frequency of gastric cancer during the past few decades, exemplified by an increase in the incidence of adenocarcinoma of the cardia region. The cause of the apparent shift in the anatomic location of gastric cancer is controversial. Because there is a lack of widespread consensus regarding the anatomic definition of the gastric cardia, it is unclear whether previously diagnosed cases of gastric cardia cancer in fact represent distal esophageal cancer involving the gastric cardia. The International Gastric Cancer Association has endorsed a classification system of gastric tumors in which type I tumors are defined as those that arise in the distal esophagus, type II as tumors in the gastric cardia, and type III as tumors in gastric mucosa distal to the cardia.³⁶ However, this classification system does not address the criteria to define tumors from each of these anatomic areas.

The increased incidence of carcinomas of the gastric cardia observed during the past several decades has shown a geographic restriction: Studies from Scandinavia and Japan have failed to report a similar trend.^4,37,38 Some investigators have suggested that the widespread use of endoscopy and improvements in diagnostic methods are responsible for these apparent changes in the distribution of gastric cancer.³⁹

There are well-known differences between cancers of the cardia and those in the distal stomach. Patients with cardia cancer show a higher male-to-female ratio, and whites are affected more frequently than African Americans.⁴⁰ There are also similarities between cardia and esophageal adenocarcinomas,^41–43 such as similar risk factors, age and distribution, and morphologic phenotypes.^43,44 However, obesity, high body mass index, smoking, and alcohol intake are not universally accepted as risk factors for cardia cancer, as they are for esophageal cancer.^38,44–48 Similarly, the association of cardia cancer with Barrett’s esophagus and gastroesophageal reflux disease is a subject of debate.⁴⁴

In some studies, cardia cancer has been significantly associated with older patient age, H. pylori infection, and intestinal metaplasia elsewhere in the stomach.^49–52 In other studies, cardia cancer has been associated with reflux disease. Some researchers suggest that both etiologies play a role in the pathogenesis of cardia cancers.⁵³ Although intestinal metaplasia has been demonstrated in adjacent mucosa in as many as 70% of carcinomas of the cardia, the actual risk of malignant transformation in patients with intestinal metaplasia has not been determined in prospective studies.^54,55 Some studies have shown that progression of intestinal metaplasia to dysplasia is slower, and less frequent, than in Barrett’s esophagus.^48,51 Currently, the finding of intestinal metaplasia in the gastric cardia is not an absolute indication for periodic endoscopic surveillance.

Early Gastric Cancer

Clinical and Pathologic Features

Invasive adenocarcinomas confined to the mucosa or submucosa, regardless of whether lymph node metastasis is present, are defined as EGC⁵ (Fig. 25.1). EGC represents an early stage in development, before invasion of the muscularis.⁵⁶ Because of an increased number of upper endoscopies being performed worldwide, detection rates for this lesion are on the rise. In Western series, EGC represents 15% to 21% of all newly diagnosed gastric cancers, whereas in Japan it accounts for more than 50% of cases.^6–9 A higher prevalence of gastric cancer, more liberal use of upper endoscopy and chromoendoscopy, and differences in diagnostic criteria help explain the differences between Western and Japanese studies.

Similar to dysplasia, most EGCs are diagnosed in men older than 50 years of age; this is a younger age than for advanced adenocarcinoma, reflecting the amount of time required for progression from early to advanced disease.^40,57 Most patients are asymptomatic, but some complain of symptoms that mimic peptic ulcer disease.^9,58 Epigastric pain and dyspepsia are the most frequently reported symptoms. They usually occur only within the last few months before diagnosis.⁵⁹ Most EGCs are small, between 2 and 5 cm, and they are typically localized on the lesser curvature around the angularis region.^5,60 In 3% to 13% of patients, multiple primary sites are present, and this has been shown to be associated with a worse prognosis.^6,61

EGCs are divided into three types based on their endoscopic appearance (Fig. 25.2): protruding (type I), superficial (type II), and excavating (type III).⁶² Type II is further subdivided into IIa (elevated; Fig. 25.3), IIb (flat), and IIc (depressed). Superficial EGCs (type II) account for the highest proportion of cases (80%), with type IIc being most common.⁶³ Type IIb accounts for 58% of tumors that are smaller than 5 mm.⁶⁴ The endoscopic appearance of EGCs has been shown to be a good indicator of the rate of lymph node metastasis, with the lowest rates reported in type I or IIa EGCs.⁵⁹

Type IIa, which is defined as a lesion that is twice as thick as normal mucosa, and type IIc, which mimics benign ulcers, are difficult to detect endoscopically, and multiple biopsies are often required for diagnosis. Subtle diagnostic signs include ease of bleeding and an irregular interface with the surrounding mucosa.^65,66

Microscopic variants of EGCs have been reported. Minute EGCs measure less than 5 mm in diameter, and although most are limited to the mucosa, submucosal extension is detected in as many as 15% of cases.^67,68 Superficial spreading EGCs are characterized by the presence of large, serpiginous ulcerations with neoplastic cells that spread laterally over a large area of mucosa.⁵

The majority of EGCs are well differentiated. Tubular and papillary variants represent 52% and 37% of cases, respectively, and may be difficult to differentiate from dysplasia because of the lack of obvious tissue invasion. Signet ring cell carcinoma (Fig. 25.4) and poorly differ­entiated carcinoma represent 26% and 14% of cases, respectively, and are usually depressed or ulcerated (types IIc and III).^5,6,69 Diffuse-type EGCs tend to show greater depths of invasion.⁵⁹

Natural History and Treatment

In a series of patients with EGC followed conservatively without surgery, 63% of EGCs progressed to advanced carcinoma during a 6- to 88-month period.⁷⁰ With resection, the prognosis of EGC is excellent, with 5-year survival rates greater than 90% reported in most series.^6,9,10,58,71 Size of the tumor and depth of invasion are the two major prognostic indicators. Larger tumors have a greater risk of submucosal infiltration.^7,72,73 However, the risk of invasion should not be overlooked even in very small tumors. In one series, 15.5% of tumors that measured 3 to 5 mm in diameter showed invasion into the submucosa.⁶⁸ Lymph node metastases have been reported in 0% to 7% of intramucosal EGCs and are associated with a 5-year survival rate of almost 100%.^6,72,73 The rate of lymph node metastases for EGCs that extend into the submucosa varies between 8% and 25%, and the 5-year survival rate for these tumors is 80% to 90%.^6,73

Endoscopic mucosal resection has become the treatment of choice for EGC. It usually is performed in association with endoscopic ultrasonography for staging. The primary criteria for identifying EGCs most amenable to endoscopic mucosal resection are (1) elevated lesion less than 2 cm in diameter, (2) depressed lesion less than 1 cm in diameter and without ulceration, and (3) absence of lymph node metastasis.^74–76 Whether eradication of H. pylori improves prognosis is unclear. In a study of 132 patients with EGC who underwent endoscopic mucosal resection, no new cases of gastric cancer were observed after H. pylori eradication. In contrast, new early-stage intestinal-type gastric cancer developed in 13.5% of untreated patients.⁷⁷

Advanced Gastric Carcinoma

Advanced adenocarcinoma is defined as a tumor that invades the gastric wall beyond the submucosa. Most patients are men (male-to-female ratio of 2 : 1) in their fifth to seventh decades of life. Clinically, symptoms include epigastric pain, dyspepsia, anemia, and weight loss. Hematemesis and symptoms of gastric outlet obstruction are not uncommon.⁵ Some patients, particularly younger ones, have intraabdominal dissemination at presentation. Metastatic ovarian lesions (Krukenberg tumors) composed of diffuse-type cancer cells may develop in female patients.⁵ Sixty-five percent of patients with gastric cancer in the United States are diagnosed at an advanced stage (beyond stage Ib).³

In North America, most gastric adenocarcinomas occur in the antrum or in the antropyloric region, and preferentially on the lesser curvature.^3,78 Approximately half of all gastric adenocarcinomas measure between 2 and 6 cm, and 30% measure 6 to 10 cm in greatest dimension. Only 15% of gastric carcinomas are larger than 10 cm at the time of diagnosis.⁵ Multiple adenocarcinomas are detected in 5% of patients.^61,79

Pathologic Features

Gross Features

Advanced gastric carcinomas may display several different gross appearances, referred to as exophytic, ulcerated, infiltrative, and combined. The Borrmann classification remains the most widely used system. It divides gastric carcinomas into four distinct types⁸⁰ (Fig. 25.5): polypoid carcinoma (type I), fungating carcinoma (type II), ulcerating carcinoma (type III), and diffusely infiltrating carcinoma (type IV) (Fig. 25.6). The latter is also referred to as linitis plastica when it involves the majority of the stomach (Fig. 25.7). Type II represents 36% of all gastric carcinomas and is frequently detected in the antrum on the lesser curvature. Types I and III each represent 25% of all advanced gastric carcinomas, and they are more common in the corpus, usually on the greater curvature.

Microscopic Features

Gastric adenocarcinomas are characterized by marked heterogeneity at both the cytologic and the architectural level, and they frequently show overlap among the four different gross patterns. Cytologically, a combination of gastric foveolar, intestinal, and endocrine cell types usually constitutes at least a portion of all tumors.^81,82 Ciliated tumor cells may also be observed.⁸³ Mucin histochemical and immunohistochemical stains (MUC1, MUC2, MUC5AC, MUC6, and CD10) may be useful in highlighting the different cellular components.^{81,82,84–86} In fact, on the basis of mucin immunohistochemistry, a new phenotypic classification of gastric cancer has been proposed that separates them into four phenotypes: G (gastric; MUC5AC+ and/or MUC6+; MUC2− and CD10−), I (intestinal; MUC2+ and/or CD10+; MUC5AC− and MUC6−), GI (gastric and intestinal); and N (null). Type I is more common in differentiated gastric cancers than in undifferentiated ones.⁸⁷ For each histologic subtype, a shift from the gastric to the intestinal phenotype is commonly observed with tumor progression.⁸⁸

Several classification systems of gastric adenocarcinoma have been proposed, most based primarily on the microscopic appearance of the tumor (Table 25.1). The three-tiered Laurén classification system is important in helping to understand the role of environmental factors and epidemiologic trends and is the system most often used by pathologists.⁸⁹ This classification scheme recognizes intestinal, diffuse, and indeterminate or unclassified types. Their relative frequencies are 50% to 67%, 29% to 35%, and 3% to 21%, respectively.⁹⁰

Table 25.1

Gastric Adenocarcinoma Classification Systems

Ming	Laurén	WHO	Goseki
Expanding	Intestinal type	Papillary adenocarcinoma Tubular adenocarcinoma

Well-differentiated tubules, intracellular mucin poor
Well-differentiated tubules, intracellular mucin rich Infiltrating Diffuse type

Poorly cohesive carcinoma

Mucinous adenocarcinoma

Poorly differentiated tubules, intracellular mucin poor Indeterminate type

Mixed adenocarcinoma

Adenosquamous carcinoma

Squamous carcinoma

Small cell carcinoma

Others*

Poorly differentiated tubules, intracellular mucin rich

^* Rare morphologic variants are classified under this heading.

WHO, World Health Organization.

The World Health Organization (WHO) recognizes four other major types of gastric adenocarcinoma (adenosquamous, squamous, small cell carcinoma, and other rare morphologic variants) in addition to those included in the Laurén classification. Several rare variants are also included in the WHO classification^1,86 (see Table 25.1).

In the WHO classification, intestinal-type adenocarcinomas characteristically form glands, but with various degrees of differentiation (Fig. 25.8). They are usually diagnosed in older patients, mostly in the antrum, and are strongly linked to chronic H. pylori infection, atrophic gastritis, and intestinal metaplasia. All papillary and tubular adenocarcinomas fall into this category. These glandular carcinomas tend to form polypoid or fungating masses.⁸⁶ The papillary variant is characterized by long epithelial projections scaffolded by central fibrovascular cores (Fig. 25.9). This variant accounts for 6% to 11% of all gastric carcinomas, affects older patients, occurs mainly in the proximal stomach, and is frequently associated with liver metastases.^91,92 A higher rate of lymph node metastases has been reported for papillary adenocarcinoma compared with other intestinal types.⁹³ The tubular variant is composed of distended or anastomosing, branching tubules of various sizes (Fig. 25.10). Mucin and cellular or inflammatory debris are often observed. In both the papillary and tubular variants, the cells may be columnar or cuboidal and may possess various degrees of nuclear atypia and mitoses. Combined papillotubular variants are also not uncommon.

Poorly cohesive carcinomas are composed of mostly single, or small, nests of neoplastic cells that diffusely infiltrate the gastric wall. This type is found most commonly in the gastric body and in younger patients. Although this type is also associated with H. pylori infection, the carcinogenetic sequence of the diffuse type of gastric cancer is not well characterized.^94,95

Pure signet ring cell carcinomas are included in the poorly cohesive type (Fig. 25.11). They are characterized by the presence of infiltrating single cells that contain distended cytoplasm and compressed, eccentrically displaced nuclei that form a crescent shape. Gland formation is not a normal component of this tumor; it grows in cords, tight clusters, and solid sheets.^1,86 By consensus, more than 50% of the tumor should be composed of signet ring cells to warrant this designation. Other variants have also been observed, such as tumors that contain cells resembling histiocytes, deeply eosinophilic cells with neutral mucin, and anaplastic cells with little or no intracellular mucin¹ (Fig. 25.12). Mitoses are typically less numerous than in the glandular type of diffuse gastric carcinoma.

Mucinous adenocarcinoma is a subtype in which pools of extracellular mucin comprise at least 50% of the tumor volume; these represent 10% of all gastric carcinomas.⁸⁶ The cellular component may be formed of glands or of irregular clusters of cells that float freely in the extracellular mucin.¹

Undifferentiated carcinomas lack cytologic and architectural differentiation and may resemble lymphomas, squamous cell carcinomas, or sarcomas.⁹⁶ They fall into the indeterminate category of the Laurén classification. Immunohistochemical analysis (positive cytokeratin immunolabeling) is often necessary to confirm their epithelial phenotype.

From a practical standpoint, some authors recommend another three-tiered classification system based on the resemblance of the tumor to either normal gastric or metaplastic intestinal epithelium.¹ In this grading system, well-differentiated adenocarcinomas are composed of well-formed glands or papillae, usually lined by mature absorptive or goblet cells. Moderately differentiated adenocarcinomas are characterized by the presence of irregularly branching glands or complex incomplete papillae. Poorly differentiated adenocarcinomas have poorly formed glands or single cells.

Other classification systems have been proposed, some of which have attempted to correlate certain pathologic features of the tumor with its prognosis. For example, Ming proposed a two-tiered classification based on the pattern of growth and degree of invasiveness of the carcinoma.⁹⁷ In this system, the expanding type represents 67% of gastric cancers and reveals tumor growth by expansion of cohesive tumor masses with a well-defined tumor–stroma interface (Fig. 25.13, A). The infiltrative type of gastric carcinoma is characterized by infiltrative single cells that grow independently or are aggregated in small nests (see Fig. 25.13, B). Expanding adenocarcinomas are characteristically well-differentiated “intestinal” tumors. These correspond to the intestinal type of tumors in the Laurén classification and have a better prognosis than infiltrative carcinomas, which correspond to Laurén diffuse-type adenocarcinomas.⁵

Finally, Goseki and colleagues proposed a four-tiered classification based on the degree of tubular differentiation and the amount of mucin production.⁹⁸ Several retrospective studies report that this system provides more accurate prognoses for advanced gastric adenocarcinomas when used with the tumor-node-metastasis (TNM) system.^98,99

Morphologic Subtypes of Gastric Adenocarcinoma

Uncommon histologic variants represent approximately 5% of all gastric cancers.

Gastric Carcinoma with Lymphoid Stroma

The morphologic subtype defined as gastric carcinoma with lymphoid stroma (GCLS), also known as medullary carcinoma or lymphoepithelioma-like carcinoma, is characterized by the presence of prominent lymphoid infiltration of the stroma. More than 80% of GCLS tumors are associated with Epstein-Barr virus (EBV) infection.¹⁰⁰ When EBV-infected gastric cancers of usual histology are excluded, GCLS represents approximately 8% of all gastric carcinomas.^101,102 GCLS affects men more frequently than women, particularly in the United States; Hispanics are also preferentially affected.^103,104 These tumors are more common in the proximal stomach and in the remnant stomach in patients who have had a subtotal gastrectomy.^105,106

GCLS usually shows a pushing tumor border and is typically composed of irregular sheets, or syncytia, of small, polygon-shaped cells embedded within a prominent lymphocytic infiltrate, with occasional lymphoid follicles¹⁰⁷ (Fig. 25.14). Rarely, giant cells may be observed.¹⁰¹ CD8+ T lymphocytes are the predominant type of inflammatory cell, although B lymphocytes and plasma cells are usually present as well. Intranuclear expression of EBV-encoded nonpolyadenylated RNA-1 can be demonstrated by in situ hybridization.

Whether EBV plays a direct role in carcinogenesis or is simply a secondary infection is a subject of debate.¹⁰⁷ However, infection occurs early in the carcinogenetic sequence, because EBV can also be found in surrounding noninvasive (dysplastic) epithelium.¹⁰⁸ The frequent loss of chromosomes 4p, 11p, and 18q seems to indicate a pathogenetic pathway different from that of most other usual types of gastric carcinoma.¹⁰² EBV-positive GCLS tumors have been shown to posses a CpG island methylator phenotype, with frequent aberrant methylation of multiple genes.¹⁰⁹ The prognosis of GCLS is considered better than that of ordinary adenocarcinomas, with survival rates of approximately 77% after 5 years, although this figure is somewhat controversial.^5,105,110

AFP Producing Carcinomas

The reported incidence of hepatoid and α-fetoprotein (AFP)-producing carcinomas ranges from 1.3% to 15% of all gastric cancers.¹¹¹ The recognition of two histologic types of AFP-producing tumors helps explain the wide variation in incidence previously reported. Hepatoid adenocarcinomas are composed of large, polygonal-shaped cells with prominent eosinophilic cytoplasm—features that resemble hepatocellular carcinoma.^112,113 Hepatoid areas are frequently interspersed with areas of more typical adenocarcinoma. Bile and periodic acid–Schiff (PAS)-positive, diastase-resistant intracytoplasmic eosinophilic globules can be observed. The diagnosis is usually straightforward in terms of the primary tumor, but it can be more challenging when one is evaluating liver metastases. In such cases, negativity for Hep-Par 1 and positivity for cytokeratin 19 (CK19) and CK20 are considered helpful in excluding a primary hepatocellular carcinoma.¹¹⁴

The second type of AFP-producing gastric cancer consists of well-differentiated papillary or tubular adenocarcinomas with clear cytoplasm¹¹⁵ (Fig. 25.15). A combination of these two types may be seen in some cases. Immunohistochemical and in situ hybridization studies have documented albumin, AFP, α₁-antichymotrypsin, and bile production within tumor cells.⁸⁶

A high level of AFP can also be detected in the serum of affected patients. This subtype of gastric carcinoma is particularly aggressive, showing a 5-year survival rate of only 12%.⁸⁶ Whether these tumors are CDX2 positive is currently unknown.