Gastric carcinomas have a variety of precursors that can be identified histologically. Precursor lesions can be broadly classified into categories of either gastric epithelial dysplasia (GED) for flat (grossly normal) lesions or gastric adenoma for lesions that are raised or polypoid. Microscopic examination alone cannot always distinguish between a flat or polypoid process, and therefore correlation with endoscopic or gross appearance is helpful in the evaluation of gastric dysplasia.
Adenocarcinomas are the most common type of carcinomas of the stomach, and these may be broadly divided into intestinal and diffuse subtypes. Overall, the prognosis of gastric carcinomas is poor. The role of the pathologist is to identify precursor lesions before they have progressed to invasive carcinoma. The early identification of precursor lesions can lead to complete resection and prevent the development of invasive carcinoma.
Neuroendocrine tumors are epithelial neoplasms that are rarely encountered in the stomach and have prognoses that span from indolent to aggressive. Microscopic examination of neuroendocrine tumors with consideration for the clinical history and appearance of the background gastric mucosa can be helpful for determining the expected prognosis.
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Gastric epithelial dysplasia
Clinical features
It is widely recognized that gastric epithelial dysplasia (GED) is a precancerous lesion with the ability to progress to gastric carcinoma. GED is associated with 40% to 100% of early gastric cancers and 5% to 80% of advanced carcinomas. In addition, approximately 60% of gastric cancers are discovered following a diagnosis of dysplasia.
Most cases of GED occur in males in the fifth to seventh decade of life. It is primarily observed in the gastric antrum. Western populations demonstrate a prevalence of GED up to 3.75% with peaks of 20% in high-risk areas such as Japan and Eastern Europe. Other risk factors for the development of GED include pernicious anemia or familial adenomatous polyposis.
In half of all cases of low-grade GED diagnosed by either biopsy or resection specimens, regression of the low-grade dysplasia may be encountered. This observation raises the possibility that low-grade dysplasia may be a reactive lesion. However, approximately 15% of patients with low-grade GED progress to either high-grade dysplasia or carcinoma.
Definition
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Dysplasia of flat gastric epithelium that has the potential for transformation to invasive carcinoma
Incidence
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More common in Westernized countries
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Prevalence ranges between 0.5% and 3.75%, up to 20% in high-risk areas
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Higher incidences reported for patients with familial adenomatous polyposis
Morbidity and mortality
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Related to risk of neoplastic progression
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Associated with 40% to 100% of early gastric cancers and 5% to 80% of advanced carcinomas
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More than half of gastric cancers are discovered after rendering a diagnosis of dysplasia
Gender, age, and race distribution
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Male predominance
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Fifth to seventh decade of life
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No known racial predominance
Clinical features
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No associated clinical symptoms
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May arise in a background of intestinal metaplasia
Prognosis
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Approximately 50% of low-grade dysplasias will undergo regression
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Twenty percent to 30% of monitored low-grade dysplasias show persistence of the lesion without progression
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Fifteen percent of cases of low-grade dysplasia show progression to carcinoma
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Progression of high-grade dysplasia to carcinoma is seen in 80% to 85% of cases
Pathologic features
Gross findings
These lesions are grossly unremarkable and are often not recognized by standard endoscopy. They are often referred to as flat dysplasias.
Microscopic findings
The diagnosis and grading of dysplasia in the stomach has historically differed between Japanese and Western pathologists. A consensus approach led to the Vienna classification of gastrointestinal epithelial neoplasia. The categories of dysplasia in the Vienna classification include: negative for dysplasia, indefinite for dysplasia, non-invasive low-grade dysplasia, non-invasive high-grade dysplasia (including carcinoma in situ), and invasive carcinoma (including both intramucosal carcinoma and submucosal carcinoma).
Architectural changes of low-grade dysplasia include mild to moderate crowding, branching, and budding of the gastric glands ( Fig. 4-1 A). Cytologically, the dysplastic cells exhibit nuclear crowding and hyperchromatism but otherwise retain their nuclear basal orientation and polarity. In high-grade dysplasia, the architectural changes become pronounced, seen as a loss of intervening stroma and back to back orientation of the dysplastic glands (see Fig. 4-1 B). In addition, the marked glandular dilatation, branching, and intraluminal folding develops into complex forms such as cribriforming. Cytologic elements associated with higher-grade lesions include loss of nuclear polarity with marked stratification of the nuclei extending to the luminal aspect of glands. There is a marked increase in the nuclear to cytoplasmic ratio, with the cells developing a more rounded nuclear form. Mitoses are prominent, and intraluminal necrotic material may be seen. When an early infiltrating carcinoma confined to the lamina propria is identified within gastric epithelial dysplasia, it is termed intramucosal carcinoma (see Fig. 4-1 C and D).
Gross findings
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Normal appearance endoscopically
Microscopic findings
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Glandular crowding, branching, and budding
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Crowded, enlarged nuclei with prominent nucleoli
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Decreased apical mucin
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Frequent mitoses
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High-grade dysplasia associated with crowding of glands, cribriform glands, loss of intervening stroma, and complete loss of nuclear polarity
Differential diagnosis
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Reactive epithelial changes
Differential diagnosis
The main differential diagnosis of GED is reactive or regenerative epithelial changes. Of note, in a single study of epithelial dysplasias of the stomach, one half of the cases considered to be dysplastic by generalists were diagnosed as non-neoplastic by gastrointestinal pathologists. Thus, when a definitive diagnosis of dysplasia cannot be rendered, the use of the term indefinite for dysplasia is encouraged. As in other organs, intraobserver variation is diminished as the severity of the lesions increases.
In differentiating low-grade dysplasia from reactive and regenerative changes it is important to note both the cytologic and architectural features of these lesions. In regenerative changes the cells are frequently cuboidal and appear immature with basophilic cytoplasm secondary to reduced mucus secretion. These regenerative nuclei are often large, vesicular, and at times pleomorphic. Yet although the nuclear features show variation, the architectural features remain that of normal epithelium with basally localized nuclei, with only mild pseudostratification ( Fig. 4-2 ). Mitotic figures, when present, are confined to the basal aspects of the glands. Finally, with transit of the epithelium from the basal portion of the glands to the luminal surface, a corresponding increase in cell maturation should be seen.
Prognosis and therapy
Although it is quoted that approximately 50% of low-grade GED will undergo regression, in some of these cases the “low-grade” dysplasia may in fact represent reactive or regenerative epithelial changes. Nonetheless, the importance of early detection is emphasized by the fact that more than half of gastric cancers are discovered after a diagnosis of dysplasia. Among all low-grade dysplasias identified, 20% to 30% of cases will show persistence of the lesion without progression and an additional 15% of cases will progress to high-grade dysplasia or infiltrating carcinoma. Progression of high-grade dysplasias to infiltrating carcinoma may be seen in 80% to 85% of cases, with regression observed in only 5% of cases. The time between the discovery of high-grade dysplasia and a diagnosis of adenocarcinoma varies between a few weeks to years.
Follow-up is usually recommended after a diagnosis of low-grade dysplasia; endoscopy every 3 to 12 months during the first year is advised, secondary to the risk of progression to carcinoma. Following a diagnosis of high-grade dysplasia, endoscopic mucosal resection offers a nonsurgical and potentially curative alternative for the treatment of dysplasia and intramucosal carcinoma. When there is question as to the severity of the lesion, clinical follow-up with repeat biopsy is recommended.
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Gastric adenomas
Clinical features
In contrast to flat gastric epithelial dysplasia, gastric adenomas are localized growths of dysplastic epithelium that project above the surrounding gastric mucosa. Gastric adenomatous polyps follow fundic gland and hyperplastic polyps in overall incidence, accounting for approximately 10% of gastric polyps in North America. This incidence increases with age and peaks in the seventh decade. The male-to-female ratio is approximately 2:1. Most adenomas are found incidentally at the time of endoscopy.
Unlike for the colon, gastric adenomas are not the major precursor for adenocarcinoma; most gastric adenocarcinomas are not associated with an adenoma. However, gastric adenomas are a direct precursor to some gastric carcinomas and also serve as markers for increased risk of adenocarcinoma in other areas of the stomach.
Gastric adenomas have been shown to harbor molecular alterations in the APC , KRAS, and Tp53 genes, similar to that described for the colon. However, although the colon demonstrates a well-characterized adenoma-carcinoma sequence of molecular genetic events, these events are only rarely present in the stomach. For example, alterations in the APC gene are frequently seen in gastric adenomas, but these alterations are rarely seen in gastric adenocarcinomas.
Definition
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Localized, neoplastic growths of dysplastic epithelium that project above the surrounding gastric mucosa
Incidence
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Account for approximately 10% of gastric polyps
Morbidity and mortality
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Related to risk for malignant progression
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Infiltrating carcinoma more common in intestinal-type adenomas > 2 cm in size
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May serve as biomarker for adenocarcinoma elsewhere in the stomach
Gender, race and age
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Males more than females
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Incidence increases with age, peaking in 7th decade
Clinical features
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Often arise in the setting of intestinal metaplasia and atrophy
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Gastric-type adenomas associated with familial adenomatous polyposis
Prognosis and therapy
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Polypectomy and complete excision are curative
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Prognosis dependent on whether infiltrating carcinoma present
Pathologic features
Gross findings
Gastric adenomas occur throughout the stomach with the antrum being the most common location. They range in size from a few millimeters to several centimeters. They may be sessile or pedunculated.
Microscopic findings
Gastric adenomas are histologically divided into intestinal and foveolar types based on the type of glandular epithelium they display. Intestinal-type adenomas resemble those seen in the colon and are characterized by the presence of goblet or Paneth cells ( Fig. 4-3 A and B). Foveolar-type adenomas are lined by gastric foveolar epithelial cells containing neutral mucin (see Fig. 4-3 C). Intestinal-type adenomas are more prevalent than the gastric foveolar-type adenoma and often arise in a background of intestinalized and atrophic gastric mucosa ( Fig. 4-4 ). Compared with gastric foveolar-type adenomas, intestinal-type adenomas have a greater likelihood to show both high-grade dysplasia and to harbor adenocarcinoma.
Both types of gastric adenoma show dysplastic epithelial changes ranging from low- to high-grade, although high-grade dysplasia is rare in gastric foveolar type adenomas. Low-grade dysplastic epithelial changes include loss of polarity, nuclear enlargement, nuclear hyperchromasia, prominent nucleoli, pseudostratification, pleomorphism, and mitoses. In high-grade dysplasia, the glandular architecture becomes increasingly complex with irregular branching, gland budding, and cribriforming. Cytologically, the nuclei show more severe atypia with enlarged, hyperchromatic, vesicular nuclei, and prominent nucleoli. There is also complete loss of nuclear polarity with the atypical nuclei reaching the luminal surface of the epithelium.
Gross features
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Pedunculated or sessile growth pattern
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Most common in the antrum
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Range in size from a few millimeters to several centimeters
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Cannot be reliably distinguished from benign gastric polyps endoscopically
Microscopic features
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Divided into intestinal-type and gastric-type
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Intestinal-type defined by presence of goblet cells or Paneth cells
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Gastric-type composed of gastric foveolar epithelial cells
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Background mucosa often shows atrophic intestinal metaplasia
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High-grade dysplasia associated with crowding of glands, cribriform glands, full-thickness nuclear stratification, and complete loss of nuclear polarity
Genetics
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Associated with genetic alterations of APC , KRAS , Tp53 , and microsatellite instability
Differential diagnosis
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Pyloric gland adenoma
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Hyperplastic polyp
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Reactive epithelial change
Differential diagnosis
The differential diagnosis is any pathologic entity in which the epithelium undergoes reactive changes can enter into the differential diagnosis with a gastric adenoma, including fundic gland polyps and hyperplastic polyps. In all cases, recognition of the lack of cytologic atypia and presence of surface maturation should lead to the correct diagnosis. Another neoplastic entity to be considered is a pyloric gland adenoma.
Prognosis and therapy
Because endoscopy cannot distinguish gastric adenomas from other benign gastric polyps, all gastric polyps should be examined histologically for evidence of neoplastic epithelium. The reported frequency of carcinoma arising within an adenoma ranges from approximately 3% up to 40%. The risk of carcinoma is greater in larger polyps (>2 cm), but even smaller adenomas can show malignant transformation. The risk of a separate gastric adenocarcinoma in the adjacent nonadenomatous mucosa may be as high as 30%. As mentioned, gastric adenomas are endoscopically indistinct from other benign gastric polyps, and, therefore, all gastric polyps should be treated with complete excision of the polyp.
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Pyloric gland adenoma
Clinical features
Pyloric gland adenoma is a rare neoplastic entity that was first reported in the 1970s but has only recently been studied and described. A retrospective study that excluded fundic gland polyps observed that pyloric gland adenomas were 2.7% of all gastric polyps. Although they are rare, they are precancerous lesions that are found frequently in association with adenocarcinoma. In separate studies, adenocarcinoma was diagnosed in 30% and 12% of each respective study of pyloric gland adenoma. There is a female predominance of disease, which has been observed in a range of 2:1 to 14:2. The mean age at diagnosis is in the seventh decade.
The genetics of pyloric gland adenoma and adenocarcinomas arising out of pyloric gland adenoma are not well characterized. In a study from the 1990s of pyloric gland adenomas of the gallbladder, no alterations were found by either APC mutational analysis, K-RAS codon 12 mutational analysis, or p53 expression. No comparable study of APC, K-RAS, or p53 has been published for gastric pyloric gland adenomas. A more recent study of changes in DNA copy numbers by microarray-based comparative genomic hybridization (CGH) revealed no significant differences between intestinal-type gastric adenomas and pyloric gland adenomas. Both intestinal-type and pyloric gland adenomas have gains in chromosomes 8, 9q, 11q, and 20 and losses in chromosomes 5q, 6, 10, and 13. The genetic basis of pyloric gland adenomas remains an area in need of further study.
Definition
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Localized, neoplastic growths of dysplastic epithelium with pyloric gland differentiation that project above the surrounding gastric mucosa
Incidence
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Not well studied; 2.7% of all gastric polyps in a single study
Morbidity and mortality
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Frequently identified with concurrent adenocarcinoma
Gender, race, and age
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Majority of patients are female
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Incidence increases with age, peaking in seventh decade
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Race is not well studied
Clinical features
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The most common background is in autoimmune gastritis
Prognosis and therapy
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Polypectomy and complete excision is curative, although data are limited
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Prognosis dependent on whether infiltrating carcinoma present
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