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[71]: 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 [29], 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 [79].

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) .

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-metaplasia-dysplasia-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 [78]. 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.

The pathologic diagnosis of gastric adenocarcinoma, particularly a poorly differentiated and nonintestinal subtype, can be challenging with a biopsy specimen. While stomach is not a common site for metastasis, a number of epithelioid neoplasms can metastasize to the gastric mucosa and the differential diagnosis between a primary gastric carcinoma and a metastasis may be difficult in small biopsies [82, 83]. Patients may be asymptomatic, present with a bleeding ulcer mimicking a primary gastric carcinoma (39 % of the cases), or with a submucosal tumor (51 % of the cases).

The most commonly observed error in the diagnosis of diffuse signet ring cell carcinoma occurs with metastatic lobular breast carcinoma, which has a propensity to metastasize and colonize the gastrointestinal tract as well as other hollow organs such as the uterus and the urinary bladder. Primary gastric diffuse signet ring cell carcinoma and lobular breast carcinoma share similar morphologic features and sometimes, the two neoplasms can be indistinguishable on the morphologic basis alone (Fig. 4.8a, b). Immunohistochemical studies can be helpful, since classic lobular breast carcinoma is usually immunoreactive to estrogen receptor (ER) (Fig. 4.8c), cytokeratin-7 (CK7), and mammaglobin; and a gastric primary carcinoma is immunoreactive for both CK7 and CK20, and should be negative for ER and mammaglobin .

Most importantly, a clinical history, even in the remote past, of breast carcinoma should prompt the appropriate work up to exclude a metastasis before the diagnosis of primary gastric diffuse signet ring cell carcinoma. Female patients with hereditary CDH1 mutation are at risk of developing both diffuse type gastric adenocarcinoma and lobular breast carcinoma, although the reported incidence of the latter is lower [45].

Gastrointestinal stromal tumor (GIST) can occur at any site of the GI tract; the stomach is one of the most common locations. When a GIST has epithelioid morphology, it can be difficult to distinguish from a poorly differentiated primary gastric carcinoma. Although subtle morphologic details may suggest the diagnosis of a GIST, such as intercellular myxoid stroma (Fig. 4.9a), a lack of cytokeratins immunoreactivity and positive reactivity to c-kit (CD117) confirms a diagnosis of GIST (Fig. 4.9b).

Other poorly differentiated malignant epithelial or epithelioid tumors, including seminoma (Fig. 4.9c), melanoma (Fig. 4.9d), and renal cell carcinoma, can metastasize to the stomach. Therefore, a poorly differentiated neoplasm in a gastric biopsy requires a thorough clinical and pathologic evacuation to exclude the possibility of a metastasis before the establishment of a primary gastric cancer. Among metastatic glandular/tubular carcinomas, pulmonary and pancreatic origins are more common than other primaries .

Adenocarcinoma confined to the gastric mucosa (pathologic stage pT1a) or submucosa (pT1b) is defined as early gastric cancer (EGC) [7], and represents an early stage in tumor development. In Western series, EGC represents 15–20 % of the newly diagnosed gastric cancers, whereas in Japan it accounts for more than 50 % of the cases [2–5]. A higher prevalence of gastric cancer, more liberal use of upper endoscopy and chromoendoscopy, and differences in diagnostic criteria may explain the differences between Western and Japanese studies.

Most EGCs are typically located on the lesser curvature, around the angularis, and majority of them are well differentiated tubular or papillary variants [7]. These features create a challenging differential diagnosis between high-grade glandular dysplasia/carcinoma in situ (pTis) (Fig. 4.10a), and minimally invasive carcinoma (pT1a). The latter may present as either (1) individual cribriform glands with an associated expansile growth pattern (Fig. 4.10b) or (2) with nominal tumor invasion in the lamina propria (Fig. 4.10c); in both histologic prototypes, the tumor has progressed beyond the level of glandular dysplasia and met the diagnostic criteria of superficial gastric adenocarcinoma. When carcinoma invades through the muscularis mucosa, the tumor is staged as pT1b (Fig. 4.10d). Diffuse-type EGCs tend to exhibit greater width and depths of invasion and thus are less challenging to diagnose.