Gastric cancers are a histologically heterogenous group of neoplasms arising from unique epidemiologic and molecular backgrounds. There is accumulating evidence that the intestinal type of gastric adenocarcinoma develops through a multistep process beginning with chronic gastritis triggered primarily by Helicobacter pylori and progressing through atrophy, intestinal metaplasia, and dysplasia (intraepithelial neoplasia) to carcinoma. Loss of E-cadherin expression resulting from CDH1 gene alterations is the primary carcinogenetic event in hereditary diffuse gastric cancer. Proximal gastric adenocarcinomas likely result from either gastroesophageal reflux or H pylori gastritis. This article provides an update of the histologic, immunohistochemical, and molecular pathways of gastric cancer and its precursors.
Key points
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The intestinal and diffuse types of gastric adenocarcinoma have unique and overlapping epidemiologic, pathogenetic, molecular, and histologic features.
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The development of the intestinal type of gastric adenocarcinoma is a multistep process starting with chronic gastritis triggered by Helicobacter pylori and progressing through atrophy, intestinal metaplasia, and dysplasia to carcinoma (Correa model).
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In addition to intestinal metaplasia a distinct type of metaplasia, spasmolytic polypeptide–expressing metaplasia, has been recognized and has a strong association with the intestinal type of gastric adenocarcinoma.
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Loss of E-cadherin expression caused by CDH1 gene alteration is the primary carcinogenic event in the Carneiro model of the hereditary diffuse gastric cancer.
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Proximal gastric adenocarcinoma results from either gastroesophageal reflux or Helicobacter pylori gastritis, each with distinct morphologic, immunohistochemical, and molecular features.
Introduction
Gastric cancer is the fourth most common malignancy and the second leading cause of cancer-related death worldwide. Although the incidence of gastric cancer in North America is lower than other parts of the world, survival remains poor. It has been recognized that gastric carcinogenesis is a multistep process. Precancerous conditions, including chronic Helicobacter pylori –associated gastritis, epithelial atrophy, intestinal and spasmolytic polypeptide–expressing metaplasia (SPEM), and precancerous lesions (dysplasia or intraepithelial neoplasia) precede the development of the intestinal type of gastric adenocarcinoma. Recent genetic advances have shed light on the molecular pathogenesis of hereditary diffuse gastric cancer (HDGC). A better understanding and definition of gastric cancer and the molecular events preceding its development is critical in the prevention, diagnosis, and targeted therapy for this malignancy.
Introduction
Gastric cancer is the fourth most common malignancy and the second leading cause of cancer-related death worldwide. Although the incidence of gastric cancer in North America is lower than other parts of the world, survival remains poor. It has been recognized that gastric carcinogenesis is a multistep process. Precancerous conditions, including chronic Helicobacter pylori –associated gastritis, epithelial atrophy, intestinal and spasmolytic polypeptide–expressing metaplasia (SPEM), and precancerous lesions (dysplasia or intraepithelial neoplasia) precede the development of the intestinal type of gastric adenocarcinoma. Recent genetic advances have shed light on the molecular pathogenesis of hereditary diffuse gastric cancer (HDGC). A better understanding and definition of gastric cancer and the molecular events preceding its development is critical in the prevention, diagnosis, and targeted therapy for this malignancy.
Classification of gastric cancer
Gastric cancer is not a single disease, but a heterogeneous group of tumors with different morphologies, molecular backgrounds, and histogenesis. Most (95%) gastric malignancies originate from glandular epithelium and are designated as adenocarcinoma. Several systems have been proposed to aid in the classification of gastric adenocarcinoma based on macroscopic features (Borrmann) or exclusively on the histologic tumor growth pattern (Ming, Carniero, Goseki). The two most commonly used histologic classifications are the Lauren and World Health Organization (WHO) systems ( Table 1 ). More recently, molecular classifications based on gene expression profiles and proteomics have been proposed; however, these have not been routinely used.
| Lauren | World Health Organization 2010 |
|---|---|
| Intestinal type | Papillary adenocarcinoma Tubular adenocarcinoma Mucinous adenocarcinoma |
| Diffuse type | Poorly cohesive carcinoma (including signet ring cell carcinoma and other variants) |
| Mixed type (equal intestinal and diffuse) | Mixed type, mixture of glandular (tubular/papillary) and poorly cohesive/signet ring |
| Indeterminate | Undifferentiated carcinoma |
| Adenosquamous carcinoma Carcinoma with lymphoid stroma (medullary carcinoma) Hepatoid adenocarcinoma Squamous cell carcinoma |
Lauren Classification: Intestinal and Diffuse Types of Gastric Cancer
A seminal classification system of gastric adenocarcinomas was introduced by Lauren in the mid-1960s. The Lauren scheme separates gastric adenocarcinomas into two primary types: intestinal and diffuse. Tumors exhibiting features of both the intestinal and diffuse types are designated as mixed-type adenocarcinoma. Table 2 summarizes the clinicopathologic features of the intestinal and diffuse types of gastric adenocarcinoma. In the past, intestinal-type tumors were considered more common, accounting for more than 50% of gastric adenocarcinomas; however, more recently the incidences of intestinal and diffuse cancers have been shown to be equal in the Western world. The intestinal type is characterized by the formation of glands exhibiting various degrees of differentiation and extracellular mucin production ( Fig. 1 A). In contrast, the diffuse type of gastric adenocarcinoma is composed of poorly cohesive cells with no gland formation (see Fig. 1 B). This type of tumor often contains cells with abundant intracytoplasmic mucin, known as “signet ring cells.”
| Intestinal Type | Diffuse Type | |
|---|---|---|
| Gender | Males > females (2:1) | Males = females |
| Age | Older age (>50 y) | Younger age (<50 y) |
| Areas | High-risk (Japan, China, Korea) | Uniform across the world |
| Incidence | Decreasing | Increasing |
| Inheritance | Hereditary nonpolyposis colorectal cancer, adenomatous polyposis coli | Hereditary diffuse gastric cancer |
| Location | Antrum (distal) | Corpus/body, but may arise anywhere in the stomach |
| Growth pattern | Usually exophytic | Flat, ulcerated, linitis plastica |
| Histology | Gland formation, extracellular mucin | Loss of cohesion, signet ring cells, no glands |
| Precursors | Correa pathway: chronic Helicobacter pylori gastritis, atrophy, metaplasia, dysplasia | Carneiro pathway: signet ring carcinoma in situ in hereditary diffuse gastric cancer |
The Lauren classification is used by pathologists in routine practice, and by epidemiologists and clinicians for evaluating the natural history of gastric adenocarcinoma, especially with regard to incidence trends, and etiologic precursors, although all existing classifications of gastric adenocarcinoma, including that of Lauren, are of limited significance in terms of therapeutic decisions.
WHO Classification of Gastric Cancer
In 2010 the WHO revised the classification of gastric adenocarcinoma according to the morphologic patterns commonly exhibited by tumors in other gastrointestinal sites, such as the small bowel, ampulla of Vater, and colon, resulting in a more uniform classification of gastrointestinal tumors as a whole. The 2010 WHO 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. Uncommon variants of gastric carcinomas include the squamous cell, adenosquamous, hepatoid, parietal cell, Paneth cell, micropapillary, and undifferentiated subtypes, and carcinoma with lymphoid stroma (medullary carcinoma).
Intestinal type of gastric adenocarcinoma and its precursors
The intestinal and diffuse subtypes of gastric adenocarcinoma are believed to result from two distinct pathogenetic pathways: the Correa pathway for the intestinal type and the Carneiro model for the hereditary diffuse type of adenocarcinoma, discussed later. Correa postulated that the intestinal type of gastric adenocarcinoma is the consequence of progressive changes in the gastric mucosa with metamorphosis of normal gastric mucosa into carcinoma through the subsequent development of inflammation, atrophy, metaplasia, and dysplasia ( Fig. 2 ). This multistep process of carcinogenesis involves several genetic alterations, which may take years or even decades to develop.
Chronic Gastritis
Chronic gastritis is the most important and well-studied risk factor for the intestinal type of gastric cancer. Helicobacter pylori –associated and autoimmune gastritis are by far the two most common inflammatory conditions leading to the development of chronic gastritis and cancer. Although the etiologic agents are different, the end result of chronic inflammation in these two entities is atrophic gastritis. For routine histopathologic evaluation, the Sydney Classification System (later updated in Houston) was developed to provide information on the grade, topography (antrum, corpus, incisura), and origin of chronic gastritis.
The morphologic attributes of chronic gastritis include inflammatory infiltrates containing mononuclear cells, predominantly lymphocytes, and plasma cells. Activity is determined by the presence of acute inflammatory cells (neutrophils) with a spectrum of grades from mild (neutrophils infiltrating the epithelium), to moderate (pit abscesses), to severe (erosions and ulcerations). To characterize the degree of chronicity, an international group of gastroenterologists and pathologists (Operative Link on Gastritis Assessment [OLGA]) developed a system for reporting the stage of gastritis, termed the OLGA Staging System. The stage of gastritis is obtained by combining the extent of atrophy as scored histologically with the sites of atrophy identified by multiple biopsies from the antrum, incisura angularis (junctional area between the anatomic antrum and body along the lesser curvature), and corpus according to the Sydney System protocol.
Chronic Helicobacter pylori –associated gastritis
Helicobacter pylori is the most common chronic bacterial infectious agent in humans (>50% of the world population is infected) and is the only bacteria classified as a class I carcinogen by the WHO. Numerous epidemiologic studies have confirmed the association of H pylori infection and gastric cancer, although only 1% to 3% of people infected with H pylori actually develop gastric cancer, suggesting that other factors, including those related to the host, may also play a role in carcinoma development. In a combined analysis of 12 studies 81% of gastric cancers were associated with H pylori infection. Although H pylori is strongly associated with the intestinal type and diffuse type of gastric cancer, the underlying carcinogenic mechanisms may be different. Specifically, in intestinal-type cancers H pylori has been implicated in the multistep process from atrophic gastritis to intestinal metaplasia (IM) and dysplasia. In contrast, diffuse-type cancers have no recognizable precursor lesions besides chronic gastritis.
Helicobacter pylori infection results in a characteristic superficial chronic active gastritis with a dense lymphoplasmacytic lamina propria infiltrate often containing germinal centers (secondary lymphoid follicles) and active inflammation involving the epithelium ( Fig. 3 A). Because of the predominant anatomic location in the distal stomach H pylori gastritis has been also termed diffuse antral gastritis and chronic superficial gastritis. The presence of these typical histologic features is predictive of H pylori infection and in most cases routine hematoxylin-eosin staining is enough to detect the curved, sea-gull shaped microorganisms, although in some cases histochemical or immunohistochemical stains for H pylori organisms may be helpful (see Fig. 3 B).
Autoimmune gastritis
Autoimmune gastritis represents less than 5% of all chronic gastritis cases. It is the consequence of an immune-mediated destruction of parietal cells, is restricted to the body and fundus, and is associated with characteristic neuroendocrine cell hyperplasia. The lack of parietal cells that secrete gastric intrinsic factor results in cobalamin deficiency and pernicious anemia, a late manifestation of autoimmune gastritis. In patients with pernicious anemia, the risk of gastric cancer increases threefold and most adenocarcinomas are of the intestinal type. Gastric type 1 neuroendocrine (carcinoid) tumors are associated with autoimmune atrophic gastritis; however, these usually are indolent in their behavior.
Atrophic Gastritis
Atrophy is defined as the loss of normal glandular epithelium. Two primary histologic variants of gastric atrophy include atrophy as the result of glandular destruction and subsequent replacement with lamina propria fibrosis, and glandular loss resulting from replacement of the native glands with metaplastic epithelium. Atrophic gastritis occurs predominantly in the gastric antrum and incisura in H pylori gastritis, and is restricted to the oxyntic mucosa in corpus/fundus in autoimmune gastritis. Atrophy involves the antral and corpus mucosa in multifocal atrophic gastritis (formerly known as environmental atrophic gastritis) or in more advanced atrophic pangastritis. The relationship between antral atrophic gastritis and multifocal atrophic gastritis remains unclear, but they likely represent different stages of the same disease. In a long-term follow-up study invasive or intraepithelial gastric neoplasia was significantly associated with the degree of atrophy using the OLGA staging system.
Metaplasia
Metaplasia is defined as a potentially reversible change in which one adult cell type is replaced by another adult cell type. This alteration in phenotype is believed to help the mucosa to withstand a more adverse environment. In the stomach, three types of metaplasia are recognized: (1) SPEM; (2) intestinal; and (3) pancreatic (the latter is of no clinical significance and is more commonly seen in the proximal stomach).
Spasmolytic polypeptide–expressing metaplasia
SPEM is a metaplastic mucous cell lineage with morphologic features and the phenotype of deep antral glands, including strong expression of trefoil factor (TFF) 2 (previously designated as spasmolytic polypeptide) and MUC6; however, it lacks gastrin-producing G cells (see Fig. 3 C). This mucous lineage has been also termed pseudopyloric metaplasia, mucous metaplasia, or antralized oxyntic mucosa. These latter terms are recognized by pathologists and commonly used in pathology reports, as opposed to SPEM.
TFFs are a group of small secretory peptides that play a role in the protection and repair of the gastrointestinal mucosa. TFF1 and TFF2 are specifically expressed in gastric epithelial cells, whereas TFF3, also termed intestinal trefoil factor, is expressed at high levels in the goblet cells of the small and large intestine in normal physiologic conditions and also in IM of the stomach and gastric carcinoma.
SPEM was detected in 68% of patients with H pylori infection and is also seen in the setting of autoimmune atrophic gastritis targeting parietal cells in the corpus. Recent studies have shown that SPEM is associated with 90% of gastric cancers and have suggested that SPEM may play a role in the preneoplastic process. There is accumulating evidence that SPEM is the first metaplastic change preceding the development of IM. SPEM may be present as a very localized phenomenon; however, extensive mapping of the stomach has revealed that in the intestinal type of gastric adenocarcinoma, atrophy in the corpus may exist as a continuous sheet of SPEM containing islands of IM (multifocal IM). It is unclear whether SPEM or IM is a true precursor for intestinal-type cancer, or if they are merely associated with the carcinogenic process.
Intestinal metaplasia
IM may arise in the background of SPEM or in the native mucous-secreting antral or cardia epithelium. Three types of IM have been recognized:
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Type I IM, also designated as the complete or small intestinal type, consists of mature enterocytes with brush borders, Paneth cells, and goblet cells, the latter secreting sialomucins (see Fig. 3 D). Complete IM is characterized by the expression of intestinal mucin MUC2, and markedly decreased levels of “gastric” mucins MUC1, MUC5AC, and MUC6. Type I IM is the predominant subtype (73%) seen in biopsies with IM and is the most commonly seen in benign conditions, 70% in gastric ulcers and 76% in chronic gastritis.
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Type II IM, or incomplete, immature, colonic type, is characterized by few or absent absorptive cells, and the presence of columnar “intermediate” cells in various stages of differentiation, secreting neutral and acid sialomucins, and goblet cells secreting sialomucins or occasionally sulfomucins (all cells contain mucin).
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Type III IM, in which the predominant mucin secreted by the “intermediate” cells is acid sulfomucin rather than sialomucin as in type II IM. Both type II and III incomplete IM maintain the expression of “gastric” mucins MUC1, MUC5AC, and MUC6. On the molecular level all types of IM exhibit expression of the intestinal transcription factor CDX2, which is expressed in the normal bowel. Type III IM has been identified in only 9.8% of all biopsies with IM and has a higher incidence in carcinoma (35%) than in benign conditions (7%).
Although some studies have demonstrated that cancer risk is increased from type I to type III of IM, currently the subtyping of IM is not recommended in routine practice because there is no conclusive evidence of the association between these subtypes and the risk of gastric cancer.
Recently, the modified OLGA system based on the assessment of IM, rather than atrophy (OLGIM) was introduced for the staging of chronic gastritis. The OLGIM system provided a significantly higher agreement between pathologists compared with the OLGA system based on atrophy alone. The practical value of this system in predicting the development of dysplasia or cancer needs to be addressed.
At present, the reversibility of metaplasia involving the gastric mucosa is considered controversial. Although eradication of H pylori was associated with the reversibility of IM in some studies, in other studies cancer risk decreased only after eradication in patients with nonatrophic mucosa.
Gastric Dysplasia (Intraepithelial Neoplasia)
In tumor pathology, dysplasia is a term that literally means abnormal growth. The WHO defines dysplasia in the gastrointestinal system as the presence of histologic unequivocal neoplastic epithelium without evidence of tissue invasion. Several classification systems of dysplasia, including the Padova, Vienna, and WHO ( Box 1 ), were developed to standardize the definition of gastric dysplasia and neoplasia between pathologists of North America and Europe and those in Japan. This standardization was necessary because gastric lesions diagnosed as high-grade dysplasia (HGD) by Western pathologists were invariably diagnosed as carcinoma by Japanese colleagues. Noninvasive carcinoma (carcinoma in situ) was included in the category of high-grade noninvasive neoplasia (dysplasia) in the Vienna and Padova classifications, which corresponds to high-grade intraepithelial neoplasia (dysplasia) in the 2010 WHO classification. The term “adenoma” is used for raised polypoid lesions, whereas nonadenomatous dysplasia is reserved for flat or depressed lesions. The latter group is not obvious with standard white light endoscopy; however, it may be visualized with chromoendoscopy or narrow-band imaging. Recently, a pit dysplasia limited to the gastric pit region without surface epithelial involvement characteristic of traditional dysplasia has been described.
- 1.
Negative for intraepithelial neoplasia (dysplasia)
- 2.
Indefinite for intraepithelial neoplasia (dysplasia)
- 3.
Intraepitehlial neoplasia (dysplasia)
- a.
Low-grade intraepithelial neoplasia (dysplasia)
- b.
High-grade intraepithelial neoplasia (dysplasia)
- a.
- 4.
Intramucosal invasive neoplasia/intramucosal carcinoma
- 5.
Invasive neoplasia
Two primary histologic types of gastric dysplasia have been described: the intestinal (adenomatous, type I) and the gastric (foveolar, type II). The intestinal type is the most common; is similar to colonic adenomas; and may be recognized histologically by hyperchromatic pseudostratified, pencillate, columnar cell nuclei. The intestinal phenotype expresses MUC2, CDX2, and CD10 by immunohistochemistry. Characteristic features of foveolar dysplasia include glands lined by a single layer of cuboidal to columnar epithelium with pale or clear cytoplasm, and round to oval nuclei with variably prominent nucleoli. Immunohistochemically, the foveolar type is characterized by the expression of gastric mucins; TFF1; and low expression of CDX2 and CD10 (MUC5AC + MUC6 + /CDX2 − /CD10 − ). Several studies have attempted to better delineate the background mucosal pathology and assess the risk of malignant progression in these two types of gastric dysplasia ; however, phenotyping of dysplasia is not recommended because the significance of these subtypes remains controversial.
The prevalence of dysplasia varies from less than 4% in the Western world to up to 20% in high-risk areas for gastric adenocarcinoma, such as Colombia and China. The natural history of gastric dysplasia depends on its grade, extent, and surface appearance (polypoid vs flat or depressed). Dysplasia is graded based on cytologic and architectural features as either low- or high-grade. Low-grade dysplasia (LGD) is characterized by minimal architectural abnormalities and only mild-to-moderate cytologic atypia. The nuclei are hyperchromatic, elongated, or pseudostratified, and mitotic activity is low ( Fig. 4 A). HGD is distinguished by the presence of architectural disarray with loss of nuclear polarity and marked cytologic atypia with rounded nuclei, high nuclear/cytoplasmic ratio, prominent nucleoli, and high mitotic activity including atypical mitotic figures (see Fig. 4 B).
LGD diagnosed on endoscopic biopsies has been shown to regress in 38% to 75% of cases, to persist in 19% to 50%, and to progress to HGD in 0% to 9% of cases. Several long-term follow-up studies have demonstrated that LGD lesions do not progress rapidly to HGD or carcinoma, thus some authors have advocated a management approach of scheduled endoscopic surveillance and rebiopsy. However, other groups have suggested removal of LGD lesions because of the histologic discrepancies found between forceps biopsy specimens and resected specimens ranging from 19% to 35%. The best independent predictors of progression of LGD to HGD or cancer are size greater than 2 cm and the presence of depression on endoscopic examination.
HGD regresses in only 0% to 16% of cases, persists in 14% to 58%, and progresses in 10% to 100% of cases to invasive carcinoma. In a cohort of patients with premalignant gastric lesions approximately 25% of patients with HGD progressed to carcinoma within 1 year of follow-up. For these reasons, a lesion diagnosed as HGD by endoscopic forceps biopsy material should be considered for endoscopic mucosal resection.
Gastric Polyps and Polyposis Syndromes
Gastric polyps are defined as lesions that project above the plain of the mucosal surface. Fundic gland polyps (FGP) are the most common and account for up to 77% of all gastric polyps, followed by hyperplastic polyps and adenomas.
FGPs occur in two different clinical settings: sporadic and syndromic. Dysplasia in sporadic FGPs is extremely rare (<1%) and there is no association between sporadic FGPs and the development of gastric cancer. FGPs may also be seen as a manifestation of familial adenomatous polyposis syndrome. In this setting patients present at a younger age and may have numerous FGPs. Although dysplasia is seen in up to 48% of these polyps, progression to carcinoma is rare in the North American population. Recently, a new hereditary gastric cancer syndrome has been identified that is associated with a significant risk of gastric carcinoma: gastric adenocarcinoma and proximal polyposis syndrome. This autosomal-dominant syndrome is characterized by the development of numerous FGPs, with areas of dysplasia or intestinal-type gastric cancer.
Most hyperplastic polyps are associated with chronic gastritis and H pylori infection. Dysplasia may be found in 1% to 3% of hyperplastic polyps, and is usually associated with size larger than 2 cm and older age. Complete excision with entire histologic examination of large hyperplastic polyps is believed to be curative even if dysplasia or intramucosal carcinoma is present.
Gastric adenomas are raised polypoid lesions that by definition exhibit low- or high-grade epithelial dysplasia and comprise 0.5% to 3.75% of all gastric polyps in the Western hemisphere, in contrast to 9% to 20% in areas of high-risk gastric cancer. The prevalence of gastric adenoma in a large nationwide US population series was 0.69%. Histologically, gastric adenomas may be classified as tubular, tubulovillous, or villous based on architecture. Gastric adenomas may be also subtyped based on the epithelial phenotype into intestinal and gastric types. The intestinal type of adenoma is more common and contains absorptive, goblet, and Paneth cells. Paneth cell adenoma, a rare variant composed exclusively of Paneth cells, has also been described. Gastric-type adenomas may be classified as foveolar or the pyloric type. Recently, an oxyntic gland polyp or adenoma has also been proposed, which likely represents the previously described variant of gastric adenocarcinoma with chief cell differentiation. The clinicopathologic characteristics of gastric adenomas are presented in Table 3 . The risk of carcinoma progression of gastric adenomas is related to the size of the lesions and is increased in lesions larger than 2 cm in diameter.
| Adenoma Type | Sex | Location | Histologic Features | Mucin | Association | Malignant Transformation |
|---|---|---|---|---|---|---|
| Intestinal | M > F | Antrum | Elongated hyperchromatic nuclei, focal goblet cells and Paneth cells | MUC2 + , 5 − , 6 − | Gastritis and IM | High |
| Foveolar | M = F | Body | Round to oval nuclei, pale or clear cytoplasm, apical mucin | MUC2 − , 5 + , 6 − | FAP | Controversial |
| Pyloric | F > M | Body | Round bland or atypical nuclei, ground glass cytoplasm | MUC2 − , 5 + , 6 + | Autoimmune gastritis and IM | High |
| Oxyntic | M≈F | Fundus/cardia | Chief cells, mucous neck cells | MUC2 − , 5 − , 6 + | Some with mild chronic gastritis | None |
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