E. Strong (ed.). Gastric cancer. Principles and practice. Springer (2015)
The location of gastric adenocarcinoma may, to some extent, reflect the pathogenesis of the disease. For example, intestinal type adenocarcinoma in the proximal stomach may be associated with a reflux etiology (Fig. 4.5a), while intestinal type adenocarcinoma in the distal stomach is more likely related with H. Pylori infection associated pathogenesis (Fig. 4.5b). Diffuse type gastric cancer is more commonly located in the middle third and body of the stomach (Fig. 4.5c), while remnant cancer is invariably located in the gastric mucosa at duodenogastric anastomosis (Fig. 4.5d). Determination of a precise tumor location can be challenging and even subjective, especially when the lesion is large and straddles multiple anatomical sites within the stomach. Nevertheless, documentation of the relative location of the tumor is important for the elucidation of potential pathogenesis and classification of the disease, as well as for the evaluation of the extent of the disease and the resection margin status.
The gross configuration of advanced gastric cancer can be classified using Borrmann classification, which designates gastric carcinomas into four distinct types: polypoid (type I), fungating (type II), ulcerating (type III), and diffusely infiltrating (type IV). Diffusely infiltrating is also referred to as linitis plastica when it involves nearly the entire stomach and it is consistently associated with the diffuse histologic subtype. In contrast, types I, II, and III are associated with other histologic subtypes. Type II, the most common subtype, represents 36% of all gastric carcinomas and is frequently detected on the lesser curvature of the antrum. 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.
Gastric cancer represents a heterogeneous group of tumors with diverse pathogenesis, morphologic features, and molecular backgrounds. While recent genomic analysis has identified several subtypes of gastric adenocarcinoma by their generic signatures , histopathologic classification remains critical for a number of clinical assessments of the disease and serves as the basis for the molecular classification of the disease [72, 73]. Several systems have been proposed to aid in the classification of gastric adenocarcinoma based on the microscopic futures of the tumor [74–76]. The two most commonly used histologic classifications are the Laurén classification and the World Health Organization (WHO) systems [77, 78]; significant correlation is seen between these two schemes .
Fig. 4.5. Gross pathology of gastric adenocarcinoma. a) A proximally located gastric adenocarcinoma with minimal extension into the squamous mucosa (arrows) of the esophagus. b) An ulcerated intestinal carcinoma is located in the distal stomach. c) A diffuse type adenocarcinoma is located in the body of the stomach with intact mucosa but rigid mucosal fold. A cross section of the mucosa reveals thickened gastric wall secondary to diffuse infiltration by tumor cells. d) A remnant gastric cacumina is located in the gastric mucosa near the anastomotic line (arrows)
The Laurén classification separates gastric adenocarcinomas into two primary subtypes: intestinal and diffuse, and tumors exhibiting features of both the intestinal and diffuse types are designated as mixed-type adenocarcinoma (Fig. 4.6a, b, c, d). The intestinal type is characterized by the formation of glands exhibiting various degrees of differentiation either with or without extracellular mucin production (Fig. 4.6a). The diffuse type of gastric adenocarcinoma is composed of poorly cohesive cells without gland formation (Fig. 4.6b, c). This type of tumor often contains cells with intracytoplasmic mucin, known as “signet ring cells” (Fig. 4.6c), although this term has been synonymously used for diffuse cancer even in the absence of intracytoplasmic mucin (Fig. 4.6c). In addition to their distinct morphologic characteristic, the intestinal and the diffuse subtypes of gastric adenocarcinoma also have different clinicopathologic features (Table 4.1).
Fig. 4.6. Lauren’s histopathology classification of Gastric Carcinoma. a) Intestinal type adenocarcinoma with wellformed glandular and tubular architecture. b) Poorly differentiated diffuse type adenocarcinoma. c) Diffuse type adenocarcinoma with intracellular mucin and signet ring cell features. d) Lauren’s mixed type adenocarcinoma with a small component of poorly differentiated intestinal phenotype (upper right) and a poorly differentiated diffuse/ poorly cohesive carcinoma with focal signet ring cell features (left)
While the basis for the initial Laurén classification was exclusively morphologic characteristics, accumulative knowledge in the epidemiology and pathogenesis of gastric carcinoma has indicated that this classification system is also valuable in defining molecular subtypes of gastric cancer [72, 73]. In the absence of significant chronic gastritis, intestinal metaplasia, or dysplasia, pure diffuse type of gastric cancer probably represents either a hereditary or sporadic ideology. However, significant components of diffuse or poorly cohesive carcinoma can be seen in mixed adenocarcinoma with inflammation-metaplasiadysplasia-carcinoma precursors, often complicating molecular analysis of the tumor.
In 2010 the WHO revised its morphologic classification to reflect the patterns exhibited throughout the gastrointestinal (GI) tract . This classification recognizes five major types of gastric adenocarcinoma based on the predominant histologic growth pattern: (1) papillary, (2) tubular, (3) mucinous (tumors with mucinous pools exceeding 50% of the tumor), (4) poorly cohesive (including signet ring cell carcinoma and other variants), and (5) mixed adenocarcinomas (Table 4.2). Uncommon variants of gastric carcinomas include the squamous cell, adenosquamous, hepatoid (Fig. 4.7a), micropapillary, carcinoma with lymphoid stroma (medullary carcinoma) (Fig. 4.7b), carcinoma with pancreatic acinar differentiation (Fig. 4.7c), choriocarcinoma [80, 81], undifferentiated subtypes (Fig. 4.7d), carcinoma with sarcomatous differentiation (Fig. 4.7e), high grade neuroendocrine carcinoma of small cell or large cell subtype (Fig. 4.7f), and carcinoma arising in gastric heterotopia in the esophagus (gastric inlet) or pancreatic heterotopia. The so called medullary carcinoma usually has an expansile growth pattern with intratumoral and peritumoral lymphocytic infiltration; this tumor phenotype is commonly associated with either EBV or microsatellite instability associated gastric carcinoma. The relevant clinical implication when encountering these rare subtypes of gastric carcinoma is that a metastasis should be excluded before entertaining a diagnosis of primary gastric carcinoma. In addition, any histologic subtype of gastric carcinoma, when poorly differentiated, can present with either partial or entirely sarcomatous features (sarcomatoid carcinoma) (Fig. 4.7e), which is not uncommon in the upper gastrointestinal tract or the pancreaticobiliary carcinoma.
Table 4.1. Clinical and pathologic features of Laurén subtype gastric adenocarcinoma
|Intestinal type||Diffuse type|
|Onset age||Older than 50 year||Younger than 50 years|
|Gender||Male > Female||Male = Female|
|Geographic distribution||Asia (China Japan, Korea)||Anywhere|
|Precursor lesion||Intestinal metaplasia/dysplasia||Signet ring cell carcinoma in situ|
|Common location||Antrum or cardia||Body|
|Borrmann classification||Type I, II, III||Type IV|
|Genetic association||HNPCC, AFP||Hereditary diffuse gastric cancer, hyperplastic polyposis|
Table 4.2. WHO classification of carcinoma of the stomach 
|Tumor type||Histologic features|
|Papillary adenocarcinoma||Exophytic with elongated frond-like tumor extensions with fibrovascular cores; usually better differentiated and low grade|
|Tubular adenocarcinoma||Dilated or slit-like branching tubules; usually low, although poorly differentiated variants are not uncommon|
|Mucinous adenocarcinoma||Contains more than 50% extracellular mucin pools. May contain scattered signet-ring cells more commonly seen in proximal/cardia location|
|Poorly cohesive carcinomas, including diffuse and signet-ring cell carcinoma and other variants||Tumor cells infiltrate as isolated single cells or small aggregates. The carcinoma is predominantly composed of signet-ring cells containing a clear droplet of cytoplasmic mucin displacing the nucleus. Other variants of poorly cohesive carcinoma may resemble mononuclear inflammatory cells|
|Mixed carcinoma||Mixture of morphologically identifiable components such as tubular, papillary, and poorly cohesive patterns|
|Adenosquamous carcinoma||Mixture of glandular and squamous neoplastic components; the squamous component should comprise at least 25% of the tumor volume|
|Carcinoma with lymphoid stroma (medullary carcinoma)||Poorly developed glandular structures associated with a prominent lymphoid infiltrate in the stroma. Associated with EBV infection or HNPCC-associated carcinoma and may have a favorable prognosis|
|Hepatoid adenocarcinoma||Large polygonal eosinophilic tumor cells resembling hepatocytes; may express α-fetoprotein|
|Squamous cell carcinoma||Both Keratinizing and nonkeratinizing forms are encountered|
|Undifferentiated carcinoma||High-grade carcinoma that cannot be further classified as adenocarcinoma, squamous cell carcinoma, or other recognized variants|
|Neuroendocrine carcinoma||Poorly differentiated high-grade carcinoma with diffuse or focal synaptophysin chromogranin-A expression. These tumors exhibit a high mitotic rate (> 20 per 10 high power field, and Ki67 is usually > 50%) marked nuclear atypia, and may have focal necrosis|
|Large cell neuroendocrine carcinoma||Tumor cells are large, with moderate amount of cytoplasm, and may contain prominent nucleoli|
|Small cell neuroendocrine carcinoma||Tumor cells are small, with finely granular chromatin and indistinct nucleoli|
|Mixed adenoneuroendocrine carcinoma||Composed of both gland-forming and neuroendocrine malignant elements, with at least 30% of each component. Identification of scattered neuroendocrine cells in adenocarcinomas by immunohistochemistry does not qualify as mixed carcinoma|
Fig. 4.7. Uncommon histopathologic variants of gastric adenocarcinoma. a) Adenocarcinoma with hepatoid features. b) Medullary adenocarcinoma with markedly increased intraepithelial and stroma lymphocytes (small blue cells). c) Adenocarcinoma with prominent pancreatic acinar differentiation. d) Undifferentiated carcinoma. e Undifferentiated carcinoma (upper right) with sarcomatous differentiated (low left). f) High grade neuroendocrine carcinoma, small cell type
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