1. Intestinal Metaplasia of the Stomach
A Review
Kent Humble MD
Assistant Professor of Family Medicine
LSU School of Medicine

2. Objectives Discuss relationship between gastric IM and gastric cancer
Review pathophysiology and epidemiology of gastric IM
Review guidelines concerning endoscopic surveillance

3. Gastric Cancer
Make clear that we are discussing distal (corpus and antrum) cancers.
Observational studies suggest that proximal cancers have a different pathogenesis than do distal cancers
Epidemiologic Characteristics
The incidence of gastric carcinoma varies widely, both worldwide and within individual country. The highest incidence (>20 per 100,000 in men) is in Japan, China, Eastern Europe, and South America, while the lowest incidence (<10 per 100,000 in men) is in North America, parts of Africa, and Southern Asia (3). In the United States, gastric cancers occur at a median age of 69 years for men and 73 for women (2). African Americans, Hispanic Americans, and Native Americans are 1.5 to 2.5 times more likely to develop gastric cancer than whites (4). On the basis of SEER data, the age-adjusted incidence of gastric cancer is 7.9 per 100,000 men and women per year (2).
In the United States, the incidence of gastric cancer has been decreasing over the past several decades, reflecting a significant reduction in distal (body and antrum) disease. The reason for the decline is not known but may be related to dietary habits, food preservation, and improved surgical morbidity and mortality rates. However, the incidence of proximal stomach and gastroesophageal junction (GEJ) adenocarcinomas has steadily increased at a rate exceeding that of any other cancers except melanoma and lung cancer (5). Observational studies suggest that proximal cancers have a different pathogenesis than do distal cancers (6). Potential causes of distal gastric cancers include Helicobacter pylori infection or E-cadherin expression loss, whereas proximal gastric cancer may behave similarly to distal esophageal and GEJ cancers, which progresses from Barrett metaplasia to dysplasia to invasive adenocarcinoma. Only 24% of newly diagnosed gastric cancers are localized. The 5-year survival rate of patients with metastatic disease is less than 5%. Thus, even in the United States, despite decreasing incidence, gastric cancer remains a public health concern because of its high fatality rate.
GASTRIC ADENOCARCINOMAAdenocarcinoma is the most common malignancy of the stomach, comprising over 90% of all gastric cancers. Early symptoms resemble those of chronic gastritis, including dyspepsia, dysphagia, and nausea. As a result, these tumors are often discovered at advanced stages, when symptoms such as weight loss, anorexia, altered bowel habits, anemia, and hemorrhage trigger further diagnostic evaluation.Epidemiology.Gastric cancer incidence varies markedly with geography. In Japan, Chile, Costa Rica, and Eastern Europe the incidence is up to 20-fold higher than in North America, northern Europe, Africa, and Southeast Asia. Mass endoscopic screening programs can be successful in regions where the incidence is high, such as Japan, where 35% of newly detected cases are early gastric cancer, tumors limited to the mucosa and submucosa. Unfortunately, mass screening programs are not cost-effective in regions where the incidence is low, and fewer than 20% of cases are detected at an early stage in North America and northern Europe.In the United States, gastric cancer rates dropped by over 85% during the twentieth century.[26] Adenocarcinoma of the stomach was the most common cause of cancer death in the United States in 1930 and remains a leading cause of cancer death worldwide, but now accounts for fewer than 2.5% of cancer deaths in the United States. Similar declines have been reported in many other Western countries, suggesting that environmental and dietary factors are responsible.[26] Consistent with this conclusion, studies of migrants from high-risk to low-risk regions have shown that gastric cancer rates in second-generation immigrants are similar to those in their new country of residence.The cause of the overall reduction in gastric cancer is unknown. One possible explanation is the decreased consumption of dietary carcinogens, such as N-nitroso compounds and benzo[a]pyrene, because of reduced use of salt and smoking for food preservation and the widespread availability of food refrigeration. Conversely, intake of green, leafy vegetables and citrus fruits, which contain antioxidants such as vitamin C, vitamin E, and beta-carotene, and is correlated with reduced risk of gastric cancers, may have increased as a result of improved food transportation networks.Gastric cancer is more common in lower socioeconomic groups and in individuals with multifocal mucosal atrophy and intestinal metaplasia. PUD does not impart an increased risk of gastric cancer, but patients who have had partial gastrectomies for PUD have a slightly higher risk of developing cancer in the residual gastric stump as a result of hypochlorhydria, bile reflux, and chronic gastritis.Although overall incidence of gastric adenocarcinoma is falling, cancer of the gastric cardia is on the rise. This is probably related to Barrett esophagus and may reflect the increasing incidence of chronic GERD and obesity.[10] Consistent with this presumed common pathogenesis, distal esophageal adenocarcinomas and gastric cardia adenocarcinomas are similar in morphology, clinical behavior, and therapeutic response.[27–29]Pathogenesis.While the majority of gastric cancers are not hereditary, the mutations identified in familial gastric cancer have provided important insights into mechanisms of carcinogenesis in sporadic cases. Germline mutations in CDH1, which encodes E-cadherin, a protein that contributes to epithelial intercellular adhesion, are associated with familial gastric cancers, which are usually of the diffuse type. Mutations in CDH1 are present in about 50% of sporadic cases of diffuse gastric tumors, while E-cadherin expression is drastically decreased in the rest, often by methylation of the CDH1 promoter. Thus, the loss of E-cadherin function seems to be a key step in the development of diffuse gastric cancer. Notably, CDH1 mutations are also common in sporadic and familial lobular carcinoma of the breast, which also tends to infiltrate as single cells, and individuals with BRCA2 mutations are at increased risk of developing diffuse gastric cancer.In contrast to diffuse gastric tumors, there is an increased risk of intestinal-type gastric cancer in individuals with FAP, particularly in Japan. This implies an interaction between host genetic background and environmental factors, since gastric cancer risk is less markedly elevated in individuals with FAP residing in areas of low gastric cancer incidence. Mutations in β-catenin, a protein that binds to both E-cadherin and adenomatous polyposis coli (APC), as well as microsatellite instability and hypermethylation of several genes including TGFβRII, BAX, IGFRII, and p16/INK4a have also been described in sporadic intestinal-type gastric cancer.Genetic variants of pro-inflammatory and immune response genes, including those that encode IL-1β, TNF, IL-10, IL-8, and Toll-like receptor 4 (TLR4), are associated with elevated risk of gastric cancer when accompanied by H. pylori infection, and p53 mutations are present in the majority of sporadic gastric cancers of both histologic types. Thus, although specific sequences of events have not been defined, it is clear that chronic inflammation promotes neoplastic progression. Other associations between chronic inflammation and cancer were discussed in  Chapter 7.Morphology. Gastric adenocarcinomas are classified according to their location in the stomach, and most importantly, according to gross and histologic morphology. Most gastric adenocarcinomas involve the gastric antrum; the lesser curvature is involved more often than the greater curvature.[28] Gastric tumors with an intestinal morphology tend to form bulky tumors (Fig A) composed of glandular structures (Fig A), while cancers with a diffuse infiltrative growth pattern (see Fig B) are more often composed of signet-ring cells (see Fig B). Although intestinal-type adenocarcinomas may penetrate the gastric wall, they typically grow along broad cohesive fronts to form either an exophytic mass or an ulcerated tumor. The neoplastic cells often contain apical mucin vacuoles, and abundant mucin may be present in gland lumens. In contrast, diffuse gastric cancer is generally composed of discohesive cells that do not form glands but instead have large mucin vacuoles that expand the cytoplasm and push the nucleus to the periphery, creating a signet-ring cell morphology. These cells permeate the mucosa and stomach wall individually or in small clusters, which makes tumor cells easy to confuse with inflammatory cells, such as macrophages, at low magnification. Extracellular mucin release in either type of gastric cancer can result in formation of large mucin lakes that dissect tissue planes.A mass may be difficult to appreciate in diffuse gastric cancer, but these infiltrative tumors often evoke a desmoplastic reaction that stiffens the gastric wall and may provide a valuable diagnostic clue. When there are large areas of infitration, diffuse rugal flattening and a rigid, thickened wall may impart a leather bottle appearance termed linitis plastica (see Fig B). Breast and lung cancers that metastasize to the stomach may also create a linitis plastica–like appearance.FIGURE 17-17  Gastric adenocarcinoma. A, Intestinal-type adenocarcinoma consisting of an elevated mass with heaped-up borders and central ulceration. Compare to the peptic ulcer in Figure 17-14A. B, Linitis plastica. The gastric wall is markedly thickened, and rugal folds are partially lost.FIGURE 17-18  Gastric adenocarcinoma. A, Intestinal-type adenocarcinoma composed of columnar, gland-forming cells infiltrating through desmoplastic stroma. B, Signet-ring cells can be recognized by their large cytoplasmic mucin vacuoles and peripherally displaced, crescent-shaped nuclei.
Clinical Features.Intestinal-type gastric cancer predominates in high-risk areas and develops from precursor lesions including flat dysplasia and adenomas. The mean age of presentation is 55 years, and the male-to-female ratio is 2 : 1. In contrast, the incidence of diffuse gastric cancer is relatively uniform across countries, there are no identified precursor lesions, and the disease occurs at similar frequencies in males and females. Notably, the remarkable decrease in gastric cancer incidence applies only to the intestinal type, which is most closely associated with atrophic gastritis and intestinal metaplasia. As a result, the incidences of intestinal and diffuse types of gastric cancers are now similar.The depth of invasion and the extent of nodal and distant metastasis at the time of diagnosis remain the most powerful prognostic indicators for gastric cancer.[30] In advanced cases gastric carcinoma may first be detected as metastases to the supraclavicular sentinel lymph node, also called Virchow's node. Gastric tumors can also metastasize to the periumbilical region to form a subcutaneous nodule, termed a Sister Mary Joseph nodule, after the nurse who first noted this lesion as a marker of metastatic carcinoma. Local invasion into the duodenum, pancreas, and retroperitoneum is also characteristic. In such cases efforts are usually focused on chemotherapy or radiation therapy and palliative care. However, when possible, surgical resection remains the preferred treatment for gastric adenocarcinoma. After surgical resection, the 5-year survival rate of early gastric cancer can exceed 90%, even if lymph node metastases are present. In contrast, the 5-year survival rate for advanced gastric cancer remains below 20%.[28] Because of the advanced stage at which most gastric cancers are discovered in the United States, the overall 5-year survival is less than 30%.[28,][31]

4. Gastric Cancer in US 2nd leading cause cancer death world wide
US incidence decreasing over last 70 years
Accounts for fewer than 2.5% of cancer deaths in the United States
Asymptomatic until late in disease
Fewer than 25% of cases are detected at an early stage in North America
The 5-year survival rate of patients with metastatic disease is less than 5%
The reason for the decline is not known but may be related to dietary habits, food preservation, and improved surgical morbidity and mortality rates
However, the incidence of proximal stomach and gastroesophageal junction (GEJ) adenocarcinomas has steadily increased at a rate exceeding that of any other cancers except melanoma and lung cancer (5). Observational studies suggest that proximal cancers have a different pathogenesis than do distal cancers
the remarkable decrease in gastric cancer incidence applies only to the intestinal type, which is most closely associated with atrophic gastritis and intestinal metaplasia. As a result, the incidences of intestinal and diffuse types of gastric cancers are now similar
Interestingly, there is a rising incidence of gastric CA in young white malesin US over past several decades.

5. US Incidence by Ethnic Background 2008 Highest Ethnic groups:
African American
Native Americans
Immigrants from Asia and Latin America
Int J Cancer 2010;127(12):2893

6. Highest incidence in East Asia, Eastern Europe, and Western South America
Japan,China,Korea,Columbia

7. Worldwide Incidence Rates

8. Intestinal Type Diffuse Type
Figure 54-2. Histopathologic types of gastric cancer. A, The intestinal type of gastric adenocarcinoma is characterized by the formation of tubular structures mimicking intestinal glands. B, The diffuse type of gastric adenocarcinoma contains singly invasive tumor cells that frequently contain abundant mucin and that lack any glandular structure.  (Courtesy of Rhonda K. Yantiss, MD, Boston, Mass.)

9. Gastric Cancer Intestinal Type Diffuse Type 70-80% of cases
Predominantly in high risk areas
Develops from precursors
Male to Female 2:1
Diffuse Type
20-30% of cases
Uniform across countries
Younger age (mean 38)
No identified precursors
Male to Female 1:1
Older age (mean 69)
Environmental factors
Genetic factors

10. What is Gastric IM?

11. Incomplete metaplasia consists of a mixture of goblet cells and mucin secreting gastric cells

12. Completely metaplastic epithelium is composed of intestinal goblet and absorptive cells. Brush border with villi
Further subclassification has been proposed based on whether the mucin produced in the metaplastic epithelium is colonic (sulfomucin; type III) or small bowel (sialomucin) in nature and whether there is glandular distortion accompanying the metaplasia.5 Unfortunately, criteria for classifying intestinal metaplasia have been confusing and sometimes vague not allowing practical application. No consensus exists regarding the diagnostic reproducibility of the various subclasses of gastric intestinal metaplasia

13. Correa Progression
Gastritis
Atrophic
Gastritis
Intestinal
Metaplasia
Dysplasia
Cancer
IM is the breaking point. There is evidence that atrophic gastritis is reversible, but once you get IM there may be little chance of going back.
Pathologists have a harder time agreeing on severity and reproduciblity of atrophy, IM diagnosis and grading may be easier. So, there is a focus now on IM grading systems like OLGIM.
GASTRIC ADENOCARCINOMAAdenocarcinoma is the most common malignancy of the stomach, comprising over 90% of all gastric cancers. Early symptoms resemble those of chronic gastritis, including dyspepsia, dysphagia, and nausea. As a result, these tumors are often discovered at advanced stages, when symptoms such as weight loss, anorexia, altered bowel habits, anemia, and hemorrhage trigger further diagnostic evaluation.Epidemiology.Gastric cancer incidence varies markedly with geography. In Japan, Chile, Costa Rica, and Eastern Europe the incidence is up to 20-fold higher than in North America, northern Europe, Africa, and Southeast Asia. Mass endoscopic screening programs can be successful in regions where the incidence is high, such as Japan, where 35% of newly detected cases are early gastric cancer, tumors limited to the mucosa and submucosa. Unfortunately, mass screening programs are not cost-effective in regions where the incidence is low, and fewer than 20% of cases are detected at an early stage in North America and northern Europe.In the United States, gastric cancer rates dropped by over 85% during the twentieth century.[26] Adenocarcinoma of the stomach was the most common cause of cancer death in the United States in 1930 and remains a leading cause of cancer death worldwide, but now accounts for fewer than 2.5% of cancer deaths in the United States. Similar declines have been reported in many other Western countries, suggesting that environmental and dietary factors are responsible.[26] Consistent with this conclusion, studies of migrants from high-risk to low-risk regions have shown that gastric cancer rates in second-generation immigrants are similar to those in their new country of residence.The cause of the overall reduction in gastric cancer is unknown. One possible explanation is the decreased consumption of dietary carcinogens, such as N-nitroso compounds and benzo[a]pyrene, because of reduced use of salt and smoking for food preservation and the widespread availability of food refrigeration. Conversely, intake of green, leafy vegetables and citrus fruits, which contain antioxidants such as vitamin C, vitamin E, and beta-carotene, and is correlated with reduced risk of gastric cancers, may have increased as a result of improved food transportation networks.Gastric cancer is more common in lower socioeconomic groups and in individuals with multifocal mucosal atrophy and intestinal metaplasia. PUD does not impart an increased risk of gastric cancer, but patients who have had partial gastrectomies for PUD have a slightly higher risk of developing cancer in the residual gastric stump as a result of hypochlorhydria, bile reflux, and chronic gastritis.Although overall incidence of gastric adenocarcinoma is falling, cancer of the gastric cardia is on the rise. This is probably related to Barrett esophagus and may reflect the increasing incidence of chronic GERD and obesity.[10] Consistent with this presumed common pathogenesis, distal esophageal adenocarcinomas and gastric cardia adenocarcinomas are similar in morphology, clinical behavior, and therapeutic response.[27–29]Pathogenesis.While the majority of gastric cancers are not hereditary, the mutations identified in familial gastric cancer have provided important insights into mechanisms of carcinogenesis in sporadic cases. Germline mutations in CDH1, which encodes E-cadherin, a protein that contributes to epithelial intercellular adhesion, are associated with familial gastric cancers, which are usually of the diffuse type. Mutations in CDH1 are present in about 50% of sporadic cases of diffuse gastric tumors, while E-cadherin expression is drastically decreased in the rest, often by methylation of the CDH1 promoter. Thus, the loss of E-cadherin function seems to be a key step in the development of diffuse gastric cancer. Notably, CDH1 mutations are also common in sporadic and familial lobular carcinoma of the breast, which also tends to infiltrate as single cells, and individuals with BRCA2 mutations are at increased risk of developing diffuse gastric cancer.In contrast to diffuse gastric tumors, there is an increased risk of intestinal-type gastric cancer in individuals with FAP, particularly in Japan. This implies an interaction between host genetic background and environmental factors, since gastric cancer risk is less markedly elevated in individuals with FAP residing in areas of low gastric cancer incidence. Mutations in β-catenin, a protein that binds to both E-cadherin and adenomatous polyposis coli (APC), as well as microsatellite instability and hypermethylation of several genes including TGFβRII, BAX, IGFRII, and p16/INK4a have also been described in sporadic intestinal-type gastric cancer.Genetic variants of pro-inflammatory and immune response genes, including those that encode IL-1β, TNF, IL-10, IL-8, and Toll-like receptor 4 (TLR4), are associated with elevated risk of gastric cancer when accompanied by H. pylori infection, and p53 mutations are present in the majority of sporadic gastric cancers of both histologic types. Thus, although specific sequences of events have not been defined, it is clear that chronic inflammation promotes neoplastic progression. Other associations between chronic inflammation and cancer were discussed in  Chapter 7.Morphology. Gastric adenocarcinomas are classified according to their location in the stomach, and most importantly, according to gross and histologic morphology. Most gastric adenocarcinomas involve the gastric antrum; the lesser curvature is involved more often than the greater curvature.[28] Gastric tumors with an intestinal morphology tend to form bulky tumors (Fig A) composed of glandular structures (Fig A), while cancers with a diffuse infiltrative growth pattern (see Fig B) are more often composed of signet-ring cells (see Fig B). Although intestinal-type adenocarcinomas may penetrate the gastric wall, they typically grow along broad cohesive fronts to form either an exophytic mass or an ulcerated tumor. The neoplastic cells often contain apical mucin vacuoles, and abundant mucin may be present in gland lumens. In contrast, diffuse gastric cancer is generally composed of discohesive cells that do not form glands but instead have large mucin vacuoles that expand the cytoplasm and push the nucleus to the periphery, creating a signet-ring cell morphology. These cells permeate the mucosa and stomach wall individually or in small clusters, which makes tumor cells easy to confuse with inflammatory cells, such as macrophages, at low magnification. Extracellular mucin release in either type of gastric cancer can result in formation of large mucin lakes that dissect tissue planes.A mass may be difficult to appreciate in diffuse gastric cancer, but these infiltrative tumors often evoke a desmoplastic reaction that stiffens the gastric wall and may provide a valuable diagnostic clue. When there are large areas of infitration, diffuse rugal flattening and a rigid, thickened wall may impart a leather bottle appearance termed linitis plastica (see Fig B). Breast and lung cancers that metastasize to the stomach may also create a linitis plastica–like appearance.FIGURE 17-17  Gastric adenocarcinoma. A, Intestinal-type adenocarcinoma consisting of an elevated mass with heaped-up borders and central ulceration. Compare to the peptic ulcer in Figure 17-14A. B, Linitis plastica. The gastric wall is markedly thickened, and rugal folds are partially lost.FIGURE 17-18  Gastric adenocarcinoma. A, Intestinal-type adenocarcinoma composed of columnar, gland-forming cells infiltrating through desmoplastic stroma. B, Signet-ring cells can be recognized by their large cytoplasmic mucin vacuoles and peripherally displaced, crescent-shaped nuclei.
Clinical Features.Intestinal-type gastric cancer predominates in high-risk areas and develops from precursor lesions including flat dysplasia and adenomas. The mean age of presentation is 55 years, and the male-to-female ratio is 2 : 1. In contrast, the incidence of diffuse gastric cancer is relatively uniform across countries, there are no identified precursor lesions, and the disease occurs at similar frequencies in males and females. Notably, the remarkable decrease in gastric cancer incidence applies only to the intestinal type, which is most closely associated with atrophic gastritis and intestinal metaplasia. As a result, the incidences of intestinal and diffuse types of gastric cancers are now similar.The depth of invasion and the extent of nodal and distant metastasis at the time of diagnosis remain the most powerful prognostic indicators for gastric cancer.[30] In advanced cases gastric carcinoma may first be detected as metastases to the supraclavicular sentinel lymph node, also called Virchow's node. Gastric tumors can also metastasize to the periumbilical region to form a subcutaneous nodule, termed a Sister Mary Joseph nodule, after the nurse who first noted this lesion as a marker of metastatic carcinoma. Local invasion into the duodenum, pancreas, and retroperitoneum is also characteristic. In such cases efforts are usually focused on chemotherapy or radiation therapy and palliative care. However, when possible, surgical resection remains the preferred treatment for gastric adenocarcinoma. After surgical resection, the 5-year survival rate of early gastric cancer can exceed 90%, even if lymph node metastases are present. In contrast, the 5-year survival rate for advanced gastric cancer remains below 20%.[28] Because of the advanced stage at which most gastric cancers are discovered in the United States, the overall 5-year survival is less than 30%.[28,][31]
Gastric IM is likely the 'breaking point' between chronic gastritis and dysplasia

14. Am J Physiol Gastrointest Liver Physiol 291: G999 –G1004, 2006
Intestinal metaplasia (IM) of the gastric mucosa has long been regarded as a key intermediate step in the pathogenesis of gastric adenocarcinoma, but the supporting evidence has been largely correlative. This mini-review presents recent animal and human-based evidence suggesting that the development of gastric neoplasia may be associated no less closely with another metaplastic lineage of mucous cell type that expresses spasmolytic polypeptide (synonymous with trefoil factor 2 [TFF2]). Conventionally referred to by pathologists as pseudopyloric or mucinous gland metaplasia, spasmolytic polypeptide-expressing metaplasia (SPEM) has hitherto been all but ignored as a potential progenitor of gastric neoplasia {1}, despite its histomorphologic similarity to the ulcer-associated metaplastic lineage commonly seen in patients with inflammatory bowel disease. Although the evidence presented herein neither resolves whether gastric cancer originates from IM or SPEM nor rules out the possibility that both lineages are commensals in the neoplastic process, it provides the basis for several novel hypotheses and a re-evaluation of the conventional gastric cancer paradigm.
One of these hypotheses is that SPEM gives rise directly to IM by way of a hyperproliferative epithelial intermediate that may be susceptible to the development and establishment of deleterious mutations. Another is that SPEM may result from the transdifferentiation of gastric chief cells, focusing new attention on this cell population as a potential cancer progenitor. Despite close histological similarity to normal antral gland epithelium, SPEM is a distinct entity which arises in the gastric body in conjunction with parietal cell atrophy, lacks gastrin-producing (G) cells and expresses different proteins. Studies of SPEM induction in mice by Helicobacter felis infection or by toxic or genetic ablation of parietal cells suggest that it derives via transdifferentiation of mature chief cells. In the H. felis mouse model, SPEM gives rise to gastritis cystica profunda and dysplasia without accompanying IM, implying a direct role in the pathogenesis of neoplasia but failing to address the role of IM. In other murine models and in Mongolian gerbils, infection with H. felis induces SPEM that may progress to IM with formation of hybrid glands comprising both types of epithelium. In human studies presented in this paper, SPEM occurs either locally in combination with hyperplasia of the mucus neck cells, suggesting that it is part of the normal repair reaction, or diffusely, typically occupying the basal aspect of the glands and coexisting with luminal IM. They also showed that the epithelium intervening between SPEM and overlying IM is hyperproliferative, i.e. strongly positive for the proliferation marker Ki67, and may therefore be susceptible to the development and expansion of deleterious mutations in stem cell or progenitor populations known to occupy the same mucous neck region of gastric glands.
SPEM appears to arise from the transdifferentiation of chief cells. These results support the concept that intrinsic mucosal metaplasiagastric of appearance the modulate and regulate influences chronicwhereas inflammation, significant of absence the in even transition.neoplastic further the for required is inflammation
Gastric Cancer Pathogenesis in Humans:
The pathway to gastric carcinogenesis is mediated through global changes in the lineages of the stomach. Studies over the past 15 years have demonstrated that the major primary cause of gastric cancer in humans is chronic infection with particular subclasses of the bacterium Helicobacter pylori (2). Indeed, the World Health Organization has designated H. pylori as a class I carcinogen. Two important factors contribute to the evolution of gastric cancer in the presence of chronic H. pylori infection: responseinflammatory prominent a elicits infection the 1) throughout the gastric mucosa (2); and 2) chronic infection leads to a loss of glandular lineages in the gastric fundus,especially acid-secreting parietal cells and pepsin-secreting chief cells. Oxyntic atrophy, either focal or global, appears as a prerequisite for the development of gastric cancer. While the areinflammation and atrophy gastric with cancer of association now well accepted, the intervening cellular events that mediate the progression from atrophy to neoplasia remain controver- sial. The loss of parietal cells leads to a number of attendant changes in cell lineages within the gastric mucosa. After oxyntic atrophy, patients may show varying levels of foveolar hyperplasia. This increase in surface cell numbers is likely a reactive response to increases in gastrin release secondary to hypochlorhydria. Oxyntic atrophy also leads to mucous cell metaplasia. Studies over the last decade have increasingly emphasized the association of precedent mucous cell metapla- sias with the development of upper gastrointestinal cancers in the esophagus, pancreas, and stomach. The development of esophageal cancer is closely linked with Barrett’s epithelial metaplasia, and pancreatic adenocarcinoma arises from dis- crete mucous cell metaplasias (1, 3). While the association of intestinal-type cancers with chronic H. pylori infection and oxyntic atrophy is well accepted, the connections between discrete metaplasias and cancer are less clear (Fig. 1). Tradi- tionally, most Western authorities have considered goblet cell intestinal metaplasia (IM) (Fig. 1) as the leading candidate for the origination of gastric cancer (5). Goblet cells are not found in the normal stomach, so the presence of cells with goblet cell morphology represents a clear metaplastic process with intes- tinal phenotype cells. Nevertheless, little evidence exists link- ing directly IM with dysplastic transformation (12). Indeed, IM is not the only possible metaplastic precursor of cancer. A number of investigators, especially in Asia, have focused attention on the presence of metaplastic glands in the fundus with a general phenotype similar to that of antral or pyloric glands (12). This phenotypic antralization of the fundus or pseudopyloric metaplasia is commonly associated with intes- tinal-type adenocarcinoma. We have described a similar meta- plastic process as spasmolytic polypeptide-expressing metapla- sia (SPEM) (22), which is characterized by the presence of trefoil factor 2 (TFF2; spasmolytic polypeptide)-immunoreac- tive cells in the gastric fundus with morphological character- istics similar to deep antral gland cells or Brunner’s gland cells (Fig. 1). SPEM was association with 90% of resected gastric cancers in three studies in the United States, Japan, and Iceland forreported recently were findings similar addition, In 22). (11, patients from Korea, and the expression of TFF2 correlated with metastasis (7). In all of these studies, SPEM was present as often or more often in association with cancer than goblet cell IM. Although TFF2 immunoreactivity was less prominent
Progression of metaplasia in humans
Current model for the origin and progression of gastric metaplasias in humans. Studies have dem- onstrated that loss of parietal cells results in chief cell transdifferentiation and the emergence of SPEM. In the presence of chronic inflammation from Helico- bacter pylori infection, SPEM evolves into intestinal metaplasia and then progresses on to gastric cancer. Establishment of biomarkers of these metaplastic lineages is a priority. Recent studies in mice identi- fied HE4 as a SPEM biomarker. In humans, HE4 is not expressed in the cells of the normal fundus. However, HE4 is detected in both SPEM and intes- tinal metaplasia (IM), supporting the hypothesis of SPEM progression to intestinal metaplasia
Am J Physiol Gastrointest Liver Physiol 291: G999 –G1004, 2006

15. What is Gastric IM?
Foci appear at junction of Antrum & Body, often at Angularis
Enlarge, coalesce, extending to Antrum & Body
Small foci of dysplasia may appear in areas of IM, subject to sampling error
Severity & tempo of progression may be influenced by virulence of H Pylori (?cagA), environmental, host genetic factors
Cag A stands for “ cytotoxin-associated gene A”

16. Epidemiology of Gastric IM

17. EPIDEMIOLOGY OF IM Found in up to 25% US Adults 13% of Caucasians
50% of Blacks/Hispanics
VA in Tuscon Arizona
440 pts, only 2 females
EGD done for numerous reasons, everyone got 2-4 biopsies of antrum and body
50% blacks and hispanics had IM!
18% native american
Much lower in whites
High risk populations:
World Wide: Eastern Asia
Eastern Europe
Andean South America
US: African American
Native American
Immigrants from Asia and Latin America
A study found that infection with cagA-positive H. pylori strains is associated with a significant increased IM preva- lence compared to those strains without it[25]
A study of U.S. patients demonstrated that among consecutive patients undergoing endoscopy, 13% of patients at very low risk for gastric cancer (Caucasians) and 50% of higher risk groups (Hispanics and Blacks) had GIM demonstrated when routine protocol-mapping biopsies of normal appearing mucosa were performed.
H. pylori infection significantly raises IM prevalence
Increases with patient age
Higher in first degree relatives with gastric cancer
Cancer Epidemiol Biomarkers Prev 1992;1:293–296.

18. EPIDEMIOLOGY OF IM Systematic review: Dutch study: Patients with IM
Gastric cancer incidence varied 0-10%
In systemati review
large variation in sample size ( pts) and followup( 2 to 23 years). Probably accounts for for such a large variation
Dutch study
In Netherlands all histopathology and cytopathology reports are kept in database since 1991( called PALGA)
Reports are linked to patient IDs
retrospective study tried to determine gastric CA risk in pts with preancerous conditions (atrophic gastritis and IM and dysplasia)
used nationwide histopathology registry and followed subsequent EGDs and surgeries to determine outcomes
this population is similar risk to US in general?
Netherlands incidence 6.9
Am J Surg Pathol 2000; 24:
Dutch study:
Histology based
61,707 pts with IM
874 developed gastric CA over 10 years
0.18%yearly
Gastroenterology 2008; 134:

19. ARE ALL PATIENTS WITH IM AT EQUAL RISK OF GASTRIC CANCER?

20. ARE ALL PATIENTS WITH IM AT EQUAL RISK OF GASTRIC CANCER?
The presence of incomplete-type IM is associated with a higher gastric cancer risk compared to complete-type IM.
Done in province of Spain with high GC risk
INCOMPLETE is bad
There is also literature that dispute the significance of differentiating IM types.
Spain study:
Mean follow-up 12.8 years
Incomplete IM: 16 of 88 pts (18.2%) developed gastric CA
Complete IM: 1 of 104 pts (0.96%) developed gastric CA
Int J Cancer 2010; 127:

21. ARE ALL PATIENTS WITH IM AT EQUAL RISK OF GASTRIC CANCER?
Gastric cancer risk is associated with IM topography.
Columbia has high incidence gastric CA
Compared 68 pts with gastric CA to 67 nonulcer dyspepsia pts
The more diffuse the higher the cancer risk
Antrum is best
Extending to angularis is next
Antrum and corpus worst
Columbia study:
Compared to antral predominate (focal)
Extension through angularis- risk 5.7 fold
Antrum plus body (diffuse)- risk 12.2 fold
Incomplete IM presents as diffuse more commonly than focal
Am J Gastroenterol 2000; 95:

22. Gastric CA incidence and incomplete type IM was associatted with a particular topographic pattern.
A thru D equals Low to Higher risk
Iffuse type found exlusively in CA pts
The four patterns of intestinal metaplasia. These patterns are extrapolated from the frequency distribution of metaplastic changes in the individual biopsy sites and are not intended to depict the precise extent of the intestinal metaplasia; rather, they represent the prevalent configuration associated with different degrees of cancer risk. A ("Focal"): scattered foci, mostly in the lesser curvature just proximal and just distal to the incisura angularis; B ("Antrum-predominant"): involving most of the antrum (both the lesser and the greater curvature) from the incisura angularis to the pylorus; C ("Magenstrae"): spread throughout the lesser curvature from the cardia to the pylorus, also involving greater curvature of the pre-pyloric antrum; and D ("Diffuse"): involving essentially the entire gastric mucosa, with the exception of the fundic areas.

23. ARE ALL PATIENTS WITH IM AT EQUAL RISK OF GASTRIC CANCER?
Extensive IM increases the risk of progression to dysplasia.
EXTENSIVE is a category that has been used in several studies that have linked it with increased risk, this Italian study is just one example, then READ the definition
Moderate/marked is usually when IM present in 20% or more of the mucosa in a biopsy specimen
471 pts with IM or IDL (indefinite for dysplasia) on biopsies were followed for median of 52 months
Repeated biopsies looking for dysplasia every 2 years
Purpose was to assess prognostic importance of EXTENSION, TOPOGRAPHY, and TYPE of IM at first examination
CA increased with increasing extension
Italian Study
The rate of gastric cancer appeared to increase with increasing IM extension
Hum Pathol 2006;
IM may be considered extensive when it involves at least two locations or when it is moderate or marked in more than one biopsy specimen

24. IS IM REVERSIBLE?

25. H. pylori eradication may slow IM progression.
IS IM REVERSIBLE?
H. pylori eradication may slow IM progression.
Hong Kong Study
In detail, only 1 study showed that IM in the antrum was reversed after H. pylori eradication and no study showed that IM in the corpus was improved following bacterial eradication.
LOOK AT THIS STUDY. You could get ?s about it.
537 pts with IM and H. Pylori randomized to treatment or placebo
H Pylori eradication prevented IM progression
Odds ratio 0.48 (95% CI: )
Gut 2004; 53:

26. IS IM REVERSIBLE? Meta-analysis of 7 studies
IM does not appear to regress following H. pylori eradication.
Meta-analysis of 7 studies
IM may be this breaking point between Atrophic gastritis and dysplasia we discussed. Once you get metaplasia, there may be no going back.
In detail, only 1 study showed that IM in the antrum was reversed after H. pylori eradication and no study showed that IM in the corpus was improved following bacterial eradication.
Unlike atrophy, no significant IM regression occurred following H. Pylori eradication
Helicobacter 2007; 12 Suppl 2: 32-38
Meta-analysis of 12 studies
Atrophy improved in the body but not antrum
IM did not improve after eradication
Digestion 2011; 83:

27. IS IM REVERSIBLE? Italian Study Taiwan Study
6 months of ascorbic acid qOD following H. Pylori eradication helped reduce IM
In addition, there have been studies on supplements and nsaids with varying degrees of success.
Some evidence that cox 2 is expressed in IM
.some evidence would suggest that a high dietary consumption of ascorbic acid tends to reduce the risk of IM development in patients with H. pylori in- fection[22
Aliment Pharma- col Ther 2000; 14:
Taiwan Study
IM regressed in 24% of 33 pts following 8 wks of treatment with celecoxib 200 mg/d after H. Pylori eradication
J Gastroenterology Hepatol 2010; 25: 48-53

28. What About Surveillance?

29. What About Surveillance?
Dutch study: Can extension be predicted?
88 patients with previous IM on gastric biopsy
Repeat EGD & blood tests done
There are 2 retrospective studies from the UK showing that surviellance endoscopies found cancers at earlier stages.
No good data about cost effectiveness though.
I found this study interesting and posted it on the listserve.
Most important predictors of extensive IM:
Family history of gastric cancer
Alcohol use 10ml per day
Marked IM of index biopsy
Pepsinogen I/II ratio < 3.0
Gastrointestinal Endoscopy Vol 70, No.1:2009

30. Serum pepsinogens (PGs) are related to atrophic changes in gastric mucosa and consist of two types: PGI, which is mainly secreted by the fundic mucosa, and PGII secreted by chief cells but also by the pyloric glands and the proximal duodenal mucosa. Inflammation of the gastric mucosa leads to an increase in both PGI and PGII serum levels, usually with a more marked increase of PGII and thus a decrease in the PGI/II ratio. With the development of atrophy and loss of specialized cells, both PGI and PGII may decrease, but PGI usually shows a more marked decrease than PGII, thus there is a further decline in the PGI/II ratio (see review by Kuipers EJ: “In through the out door: serology for atrophic gastritis,” Eur J Gastroenterol Hepatol 2003: 877–879). Thus, a low PGI level, a low PGI/II ratio, or both, are good indicators of atrophic changes in the gastric mucosa.
With INFLAMMATION both go up, but PG II goes up more( there is more stomach producing PGII) and the PGI/PGII ratio goes down.
Once you get ATROPHY both come down but PGI comes down more (less of the stomach makes PGI), so PGI/PGII ratio gets even lower.
PG I & II
PG II
PG II

31. What do Guidelines say?

32. Gastrointestinal Endoscopy Volume 63, No. 4 : 2006
2006 ASGE Guideline
Endoscopic surveillance for gastric intestinal metaplasia has not been extensively studied in the U.S. and therefore cannot be uniformly recommended
Patients at increased risk for gastric cancer due to ethnic background or family history may benefit from surveillance
Endoscopic surveillance should incorporate topo- graphic mapping of the entire stomach
Gastrointestinal Endoscopy Volume 63, No. 4 : 2006

33. This is the random non targetted biopsy scheme used in the Dutch study we just discussed.
The Updated Sydney System (from the 1990s) uses 5 non targetted sites when you suspect gastritis, 2 antrum, 2 body, and 1 angularis.
The new OLGA and OLGIM staging systems use the same scheme.

34. Virchows Arch. 2012 Jan;460(1):19-46. Epub 2011 Dec 22.
2012 European Guideline
Conventional white light endoscopy cannot accurately differentiate between benign and precancerous gastric conditions/lesions
Magnification chromoendoscopy (MCE) or narrow-band imaging (NBI) endoscopy with or without magnification may be offered in these cases as it improves diagnosis of such lesions
“Light blue crests” (LBC) provided the highest likelihood ratio over villous pattern(VP) and large long crests (LLC)
At least four non-targeted biopsies of the proximal and distal stomach, on the lesser and greater curvatures, are needed for adequate assessment of premalignant gastric conditions
Virchows Arch Jan;460(1): Epub 2011 Dec 22.

35. Virchows Arch. 2012 Jan;460(1):19-46. Epub 2011 Dec 22.
2012 European Guideline
Patients with extensive atrophy and/or extensive IM should be offered endoscopic surveillance every 3 years
IM may be considered extensive when it involves at least two locations or when it is moderate or marked in more than one biopsy site (16).
Further studies are needed however, to accurately estimate the cost–effectiveness of such an approach
Patients with mild to moderate atrophy/IM only in Antrum do not need follow-up
Sub-typing of IM is not recommended for clinical practice
Virchows Arch Jan;460(1): Epub 2011 Dec 22.

36. Virchows Arch. 2012 Jan;460(1):19-46. Epub 2011 Dec 22.
2012 European Guideline
COX-2 inhibitors, or the use of dietary supplementation with antioxidants (ascorbic acid and beta-carotene) are not endorsed as approaches to decrease the risk of progression of gastric precancerous lesions
Neither age, gender, H. pylori virulence factors, or host genetic variations change these clinical recommendations
Virchows Arch Jan;460(1): Epub 2011 Dec 22.

37. Virchows Arch. 2012 Jan;460(1):19-46. Epub 2011 Dec 22.
2012 European Guideline
Virchows Arch Jan;460(1): Epub 2011 Dec 22.
IM may be considered extensive when it involves at least two locations or when it is moderate or marked in more than one biopsy specimen

38. What's new? OLGA OLGIM Operative Link for Gastritis Assessment
Atrophic gastritis (resulting mainly from long-standing Helicobacter pylori infection) is a major risk factor for (intestinal-type) gastric risk.cancer of degree the with correlates significantly changes atrophic the of topography extent/the and development cancer The current format for histology reporting in cases of gastritis fails to establish an immediate link between gastritis phenotype and risk of malignancy. The histology report consequently does not give clinical practitioners and gastroenterologists an explicit message of use in orienting an individual patient’s clinical management. Building on current knowledge of the biology of gastritis and incorporating experience gained worldwide by applying the Sydney System for more than 15 years, an international group of pathologists (Operative Link for Gastritis Assessment) has proposed a system for reporting gastritis in terms of stage (the OLGA staging system). Gastritis staging arranges the histological phenotypes of gastritis along a scale of progressively increasing gastric cancer risk, from the lowest (stage 0) to the highest (stage IV).
OLGIM
Operative link on Gastric Intestinal Metaplasia Assessment.
Gastritis staging systems that arrange histological phenotypes of gastritis along a scale of progressively increasing gastric cancer risk, from the lowest (stage 0) to the highest (stage IV).

39. There is good correlation between stages 3 & 4 and risk of gastric cancer

40. Thank You