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• Gastric cancer is the second most common type of cancer worldwide • The highest incidence of gastric cancer is in Asia, central Europe, and South America • In the United States, gastric cancer is the seventh most frequent cause of cancer-related death • Carcinomas of the gastric cardia now represent close to 30% of all gastric cancers • Early gastric cancer now represents close to 20% of all newly diagnosed cancers in the United States, and up to 50% in Japan. PATHOGENESIS • The carcinogenic process involves a progression from • chronic gastritis to atrophy with hypochlorhydria or achlorhydria, intestinal meta-plasia, dysplasia, and, ultimately, adenocarcinoma. [10], [11] • Intestinal metaplasia, and subsequently dysplasia and early adenocarcinoma, develops initially in the neck region of the antral or fundic glands of the stomach, which supports the hypothesis that precursor cells are located in this region. [ • Long-standing H. pylori infection induces chronic gastritis that gradually results in atrophy and intestinal metaplasia. [16], [17] • There is a four- to ninefold increased risk of gastric lesions in patients with H. pylori infection, particularly if infection begins in early childhood. [18– 20] • Chronic acid suppression also increases the risk for development of atrophy in patients with H. pylori gastritis.[21] • For instance, cytotoxin-associated gene A (CagA)– positive strains of H. pylori, which produce higher levels of interleukin-8, elicit more intense inflammation and are associated with an increased risk of gastric carcinoma. [22] • However, the majority of H. pylori–infected individuals do not develop gastric cancer, and, conversely, • up to 20% of patients in whom gastric cancer develops are H. pylori seronegative • Diets rich in salt (dried and salted fish and meats, soy sauce, smoked fish, pickled foods) and containing low levels of micronutrients, vitamins, and antioxidants[14] favor intraluminal formation of genotoxic agents, such as specific N-nitroso compounds (formed by nitrosation of ingested nitrates), and have been found to be associated with the development 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 intestinal-type gastric cancer 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] • The vast majority of gastric epithelial dysplasias (or adenomas) have an “intestinal” phenotype, 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] EARLY GASTRIC CANCER • Invasive adenocarcinomas confined to the mucosa or submucosa, regardless of whether lymph node metastasis is present, are defined as early gastric cancer • EGC represents between 15% and 21% of all newly diagnosed gastric cancers, whereas in Japan it accounts for over 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. • Most EGCs are small, measuring between 2 and 5 cm, and are typically localized on the lesser curvature around the angularis region.[ • In 3% to 13% of patients, multiple primary sites are present and this has been shown to be associated with a worse prognosis • vided into three types based on their endoscopic appearance (Fig. 21-2): protruding (type I), superficial (type II), and excavating (type III).[ • Signet ring cell carcinoma (Fig. 21-4) 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 ADVANCED GASTRIC CARCINOMA • Advanced adenocarcinoma is defined as a tumor that invades the gastric wall beyond the submucosa • Approximately half of all gastric adenocarcinomas measure between 2 and 6 cm in size, 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] • exophytic, ulcerated, infiltrative, or combined. • Cytologically, a combination of gastric foveolar, intestinal, and endocrine cell types usually constitutes at least a portion of all tumors. • G type (gastric phenotype; MUC5AC+ and/or MUC6+; MUC2− and CD10−), type I (intestinal phenotype; MUC2+ and/or CD10+; MUC5AC− and MUC6−), GI type (gastric and intestinal), and N type (null phenotype). LAURÉN CLASSIFICATION • intestinal, • diffuse, and • indeterminate/unclassified types. • The relative frequencies are 50% to 67% for the intestinal type, 29% to 35% for the diffuse type, and 3% to 21% for the indeterminate/unclassified type. [90] • WHO INTESTINAL TYPE • Papillary adenocarcinoma • Tubular adenocarcinoma • A higher rate of lymph node metastases has been reported for papillary adenocarcinoma • Diffuse type • Signet ring cell carcinoma • Mucinous adenocarcinoma • Diffuse-type adenocarcinomas 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 also associated with H. pylori infection, the carcinogenetic sequence of the diffuse type of gastric cancer is not well characterized • Pure signet ring cell carcinomas are included in the diffuse type (Fig. 21-11). They are characterized by the presence of infiltrating single cells containing 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 • By consensus, over 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 mucin[1] (Fig. 21-12). Mitoses are typically less numerous than in the glandular type of diffuse gastric carcinoma. • Also included in the diffuse type are mucinous adenocarcinomas, 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 • Undifferentiated carcinomas • Adenosquamous carcinoma • Squamous carcinoma • Small cell carcinoma • Others[*] SUBTYPES OF GASTRIC ADENOCARCINOMA • This subtype, 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 gastric carcinomas with lymphoid stroma (GCLS) are associated with Epstein-Barr virus (EBV) infection.[100] • The prognosis of GCLS is considered better than that of ordinary adenocarcinomas, with survival rates close to 77% after 5 years, although this is somewhat controversial. [5], [105], [110] HEPATOID AND Α-FETOPROTEIN–PRODUCING CARCINOMAS • This subtype of gastric carcinoma is particularly aggressive, showing a 5-year survival rate of only 12 ADENOSQUAMOUS AND SQUAMOUS CELL CARCINOMA • Adenosquamous carcinoma, which accounts for 0.5% of all gastric cancers, is defined as a tumor in which the neoplastic squamous component comprises at least 25% of the tumor volume.[8], [116] • These tumors are usually deeply penetrating and associated with lymphovascular invasion, and carry a relatively poor prognosis • For tumors of the cardia region, caudal extension of a primary esophageal squamous cell carcinoma should be excluded. • Gastric squamous cell carcinomas are often diagnosed at a late stage, and their prognosis is generally poor, despite response to chemotherapy CARCINOSARCOMA • Gastric carcinosarcomas are rare tumors composed of varying amounts of adenocarcinomatous and sarcomatous elements. • Sarcomatous elements may consist of uncommitted cells or demonstrate light microscopic or immunohistochemical features of chondrosarcoma, osteosarcoma, rhabdomyosarcoma, or leiomyosarcoma differentiation.[60,130–132] • Tumors with adenosquamous and neuroendocrine components have also been reported. [133–135] • Most gastric carcinosarcomas are large polypoid tumors and are associated with a poor outcome.[136] • A single case of gastric adenosarcoma composed of benign tubular and cystic glands embedded in an otherwise typical leiomyosarcoma stroma has been reported.[137] SMALL CELL CARCINOMA • About 100 cases of small cell carcinoma (oat cell carcinoma or neuroendocrine carcinoma) have been reported in the stomach. [138] Because these tumors are frequently diagnosed at an advanced stage, the prognosis is generally quite poor, with most patients dying within 1 year of diagnosis. [139], [140] However, long-term survival can be observed with aggressive adjuvant therapy.[141] • Immunohistochemically, carcinoembryonic antigen (CEA) is usually negative,[142] whereas neuron-specific enolase (NSE) and chromogranin A are often positive; electron microscopy can help demonstrate the characteristic neurosecretory granules in these tumors PARIETAL CELL CARCINOMA AND ONCOCYTIC CARCINOMA • Rare examples of parietal cell carcinoma have been reported. These tumors are composed of solid sheets of polygonal cells with abundant, finely granular, eosinophilic cytoplasm that stains with phosphotungstic acid–hematoxylin. GASTRIC MUCOEPIDERMOID AND PANETH CELL CARCINOMAS • Very few of these tumors have been reported. Mucoepidermoid carcinomas show a mixture of mucusproducing and squamous epithelium. [150], [151] One case has been shown to arise from submucosal ectopic glands.[151] The prognosis is reportedly poor. A few Paneth cell carcinomas have been reported as well. These are characterized by tumors with a predominance of cells with Paneth cell differentiation, characteristically showing eosinophilic cytoplasmic granules that are positive for lysozyme by immunohistochemistry.[146], [147] METASTATIC CARCINOMAS • Metastases to the stomach are uncommon. They are reported in less than 5.4% of individuals in autopsy series of patients with cancer. [155], [156] • They can be completely asymptomatic, [157] or present clinically as a large bleeding ulcer mimicking a primary carcinoma (39% of cases), or as submucosal tumor (51% of cases).[156] • When diagnosed endoscopically, 65% to 80% of gastric metastases are solitary lesions. • In some studies, there is a predilection for involvement of the middle and proximal stomach • Malignant melanoma and lung and breast carcinomas are the most commonly reported primaries.[156], [158], [159] • However, primary tumors originating from the kidney, pancreas, esophagus, skin, testis, cervix, and colon have been reported as well.[155], [156] • In 50% of cases, concomitant metastases are noted in other organs.[160] • In patients with metastasis, infiltration of the deep layers of the gastric wall, combined with a reactive hyperplastic appearance of the overlying mucosa, may mimic benign hypertrophic gastritis. • Metastatic lobular breast carcinoma deserves special attention because its typical single-file growth pattern can resemble diffuse-type carcinoma, signet ring cell carcinoma, or linitis plastica. • an immunohistochemical profile consisting of gross cystic disease fluid protein-15 (GCDFP-15), estrogen and progesterone receptors, and CK-7 (all positive in breast carcinoma) and CK-20 (negative in breast carcinoma) has been noted to be useful in establishing a correct diagnosis. [161–163] • More recently, negativity for CDX2, MUC2, MUC5AC, MUC6, and DAS-1 (negative in breast and variably positive in gastric cancer) has been shown to be useful in diagnosing metastatic breast carcinoma.[161], [164], [165]