Gastric Cancer Overview

olGastric cancer is the second most common cancer type worldwide

• Approximately 800,000 new cases and 650,000 deaths are reported yearly
• There is wide variation in incidence across continents, incidence is highest in Asia, central Europe and South America
• In the US, gastric cancer is the seventh most frequent cancer-related death cause
• The National Cancer Institute estimates almost 22,000 new cases will be diagnosed, and 11,000 deaths will be attributed to the disease in 2013.

Changes in Topographic Distribution

• Proximal gastric tumor incidence has risen since the early 1980s
• Carcinomas of the gastric cardia represent ~30% of all gastric cancers
• Changes in clinical practice have led to diagnosing a higher percentage of early-stage cancers
• Endoscopy has led to more frequent superficial cancer detection
• Early gastric cancer (EGC) now represents almost 20% of newly diagnosed US cancers and 50% in Japan
• Gastric cancer is now considered potentially curable if detected early

Pathogenesis of Sporadic Gastric Carcinoma

• Involves a progression from chronic gastritis to atrophy with hypochlorhydria or achlorhydria, intestinal metaplasia, dysplasia, and ultimately adenocarcinoma
• Intestinal metaplasia, dysplasia, and early adenocarcinoma develop initially in the neck region of the antral or fundic glands, supporting the hypothesis that precursor cells are located there
• Geographic variations in incidence underscore environmental influences in intestinal-type gastric carcinoma development
• Intestinal-type gastric cancer decrease parallels decline in Helicobacter pylori infection, confirming it as a major environmental cause

H. pylori Infection

• Long-standing H. pylori infection gradually results in atrophy and intestinal metaplasia
• Patients with H. pylori infection have a fourfold to ninefold increased risk of gastric lesions, particularly if infection began in early childhood
• Chronic acid suppression also increases atrophy risk in patients with H. pylori gastritis

H. pylori virulence

• Aspects have been associated with risk of gastric cancer
• H. pylori strains positive for cytotoxin-associated gene A (CagA) produce higher interleukin 8 levels, elicit more intense inflammation, and are associated with increased gastric carcinoma risk

Other environmental and host factors

• Diets rich in salt and low in micronutrients, vitamins, and antioxidants favor intraluminal formation of genotoxic agents, such as specific N-nitroso compounds
• These diets are associated with gastric cancer development
• Diets rich in fresh vegetables, citrus fruits, and ascorbic acid are inversely associated with risk
• Bile reflux is associated with adenocarcinoma development in surgical stumps
• Polymorphisms of the interleukin 1 gene have been associated with increased gastric cancer risk in H. pylori-infected individuals
• A proinflammatory interleukin 1 genotype, playing a role in hypochlorhydria and atrophy, is associated with an increased intestinal-type risk, but not the diffuse type

Diffuse Type

• More common in younger individuals
• Observed with equal incidence in both high- and low-risk geographic regions
• Development is more regulated by genetic factors than is intestinal-type gastric cancer
• Importance of genetic factors is underscored by familial clustering and by increased atrophic gastritis incidence in relatives of patients with gastric cancer

Histologic Precursors of Gastric Cancer

• Gastric adenocarcinoma development represents culmination of inflammation-metaplasia-dysplasia-carcinoma sequence
• Mucosal atrophy and intestinal metaplasia confer a high risk for gastric cancer development
• Gastric epithelial dysplasia (or adenoma, if it is a polypoid lesion) represents a direct neoplastic precursor lesion
• Almost all gastric epithelial dysplasias (or adenomas) have an "intestinal" phenotype (type I)
• Another, less common, histologic variant is hyperplastic (type II) dysplasia
• The exceedingly rare tubule neck (or globoid) dysplasia is believed to be a diffuse-type gastric carcinoma precursor

Anatomic Distribution

• There has been an important epidemiologic shift in the location and frequency of gastric cancer
• There is an increase in adenocarcinoma incidence of the cardia region
• The cause of the apparent shift in the anatomic location of gastric cancer is controversial

Location of Gastric Cancer

• There is a lack of widespread consensus regarding the anatomic definition of the gastric cardia
• It is unclear whether previously diagnosed cardia cancer cases actually represent distal esophageal cancer involving the gastric cardia
• The International Gastric Cancer Association has endorsed a classification system of gastric tumors in which:
  • Type I tumors arise in the distal esophagus
  • Type II tumors are in the gastric cardia
  • Type III tumors originate in gastric mucosa distal to the cardia
• The classification system does not address criteria to define tumors from each of these anatomic areas
• Increased incidence of gastric cardia carcinomas observed during past decades has shown a geographic restriction
• Studies from Scandinavia and Japan have not reported the trend
• Some investigators have suggested that the distribution changes are due to the widespread use of endoscopy and improvements in diagnostic methods

Differences Between Cancers of the Cardia

• Differences exist between cancers of the cardia and those in the distal stomach
• Patients with cardia cancer show a higher male-to-female ratio and whites are affected more frequently than African Americans
• There are similarities between cardia and esophageal adenocarcinomas, such as similar risk factors, age and distribution, and morphologic phenotypes
• Obesity, high body mass index, smoking, and alcohol intake are not universally accepted as risk factors for cardia cancer, as they are for esophageal cancer
• Similarly, cardia cancer association with Barrett's esophagus and gastroesophageal reflux disease is a subject of debate
• Some studies show cardia cancer has been significantly associated with older patient age, H. pylori infection, and intestinal metaplasia elsewhere in the stomach
• Other studies show cardia cancer has been associated with reflux disease
• Some researchers suggest both etiologies play a role in cardia cancer pathogenesis
• Although intestinal metaplasia has been demonstrated in adjacent mucosa in as many as 70% of cardia carcinomas, the actual risk of malignant transformation in patients with intestinal metaplasia has not been determined in prospective studies
• Some studies have shown that progression of intestinal metaplasia to dysplasia is slower, and less frequent, than in Barrett's esophagus
• Currently, gastric cardia intestinal metaplasia is not an absolute indication for periodic endoscopic surveillance

Early Gastric Cancer (EGC)

• Invasive adenocarcinomas confined to the mucosa or submucosa, regardless of whether lymph node metastasis is present
• Represents an early stage in development, before invasion of the muscularis
• Increased upper endoscopies being performed worldwide have increased detection rates for this lesion
• EGC represents 15% to 21% of all newly diagnosed gastric cancers in Western series
• EGC accounts for >50% of cases in Japan

Diagnostic Criteria

• A higher prevalence of gastric cancer, more liberal upper endoscopy and chromoendoscopy use, and differences in diagnostic criteria help explain the differences between Western and Japanese studies
• Similar to dysplasia, most EGCs are diagnosed in men older than 50 years of age; this is a younger age than for advanced adenocarcinoma, reflecting the time required for progression from early to advanced disease
• Most patients are asymptomatic, but some complain of symptoms that mimic peptic ulcer disease
• Epigastric pain and dyspepsia are the most reported symptoms
• They typically occur within the last few months before diagnosis
• Most EGCs are small, between 2 and 5 cm, and are typically localized on the lesser curvature around the angularis region
• Multiple primary sites are present in 3% to 13% of patients, this has been shown to be associated with a worse prognosis

Division of EGCs

• Divided into three types, based on their endoscopic appearance
  • Protruding (type I)
  • Superficial (type II)
  • Excavating (type III) Type II is further subdivided into
  • IIa (elevated),
  • IIb (flat),
  • and IIc (depressed)
• Superficial EGCs account for the highest proportion of cases (80%)
• Type IIc is the most common
• Type IIb accounts for 58% of tumors smaller than 5 mm
• Endoscopic appearance of EGCs is a good indicator of lymph node metastasis rate, with the lowest rates reported in type I or IIa EGCs

Diagnostic Challenges

• Type IIa, which is twice as thick as normal mucosa, and type IIc, which mimics benign ulcers, are difficult to detect endoscopically
• Often require multiple biopsies for diagnosis
• Subtle diagnostic signs include ease of bleeding and an irregular interface with the surrounding mucosa

Variants

• Minute EGCs measure <5 mm in diameter, and although most are limited to the mucosa, submucosal extension is detected in as many as 15% of cases
• Superficial spreading EGCs are characterized by large, serpiginous ulcerations with neoplastic cells that spread laterally over a large mucosa area
• The majority of EGCs are well differentiated
• Tubular and papillary variants represent 52% and 37% of cases, respectively
• May be difficult to differentiate from dysplasia because of the lack of obvious tissue invasion
• Signet ring cell carcinoma and poorly differentiated carcinoma represent 26% and 14% of cases, respectively, and are usually depressed or ulcerated (types IIc and III)
• Diffuse-type EGCs tend to show greater depths of invasion

Natural History

• In a series of patients with EGC followed conservatively without surgery, 63% of EGCs progressed to advanced carcinoma during a 6- to 88-month period
• With resection, the prognosis of EGC is excellent with >90% 5-year survival rates
• Tumor size and invasion depth are the two major prognostic indicators

Other Facts

• Larger tumors have a greater risk of submucosal infiltration
• Risk of invasion should not be overlooked even in very small tumors
• In one series, 15.5% of tumors measuring 3 to 5 mm in diameter showed submucosa invasion
• Lymph node metastases have been reported in 0% to 7% of intramucosal EGCs and are associated with a 5-year survival rate of almost 100%
• Lymph node metastases rate for EGCs that extend into the submucosa varies between 8% and 25%, and the 5-year survival rate for these tumors is 80% to 90%
• Endoscopic mucosal resection has become the treatment choice for EGCs
• It is usually performed in association with endoscopic ultrasonography for staging
• The primary criteria for identifying EGCs most amenable to endoscopic mucosal resection
  • elevated lesion <2 cm in diameter
  • depressed lesion <1 cm in diameter and without ulceration
  • absence of lymph node metastasis
• Whether H. pylori eradication improves prognosis is unclear
• In a study of 132 patients with EGC who underwent endoscopic mucosal resection, no new gastric cancer cases were observed after H. pylori eradication
• New early-stage intestinal-type gastric cancer developed in 13.5% of untreated patients

Advanced Gastric Carcinoma

• Is defined as a tumor that invades the gastric wall beyond the submucosa
• Most patients are men (male-to-female ratio of 2:1) in their fifth to seventh decades of life
• Symptoms include epigastric pain, dyspepsia, anemia, and weight loss
• Hematemesis and symptoms of gastric outlet obstruction are not uncommon
• Some patients, particularly younger ones, have intraabdominal dissemination at presentation
• Metastatic ovarian lesions (Krukenberg tumors) composed of diffuse-type cancer cells may develop in female patients
• 65% of patients with gastric cancer in the United States are diagnosed at an advanced stage (beyond stage Ib)
• In North America, most gastric adenocarcinomas occur in the antrum or in the antropyloric region, and preferentially on the lesser curvature
• Approximately half measure between 2 and 6 cm, and 30% measure 6 to 10 cm in greatest dimension
• Only 15% are larger than 10 cm at the time of diagnosis
• Multiple adenocarcinomas are detected in 5% of patients

Gross Features

• Advanced gastric carcinomas may display several different gross appearances, referred to as
  • exophytic
  • ulcerated
  • infiltrative
  • combined

Microscopic

• Gastric adenocarcinomas are characterized by marked heterogeneity at both the cytologic and the architectural level
• They frequently show overlap among the four different gross patterns
• Cytologically, a combination of gastric foveolar, intestinal, and endocrine cell types usually constitutes at least a portion of all tumors
• Ciliated tumor cells may also be observed
• Mucin histochemical and immunohistochemical stains may be useful in highlighting the different cellular components
• There is a new phenotypic classification of gastric cancer based on mucin immunohistochemistry
• separates them into four phenotypes
  • G (gastric)
  • I (intestinal),
  • GI (gastric and intestinal)
  • N (null)
• Type I is more common in differentiated gastric cancers than in undifferentiated ones
• For each histologic subtype, a shift from the gastric to the intestinal phenotype is commonly observed with tumor progression
• Several classification systems of gastric adenocarcinoma have been proposed, most based primarily on the tumors microscopic appearance
• The three-tiered Laurén classification system is important in helping to understand the role of environmental factors and epidemiologic trends and is the system most often used by pathologists
• This classification scheme recognizes intestinal, diffuse, and indeterminate or unclassified types
• Their relative frequencies are 50% to 67%, 29% to 35%, and 3% to 21%, respectively
• The World Health Organization (WHO) recognizes four other major types of gastric adenocarcinoma
  • (adenosquamous
  • squamous
  • small cell carcinoma
  • and other rare morphologic variants)
• Intestinal-type adenocarcinomas characteristically form glands with various differentiation degrees
• They are usually diagnosed in older patients, mostly in the antrum, and are strongly linked to chronic H. pylori infection, atrophic gastritis, and intestinal metaplasia
• The papillary variant accounts for 6% to 11% of all gastric carcinomas, affects older patients, occurs mainly in the proximal stomach, and is frequently associated with liver metastases
• A higher rate of lymph node metastases has been reported for papillary adenocarcinoma compared with other intestinal types
• The tubular variant is composed of distended or anastomosing, branching tubules of various sizes
• Mucin and cellular or inflammatory debris are often observed
• In both papillary and tubular variants, the cells may be columnar or cuboidal and may possess various degrees of nuclear atypia and mitoses
• Combined papillotubular variants are also not uncommon.

Poorly cohesive carcinomas

• Are composed of mostly single, or small, nests of neoplastic cells that diffusely infiltrate the gastric wall
• This type is found most commonly in the gastric body and in younger patients
• Although this type is also associated with H. pylori infection, the diffuse type of gastric cancer's is not well characterized
• Pure signet ring cell carcinomas are included in the poorly cohesive type
• They are characterized by infiltrating single cells with a distended cytoplasm and a compressed, eccentrically displaced nucleus that forms a crescent shape
• Gland formation is not a normal component of this tumor; it grows in cords, tight clusters, and solid sheets
• Is defined as >50% of the tumor should be composed of signet ring cells to warrant this designation

Mucinous adenocarcinoma

• A subtype in which extracellular mucin pools comprise at least 50% of tumor volume; represent 10% of all gastric carcinomas
• The cellular component may be formed of glands or of irregular clusters of cells that float freely in the extracellular mucin
• Undifferentiated carcinomas lack cytologic and architectural differentiation and may resemble lymphomas, squamous cell carcinomas, or sarcomas
• From a practical standpoint, some authors recommend another three-tiered classification system based on the tumor's resemblance to either normal gastric or metaplastic intestinal epithelium
• Well-differentiated adenocarcinomas are are composed of well-formed glands or papillae, usually lined by mature absorptive or goblet cells Moderately differentiated adenocarcinomas are characterized irregular glands
• Poorly differentiated adenocarcinomas have poorly formed glands or single cells
• The morphologic subtype, gastric carcinoma with lymphoid stroma (GCLS), medullary carcinoma, or lymphoepithelioma-like carcinoma, is characterized by the presence of prominent lymphoid infiltration of the stroma
• 80% of GCLS tumors are associated with Epstein-Barr virus (EBV) infection GCLS represents 8% of all gastric carcinomas
• GCLS affects men more frequently than women, particularly in the US
• Hispanics are also preferentially affected
• These tumors are more common in the proximal stomach and in the remnant stomach in patients who have had a subtotal gastrectomy GCLS usually shows a pushing tumor border
• Is typically composed of small polygon-shaped cells
• Embedded within a prominent lymphocytic infiltrate, with occasional lymphoid follicles Rarely, giant cells may be observed
• Intranuclear expression of EBV-encoded nonpolyadenylated RNA-1 can be demonstrated by in situ hybridization EBV's role is up for debate Infection occurs early in the sequence, because EBV can also be found in surrounding noninvasive dysplastic epithelium Frequent loss of chromosomes 4p, 11p, and 18q seems to show a pathogenetic pathway different from that of most other usual types

Morphologic Facts

• EBV-positive GCLS tumors have been shown to posses a CpG island methylator phenotype, with frequent aberrant methylation of multiple genes
• The prognosis of GCLS is considered better than that of ordinary adenocarcinomas
• 77% survival rate after 5 years, although this figure is somewhat controversial

Producing Carcinomas

• Hepatoid and a-fetoprotein (AFP)-producing carcinomas ranges from 1.3% to 15% of all gastric cancers Types of AFP-producing tumors help explain the wide variation in incidence previously reported
• Hepatoid adenocarcinomas are composed of large with polygonal-shaped cells.
• Bile and periodic acid-Schiff (PAS)-positive, diastase-resistant intracytoplasmic eosinophilic globules can be observed
• Usually straightforward in terms in the primary tumor
• Hep can be more difficult evaluating liver is metastasized

ImmunohistoFacts

• Negativity for Hep-Par 1
• Positivity for cytokeratin 19 (CK19) and CK20 are considered helpful in excluding a primary hepatocellular carcinoma
• High level of AFP can also be detected in the serum in affected patients
• Tumors are more aggressive

Adenosquamous and Squamous Cell Carcinoma

-Adenosquamous -Defined/neoplastic of squamous composes 25% of volume. Tumors are usually penetrating and associated with lvm invasion and is relatively poor Only a few cases limited to mucosa

• Pure squamous cell carcinomas -Represent: 0.04% to 0.09% of all -More common in Men: Four Times
  • Degree of varies, from moderately differentiated with keratin pearl formation to poorly differentiated

Pathogenesis

• This tumor is unknown
• Squamous may arise from squamous metaplasia of adenocarci- noma cells,from a focus of heterotopic squamous epithelium, or from cells that show bidirectional differentiation Extension of primary esophagel sqamous cell not included Metastatic: Carcinomas are large tumors and have small number in autoposys series

Types

• Gastric show predominance of mucin(Rare)

• Gastric shows predominantly cell differentiation that show eosinophilic cytoplasmic granules

• Gastic shows for vimentin The (L) or round to polygonal shape,with eosinophilic or clear cyto that show positive cells, These tumors are dismal for prog

Other Tumors

Show combination of the syncytiotrophoblast

Clinical Circumstances

• Gastric Stump surgery associated with cancer increased which occur later after surgey and usually male. Most carcinoma is diagnosed as residual residual

facts

• Stump tumor or the lesions may have different origin
• Patients may see intestinal area or cell growth of the glands with Dysplasia. -Show different cancer progression and results
• Has high association with H.Polyl infect to affect
• Lymph system shows changes from usual cancer due to changes in surgerys
• Age is a factor when cancer has an affect. More commin if younger with similar problems of older patients and gender or origin

Familial genetics and tumors

Familial: Attributable to low numbers (3%) and show rare but heriditary

• Germline show CDH1 has increased the risk -Genetic risk =High cancer risk has a positive family

Risk Tumors

Patients can see a variety like Polps(Herediraty)and high risk and a variety in system/disorders

Natural History

• Natural History has a long story to tell or progress from a few years
• Staging is important because 5 year can increase from 80 % or more
• Japan overall has higher survival rates then the west
• Lymph location shows to cause more issues on the effects of tumors.

Molecular Facts

Cancer is cause from pre environment ,the change in genes and abnormalitys affects tumors , DNA, cellular areas ect for a important re