The Neoplastic Stomach

The Neoplastic Stomach

Rebecca Wilcox

Gastric neoplasms constitute a heterogeneous group of tumors; most are adenocarcinomas. Less common gastric cancers, such as lymphomas, neuroendocrine tumors, and mesenchymal tumors, are discussed in Chapters 17, 18 and 19.


The epidemiologic background and temporal trends of noncardia gastric adenocarcinoma (NCGA) are distinctly different from those arising in the cardia. Carcinomas of the cardia are generally linked with Barrett-associated adenocarcinomas of the esophagus as they share similar risk factors, temporal trends, and molecular profiles. These two cancers constitute gastroesophageal junction (GEJ) cancer and are discussed in Chapter 3.


There is a striking geographic variation in the frequency of NCGA. The majority of gastric cancer cases occur in developing countries with 60% of the world total occurring in three eastern Asian countries: China, Japan, and Korea (Table 5.1) (1,2). First-generation migrants from high-risk countries to low-risk countries continue to experience the high rates of their motherland, whereas their children and grandchildren show rates that approach those of the host country (3). This supports the concept that environmental exposures in early life generate cancer precursors that persist into adulthood and are not reversed by a more favorable environment.

The overall incidence of NCGA has shown a significant decrease worldwide as early global estimates in the mid-1970s document this as the most commonly encountered malignancy (1). This decline also shows geographic variation. Incidence rates in the United States have decreased by more than 80% since 1950 making NCGA less common than cancers of the GEJ in US white males (4,5). However, in the high- and intermediate-incidence countries (Table 5.1), the decline in frequency has not been as steep. Overall, the decrease in NCGA has been attributed to modern refrigeration of foods, decreased dependence on salted and preserved foods, year-round access to fresh fruits and vegetables, improved public health measures emphasizing treatment of Helicobacter pylori infections, and increased screening in many high-risk countries.

Despite the decline in frequency, the mortality of NCGA remains high. Although the fifth most common malignancy in the world, it is the third leading cause of cancer death worldwide. A look at case fatality rates, defined as the ratio of the mortality rate to the incidence rate (constructed from 2002 IARC), revealed gastric cancer to have a case fatality rate of 74.5% (6). In comparison, the far more commonly encountered colorectal cancer carried a case fatality rate of 50.4%. Interestingly, there was a significant difference in the case fatality rate for NCGA for low-income countries when compared to high-income countries (81.6% vs. 58.3%), but no difference when comparing genders.

Predisposing Factors and Conditions

The persons at highest risk of acquiring gastric cancer are concentrated in the lower economic strata of developing countries. The initial steps in cancer induction occur in childhood with infection by H. pylori (7). The youngest children of large families living in crowded, unsanitary conditions are at highest risk (8). Familial clusters of stomach cancer result from a shared exposure to environmental hazards and to inherited factors (9).

Environmental Factors

Environmental factors may affect gastric cancer risk directly or inversely. Several environmental hazards combine to induce distal stomach cancer; other environmental factors protect the stomach from exposure to these hazards. The risk of acquiring stomach cancer ultimately depends on which prevails.


Age-Standardized Incidence Rate of Gastric Cancer (per 100,000)

Helicobacter pylori Prevalence (%)




High Risk













Intermediate Risk





Hong Kong








Low Risk

United States












Helicobacter pylori Infection

Helicobacter pylori infection is the single most important factor in the development of gastric cancer. The infection is acquired in childhood (10). Infected children carry the infection and its anatomic consequences into middle and old age (7). Helicobacter pylori gastritis affects 40% to 75% of persons in high-risk populations, yet only 3% to 5% of these infected individuals develop stomach cancer (11,12), indicating that infection alone is not sufficient for carcinogenesis. When compared to other H. pylori strains, the CagA-positive strain is associated with an increased risk of gastric cancer (13). CagA-producing H. Pylori has also been shown to elicit a more robust inflammatory response (14,15). Increased inflammation is an important aspect in the mechanism by which H. pylori infection may increase stomach cancer risk. The inflammatory response leads to exposure of replicating cells to reactive oxygen and nitrogen species, increasing opportunities for DNA damage and somatic mutations. In addition, recent studies have specifically documented CagA-positive H. pylori’s ability to inhibit tumor suppressor genes such as TP53 and RUNX3 (16,17,18). A few countries are noted to have a dramatically low gastric cancer incidence despite a high frequency of H. pylori infection. For example, Bangladesh and Nigeria, two countries noted to be among the lowest in gastric cancer incidence (see Table 5.1), both have a documented H. Pylori prevalence of greater than 90% (1,2,19). Variation of H. pylori strains, combined with other extrinsic and intrinsic risk factors, may account for this paradox.

The initial manifestation of H. pylori infection is severe superficial gastritis, followed by the development of multifocal atrophic gastritis (MAG) and intestinal metaplasia (IM) (see Chapter 4). The process begins at the antral-corpus junction and along the lesser curvature of the antrum. Classically, over time, the atrophic foci expand and fuse so that in old age much of the oxyntic mucosa is replaced by intestinalized tissue. However, the pervasive use of proton pump inhibitors (PPIs) has altered the general pattern of H. pylori-associated gastritis and atrophy. Although still beginning in the antral-corpus junction, the decreased acid production secondary to PPI use provides an earlier opportunity for H. pylori to spread to the gastric body leading to a corpus-predominant pangastritis (20,21). Cancer risk is highest in H. pylori-infected persons with severe gastric atrophy, corpus-predominate pangastritis, and IM (12). Recent reports from both the World Health Organization’s IARC working group and the Kyoto global consensus committee on H. Pylori gastritis emphasize the need for eradication therapy, ideally as a primary prevention of gastric cancer before atrophic changes have occurred (22,23,24).


The pattern of food consumption may increase or reduce the risk of acquiring stomach cancer. The addition of nitroso compounds to the diet of experimental animals produces gastric cancer and its precursor, IM (22). Epidemiologic studies show a direct association between the development of IM and nitrate/nitrite consumption in humans (23). Salt intake also directly relates to stomach cancer risk in humans (24,25). The consumption of dried, salted fish in Japan and the consumption of salted, nitrosated foods through the winter months in northern countries are examples of dietary practices that increase stomach cancer risk. In contrast, fresh fruits and vegetables provide antinitrosating effects that protect the stomach from both exogenous and endogenous mutagenic nitroso compounds. Fresh fruits and vegetables function as antioxidants and contain substantial amounts of folate, ascorbic acid, carotene, and tocopherol. Epidemiologic studies of Japanese and European populations suggest that raw green and yellow vegetables protect against the development of gastric cancer (26), and a Japanese cohort study showed that increased fresh produce consumption and reduced consumption of pickled food reduced the gastric cancer risk, even in the presence of atrophic gastritis (27).
The year-round availability of fresh produce eliminates the need to use salt to preserve vegetables. Smoking and salting of meat is no longer a necessity with the advent of universal household refrigeration. These two factors have contributed to the dramatic decrease in stomach cancer rates in Western countries after World War II.


The International Agency for Research on Cancer (IARC) estimates that smoking is responsible for 10% of all gastric adenocarcinomas (1). Although this association is stronger in adenocarcinomas of the cardia, smoking is also associated with an increased risk of NCGA (28). A meta-analysis looking at 34,557 gastric cancer cases showed a lack of association between moderate alcohol drinking and gastric cancer risk (29). However, there was a positive association with heavy alcohol drinking, defined as greater than or equal to four 12.5 g of ethanol drinks per day. Unfortunately, none of the studies in this meta-analysis reported a relative risk for alcohol consumption and gastric cancer adjusted for H. pylori infection.


A dose-dependent increase in gastric cancer frequency has occurred among Japanese atomic bomb survivors, suggesting that ionizing radiation may play a role in gastric carcinogenesis (30,31). Additionally, radiotherapy in young patients increases their risk of gastric cancer when lymph nodes of the upper abdomen are included in the radiation field, as may occur in the treatment of lymphoma and testicular cancer (32,33).

Previous Gastric Surgery

The creation of a gastroenterostomy after subtotal gastrectomy for peptic ulcer is a well-established risk factor for the development of cancer in the gastric stump (Fig. 5.1) (34). The cancer may not be apparent until 20 years after the creation of the anastomosis. It is preceded by the appearance of gastritis and hyperplastic polyps (HPs) at the anastomotic line (35). The cause of the increased risk is attributed to the reflux of bile and pancreatic juice into the gastric remnant, a hypothesis that is supported by rodent experiments that show the sequential development of gastritis, hyperplasia, metaplasia, and adenocarcinoma after duodenal contents were diverted into the stomach (36). Since subtotal gastrectomy is no longer employed to treat peptic ulcer, it is increasingly rare for patients to carry this risk factor. Another potential source of postenterostomy stomach cancer is the Roux-en-Y gastrojejunostomy used to treat morbid obesity. Up to 30 cases of gastric cancer in patients who previously underwent bariatric surgery have been described between the years of 2007 and 2014 (37,38). The majority of these cancers were noted to occur in the excluded gastric segment, which is subject to the reflux of bile and alkaline secretions and the subsequent development of gastritis (39).

FIG. 5.1 Large polypoid gastric cancer originating in the gastric stump. The small bowel mucosa is seen on the left.

Host Factors

There are a number of genetic and epigenetic changes that play a role in the predisposition to or the development of gastric carcinoma. These include activation of oncogenes, growth factors and growth factor receptors, inactivation of tumor suppressor genes, DNA repair genes, and cell adhesion molecules, as well as alterations in cell cycle regulatory genes. Inherited factors interact with environmental hazards to increase gastric cancer risk in two ways: (a) inherited polymorphisms in inflammatory cytokine genes may work with environmental toxins to increase cancer risk and (b) although infrequent, germline mutations account for a well-defined group of familial cancer syndromes. Other types of changes occur in sporadic tumors.

Genetic Polymorphisms That Influence Gastric Cancer

By 1966, a number of studies had found a consistent relationship between the diffuse type of stomach cancer and blood type A (40). A recent cohort study using the Scandinavian Donations and Transfusions database confirmed this association (41). It seems unlikely that blood type A has a direct role in the carcinogenic process, but it may serve as a marker for an as yet unidentified mutation or a genetic polymorphism that increases the cancer risk by modulating the host reaction to environmental hazards. Host-related factors are clearly a piece of the multifactorial cause of gastric carcinoma given that only 1% to 5% of individuals infected with H. pylori develop gastric cancer. Certain genetic polymorphisms, particularly single nucleated polymorphisms (SNPs), have been associated with gastric cancer. For example, the interleukin-1 (IL-1) B gene is highly polymorphic with polymorphisms that are associated with either increased or decreased expression of the proinflammatory cytokine IL-1B (42). Gastric cancer patients are more likely to have the IL-1B-31T/IL-1RN* phenotype. Such persons mount an especially strong inflammatory response to H. pylori infection through IL-1 overexpression. The level of gastric cancer risk varies greatly depending on the association of specific genotypes of
the infecting organism with different IL-B phenotypes, with an odds ratio (OR) of 87 (CI = 11 to 697) when the vacAs1 strain associates with IL-B-511*T (43). In contrast, when H. pylori strain vacAm1 associates with this phenotype, the OR is substantial but falls to 7.4 (CI = 3.2 to 17). Importantly, this relationship between high IL-B expression and gastric cancer requires the presence of H. pylori emphasizing the importance of host-environment interactions in the progression to gastric carcinoma (42).

FIG. 5.2 Hereditary diffuse gastric cancer in a young male who underwent prophylactic gastrectomy for a known CDH1 mutation. A: At a low-power cursory glance, the mucosa appears to be more or less normal. B: Higher magnification discloses multiple foci of intramucosal diffuse (signet-ring cell) gastric carcinoma. C: E-cadherin immunostain showing staining of the nonneoplastic gastric glands and absence of staining in the tumor cells in the lamina propria and a few isolated tumor cells in the glands (lower right). D: Ki-67 immunostain showing the low proliferative index of the tumor cells. A portion of a nonneoplastic gland shows some proliferation (lower right).

Hereditary Tumor Syndromes

Hereditary Diffuse Gastric Cancer

Only a small number, approximately 2% to 8%, of all gastric carcinomas arise from inherited gastric cancer syndromes (44,45). The majority of families with familial gastric carcinoma will have the autosomal dominate hereditary diffuse gastric cancer (HDGC). A germline mutation in the tumor suppressor gene CHD1 (E-cadherin) is identified in approximately 25% to 48% of individuals with HDGC. E-cadherin is a cell adhesion protein (46,47). The loss of its function (and loss of its normal expression on the cell membrane) (Fig. 5.2) due to genetic mutations results in the discohesive cells that characterize sporadic diffuse gastric cancers and lobular breast cancers. It is not surprising, therefore, that familial gastric cancers associated with germline mutations in this gene are diffuse in type and that HDGC kindreds also show an increased frequency of lobular breast cancer (46,48). The CDH1 mutation carries a high penetrance. For those that carry the germline mutation, the estimate lifetime risk of developing gastric cancer is 67% for men and 83% for women (47,48). In general, cancers in HDGC occur at a relatively early age, with the average age of presentation with diffuse gastric carcinoma being 38 years of age (49). Patients who are known to carry the HDGC mutation are generally treated with prophylactic gastrectomy since the early lesions are endoscopically undetectable (50). Multiple superficial mucosal cancers may be found at the time of gastrectomy (Fig. 5.2). The chance discovery of similar lesions in an endoscopic biopsy should alert the pathologist to a possible HDGC mutation (51,52). Lynch et al. (53) suggest that these superficial neoplastic foci represent a widespread field effect due to promoter hypermethylation and that dysregulation of genes required for invasion and metastases are much less common.

FIG. 5.3 Gastric dysplasia in a patient with Lynch syndrome. A: Gastric dysplasia occurring in a background of relatively normal gastric body mucosa. B: MSH2 immunostain shows loss of expression in dysplastic focus with retained expression in background stomach.

Lynch Syndrome (Hereditary Nonpolyposis Colon Cancer Syndrome)

The lifetime risk for gastric cancer in patients with Lynch syndrome is 6% to 13% (54). The Netherlands’ Hereditary Cancer Registry documents gastric cancer risk as being 3.4 times higher in Lynch syndrome patients when compared to the general population, specifically those with MSH2 (Fig. 5.3) or MLH1 mutations (55). Lynch syndrome is more extensively discussed in Chapter 12.

Familial Adenomatous Polyposis

Familial adenomatous polyposis (FAP) may involve the stomach as well as the small intestine and colon. Fundic gland polyps (FGPs) are the most common gastric polyps encountered in FAP patients. Unlike those encountered sporadically, FGPs associated with FAP patients tend to be more numerous (Fig. 5.4A) and are known to be neoplastic (Fig. 5.4B) as they frequently carry somatic adenomatous polyposis (APC) gene alterations (56). Although dysplasia, predominately low grade, is present in up to 50% of FAP-associated FGPs, invasive adenocarcinoma is rarely encountered (57,58,59,60). The precursor lesion to FAP-associated gastric cancer may be a flat polypoid adenoma unrelated to FGPs. In a recent review of the clinical characteristics of gastric cancer in Japanese FAP patients, none of the patients with gastric cancer had detectable FGPs (61). In general, Japanese and Korean patients with FAP have more frequent gastric adenomas and neoplastic transformation than Westerners with FAP (62,63,64). This observation may be related to differing environmental risk factors, or it may be genetic given that the location of the mutation in the large APC gene is known to have a striking effect on the FAP phenotype (see Chapter 12).

Gastric Adenocarcinoma and Proximal Polyposis of the Stomach

Gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS) is a recently described autosomal dominant gastric polyposis syndrome that carries a significant risk of gastric cancer (65). The syndrome is unique in that the polyposis consists of greater than 100 FGPs that are restricted to the gastric body and fundus. Patients with GAPPS have no duodenal or colorectal polyposis. The proximal stomach polyps are predominately FGPs, with and without dysplasia; however, among the FGPs, GAPPS patients were also noted to have HPs, pure adenomatous polyps, and some mixed-morphology polyps. The earliest gastric carcinoma arising in the setting of GAPPS occurred at 33 years of age (65). The causal genetic defect in GAPPS has yet to be identified. Exclusion of other heritable gastric polyposis syndromes is essential before the diagnosis can be made.

Other Inherited Cancer Syndromes

Early-onset gastric cancer has been described in association with other inherited cancer syndromes including Li-Fraumeni syndrome in which affected individuals have germline mutation of the TP53 gene (66), Peutz-Jeghers syndrome (67,68), and possibly Cowden syndrome (69). Carriers of BRCA1/2 mutations have a substantial increase in the lifetime risk of breast and ovarian cancer. These mutations have been related to a variety of other sites as well, including the stomach. The Swedish Family Cancer Database assessed the cancer incidence in classified family members (n = 944,723) and compared their cancer experience with that of the general population of Sweden and found a twofold increase in the risk of acquiring stomach cancer before age 70 among male members of families with breast and ovarian cancer (70). Family aggregations of breast cancer and stomach cancer have been well documented, with 20.7% of families harboring both gastric and breast malignancies having mutations in BRCA2 (71,72). It is currently unknown if mutations in specific regions of the BRCA gene predispose patients to an increased gastric cancer risk (72).

FIG. 5.4 Fundic gland polyps (FGP) in an FAP patient. A: Gross specimen: Multiple fundic gland polyps. B: Characteristic FGP with areas of surface low-grade dysplasia. C: High power of low-grade dysplasia.

Predisposing Gastric Lesions

Gastric cancer does not generally arise de novo from normal mucosa. Gastritis is usually the first step in cancer induction, whatever the underlying cause. In persons with polymorphisms that render them especially vulnerable to exogenous or endogenous carcinogens, an intense superficial gastritis may be the only anatomic precursor to cancer induction.

Multifocal Atrophic Gastritis and Intestinal Metaplasia

The intestinal-type cancer so characteristic of high-risk populations follows a sequence of morphologic changes, known as the Correa cascade (73,74). This sequence begins with inflammation and passes through atrophy and IM to dysplasia and ultimately to invasive cancer (Fig. 5.5). These changes are initiated in childhood by H. pylori infection. The dense leukocytic response that affects the superficial lamina propria and the epithelium of the mucous neck region of the gastric glands, as discussed in Chapter 4, is followed by the appearance of foci of atrophic, intestinalized mucosa at the antral-corpus junction. These changes become apparent in adolescents and young adults. The metaplastic glands and the mucosa adjacent to them show increased cell proliferation. The foci of MAG enlarge, fuse, and expand proximally and distally so that, by the sixth or seventh decade of life, all but a small portion of the proximal greater curvature of the corpus may be lined by intestinalized mucosa.

Helicobacter pylori-induced inflammation is the initiator of the Correa cascade; however, the progression to carcinoma can continue even after its eradication (75). Many studies have shown that atrophy and IM are premalignant lesions to gastric carcinoma and that there is a direct relationship
between the degree and extent of these precursor lesions and increased risk of gastric cancer (11,12,76). This holds true even in low-risk, Western populations as observed by a Swedish registry biopsy cohort study, which assessed the incidence of gastric cancer based on the patient’s stage on Correa cascade at initial diagnosis (77). This study predicted that about 1 in 256 people with normal mucosa, 1 in 85 with gastritis, 1 in 50 with atrophic gastritis, 1 in 39 with IM, and 1 in 19 with dysplasia will develop gastric cancer within 20 years after gastroscopy.

FIG. 5.5 Histologic features of the Correa cascade. A: Marked inactive gastritis with atrophy. B: Early, low-grade dysplasia (upper left-hand corner) arising in a background of extensive intestinal metaplasia. C: Invasive carcinoma arising in atrophic gastritis with intestinal metaplasia.

Although endoscopy with biopsy is the most common means of diagnosing precursor lesions to gastric cancer, serum pepsinogen is used in high-risk populations as a noninvasive and cost-effective means of screening for atrophy, IM, and gastric cancer (78). Serum pepsinogen levels reflect the extent of gastric mucosal intestinalization. Pepsinogen is a proenzyme activated by gastric acid to produce pepsin. It is produced in two forms: pepsinogen group I (PGI) is only produced in the oxyntic mucosa, while pepsinogen group II (PGII) is made throughout the stomach and in Brunner glands. Replacement of oxyntic mucosa by IM results in decreasing PGI serum levels (79). A PGI level less than 30 &egr;g/mL or a PGI:PGII ratio less than 2 are established cut-points used in screening programs to identify patients with extensive IM and who are at especially high risk of gastric cancer (80). The predictive value of the PGI level is improved when it is combined with the H. pylori serum antibody levels, as shown in Table 5.2, adapted from a case-control study (81). Similar trends are observed with the PGI:PGII ratio.


All Cancers



Distal to Cardia

HP/CagA negative, PGI normal




HP/CagA negative, PGI low

5.4 (2.61-11.2)

5.06 (2.43-10.97)

8.92 (1.48-53.6)

HP/CagA positive, PGI normal

4.86 (2.9-8.13)

3.64 (2.05-6.45)

14.84 (9.51-54.4)

HP/CagA positive, PGI low

9.21 (4.95-17.13)

6.91 (3.53-13.53)

40.74 (9.51-174.6)

FIG. 5.6 Focal adenocarcinoma arising in a large hyperplastic polyp. A: Large, hyperplastic polyp occurring at an anastomotic site. B: Closer view reveals early invasive carcinoma, poorly cohesive morphology.

Autoimmune Gastritis

Autoimmune gastritis, as discussed in Chapter 4, is a wellrecognized, but less common, gastric cancer precursor than MAG. Risk estimates for gastric cancer in patients with pernicious anemia have a documented relative risk of 2.2 to 5.6 (82). A more recent meta-analysis that limited their study patients to those with endoscopy-histology follow-up found a higher relative risk of 7 (83). To add to the complexity, autoimmune atrophic gastritis and H. pylori gastritis may coexist in some patients. Autoimmune atrophic gastritis may be distinguished from late-stage MAG by the absence of antral inflammation and atrophy (Fig. 5.5). The increased risk stems from several factors: (a) loss of gastric acidity favors the growth of bacteria that may generate endogenous nitroso compounds from dietary amines. (b) Gastrin production is greatly increased in response to prolonged achlorhydria. The trophic effects of hypergastrinemia result in accelerated cell turnover in a replicating compartment already expanded due to the loss of parietal and chief cells. (c) These replicating cells are exposed to reactive oxygen species from inflammatory cells.

Gastric Ulcer

A stage is reached in the early phases of the expansion of MAG when the proximal antral intestinalized mucosa is exposed to the acid produced by the still intact oxyntic mucosa. The intestinalized mucosa lacks the protective mucous barrier of the normal antrum, so that it is vulnerable to peptic ulceration. Patients with gastric ulcer are at greatly increased risk of gastric cancer. This is not surprising since gastric ulcer and gastric cancer share the same risk factors: H. pylori gastritis, a diet rich in salt, smoking (84), and a declining frequency in Western countries (85). As may be expected among patients who have retained the ability to make acid, the mean age of gastric ulcer patients is 10 years younger than the mean age of patients with cancer. Reepithelialization of the ulcer associates with expansion of the replication zone of the glands bordering the ulcer, exposing a larger number of vulnerable proliferating cells to genotoxic hazards. In contrast, the regenerating epithelial cells that migrate over the ulcer base are arrested in the postmitotic phase of the cell cycle, accounting for the observation that the gastric mucosa bordering the ulcer, rather than the ulcer base, is a common site of early cancer.

The term ulcer cancer defines a gastric carcinoma that arises in a preexisting peptic ulcer. Tumors arising in this setting account for less than 1% of all gastric carcinomas. In order to be accepted as an ulcer cancer, the case must show definite evidence of preexisting chronic peptic ulcer and evidence of coexisting malignancy. About 5% of endoscopically benign ulcers eventually prove to be malignant, but some lesions may require more than one biopsy to detect the underlying malignancy (86). Underestimation of the depth of invasion may occur when the tumor develops from the epithelium of a healed ulcer in which the submucosa and muscularis propria are no longer recognizable because of scarring.

Hyperplastic Polyps

Hyperplastic polyps (HPs) are commonly encountered in the stomach, second only to FGPs (87). HPs are not thought to be neoplastic but instead likely represent an exuberant regenerative change. Therefore, their presence is often associated with mucosal injury secondary to H. pylori gastritis, autoimmune atrophic gastritis, ulceration, or anastomosis after gastroenterostomy (Fig. 5.6). Clinical factors predicting neoplastic transformation of gastric HPs include size greater than 1 cm, pedunculated shape, postgastrectomy state, and the presence of synchronous neoplastic lesions (88). The reported incidence of malignant transformation of hyperplastic gastric polyps has generally been low, ranging from 1.5% to 3% (89,90); however, the reported incidence is higher, 8.4%, when specifically looking at HPs greater than 1 cm in size (91). When cancer does arise in an HP, it occurs through a multistep process and is preceded by dysplasia (92).

FIG. 5.7 Regenerative hyperplasia. An increased nuclear-to-cytoplasmic ratio and mitotic rate are present. The reactive nuclei show the characteristic open, finely granular cytoplasm with prominent nucleoli.


Dysplasia is the first microscopically detectable anatomic change in the neoplastic process. The growth pattern of gastric dysplasia is variable. Foci of dysplasia can be grossly inconspicuous, flat or depressed, or polypoid lesions recognizable as adenomas. Histologically, dysplastic changes encompass both cytologic and architectural alterations. Diagnostic challenges associated with gastric epithelial dysplasia are threefold (i) one must be able to separate dysplasia from atypical regenerative changes, (ii) one should be able to distinguish high-grade from low-grade dysplasia, and (iii) the dysplasia should be separable from invasive carcinoma.

Dysplasia versus Regenerative (Reactive) Atypia

Atypical regenerative changes are usually accompanied by active inflammation without significant architectural or differentiation abnormalities. Regenerative cells show increased nuclear-to-cytoplasmic ratio, frequent mitosis, and prominent nucleoli. However, one cytologic clue to regenerative atypia is the ease in identifying nucleoli in the background of characteristically open, finely granular chromatin (Fig. 5.7). In contrast, dysplastic cells show one or more nuclear abnormalities including hyperchromasia with coarsely granular cytoplasm, irregular nuclear borders, and atypical mitoses and form architecturally abnormal glands with branching and occasional back-to-back configuration.

The identification of dysplasia is critical to the management of patients in high-risk populations, but the assignment of grades is subjective, with wide inter- and intravariations in grade selection. A workshop convened to resolve international differences in the definitions of different grades of gastric epithelial dysplasia resulted in the Padova classification (93), as summarized in Table 5.3.


Negative for dysplasia

Reactive foveolar hyperplasia

Intestinal metaplasia (IM)

IM, complete type

IM, incomplete type

Indefinite for dysplasia

Foveolar hyperproliferation

Hyperproliferative IM

Noninvasive neoplasia (flat or elevated [synonym, adenoma])

Low grade

High grade

Including suspicious for carcinoma without invasion (intraglandular)

Including carcinoma without invasion (intraglandular)

Suspicious for invasive carcinoma

Invasive carcinoma

Low-Grade versus High-Grade Dysplasia

In low-grade dysplasia, the gastric mucosal architecture is generally preserved, although abnormalities sometimes occur, including pseudovilli, irregular branching papillary infoldings, crypt lengthening with serration, and cystic changes. Low-grade nuclei are elongated, have mild-to-moderate cytologic atypia and polarization is preserved (Fig. 5.8A) (94). The nuclei of high-grade gastric dysplasia change from the “pencilate” form, characteristic of low grade, to a more rounded/cuboidal form. These nuclear changes occur with loss of polarity, with nuclei moving from their basal location to the luminal aspect of the cell. Finally, glandular crowding and architectural changes are generally evident in high-grade dysplasia (Fig. 5.8B). Regardless of grade, flat/depressed lesions are general given the term dysplasia (intraepithelial neoplasia), and polypoid lesions are referred to as adenomas.

Dysplasia versus Intramucosal Carcinoma

Intramucosal carcinoma is defined by invasion of the lamina propria. In the stomach, this diagnosis indicates a risk of lymphovascular invasion and lymph node metastasis. The distinction between high-grade dysplasia and intramucosal carcinoma can be challenging on biopsy specimens where fragmentation and lack of desmoplastic response are common. Using the Padova classification (Table 5.3), a diagnosis of high-grade dysplasia suspicious for invasive carcinoma is often appropriate in this setting. Histologic features favoring intramucosal carcinoma include marked glandular crowding, budding (Fig. 5.9A), and intraluminal necrotic debris (Fig. 5.9B) (95). Although there is an increased risk for lymphovascular invasion in gastric intramucosal carcinomas, it is small (<3%) when compared to more advanced stages (96). For this reason, an endoscopic approach (Fig. 5.10), rather than surgical
resection, may be a reasonable treatment option for patients with small intramucosal carcinomas (97).

FIG. 5.8 Gastric dysplasia. A: Low-grade dysplasia as illustrated here is characterized by cellular elongation, generally basally located nuclei, few mitoses, little cellular stratification, mucin depletion, and hyperchromasia. Compare to background intestinal metaplasia. B: In high-grade dysplasia, the cells are hyperchromatic, pleomorphic, and disorganized. The chromatin pattern is distinct from that of reactive/regenerative hyperplasia (Fig. 5.7).

Gastric Adenomas

Like gastric adenocarcinoma, the prevalence of gastric adenomas has marked geographic variation. Gastric and colon polyps share some morphologic features. Grossly, they have a lobulated or mamillated surface and are often covered by a reddened, velvety mucosa (Fig. 5.11). A villous configuration may predominate in larger lesions (Fig. 5.12). The majority of gastric adenomas are intestinal type with some evidence of intestinal differentiation including goblet cells, endocrine cells, or Paneth cells. In addition, this type of adenoma occurs in a background of atrophy and IM (see Fig. 5.5).

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Oct 28, 2018 | Posted by in GASTROENTEROLOGY | Comments Off on The Neoplastic Stomach
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